Ocular Myasthenia Gravis
Robert H. Spector, M.D.
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Ocular Myasthenia Gravis
Robert H Spector, MD.
Much has been written about myasthenia gravis (MG) in recent years, because there now seems to be a plausible, scientific explanation for the cause of this disease. The word "gravis" seems no longer appropriate, as current forms of treatment virtually have allowed patients to live fully functional and independent lives. This review will summarize the therapeutic advances that have been made in the ocular form of MG, stressing the most effective and practical ways to manage double vision (diplopia) and droopiness of one or both lids (ptosis).
Anatomy and Pathophysiology
MG is the paradigm of an autoimmune disorder, i.e., it is caused by an antibody which attacks and diminishes the integrity of one of the body's own components. Making antibodies is a normal daily process from the moment we're born and exposed to such foreign proteins as viruses and bacteria, or even snake venom. When a patient makes an antibody against themselves, as in MG in which there is an anomalous antibody produced against the receptor end plate of voluntary muscles, it is referred to as autoimmune. This autoimmune attack on the muscles end plate accounts for the symptoms and signs of ocular and generalized MG.
All the muscles in our body are activated by nerve impulses which travel along nerve trunks emanating from the brain and spinal cord. When these nerve impulses reach the neuromuscular junction, the point at which a nerve fiber synapses with or terminates on a muscle fiber, a chemical is released called acetylcholine (AcH), which attaches to a receptor on the muscle membrane, resulting in a muscular contraction.
Patients with MG enigmatically produce a blocking antibody which deposits on the receptor muscle membrane and prevents the entry of AcH molecules. The resulting attenuation of neuromuscular transmission leads to muscular fatigue and sometimes frank paralysis. Characteristic of MG is the randomness of neuromuscular blockade. It may be confined only to a small muscle which moves one eye upward, outward, downward or laterally; or to one of the larger muscles which moves the face, arm or leg or breathing muscles. Regardless of the muscles involved, the goal of effective treatment is to either reduce the concentration of the blocking antibody or to increase the concentration of AcH at the neuromuscular junction.
Ocular MG is characterized by the abrupt or insidious onset of weakness and fatigability of one or both lids or the eye muscles. If the lid is involved it droops otherwise known as ptosis; with extraocular muscle involvement the patient sees double looking in the direction of the weak muscle. For instance, they may see well in all directions except upward, which tells the examiner that one of the elevator muscles is weak. To compensate for the weakness, the patient can tilt their head or turn their face to allow the relatively stronger eye muscles to work. In the above example, the patient would tilt their head back, thus throwing their eyes relatively downward out of the field of action of the relatively weak elevator muscle.
Because of the frequency with which eye muscles are involved in MG, droopiness of one or both upper eyelids (ptosis) and double vision (diplopia) are common impediments. Diplopia or ptosis eventually occur in 90% of patients with MG and account for the initial complaint in 75%. About 80% of patients with ocular onset MG will progress to involvement of other muscle groups within the first two years; thus only 20% of patients have pure ocular MG. Patients in whom the disease has been confined to the ocular muscles for three or more years seem unlikely to progress to generalized disease.
Eye muscle strength in MG, similar to swallowing, speech, and leg strength may be normal or mildly affected in well rested patients, but weakness can usually be elicited with exercise. For instance, if a patient is asked to look upward for 60 seconds, thereby testing the endurance of the vertical eye muscles and the upper lid which concomitantly rises, the patient may evolve from a normal state to extreme weakness with flagrant diplopia or ptosis.
Although upward eye movements are said to be involved earliest, extraocular muscle involvement does not follow any set pattern. In my experience, weakness of medial eye movement along the horizontal plane is equally as common. Essentially any pattern of dysfunctional ocular movement may develop so that isolated muscle palsies or total immobility of the eyes will accrue, sometimes mimicking other medical conditions such as strokes, tumors, thyroid eye disease, infections and multiple sclerosis
The natural history of ocular myasthenia has been well studied. Of 168 patients with generalized MG, in whom the average follow-up was twelve years, and the last examination was compared with the initial examination, 68% were unchanged, 14% improved, 14% in complete remission and 5% were worse. Most of the worsening seemed to occur during the first 3-5 years of illness during which time the incidence of a severe exacerbation is highest. More specifically, of those patients who present with ocular manifestations alone, i.e., pure ocular MG, 58% will show symptoms of generalized muscular weakness during the first seven months of their illness, another 29% between 7 months and 13 months, 7% during the 2 and 3 years and only 6% after the third year. Therefore, if a patient with ocular MG continues to have only ocular symptoms after three years, there is a 94% chance that his symptoms will not increase.
The salient symptoms of ocular MG, double vision and droopiness of one or both lids, are frequently influenced by environmental, emotional and physical factors. Bright sunlight, emotional stress, viral illness, surgery, menstruation, pregnancy, immunizations and other physical factors all may precipitate a change in the expression of ocular MG, although not in a predictable direction.
Spontaneous remissions can occur in any patient and sometimes persist for years. Most patients with MG show a fluctuating course, often with a particular muscle group (e.g., ocular, speech, swallowing, arm or leg strength) being maximally involved. Fortunately MG only rarely follows an acutely or chronically progressive course. Age, sex and pattern of onset are not used to predict the eventual course of the disease.
