What is the role of the thymus gland in myasthenia gravis?

The thymus gland, which lies in the upper chest area beneath the breastbone, plays an important role in the development of the immune system in early life. Its cells form a part of the body's normal immune system. The gland is somewhat large in infants, grows gradually until puberty, and then gets smaller and is replaced by fat with age. In adults with myasthenia gravis, the thymus gland is abnormal. It contains certain clusters of immune cells indicative of lymphoid hyperplasia - a condition usually found only in the spleen and lymph nodes during an active immune response. Some individuals with myasthenia gravis develop thymomas or tumors of the thymus gland. Generally thymomas are benign, but they can become malignant. The relationship between the thymus gland and myasthenia gravis is not yet fully understood. Scientists believe the thymus gland may give incorrect instructions to developing immune cells, ultimately resulting in autoimmunity and the production of the acetylcholine receptor antibodies, thereby setting the stage for the attack on neuromuscular transmission.

What are the symptoms of myasthenia gravis?

In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in myasthenia gravis varies greatly 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, which vary in type and severity, may include a drooping of one or both eyelids (ptosis), blurred or double vision (diplopia) due to weakness of the muscles that control eye movements, unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, difficulty in swallowing and shortness of breath, and impaired speech (dysarthria).

What are myasthenic crises?

A myasthenic crisis occurs when the muscles that control breathing weaken to the point that ventilation is inadequate, creating a medical emergency and requiring a respirator for assisted ventilation. In patients whose respiratory muscles are weak, crises - which generally call for immediate medical attention - may be triggered by infection, fever, or an adverse reaction to medication.
Myasthenia Gravis (MG) is a neuromuscular autoimmune disease that affects the use of muscles - normal communication between the nerve and the muscle is interrupted, leaving the muscle weak and fatigued. An autoimmune disease is one where the body's immune system appears to attack healthy tissue and produces so many antibodies (immune blood proteins that recognise and fight infections and other foreign things in the body) that the healthy tissue becomes damaged. With MG, it is the voluntary (striated) muscles that are weakened. Voluntary muscles are the muscles that we can control, where the message is transmitted via our nervous system to contract the muscle. They are the muscles in our legs, our arms and our neck; those that move the eyeball and keep the eyelids open; some of those involved with facial expression, and those involving chewing, swallowing and breathing. MG does not affect bowel and bladder function or the myasthenic's mental capacity. Nor is it restricted to humans! For a muscle to contract, the chemical acetylcholine normally transmits nerve impulses to muscle fibres at the place where the nerve and muscle connect (the neuromuscular junction). The physical weakness of the myasthenic's muscle is caused by a defect at this neuromuscular junction. However, whilst the he myasthenic has a problem with the transmission of nerve impulses to the muscle, the nerves and muscles themselves may remain normal. Research has shown that most myasthenics form abnormal antibodies against the acetylcholine receptor (sites at which the chemical can be received on the surface of the muscle). The number of acetylcholine receptors in a myasthenic is reduced due to an attack on the receptors by the body's immune system - if receptors are missing, the response of the muscle to the nerve impulses is poor, and so weakness occurs.

Scientists are investigating what triggers the body to develop an autoimmune response. In many myathenics, the thymus gland appears to be involved.

What causes Myasthenia Gravis?

The muscles work by transforming chemical energy into mechanical energy, which moves the human body. In summary, for a muscle to contract, the following must happen:

an electrical impulse travels from the brain, through the spinal cord down a nerve (the nerves that command the muscle are called motorneurons) the nerve ending releases a neurotransmitter substance called acetylcholine (ACh) the acetylcholine travels through a small gap between the nerve and the muscle (at the neuromuscular junction) and binds to a protein (receptor) on the surface of the muscle (the muscle membrane) to which the nerve is attached resulting in the contraction of that muscle.

In MG, the receptors at the muscle surface are destroyed or deformed by antibodies that prevent a normal musclar reaction from occurring. Antibodies are proteins produced by the immune system to fight infection and disease. With autoimmune diseases such as MG, the body mistakenly sends out antibodies to attack healthy tissue. In MG specifically, the immune system gets triggered to attack an otherwise healthy neuromuscular junction. The antibodies bind to the muscle's membrane and initiate a series of events that destroy the membrane and prevent ACh from binding. ACh plays a critical role in muscle contraction. When a nerve sends a message telling a muscle to contract, a large amount of ACh is released. If ACh can't bind to the muscle, the muscle won't contract.

Model of normal neuromuscular junction on the left, compared with myasthenia neuromuscular junction on the right.

