Authored by MCN Neurologists
Myasthenia gravis (MG) is an autoimmune disorder that results in neuromuscular junction dysfunction.
Clinically, MG is characterized by muscle weakness in a variable number of different skeletal muscle groups of fluctuating severity over the course of the disease. The most commonly affected muscles are ocular (related to the eye), facial, bulbar, axial, proximal limbs and respiratory.
MG is relatively uncommon. The annual incidence rate is approximately one per 300,000. Almost 43-84 per million live with MG. The disorder’s age of onset has two peaks. The first peak occurs between 20-30 years of age; during this age interval, women are two to three times more likely to be affected than men. The second peak is between 50-60 years of age; during this age interval, men have a slightly higher risk than women.
Causes of Myasthenia Gravis
Currently, two types of autoimmune antibodies are known to cause MG. The most common type is the Acetylcholine receptors (AchR) antibody. The less common type, discovered relatively recently, is the anti-muscle-specific receptor tyrosine (MuSK) antibody. Both autoimmune antibodies attack proteins in the postsynaptic membrane of the neuromuscular junction.
The thymus gland plays a role in the origin and development of MG. It is known that about 50% of anti-AchR positive patients have thymus hyperplasia and 10-15% have a thymic tumor. Of those patients with a thymoma, the majority tend to be male with an age of onset between 50-60 years of age.
Symptoms of Myasthenia Gravis and What Your Neurologist Will Want to Know
MG is usually insidious in its onset. The disease progresses slowly and often shows a pattern of fluctuating skeletal muscle weakness. The weakness can be more noticeable in the later hours of the day or after repeated movement of certain muscles, and then improves with a period of muscle rest.
MG can be classified into two main clinical forms: ocular and generalized.
Ocular MG: For these patients, muscle weakness is limited to the eyelids and extraocular muscles. Ptosis (droopy eyelid) and diplopia (double vision) are the main symptoms.
Generalized MG: Besides ocular involvement, multiple other muscle groups can also be affected,and the symptomatic presentation is usually highly variable. Non-ocular muscles affected may include:
• Bulbar muscles: Patients will have speech difficulty (dysarthria), chewing fatigue and dysphagia (swallowing difficulty).
• Facial muscle: Patients will have facial muscle weakness and “lost smile” or “jaw drop” appearance.
• Limb muscle: Patients will have difficulty climbing stairs, lifting arms above the shoulders or extending the arms and fingers.
• Other less common presentations may include isolated neck weakness (drop head syndrome), distal limb weakness or isolated respiratory muscle weakness.
Myasthenia Crisis: Some patients can develop a life-threatening myasthenic crisis, characterized by acute or subacute respiratory failure due to respiratory muscle weakness. This may occur during an active stage of the disease, or be precipitated by the co-existence of certain unfavorable conditions, such as a major surgery, infections, medications, etc.
Myasthenia Gravis Examination and Tests
Your doctor will take a thorough history about the onset, duration and fluctuation of your symptoms. Particular attention will be paid to distinctive symptoms, such as droopy eyelids, double vision, difficulty of chewing or swallowing food, difficulty with breathing, etc.
During the physical examination, your doctor will evaluate your eye movements, looking for droopy eyelids, double vision, weakness of facial muscles and trouble with articulation. Your doctor will test your muscle strength. Due to the fluctuating nature of the disease, the initial muscle strength testing may be normal. Repeat muscle strength tests during follow-up visits may be performed.
Additional laboratory-based examinations that may be recommended include:
Although this injection-based clinical test was commonly used for MG, it is less frequently done today due to decreased commercial availability of the testing agent, edrophonium. The test itself is also considered relatively unreliable and nonspecific.
Antibody Tests – It should be emphasized that, although a positive result can help to confirm the diagnosis, a negative antibody result cannot rule out MG. Purely ocular MG patients are more likely to have seronegative MG.
Acetylcholine Receptor Antibodies (AChR): AChR antibody is positive in 80-90% of patients with generalized MG and 40-55% of patients with ocular MG. Almost all patients (98-100%) with MG and thymoma are AchR antibody positive; however, for reasons we do not fully understand, quantitative AChR-Ab levels do not predict the severity of MG very well.
