SYSTEMIC CONDITIONS
Myasthenia Gravis
Ocular manifestations are often the first sign a patient has this rare disease.

Myasthenia gravis (MG) is a common immunological disorder of neuromuscular transmission. As primary care optometrists, many of us see patients with the ocular manifestations of this disease. Proper management includes interaction with both the patient's primary care physician and neurologist, so we must all have a working knowledge of the essentials of this condition.

Presentation

Fortunately, this condition is relatively rare, with a prevalence of 14 per 100,000 Americans. This translates to roughly 36,000 cases in the United States. The disease demonstrates no racial preference and is usually found at any age in both sexes. Patients with myasthenia gravis usually have a chief complaint centered around a specific muscle weakness vs. generalized fatigue. This muscle fatigue is generally brought on by sustained or repeated muscle activity.

The most common ocular manifestations — ptosis or diplopia — are the initial symptoms of MG in nearly two-thirds of patients. Ocular involvement can occur in isolation or in association with generalized disease. It's estimated that ocular involvement is present in up to 90% of patients at some point during the course of the disease. It is the initial presentation in 84% of cases and is the sole presentation in roughly half. The most commonly involved ocular structure is the levator palpebrae. Extraocular muscle involvement is also common, with a variety of presentations including diplopia and blurred vision.

Another 15% complain of oropharyngeal muscle weakness, difficulty chewing, swallowing, or talking as the initial symptom. Finally, limb weakness is the presenting complaint in 10%. The most common presentation of weakness fluctuates, being the least severe in the morning and worse as the day progresses, especially after prolonged use of affected muscles.

The clinical presentation of MG includes muscle fatigue after repeated or prolonged use of the muscle, with improvement seen after a period of rest. Signs and symptoms include limb and facial weakness, slurred speech and pharyngeal weakness. The severity of symptoms usually peaks between one and three years after the onset of symptoms.

The course of MG is variable but usually progressive. Maximum weakness occurs during the first year in two-thirds of patients. In the early stages of the disease, patients will often exhibit spontaneous improvement of these symptoms. During the active stage of the disease, these symptoms tend to fluctuate over a relatively short period of time and then become progressively severe for several years. The active stage is followed by an inactive state, in which fluctuations in strength still occur but are attributable to fatigue, inter-current illness, or other identifiable factors. After 15 to 20 years, patients' recovery from the weakness diminishes and the most severely involved muscles frequently atrophy (burnt-out stage). Factors that worsen the symptoms of MG are emotional stress, systemic illness (especially viral respiratory infections), pregnancy, the menstrual cycle, drugs affecting neuromuscular transmission and fever.

he most severely involved muscles in MG frequently atrophy over time.

Pathophysiology

Myasthenia affects the postsynaptic neuromuscular junction. The normal neuromuscular junction releases acetylcholine (ACh) in response to stimulation of the motor nerve. ACh is released from the motor nerve terminal in discrete packages called quanta. The ACh quanta diffuse across the synaptic cleft where they bind to receptors on the folded muscle end-plate membrane. This quantum of ACh then causes depolarization of the muscle end-plate region, causing a cascade of reactions that ulti-mately lead to muscle contraction. In MG, we believe the concentration of ACh receptors on the muscle end-plate membrane is reduced. Some patients also exhibit an attachment of antibodies to the membrane. ACh is released at normal levels, but its effect on the post-synaptic membrane is reduced, thus reducing the chance of any nerve impulse to cause a muscle action.

While the precise mechanism is unknown, the thymus plays some role in the pathogenesis of MG. It's estimated that nearly 75% of MG patients have a degree of thymus abnormality (e.g., hyperplasia in 85% of cases, thymoma in 15% of cases).

