MYASTHENIA GRAVIS

MYASTHENIA GRAVIS

Current Diagnosis

• Myasthenia gravis is an autoimmune disease that affects the neuromuscular junction.

• Symptoms include fluctuating skeletal, ocular, or bulbar muscle weakness in any combination and of varying degrees of severity.

• Depending on the clinical severity, treatment can focus on controlling symptoms or can require chronic immunomodulating therapy. Thymectomy may also induce remission in many patients.

• Myasthenic crisis can be potentially life threatening due to rapid respiratory compromise and can be triggered by a wide variety of medications and acute illness.

Current Therapy

• Mild symptoms respond very well to anticholinesterase inhibitors, with pyridostigmine (Mestinon) being the most commonly used.

• Chronic control of symptoms can require oral immunosuppressive agents such as steroids, azathioprine (Imuran),1 or mycophenolate mofetil (Cellcept).1 If necessary, plasmapheresis or IV immunoglobulin (IVIg; Gammagard)1 can be helpful to treat worsening symptoms or as maintenance therapy.

• A diverse range of medications can exacerbate myasthenic symptoms. Clinicians need to be mindful of this with their prescriptions for myasthenic patients.

• Myasthenic crisis is a medical emergency and requires aggressive supportive care. Such patients need to be hospitalized in an intensive care setting with close respiratory monitoring and intubation if necessary. Such patients require acute immunologic treatment with plasmapheresis or IVIg1 to accelerate recovery followed by chronic immunomodulating therapy.

1 Not FDA approved for this  indication.

Epidemiology

Myasthenia gravis is often described as a disease of young women and old men. The disease most commonly occurs in women younger than 40 years and men between the ages of 50 and 70 years. However, it can certainly occur in men and women outside of these age ranges.

Risk Factors

Patients with immediate family members who have a history of autoimmune disease may be at higher risk for developing myasthenia gravis.

Pathophysiology

Myasthenia gravis may be the best understood of all the autoimmune disorders. Before discussing the pathophysiology, a brief overview of the neuromuscular junction may be useful.

The neuromuscular junction is the synapse between the motor unit axon and the motor end plate. An action potential arriving at the neuromuscular junction opens voltage-gated calcium channels, which trigger the release of acetylcholine into the synaptic cleft. The acetylcholine diffuses across the cleft and binds to receptors in the motor end plate, which leads to depolarization and ultimately to muscle activation. To prevent involuntary sustained muscle activation, the acetylcholine is rapidly broken down by acetylcholinesterase in the synaptic cleft.

In myasthenia gravis, autoantibodies bind to the acetylcholine receptors in the motor end plate but do not activate them. Thus, there is competitive inhibition with the endogenous acetylcholine released in the synaptic cleft, leading to reduced activation of the motor end plate.

The muscle tissue itself is healthy and a muscle biopsy is unremarkable.

Prevention

The primary disease itself is not preventable. However, myasthenic exacerbations can be triggered by many types of medications, particularly β-blockers, aminoglycosides, and neuromuscular junction–blocking agents, among many others (Box 1). These agents should be avoided if possible or used with extreme caution if they are medically necessary. Systemic medical illnesses can also trigger myasthenic crisis, particularly upper respiratory infections. These patients can deteriorate quickly, so close monitoring is essential.

Box 1  
Common Drugs That Can Exacerbate Myasthenia Gravis
Anesthetics

Halothane (Fluothane)

Ketamine (Ketalar)

Lidocaine (Xylocaine)

All neuromuscular blocking agents

Procaine

Antibiotics

Aminoglycosides

Fluoroquinolones

Tetracyclines

Erythromycin

Clarithromycin (Biaxin)

Clindamycin (Clecoin)

Antiepileptics

Gabapentin (Neurontin)

Phenytoin(Dilantin)

Antipsychotics

Chloropromazine (Thorazine)

Lithium (Eskalith, Lithobid)

Phenothiazines

Cardiovascular Agents

β-Blockers

Calcium channel blockers

Procainamide (Pronestyl)

