Neuroscience Clerkship at UH/VA
 
Myasthenia Gravis
 
MG is caused by an autoimmune attack at the nicotinic acetylcholine receptors (AchR) that impairs neuromuscular junction (NMJ) transmission. The disease is characterized by muscular weakness that manifests or worsens with use. The cause of the autoimmune attack is unknown but is related to aberrant thymus function, since of MG patients have thymus abnormalities. Ten percent have a benign tumor of the thymus (thymoma). Incidence is 1/7500.
Clinical Presentation
 

Patients with MG present with muscle weakness and fatigue. As the disorder is limited to the NMJ, there is no abnormality of mental state, sensory function, or autonomic function. Myasthenic weakness characteristically affects the:

  • Extraocular muscles
  • Bulbar muscles
  • Proximal limb muscles
  • Or a combination of these

Eye findings are the most common with ptosis and extraocular muscle weakness occurring in more than 50 percent of patients at the time of presentation and developing in more than 90 percent at some time during their illness. Frequently, extraocular weakness may begin asymmetrically with one eye involved and the other spared. A very small amount of extraocular weakness will be subjectively noticed by the patient as visual blurring or frank double vision. Myasthenic weakness has been known to mimic third, fourth, and sixth cranial nerve palsies as well as, rarely, an intranuclear ophthalmoplegia. Unlike third nerve palsies, however, MG never affects pupillary function. Fixed extraocular weakness tends to occur later.

Figure Above:  Typical picture of ptosis in a patient with MG


After extraocular weakness, bulbar muscle weakness is most common, with difficulty in chewing, swallowing, and speaking. Some patients experience severe fatiguability and weakness of mastication, and are unable to keep the jaw closed after chewing. Myasthenic speech is nasal (from weakness of the soft palate) and slurred (from weakness of the tongue, lips, and face) but without any difficulty with fluency.

When limb weakness develops in patients with MG, the proximal musculature is usually affected, often in a symmetric pattern. Patients complain of difficulty arising from chairs or going up and down stairs, reaching with their arms, or holding their head up. Rare patients will present with a "limb-girdle" form of myasthenia gravis alone, without weakness of eye movement or bulbar muscles.

The hallmark of MG is pathologic fatigability, that is, progressive muscle weakness with use. Patients typically improve after rest or upon arising in the morning, with worsening as the day passes. Generalized fatigue is a common complaint in many neurologic and non-neurologic disorders. In MG and other disorders of the NMJ, fatigue is limited to muscular fatigue alone and often progresses to frank muscle weakness. Patients with MG do not generally experience a sense of mental fatigue, tiredness, or sleepiness.


Evaluation:

Tensilon Test.  Tensilon, a short term AchE inhibitor test allows strength to improve because the excess of Ach overcomes the loss of Ach receptors. Start with 2mg IV, assess and then give the remaining 8 mg IV. Unequivocal improved muscle strength is considered a positive test. Cardiac monitoring is required as some patients may become bradycardiac. Atropine should be readily available.

 

Electromyography (EMG) with slow (2-3 Hz) repetitive nerve stimulation characteristically shows a decrement in the muscle action potential of more than 10%.
 

Figure Above:  3 Hz Repetitive Nerve Stimulation in a patient with MG. In this case, the maximal decrement of amplitude can calculated at 57% (normal is < 10%)
 

Serum testing for anti-Ach receptor antibodies (sensitivity is approximately 80% of patients with MG with weakness beyond ocular muscles with a very high specificity).
 

Single-fiber EMG is an extremely sensitive, but not specific test for MG. Single-fiber evaluates “jitter”, a measure of neuromuscular junction integrity. Single-fiber is useful in patients suspected of having MG but in whom the tensilon test, repetitive nerve stimulation and AChR antibodies are normal or equivocal.

All patients should have a Chest CT or MRI looking for a thymoma or thymic hyperplasia.

Thymoma Aorta Trachea Sternum Lung Lung Vertebral Body Spinal Cord Spinous Process Paraspinal Muscles Scapula Scapula Shoulder girdle muscles Shoulder Girdle Muscles Rib Rib

Figure Above:  CT scan of the chest demonstrating a mass in the anterior mediastinum, consistent with a thymoma (place the cursor over the image and anatomic structure name is appear).
Treatment


The treatment of patients with MG has improved substantially. Many options are available. Treatment consists of symptomatic agents (acetylcholinesterase inhibitors), immunosuppressives (steroids, azathioprine, cyclosporine), plasma exchange, intravenous immunoglobulin, and thymectomy.