Diagnostic procedures

The following tests can help diagnose MG:

• The edrophonium chloride (Tensilon) test. In this procedure, the patient is given an intraven-ous dose of edrophonium chloride. If the weakness is due to abnormal neuromuscular transmission, the patient's symptoms will improve. If the symptoms are subtle or if the patient doesn't respond, he or she may respond to intramuscular neostigmine due to the longer duration of action. Intramuscular neostigmine is particularly useful in young patients such as infants, whose response to intravenous edrophonium chloride may be too brief for adequate observation. In rare cases, a therapeutic trial of daily oral pyridostigmine may produce improvement in patient symptoms that weren't apparent after a single dose of edrophonium chloride or neostigmine. As with many other diagnostic proced-ures, a positive response for this test is not pathognomic for MG. In particular, patients with amyotrophic lateral sclerosis will usually also respond to edrophonium with increased strength.

In terms of procedures, a patient's airway and ventilation are secured before dispensing an initial test dose of edrophonium. The initial dose for most patients is usually 1mg. If no adverse reaction occurs and no improvement in patient symptoms is seen, consider another dose (3mg) of edrophonium. If no improvement occurs with this second dose, an additional dose of 5mg can be administered to total no more than 10mg. Most patients who are going to show improvement will demonstrate a dramatic increase in muscle strength, regaining facial expression, posture and respiratory function within one minute of injection. Intravenous edrophonium chloride is often diagnostic in patients with ptosis or ophthalmoparesis, but is less useful when other muscles are weak.

• Antibodies Against Acetylcholine Receptor (AChR). An elevated concentration of AChR-binding antibodies in a patient with compatible clinical features helps to confirm the diagnosis of MG, but normal antibody concentrations do not exclude the diagnosis. It's been estimated that nearly three quarters of patients with acquired generalized myasthenia and over half with ocular myasthenia have serum antibodies that bind human AChR. Although this test is fairly reliable, a high percentage of false positive tests are reported when blood is drawn within 48 hours of a surgical procedure involving the use of general anesthesia and muscle relaxants.

• Cogan's lid twitch. This is commonly observed in the ptotic lid when the patient is instructed to look from the down position to primary gaze. The involved lid will demonstrate an overshoot or upward twitch movement. This is caused by the levator as it relaxes or recovers in the down position, elevates to the primary position, and then rapidly fatigues or falls, giving a flutter or twitch-like appearance.

• Ice pack test. This is a relatively easy diagnostic tool that can be done in most optometry offices. It is based on the premise that cooling may improve neuro-muscular transmission and alleviate the symptoms associated with myasthenia. In a patient with ptosis caused by myasthenia, placing ice over an eyelid will typically result in an improvement of the ptosis. Clear resolution of the ptosis is a positive test result. The test is thought to be positive in about 80% of patients with ocular myasthenia.

• Electromyography. The measure of jitter by this method is the most sensitive clinical test of neuromuscular transmission and is abnormal in almost all patients with MG. This jitter is most pronounced in weak muscles but may be abnormal in muscles with normal strength. Increased jitter is a nonspecific sign of abnormal neuromuscular transmission. This test is used in conjunction with other clinical findings to confirm diagnosis. Normal jitter in a weak muscle excludes abnormal neuromuscular transmission as the cause of weakness.

Contributing factors

Many medications may exacerbate myasthenia symptoms. Therefore, take special care before prescribing them. Some of the more common medications reported to cause exacerbations of myasthenia are:

• Antibiotics. Macrolides, fluoroquinolones, aminoglycosides, tetracycline and chloroquine

• Antidysrhythmic agents. Beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide, and trimethaphan

• Miscellaneous. Diphenylhydantoin, lithium, chlorproma-zine, muscle relaxants, levothy- roxine, and adrenocorticotropic hormone (ACTH).

Management

Management goals for this disease are to improve neuro-muscular transmission and/or control the autoimmune involvement with minimal side effects. There is no general consensus in terms of precise treatment regimens for patients with MG. One reason for this is the absence of a controlled clinical trial for any medical or surgical modality used to treat MG. Instead, treatment plans are generally based on knowledge of the natural history of disease in each patient and the predicted response to a specific form of therapy. As with any condition, treat-ment goals must be individualized according to the severity of disease, the patient's age and sex, and the degree of functional impairment.