Quinidine

Others

Anticholinergic agents

Cholinesterase inhibitors

Glucocorticoids

Narcotics

Statins

Clinical Manifestations

The hallmark of myasthenia gravis is pure motor weakness involving ocular, bulbar, or skeletal muscles in any combination and that fluctuates over time. Ocular myasthenic symptoms generally include diplopia and ptosis. Patients can present with oculoparesis that can mimic isolated cranial nerve III, IV, or VI palsies in any combination and is a common feature in myasthenic patients. Bulbar symptoms include dysarthria and dysphagia. Skeletal muscle weakness is usually affected more in the proximal muscles than the distal muscles. A common complaint is difficulty walking up stairs owing to hip flexor weakness, but any muscle group can be affected. There also tends to be a diurnal variation of the symptoms, with the weakness tending to get worse toward the end of the day after exertion but improving with rest. About half of patients with only ocular symptoms on initial presentation develop more generalized symptoms later in life.

Diagnosis

The diagnosis of myasthenia can often be made based on a careful history and detailed neurologic examination demonstrating the pattern of weakness and its variable nature. Laboratory testing and electromyography help to confirm the diagnosis. If the patient is not presenting with any symptoms at the time of the examination, muscle fatigability can often be induced. Sustained upward gaze can induce ptosis and unmask oculoparesis leading to diplopia. Prolonged speech can induce slurring or a nasal quality to the voice. Repetitive muscle movements can lead to clinically detectable weakness.

Another helpful bedside examination finding is the ice pack test. In a patient presenting with ptosis, applying an ice pack over the affected eye can lead to demonstrable improvement, supporting the diagnosis of myasthenia gravis.

Another way to confirm the diagnosis clinically is a Tensilon (edrophonium) test. To do this, there needs to be a clear observable sign of weakness, preferably ptosis, because this is difficult for the patient to simulate factitiously. Because of the risk of bradycardia, this test needs to be done with telemetry monitoring, with atropine 1 mg on hand at the bedside. An initial test dose of edrophonium 2 mg is given intravenously and the patient is observed for any side effects. If the patient tolerates this dose, another 8 mg (10 mg total) is given. The patient is monitored for any clinical improvement in the weakness being observed; improvement supports the diagnosis of myasthenia.

Some clinicians, if a skeletal muscle is observed, administer a placebo before the edrophonium. Improvement in symptoms with the placebo suggests a psychogenic component to the symptoms.

Serologic tests are available for confirming the clinical diagnosis of myasthenia gravis; the most useful are assays for detecting acetylcholine receptor antibodies (AChR-Ab). This test is very specific and has very low false-positive rates. It is fairly sensitive in generalized myasthenia (more than 80%) but less sensitive in detecting milder forms like ocular myasthenia (as low as 50%). In cases where clinical suspicion is high but the patient is AchR-Ab negative, another assay for antibodies to muscle-specific receptor tyrosine kinase (anti-MuSK) is available. Anti-MuSK is positive in up to 50% of AchR-Ab negative patients with myasthenia gravis. Up to 10% of patients with myasthenia gravis are seronegative for both assays.

Notably, patients who are AchR-Ab positive are more likely to have thymic abnormalities and thus can be predicted to benefit more from thymectomy. Conversely, patients who are seronegative or have anti- MuSK antibodies alone are less likely to have thymic pathology and may be expected to receive less benefit from thymectomy. Otherwise the medical approach to treatment is unchanged regardless of the presence or absence of serologic markers.

An autoimmune screen is also recommended in any patient being worked up for myasthenia gravis. Thus checking erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, and thyroid-stimulating hormone levels is advised.

Electromyography is very useful in confirming the diagnosis of myasthenia gravis as well as excluding other possible neuromuscular diagnoses. Electromyography should be viewed as an extension of the neurologic examination. If myasthenia gravis is suspected, the ordering physician should request that repetitive nerve stimulation and single-fiber electromyography (EMG) be done if the equipment is available. In repetitive nerve stimulation, a motor nerve to a clinically affected muscle is stimulated repeatedly at low frequencies. In myasthenia gravis, this test should demonstrate decrement in amplitude of the compound motor action potentials and has a sensitivity of roughly 75% for generalized myasthenia. Single-fiber EMG is a more time-consuming and technically difficult test that involves simultaneously measuring the motor action potentials of two muscle fibers innervated by the same motor nerve. The time between action potentials (referred to as “jitter”) is measured, and increased jitter strongly suggests delayed neuromuscular transmission. Single- fiber EMG has a sensitivity up to 95%. Milder forms such as ocular myasthenia are more likely to have false negatives in either of these tests. However, even with single-fiber EMG, the sensitivity in these cases is greater than 90%.