The Symptoms of Myasthenia Gravis

The symptoms of MG often consist of muscle fatigability with the myasthenic complaining of worsening of symptoms later in the day after their muscles have been fatigued or after being repetitively exercised. Usually, weakness of the eye muscle is the first noticeable symptom. The disease may stay there, or it may progress to the rest of the body. The symptoms range from difficulty in eye motion resulting in double vision or droopy eyelids, to weakness and fatigability in the arms and legs. Other symptoms may include fatigue of throat muscles, resulting in swallowing difficulties and choking, fatigue of the muscles of speech, resulting in slurred and unintelligible speech, or difficulty in breathing.

Ocular Symptoms Ocular myasthenia is when MG confines itself to the eye muscles. The impact of the condition on eye muscles include:

 a drooping of one or both eyelids, double or blurred vision weakness of the muscles that move the eyeballs. During a fatigue ocular episode, a myasthenic's window of vision becomes restricted to the narrow slits between the droopy upper lids and the lower lid. For this reason, a number of myasthenics walk around with their noses in the air (when their neck muscles are strong enough to support their head)! Bright lights can aggravate the symptom. Oral Symptoms Muscle weakness in the pharynx (the section of the alimentary canal that extends from the mouth and nasal cavities to the larynx, where it becomes continuous with the esophagus) is another early sign of MG. Swallowing difficulties are of particular concern as they can be dangerous. Myasthenics typically do well at the beginning of a meal but tire at the end, making swallowing too difficult. Some deteriorate to a point where there is total loss of ability to chew and swallow. At this point, food may stick in the throat, or food and drink may start to go the wrong way, for example into the windpipe, causing coughing and choking. Foods which may trigger MG symptoms may be: . very hot . spicy . dry and britty Foods which require a lot of chewing effort, such as tough meats or chewy sweets, could also tire out the myasthenic and cause difficulty in swallowing. In situations where swallowing is too difficult, then the myasthenic may be advised not to eat or drink at all until symptoms improve. They will be alternatively fed in accordance with a dietician's recommendation or be fed intravenously. MG can affect one's speech in a number of ways. Fatigue sets into muscles of: the throat (not allowing one to swallow their saliva) the tongue (not allowing one to adequately move the tongue around the mouth, and not move it quickly enough) the jaw (not being able to move it quickly enough) the mouth (not being able to manipulate the mouth to form the sounds) One's speech may sound nasal or slurred. And the weakness of the facial muscles results in the inability to even smile. In a minority of myasthenics, the voice box may be affected resulting in an inability to talk at all. MG also affects the ability to breath. Deterioration can be abrupt and may lead to the patient being put on a respirator. If breathing or coughing becomes insufficient, the patient is said to be in "crisis," and mechanical breathing assistance in a hospital may be necessary. In a myasthenic crisis, a respirator may be necessary for breathing. A study found that of 175 myasthenics surveyed: 30% had oral, pharyngeal (throat) or laryngeal (voice) complaints. half of that 30% had swallowing disorders. 13% had dysarthria (slurring, fatiguing speech) 2% had dysphonia (voice disorders).

Generalised MG (Head, Neck, Arms and Legs) This is where many muscle groups are affected. The typical myasthenic may feel strong on awakening from a night's rest or a nap, but experiences increasing muscle fatigue as the day progresses. Within the first year after onset about half of the ocular myasthenics will go on to experience involvement of other muscles, and another 30% do so during the next two years. Numbness, heaviness, muscular spasm, or loss of control of the limb can be experienced by the myasthenic. Limb weakness is often not symmetrical, with one side being weaker than the other. Shoulder weakness is demonstrated by trouble holding up an arm to comb or shampoo one's hair, or to shave or put on makeup. The grip may become weak opening jars (and child-proof medicine bottles), hips may be weak getting out of deep chairs or the bathtub, and legs may tire climbing stairs or when walking distances. MG is in itself painless, but the strain of supporting weak limbs or the neck can be painful. Another symptom, which is not often mentioned in literature, but complained of by some mysthenics is a sense of loss of balance. The problem with MG, particularly in the undiagnosed myasthenic, is that an episode can occur without warning and can make what is normally a non-threatening activity into a dangerous one. For example, a myasthenic can really injure themselves if there is sudden muscular weakness as they take a step and suddenly find themselves flat on the footpath! Even worse is the sudden muscular weakness whilst driving a car - sudden double vision, heavy eyelids, loss of control of the right leg, weakening arm muscles - all make a terrifying trip for the unsuspecting undiagnosed myasthenic.