Cholinesterase Inhibitors

The mechanism of action of cholinesterase inhibitors is accomplish-ed through the retardation of the enzymatic hydrolysis of acetyl-choline at cholinergic synapses. The net result is that acetyl-choline accumulates at the neuromuscular junction and its effect is prolonged. In theory this drug should work effectively in nearly all cases of MG; in reality, it demonstrates considerable improvement in some patients and little to none in others. The most commonly used cholinesterase inhibitors include pyridostigmine bromide (Mestinon, Valeant Pharmaceuticals) and neostigmine bromide (Prostigim, ICN Pharmaceuticals).

However, this excess accumulation of acetylcholine at muscarinic receptors may have an adverse effect on smooth muscle and autonomic glands and at nicotinic receptors of skeletal muscle. Gastrointestinal complaints are common: queasiness, loose stools, nausea, vomiting, abdominal cramps and diarrhea. Increased bronchial and oral secretions caused by cholinesterase inhibitors may present a serious problem in patients with swallowing or respiratory insufficien-cy. In addition, excessive nicotin- ic receptor overdose results in Myasthenic Crisis, which is characterized by severe generalized weakness and respiratory failure.

Thymectomy

Some clinicians recommend a thymectomy for patients with MG. This procedure generally demonstrates a maximum favorable response two to five years after surgery. However, response varies widely and significant impairment may continue for months or years after surgery. The best candidates for this procedure are young people in the early stages of the disease or patients with moderate to severe symptoms. Patients with onset after age 60 rarely show substantial improvement.

Corticosteroids

The vast majority of patients with MG demonstrate significant improvement or complete relief of symptoms with prednisone treatment. Most of the improvement occurs in the first six to eight weeks, but strength may increase to total remission in the following six to 12 months. The most predictable response to prednisone occurs when treatment begins with a daily dose of 1.5 to 2mg/kg/day. About one-third of patients become weaker temporarily after starting prednisone, usually within the first seven to 10 days, and lasting for up to six days. Following this initial break-in period, the dose is then slowly increased until improvement occurs. The major disadvantages of chronic corticosteroid therapy are the side effects, which include, but are not limited to, weight gain, cataracts, diabetes mellitus, gastric ulcer and hypertension.

Immunosuppressant drugs

Azathioprine (Imuran, Prometheus Laboratories) has been shown to produce a dramatic improvement in symptoms in patients with myasthenia, but the effect can take as long as four to eight months to manifest. Once improvement begins, it is generally maintained for as long as the patient is on the drug. If the drug is discontinued, the symptoms recur two to three months later. Because response to azathioprine is delayed, many clinicians start patients on both azathioprine and corticosteroids with the intent of rapidly tapering prednisone when azathio-prine becomes effective. Side effects of azathioprine include bone marrow dysfunction, hepatic dysfunction, and gastrointestinal disturbances.

Some patients with myasthenia may obtain some benefit from cyclosporine, which inhibits predominantly T-lymphocyte-dependent immune responses. Most patients with MG improve one to two months after starting cyclosporine and improvement is maintained as long as therapeutic doses are given. Maximum benefit generally takes six months to achieve. After achieving the maximal response, the dose is gradually reduced to the minimum effective amount. The most important adverse reactions to watch out for are renal toxicity and hypertension.

Plasma exchange

Plasma exchange is basically used as a last resort plan for patients whose condition is non-responsive to all other modal- ities. In addition, it is sometimes used as a short-term intervention for patients with sudden worsening of myasthenic symptoms for any reason and to rapidly im-prove strength before surgery. In this procedure, the blood is removed, with plasma separated from the formed elements. The formed elements and replaced plasma are then re-infused. It's thought that the mode of action in myasthenia is related to the removal of acetylcholine receptor antibodies. Almost all patients with acquired MG demonstrate some level of temporary improvement following plasma exchange. Maximum improvement may be reached as early as the first exchange. This improvement, however, is not permanent in that it generally lasts for weeks or months. At that point, the effect is lost unless the exchange is followed by thymectomy or immunosuppressive therapy. 

Dr. Gupta practices full scope optometry in Stamford, Conn. He's also clinical director of The Center for Keratoconus at Stamford Ophthalmology. E-mail him at Deegup4919@hotmail. com.