In patients with a confirmed diagnosis of myasthenia gravis, a chest CT scan is recommended to evaluate for any gross thymic pathology. All myasthenic patients should be considered for thymectomy if there are no medical contraindications, even if there are no gross abnormalities on imaging.

Differential Diagnosis

Other neuromuscular junction disorders can manifest with features similar to myasthenia gravis, such as botulism, Lambert-Eaton syndrome, and cholinergic crisis. However, usually these conditions can be distinguished clinically, particularly by the presence of autonomic features that are not present in myasthenia gravis.

Botulism is associated with ingestion of toxin from the bacteria Clostridium botulinum, usually from home-canned food, and generally occurs in infants rather than adults. In addition to oculobulbar and generalized weakness, these patients also present with dilated pupils, dry skin, and dry mucosal membranes. Lambert-Eaton myasthenic syndrome (LEMS) is due to autoantibodies to the presynaptic voltage- gated calcium channels and is often associated with underlying malignancy, usually small cell lung cancer. In contrast to myasthenia, weakness often spares the oculobulbar muscles and the weakness tends to improve rather than worsen with exercise. These patients are usually areflexic and also have other autonomic symptoms such as dry mouth and sexual dysfunction. Cholinergic crisis can occur with overdose of acetylcholine esterase inhibitors or exposure to pesticides with organophosphates, leading to excess cholinergic activity in the neuromuscular junction. In addition to bulbar, generalized, and respiratory weakness, these patients usually present with autonomic signs of cholinergic excess such as pupillary constriction, hypersalivation, and sweating.

Other neuromuscular conditions can lead to weakness that can mimic myasthenia gravis. Acute demyelinating polyneuropathy (Guillain-Barré syndrome), if severe, could appear similar to myasthenic crisis. However, the cerebrospinal fluid usually shows elevated protein, and EMG findings should show demyelination. Critical illness polyneuropathy and myopathy occur in patients with prolonged ICU courses, particularly if sepsis is part of the clinical picture, and EMG studies are helpful in clarifying the diagnosis.

Inflammatory myopathies and motor neuron disease are also in the differential diagnosis, and EMG studies should be very helpful to elucidate the diagnosis in clinically uncertain cases.

In cases of pure ocular myasthenia, third, fourth, or sixth cranial neuropathies in any combination could be considered in the differential diagnosis. In the case of third nerve palsy, the pupil is usually involved as well, and the affected eye is deviated down and outward. There can also be ptosis. In fourth nerve palsy, the affected eye is usually elevated compared to the normal eye, leading to a vertical diplopia. In sixth nerve palsies, the eye is deviated inward and there is clear weakness in abducting the affected eye. Conversely, myasthenia gravis should be considered in any patients with isolated ocular weakness.

Treatment

Treatment for myasthenia gravis can be divided into symptomatic control, immunosuppression, and, in selected patients, thymectomy, depending on the severity of the disease.

Symptoms can be controlled in many patients with acetylcholinesterase inhibitors. Inhibition of acetylcholinesterase leads to prolonged action of acetylcholine in the synaptic cleft, partially overcoming the competitive inhibition with acetylcholine-receptor antibodies. This may be sufficient alone to address mild forms of the disease, such as in ocular myasthenia. The most commonly used agent in this class is pyridostigmine (Mestinon). Neostigmine (Prostigmin) is another alternative, though it is less often used.

Pyridostigmine

Pyridostigmine is effective for controlling mild symptoms. It should not be relied on as therapy for suspected myasthenic crisis or if respiratory compromise is a concern.

The dose is 30 to 90 mg, generally used every 3 to 6 hours as needed, and tailored to clinical response. Maximum dose should not exceed 120 mg per single dose. Patients typically get a response within 30 minutes. It is also available in a long-acting formulation (Mestinon TS 180 mg). The long-acting form is generally not recommended for daytime use owing to a less-predictable onset of action. It may be useful as a bedtime dose for patients who have severe morning weakness on awakening.