Normal Anatomy and Physiology of the Neuromuscular Junction The concept of the physiologic neuromuscular transmission was based on Guytons Medical Physiology (2006) wherein it is stated that the skeletal muscle fibers are innervated by large myelinated nerve fibers that originate from large motoneurons in the anterior horns of the spinal cord. Each nerve fiber normally branches and stimulates from three to several hundred skeletal muscle fibers. Each nerve ending makes a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. As shown in the figure below, the nerve fiber forms a complex of branching nerve terminals that invaginate into the surface of the muscle fiber but lie outside the muscle fiber plasma membrane. The entire structure is called the motor end plate.

To clearly visualize the relation of the muscle fiber to the nerve fiber, Figure 2 is also used. This is where the junction between a single axon terminal and the muscle fiber membrane exists. The invaginated membrane is called the synaptic gutter, and the space between the terminal and the fiber membrane is called the synaptic cleft. At the bottom of the gutter are numerous smaller folds on the muscle membrane called subneural clefts, which increase the surface area at which the synaptic transmitter can act.

In the axon terminal are many mitochondria that supply adenosine triphosphate (ATP), the energy source that is used for synthesis of an excitatory transmitter acetylcholine. The acetylcholine in turn excites the muscle fiber membrane. Acetylcholine is synthesized in the cytoplasm of the terminal, but it is absorbed rapidly into many small synaptic vesicles, about 300,000 of which are normally in the terminals of a single end plate. In the synaptic space are large quantities of the enzyme acetylcholinesterase, which destroys acetylcholine a few milliseconds after it has been released from the synaptic vesicles. Acetylcholine Aids in Muscle Contraction

Normally, a nerve impulse reaches the neuromuscular junction which allows the release of acetylcholine from the axon terminals into the synaptic cleft. In detail, acetylcholine is released from the synaptic vesicles at the neural membrane of the neuromuscular junction which contains voltage-gated calcium channels. These channels open and allow calcium ions to diffuse from the synaptic cleft to the interior of the nerve terminal. The calcium ions attract the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense bars. The vesicles then fuse with the neural membrane and empty their acetylcholine into the synaptic cleft by the process of exocytosis. On the other hand, the muscle fiber membrane contains acetylcholine receptors which are acetylcholine-gated ion channels. Its principal effect is to allow large numbers of sodium ions to pour to the inside of the fiber, creating a local positive potential change inside the muscle fiber membrane, called the end plate potential. In turn, this end plate potential initiates an action potential that spreads along the muscle membrane and thus causes muscle contraction. Once the acetylcholine is released into the synaptic cleft, it continues to activate the acetylcholine receptors. However, acetylcholine will be removed rapidly by the enzyme acetylcholinesterase and the diffusion of the small amount of acetylcholine out of the synaptic cleft, preventing it to act on the muscle fiber membrane. Fatigue of the neuromuscular junction or the repetitive stimulation of the nerve fiber at rates greater than 100 times per second for several minutes often diminishes the number of acetylcholine vesicles that it may fail to pass into the muscle fiber. 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 150200 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.

In Myasthenia Gravis, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or simplified (shown in Figure 4-B). These neuromuscular abnormalities are brought about by an autoimmune response mediated by specific anti-AChR antibodies. Basically, Myasthenia Gravis is recognized as an autoimmune channelopathy : it features antibodies directed against the bodys own proteins. While in various similar diseases the disease has been linked to a crossreaction with an infective agent, there is no known causative pathogen that could account for myasthenia. How the autoimmune response is initiated and maintained in MG is not completely understood. However, the thymus appears to play a role in this process. Up to 75% of patients have an abnormality of the thymus; 10% have a thymoma, a tumor (either benign or malignant) of the thymus, and other abnormalities are frequently found. The disease process generally remains stationary after thymectomy (removal of the thymus). Muscle-like cells within the thymus (myoid cells), which bear AChRs on their surface, may serve as a source of autoantigen and trigger the autoimmune reaction within the thymus gland. There is also a slight genetic predisposition: particular HLA types (human leukocyte antigen) seem to predispose for Myasthenia Gravis. 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. 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.

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 o Class IIa: Predominantly limb or axial muscles o Class IIb: Predominantly bulbar and/or respiratory muscles Class III: Eye muscle weakness of any severity Moderate weakness of other muscles o Class IIIa: Predominantly limb or axial muscles o Class IIIb: Predominantly bulbar and/or respiratory muscles Class IV: Eye muscle weakness of any severity, severe weakness of other muscles o Class IVa: Predominantly limb or axial muscles o Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation) Class V: Intubation needed to maintain airway