     Acetylcholinesterase Inhibitors

Symptomatic treatment consists primarily of giving acetylcholinesterase inhibitors, such as pyridostigmine (Mestinon). These agents slow the degradation of acetylcholine in the synaptic cleft and effectively increase the amount of neurotransmitter available at the postsynaptic junction. Mestinon has a short half-life and must be dosed every 4 to 6 hours. The optimal dose will vary widely between patients. Patients are typically begun on half a tablet (30 mg) of Mestinon every 6 hours and slowly titrated to a higher dose or more frequent dosing interval. There is no correct dosage. Some patients improve substantially on 3 to 4 tablets a day; others require far more. The major side effects are those of cholinergic excess, especially abdominal cramping and diarrhea, excessive perspiration, and salivation. Of course, excessive amounts can also cause weakness (cholinergic crisis). Most patients with MG will respond well, at least initially, to these medications. Restricted ocular MG tends to be more refractory than generalized disease. For patients who have difficulty upon awakening in the morning, a slow release form (Mestinon Timespan) is available as a 180-mg dose to be taken at bedtime.

     Immunosuppressives

Although acetylcholinesterase inhibitors are effective in most patients, the response is generally not completely satisfactory and most patients have a better long-term response by attacking the primary pathophysiology of the disease, the immune mechanism. This consists of immunomodulating treatments, such as steroids, other immunosuppressives, intravenous immunoglobulin, plasma exchange, and thymectomy.

Steroids are the mainstay of therapy in MG. Improvement, including remission, can usually be obtained with oral steroids. The typical dose of prednisone is 1 mg/kg/day taken as a single dose in the morning. Patients are often started on a low dose (10 to 20 mg qd) while under close supervision, or in the hospital because steroids, especially in high doses, may cause transient worsening of myasthenia during the first 2 to 3 weeks. The dose is slowly titrated up by 5 mg/day every 3 to 7 days until clinical benefit is obtained or a dose of 1 mg/kg is obtained. Improvement often begins in 1 or 2 months with maximal improvement occurring at 6 to 12 months. After remission, patients can be switched to alternate-day steroids with the same total dose, and then slowly tapered. The chance of a successful taper is improved when the steroid dose on the "on day" is tapered no faster than 5 mg/day/month. When the dose reaches 40 to 50 mg every other day, tapering is best slowed to 2.5 mg/ day/month. Often patients will relapse several months after a successful taper and subsequent discontinuance. Many patients require the chronic administration of a low dose of steroids every other day to sustain a remission. The goal is to determine the lowest dose of every-other-day therapy that will prevent a relapse. Unfortunately, when patients relapse, they often require a higher dose of steroids dosed daily in order to go back into remission, which must then be followed by another long, slow, tapering process.

Many patients, especially the elderly, cannot tolerate the side effects of steroids (hypertension, weight gain, glucose intolerance, osteoporosis, cataracts, ulcers, etc.) and may require other types of immunosuppression. Azathioprine (AZA, Imuran) has gained wide acceptance in the treatment of myasthenia, and in many patients is now the drug of choice. The concomitant use of AZA therapy commonly allows steroids to be tapered or discontinued. Clinical improvement is commonly delayed for 2 to 4 months, but may not reach maximal benefit until the first year or two. Patients are typically started on 50 mg qd as a single morning dose and slowly increased to 2 to 3 mg/kg/day over the following several weeks. Most patients tolerate AZA without difficulty. However, adverse reactions may occur. The most common is hematologic (anemia, leukopenia, thrombocytopenia) which require close monitoring of blood counts during therapy (every 1 to 2 weeks initially). A typical hematologic endpoint is to let the white blood cell (WBC) count drop to 3500-4000/mm3 or the absolute lymphocyte count to drop to 5 to 10 percent. In addition, gastrointestinal, disturbance elevation of liver enzymes (2 to 3 times normal), and susceptibility to serious infections may occur. Most of these complications can be dealt with by reducing the dose (hematologic and liver enzyme abnormalities) or dividing the dose with meals (gastrointestinal disturbance). Rarely, patients develop an acute, toxic hypersensitivity reaction to AZA with fever, abdominal pain, and rash, which requires prompt and permanent discontinuance of the drug. Also of concern is the slight increased risk of malignancy, especially lymphoma, which has been reported in non-myasthenic patients treated with AZA.

Cyclosporin A (CSA), a drug that inhibits interleukin-2 and subsequently blocks cytotoxic lymphocytes and the proliferation of T-helper cells, is effective in preventing rejection in organ transplantation. This drug has also been found effective in several small studies of patients with MG. A typical induction dose is 5 mg/kg given as a divided dose in the morning and evening. After remission, the dose may be gradually reduced to a maintenance dose of 2 to 3 mg/kg. As with the other immunosuppressives, the goal is to determine the lowest dose that prevents a clinical relapse. Trough CSA levels need to be closely followed to maintain a level in the 100 to 200 ng/ml range. Blood pressure and renal function must be carefully followed. In regard to side effects, CSA is superior to other immunosuppressives in not suppressing the bone marrow. The major risks involve nephrotoxicity and hypertension. In addition, there are many potential drug interactions, most importantly, the high likelihood of nephrotoxicity with the concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Prednisone, AZA, and CSA are first-line therapies in the treatment of MG. The choice among the three is primarily based on the experience of the treating physician, with special emphasis on the side-effect profile for the individual patient. Each of these agents has potential serious side effects. Obviously, they should never be used in any patient unless adequate compliance and follow-up are possible. The major errors in using these agents are in prescribing a dose that is too low, for a duration that is too short, or nonaggressive treatment of side effects.