Side effects for acetylcholine esterase inhibitors are mostly gastrointestinal, with abdominal cramping, nausea and vomiting, and diarrhea being most common. Patients might find it helpful to take the medicine with some food. Other symptoms of cholinergic excess such as miosis, sweating, and hypersalivation can also occur. Overdose can lead to cholinergic crisis, with severe weakness, bradycardia, and hypotension being potentially life-threatening, but these effects generally do not occur if the medication is taken within recommended parameters.

If necessary, side effects can be alleviated with certain anticholinergic medications with little or no activation of nicotinic receptors. A commonly used agent for this purpose is glycopyrrolate (Robinul)1 1 mg taken with each pyridostigmine dose or as a stand- alone dose three times a day.

In patients with baseline weakness beyond mild bulbar or ocular symptoms or with progressively worsening symptoms, chronic immunosuppression may be necessary. The most commonly used agents are prednisone,1  azathioprine (Imuran),1 mycophenolate mofetil (Cellcept),1 and cyclosporine (Sandimmune, Neoral), each with its own advantages and disadvantages.

Prednisone

Prednisone1 is often the first agent used in long-term management of generalized myasthenia. Prednisone has the advantage of having relatively quick onset of action compared to other immunosuppressive agents used for chronic myasthenia. Some clinicians favor starting patients on high doses (1.5 mg/kg to a maximum dose of 100 mg) to achieve a quick clinical response initially, then tapering to the lowest dose possible to maintain control of symptoms. Other immunosuppressive treatments can be used in conjunction as steroid-sparing agents. The disadvantage with this strategy is that for unclear reasons, prednisone can exacerbate symptoms in the short term, and this risk increases with higher doses. Thus this strategy is generally initiated in the inpatient setting. Most clinicians, if possible, favor avoiding the risk of exacerbating symptoms and instead start at a lower dose (15–20 mg) and titrate the dose slowly based on the patient’s clinical response. The drawback is that it generally takes longer to achieve significant symptomatic improvement.

Azathioprine

Azathioprine1 can be used for chronic immunosuppression as a steroid-sparing agent. Patients are started on 50 mg/day and then titrated 50 mg/week to a target dose of 2 to 3 mg/kg/day. During the first few weeks, some patients have to discontinue the medication owing to a systemic reaction involving fever, abdominal pain, nausea, and vomiting. Patients also require weekly monitoring of complete blood counts and liver function during the titration phase. Upon reaching the target dose, monitoring can be extended to every 3 months. The medication can take up to 6 months to take effect.

Mycophenolate Mofetil

Mycophenolate mofetil1 is less well studied than azathioprine, but from clinical experience, it appears to be efficacious in chronic treatment of myasthenia and has become preferred owing to better side-effect profile, faster onset of action (usually within 3 months), and no need for regular monitoring of liver function. Patients start on 1 g twice a day, titrated by 500 mg a month until a target dose of 1.5 g twice a day is reached. Side effects include diarrhea, abdominal pain, and nausea. Less commonly, leukopenia can occur.

Cyclosporine

Cyclosporine1 is viewed by most clinicians as a second-line agent for patients who fail treatment with azathioprine and mycophenolate mofetil. Patients can start on 3 mg/kg daily divided in two doses, titrated up to 6 mg/kg daily. The dose should be adjusted to a trough cyclosporine level between 50 and 150 ng/mL. Kidney function also needs to be monitored. Cyclosporine tends to take effect within 2 to 3 months of drug initiation.

Plasmapheresis and Intravenous Immunoglobulin

Plasmapheresis and intravenous immunoglobulin (IVIg, Gammagard)1 have been shown to be effective in the acute management of myasthenia and are mainstays of treatment in myasthenic crisis. These treatments are also useful as bridging therapies in patients transitioning to chronic immunosuppression or as prophylaxis for patients at risk for myasthenic crisis.

Plasmapheresis directly removes circulating acetylcholine receptor antibodies, leading to alleviation of symptoms. The mechanism of action of intravenous immunoglobulin is less clear. It may be due to the pooled immunoglobulin binding to the autoantibodies, in turn preventing them from binding to the acetylcholine receptors.