It used to be felt that MG has no racial or geographic predilection. However in 1981 a number of interesting observations were made regarding difference in ocular and generalized MG. In ocular MG, equal numbers of males and females are affected, the Chinese race has an unusually high incidence, and patients with ocular MG often have abnormal levels of autoantibodies against the thyroid gland and show concomitant disorders of thyroid function. Victims of generalized MG, in contrast, are more commonly female, ethnically more likely to be Italian and show much fewer abnormalities of thyroid function.
The diagnosis of ocular MG depends heavily on the patient's history, physical findings and their response to intravenously administered edrophonium chloride (Tensilon). Falsely negative or equivocal tensilon tests are annoyingly common and represent a distinct problem in the diagnosis and subsequent management of MG.
When weakness of lid elevation or eye movement is moderate or marked, evaluation of tensilon responsiveness is usually a simple response can be difficult to evaluate. The patient's history is often the critical determinant of accurate diagnosis. Alternating ptosis, i.e., unilateral ptosis that remits and is followed a variable interval by ptosis of the other eye, is highly suggestive, as is diurnal fatigue of an extraocular muscle causing diplopia to develop and worsen as the day progresses. Unfortunately, in the mild or incipient cases, the patient may give a strongly suggestive history, but have no physical findings on examination to confirm the diagnosis. In such cases the most practical approach is to invite the patient back for follow-up later in the day or after exposure to bright sunlight to provoke their symptoms.
With the development of an assay for measuring the amount of blocking antibody, the diagnosis cam sometimes be confirmed by blood work. However, there are both false positive and false negative blood test results. Active antibodies may be present even in patients in clinical remission. Furthermore, only about 70% of patients with ocular myasthenia have detectable antibody levels while 90% of patients with generalized MG have elevated antibody titre. Although the blood tests when positive is highly specific, it is not particularly sensitive. In my practice I do not rely upon the results of blood acetylcholine receptor levels to establish a diagnosis. The diagnosis is based purely on clinical observations and the response to intravenous tensilon.
The major landmarks in the medical treatment of MG have been the introduction of anticholinesterases in 1934, the advent of modem positive pressure, volume or pressure controlled respirators in 1960, the use of steroids in 1966, of non-steroidal immunosuppressive agents, mainly Imuran, in the 1970's and the more or less routine use of plasmapheresis since 1976. The impact of all these advances on the treatment of ocular myasthenia has been difficult to measure since most patients with symptoms limited to double vision and ptosis are not deemed candidates for the newer treatments with invasive or dangerous methods. The decision to institute these measures should be deliberate and based upon a balance between the risks and complications of each procedure or drug and the gravity of the patient's clinical disability.
Long term, relatively high dose steroids (cortisone, deltasone, prednisone) may cause serious abnormalities of bodily function such as a peptic ulcer, hypertension, diabetes, osteoporosis (softening of bone), depression, anxiety and even frank psychosis. Similarly, Imuran taken regularly over long periods, though seemingly safe according to most published series, can present hazards due to uncontrollable infections and possibly cancer. Plasmapheresis is expensive, invasive and has a certain element of risk in terms of long term of immunosuppression and the possibility of unusual infections.
The anti-cholinesterase medications, particularly Mestinon, is the comer stone of medical therapy. Used judiciously, it can relieve a large majority of the ocular complaints. Previously, it had been said that Mestinon didn't help the ocular symptoms of MG. But my own experience contrasts sharply with this dictum as most of the ocular manifestations can be managed successfully if the drug's dosage and dosage intervals are manipulated properly. There are five basis reasons why mestinon fails to effect success: (1) It simply may not be effective; (2) the diplopia may be only partially relieved and still be bothersome; (3) the supervising physician may have limited experience with the subtleties of prescribing the drug (4) Mestinon may improve the ptosis and unmask the diplopia in which case the patient is better off with the ptotic lids serving as a natural patch; and (5) The gastrointestinal side effects may be intolerable, especially in the older patients who seem to suffer from a chronic drug-induced colitis.
If these medications are ineffective or not tolerated, other modalities can be used to relieve the patient's ptosis and double vision. Fresnel lenses, for instance, are flat, plastic prisms which can be attached to a diplopic patient's eyeglasses to relieve them of diplopia. By optically "bending light," the patient can comfortably look straight ahead and downward to read with both eyes open.
Ptosis crutches have been used in some patients to mechanically elevate a ptotic lid. These are manufactured and fitted by only a handful of opticians and should be prescribed only in extreme circumstances. Sometimes just taping a portion of an eyeglass can avert diplopia, or teaching he patient to tilt their heads in a compensatory manner to minimize the action of the weakened eye muscle( s), Certain preparations sometimes can "boost" the effect of the more traditional myasthenia medications. These include potassium and ephedrine.
A discussion of the treatment of MG is not complete without a few words on the thymus gland. years ago it was felt that the antibody which blocks the AcH receptors arose solely from the thymus gland. This gland, located below the breast bone and in front of the heart, functions as an important immunological gland in children but involutes during adulthood. When this thymus theory gained popularity, large numbers of MG patients, with both ocular and generalized myasthenia, underwent thymectomy (surgical removal of the thymus gland). However, it's been subsequently shown that thymectomy helps some patients but not all. It is specifically reserved for the young patient with acute disease who has had the disease for less than three years; or for those in whom X-ray studies show an enlarged thymus gland and the operation does not pose significant risk; or for the patient with generalized MG who fails to respond to adequate medical therapy.
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