Muscle-Specific Receptor Tyrosine Antibody (MuSK): MuSK antibodies are present in 38-50% of generalized MG patients who are AChR-Ab negative.
Other Antibodies: Anti-striated muscle antibodies are present in 30% of patients with MG and in 80% of those with thymoma. Antibodies against titin and the ryanodine receptor may be helpful in predicting the presence of thymoma.
A CT or MRI scan of the chest can help to evaluate thymoma or thymus hyperplasia.
Repetitive Nerve Stimulation (RNS) Studies: RNS is the most frequently used electrodiagnostic test for MG. Its sensitivity in generalized MG is about 75%. The test is performed by placing a recording electrode over the endplate region of a muscle and stimulating the related motor nerve. The electrical nerve stimulation is set at a frequency rate (2 or 3 Hertz). The compound muscle action potential (CMAP) amplitude is then recorded from the electrodes over the muscle. In normal muscles, there is no change in CMAP amplitude with repetitive nerve stimulation. In MG, there may be a progressive decline in the CMAP amplitude with the first 4-5 stimuli. An RNS study is considered positive if the decrement is greater than 10%.
Single-Fiber Electromyography (SFEMG): SFEMG is more technically demanding than RNS and is less widely available, but it is considered a more sensitive test for MG. SFEMG is positive in greater than 95% of those with generalized MG and 90-95% inocular MG patients.
Treatments Available for Myasthenia Gravis
MG used to be a disabling disease, and at times, a fatal disorder. Nowadays, most patients are able to manage their conditions effectively with therapeutic agents. Some achieve sustained remission. Patients will have different treatment strategies, each tailored according to the symptom classification (purely ocular MG versus generalized MG), severity of the disease, age of the patient, respiratory or bulbar involvement and other variables. Four basic treatment strategies exist:
Acetyl cholinesterase inhibitors are the first line of treatment choice. Pyridostigmine bromide (Mestinon), the main cholinesterase inhibitor currently in use, is available as scored 60 mg tablets. A common starting dose is 30 mg three times a day. Pyridostigmine has a rapid onset of action (15 to 30 minutes) with peak action at about two hours, and its effects last for three to four hours, sometimes longer. A long-acting formulation of pyridostigmine (Mestinon TS, 180 mg) is also available.
Chronic Immunomodulating Treatment
Currently, the commonly used immunotherapeutic drugs in MG are prednisone, azathioprine, cyclosporine and mycophenolate mofetil. Administering moderate or high doses of steroids can lead to remission in 30% of patients and marked symptom improvement in another 50%. The onset of benefit generally begins within two to three weeks. It should be noted that a transient deterioration can occur in up to 50% of MG patients. Your doctor may choose other immunosuppression medications to reduce this risk.
Rapid Immunomodulating Treatment
Both plasma exchange and intravenous immune globulin (IVIG) work quickly, but these regimens have a short duration of action. They are also expensive and usually reserved for a few selective situations, such as myasthenic crisis, refractory MG (used as an adjuvant to other immunotherapeutic medications), or before thymectomy (used as a “bridge” therapy while initiating Prednisone).
Although well-designed randomized clinical trials are lacking, thymectomy is thought to benefit those patients who are younger than age 65 (note that the benefits of the surgery may take years to accrue) and those who have generalized MG without thymoma.
Prevention of Myasthenia Gravis
Primary prevention for MG is currently lacking because what triggers the autoimmune reaction to the neuromuscular junctions is unknown. Certain situations, however, that can make MG symptoms worse, such as hot or humid weather, increased body temperature or infection, are not inevitable and should be avoided when possible. Also, many drugs can exacerbate MG symptoms (see the list below). Individual patients should consult with their treating doctors before starting a new medication.
A partial list of medications that can exacerbate MG:
Neuromuscular blocking agents (used during anesthesia)
Certain antibiotics (Azithromycin, Clarithromycin, Telithromycin, Fluoroquinolone, etc)
For further information about Myasthenia Gravis, click on the following links:
www.myasthenia.org (Myasthenia Gravis Foundation of America, Inc.)
www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm (National Institute of Neurological Disorders and Stroke website)