Plasma exchange typically involves five sessions spread over 1 to 2 weeks. Clinical response correlates with the reduction in acetylcholine receptor antibody levels, though it is not necessary to check levels routinely during exchanges. Patients often have a clinical response within a few days after initiation of treatment. The most common significant complication of the procedure is hypotension and other cardiac issues. Because the procedure requires catheter placement, infection and thrombosis are also potential risks.

IVIg therapy is typically given at a dose of 2 g/kg divided over 5 days. An IgA level should be checked before starting the therapy in a treatment-naïve patient because patients with IgA deficiency are at risk for developing an anaphylactic reaction to the infusion. Patients generally respond within a week of initiation. Complications of treatment are uncommon but include thrombotic events such as stroke and myocardial infarction. It should also be used with caution in patients with congestive heart failure owing to the fluid load. There is also a risk of acute renal failure. Aseptic meningitis can also occur.

Comparatively, plasmapheresis and IVIg have roughly equivalent efficacy, so the choice is based on the clinical scenario, preference of the treating physician, and available resources. If one treatment fails to confer any clinical improvement, it is perfectly reasonable to attempt the other.

Thymectomy

Thymectomy should be strongly considered in any patient who is younger than 60 years and has no medical contraindications for the surgery. It should also be considered in older patients with significant weakness beyond mild ocular or bulbar symptoms. A significant number of patients achieve significant improvement or full remission of symptoms after thymectomy, even if no thymic pathology is found at the time of surgery.

Myasthenic Crisis

Any myasthenic patient, regardless of how mild the baseline symptoms are, has a risk of developing myasthenic crisis at some point in his or her lifetime. Myasthenic crisis is often precipitated by systemic illness, particularly upper respiratory infections, and a wide variety of medications are also known to exacerbate myasthenia symptoms. Any myasthenic patient complaining of worsening symptoms, particularly dyspnea, should be evaluated urgently because the patient can quickly decompensate. Such patients also should not be managed by adjusting their cholinesterase inhibitor regimen alone because symptomatic control is insufficient to forestall further progression into crisis.

These patients require immunomodulating therapy with either plasmapheresis or IVIg.1 They should also be monitored in an intensive care unit setting with frequent respiratory mechanics assessed at least two or three times a day. If forced vital capacity (FVC) is less than 20 mg/kg or the net inspiratory force (NIF) is less than −30 cm H2O, elective intubation is strongly advised. Either plasmapheresis or IVIg therapy should be started. A thorough work- up should be done to search for the underlying trigger (e.g., infection, new medication), and any triggers that are found should be treated or removed. Once stabilized, the patient should also begin taking chronic immunomodulation, if this medication is not already used.

Prednisone1 is most commonly used initially because its onset of action is faster than the other options.

Monitoring

Patients should be monitored as outpatients on a regular basis to ensure stability of symptoms and adequate symptomatic response, as well as monitoring laboratory studies, depending on the chronic immunomodulating medication being used. Acute deterioration in symptoms needs to taken very seriously, with a low threshold for urgent evaluation and hospitalization.

Complications

The dreaded complication of myasthenia is myasthenic crisis leading to fulminant generalized weakness and respiratory failure, often precipitated by systemic illness or other medications. Because patients can deteriorate rapidly, patients in whom symptoms appear to be worsening acutely need to be evaluated urgently. See “Myasthenic Crisis” earlier for further discussion.

References

1.     Drachman D.B. Myasthenia gravis. N Engl J Med. 1994;330:1797– 1810.

2.    Hoch W., McConville J., Helms S., et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001;7:365–368.

3.     Keesey J.C. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. 2004;29(4):484–505.

4.    McConville J., Farrugia M.E., Beeson D., et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol. 2004;55:580–584.

5.     Ropper A.H., Brown R.H. Adam and Victor’s Principles of Neurology. ed 8 New York: McGraw-Hill; 2005.

6.      Saperstein D.S., Barohn R.J. Management of myasthenia gravis. Semin Neurol. 2004;24:41–48.

1 Not FDA approved for this indication

1 Not FDA approved for this indication

1  Not FDA approved for this  indication

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