     Plasma Exchange

Removal of antibody allows clinical recovery in patients with MG. Often 3 to 5 large-volume plasma exchanges are required to sufficiently reduce the antibody level. Plasma exchange is most appropriately performed when a patient has suddenly deteriorated and is in crisis, or before major surgery such as thymectomy. It is in this situation, when rapid reversal of clinical weakness is required, that plasma exchange is most useful in minimizing further worsening or serious complications, such as intubation or pneumonia. However, as routine treatment for MG, plasma exchange is invasive and only temporary, and is best reserved for those unusual patients who do not respond to other immunomodulating therapy.

     Intravenous Immunoglobulin

Intravenous immunoglobulin is used successfully in a variety of autoimmune diseases. Several reports have confirmed the efficacy of intravenous immunoglobulin in MG, including refractory patients who have failed other traditional therapies. Like plasma exchange, intravenous immunoglobulin is most useful when a patient with MG has suddenly deteriorated and rapid reversal of the weakness is important. It may also be useful in selected patients whom plasma exchange is associated with side effects or difficulties with large volume intravenous access. Similar to other autoimmune conditions, patients are initially treated with doses of 400 mg/kg/day for 5 days. Additional single doses are then given every one to six weeks, depending on the clinical response.

     Thymectomy

Using the above approach, most patients are successfully treated. The disease can be controlled in most patients, and it is now rare for patients to die of their illness. Myasthenia tends to be lifelong, and patients usually require prolonged therapy. Spontaneous remissions can occur, but relapses often occur again in the future. Immunosuppressives, especially prednisone, are often associated with potential long tem side effects.

Although there has never been a prospective randomized trial, thymectomy is associated with an increased chance of complete remission or substantial improvement in MG patients. Patients with milder disease and relatively recent onset of symptoms (less than 3 years), without thymoma, are reported to respond best with thymectomy. Young patients with early myasthenia tend to do particularly well. Clinical improvement is commonly delayed 6 to 12 months after the operation and may continue for 5 years or more. In many centers, thymectomy is often not advised in patients older than age 60, because of other medical conditions which increase the risk of surgery (e.g., coronary artery disease) and the frequent observation that the thymus is atrophic in the elderly. However, some studies have shown beneficial results in elderly patients. Thus, each case must be individualized regarding the recommendation for surgery.

The other indication for thymectomy, of course, is the presence of a thymoma. The myasthenia of patients with thymoma tends to be more severe, compared to other myasthenic patients, and often require the combination of surgery and aggressive medical therapy.


Treatment Options Summary:


AchE inhibitors (i.e., mestinon) is used for symptomatic therapy. Dosage is typically 30 – 90 mg q 3-4 hours.
 

Surgical thymectomy is used for thymomas. In the absence of thymoma, thymectomy may provide long-term improvement or remission. Thymectomy is generally advised for patients who are younger; have mild to moderate MG, and who have had their disease for less than 2 years.
 

Immunosuppresants. A variety of immunosuppresants are useful in MG. Steroids are often the first line of treatment. Cyclosporin and Azathioprine are also efficacious. Due to possible side effects, patients must be reassessed frequently to look for improvement or signs of deterioration. These medications may not show their beneficial effects for months.
 

Plasmapheresis to remove anti Ach receptor antibodies can provide temporary improvement. Intravenous Gammaglobulin (IVIG) has similar efficacy.


Special note on Myasthenic Crisis:


Myasthenic crisis is defined as respiratory failure or delayed postoperative extubation for more than 24 hours resulting from myasthenic weakness. Crisis results from either 1) weakness of the upper respiratory muscles that leads to aspiration and obstruction or 2) frank weakness of the diaphragm and other muscles of respiration. A crisis can be precipated by respiratory infection, aspiration, sepsis, surgical procedures, rapid tapering of immune modulation, and pregnancy.

Myasthenic crisis most often occurs in patients with known myasthenia. However, a small number of patients with myasthenia will present initially with crisis. Myasthenic crisis occurs in about 20% of patients in the first year of the illness. Over the last 40 years, effective treatment has decreased mortality significantly, from 75% to less than 5%. Myasthenia crisis should not be fatal if patients receive respiratory support and appropriate immunotherapy. Currently plasma exchange and IVIG are the treatments of choice for myasthenic crisis. In any patient with myasthenia, the following drugs should be avoided as they can produce increasing weakness and crisis:

Neuromuscular blocking agents

Antibiotics

Aminoglycosides, particularly gentamycin
Marcolides, particularly erythromycin and azithromycin

Cardiovascular Agents: Beta-Blockers, Calcium Channel Blockers, and Procainamide

Quinidine

Corticosteroids

Magnesium Salts

Iodinated Contrast Agents

D-penicillamine

Impending myasthenic crisis is essential to recognize. Any myasthenic patient with worsening bulbar or respiratory function needs to be managed in the ICU where their respiratory status can be aggressively monitored. In most, plasmapheresis is used to quickly improve myasthenic weakness.