of neuromuscular transmission in which acetylcholine receptor antibodies attack the postsynaptic membrane of the neuromuscular junction. Reduction in the number of acetylcholine receptors and structural damage to the membrane impair synaptic transmission from motor axons to muscle and result in the weakness and fatigability that characterize this disease. The muscle weakness worsens with exertion or sustained activity. MG can weaken any striated voluntary muscles, and may produce life-threatening symptoms such as dysphagia and respiratory failure. Fortunately therapeutic advances have increased patients' survival and life expectancy (1-4). DEMOGRAPHICS: The prevalence of MG is now felt to be as high as 50 to 125 cases per million population, or roughly 25,000 people in the United States (2). The disease can begin at any age, but the peak incidence occurs in the third decade in women (average age of onset 28), and in the fifth decade in men (average age of onset 42). The overall female to male ratio is 3:2 (5). Neonatal MG results from the passive transfer of anti-acetylcholine receptor antibodies from an affected mother to her newborn infant, and produces symptoms in about one in seven babies born to mothers with MG. The symptoms are usually transient and appear within the first 72 hours of life. The mean duration of neonatal MG is 18 days, and may require short-term treatment with assisted ventilation, IV prostigmine and/or oral mestinon. CLINICAL FEATURES OF PATIENTS WITH MG A physiologist by the name of Thomas Willis was the first to describe the clinical features of MG in 1672 (6-8). The main features of MG are muscle weakness and fatigability. The extra-ocular muscles and periorbital muscles are affected most frequently. Patients will often present with ptosis, and/or diplopia with or without other systemic symptoms of fatigue, muscle pain or weakness. At initial presentation, 75% of patients with MG have only ptosis and /or diplopia, but only 15% of all patients will remain exclusively ocular myasthenics. Fifty percent of ocular myasthenics do not have measurable acetylcholine receptor antibody titers (9,10), but 60% of all myasthenics develop systemic features such as proximal muscle weakness or difficulty with speech and swallowing within two years after the onset of ocular symptoms. On the other hand, during the course of systemic MG, 90% of patients develop neuro-ophthalmologic signs (11). Sixty five percent of patients with MG have thymic hyperplasia, and 15% actually have a thymoma (12). It is believed that the myoid cells in the thymus gland can differentiate and express acetylcholine like receptor autoantigens, and that the B-lymphocytes in the gland can produce acetylcholine specific receptor antibodies (5). Because of this belief that the thymus gland is likely a site of autosensitization, it is now recommended that
all patients with thymomas and all patients under 65
years of age with thymic hyperplasia undergo thymectomy (14,15). Though 15-20% of myasthenics go into permanent remission, spontaneously, it is believed that an additional 20% will go into remission following thymectomy. For those who do not go into remission following thymectomy, a substantial percentage show marked improvement in their disease state, with less need for maintenance medication. Myasthenia coexists with many other autoimmune diseases including thyroid disease (hyperthyroidism 5%, all thyroid disease states 9-18%), rheumatoid arthritis, ankylosing spondylitis, aplastic and pernicious anemias, systemic lupus erythematosis, ulcerative colitis, sarcoid, pemphigus, Sjogrens disease, diabetes mellitus, and autoimmune hepatitis (5). A few patients have been reported to have acquired MG after bone marrow transplantation. Many drugs are known to exacerbate MG including: neuromuscular blocking agents, antibiotics (especially aminoglycosides), quinine, quinidine, chloroquine, procainamide, calcium channel blockers, phenytoin, lithium, antidepressants, Beta blockers (including ophthalmic glaucoma drops), and others (16). OCULAR SIGNS IN MG The levator palpebrae superioris is the most frequently affected muscle in MG, and its weakness results in ptosis, with or without the Cogan's lid twitch (2). Though ptosis may first be noticed in one eye, it almost always becomes bilateral with time. Ptosis may be absent on awakening in the morning, and usually becomes more pronounced as the day proceeds. Ptosis can be partial or complete and the levator usually fatigues easily with prolonged upgaze, causing the ptosis to worsen. Many patients with severe ptosis adopt a chin-up position so as to peek under their lids, and some require a lid crutch. An elevated brow on one side is also a common finding in these patients; there is sometimes associated lid retraction. If one elevates the more ptotic lid in a patient with MG, the opposite lid will often drop because of Herring's law of equal innervation (seesaw phenomenon or enhanced ptosis). Though ptosis may be an isolated finding in MG, it is often seen in association with orbicularis weakness. Having the patient perform forced lid closure tests this. The examiner then either looks for the "peek sign" as the muscles weaken, or forcibly attempts to open the patient's lids manually. The extraocular muscles that rotate the globe are the second most common group of muscles affected in MG and their involvement causes diplopia, ophthalmoplegia, and nystagmus. One or more of the muscles may be affected either partially or completely and, in severe cases, complete external ophthalmoplegia can occur. The most frequently involved muscles are the medial rectus, inferior rectus and superior oblique. Patients with unilateral ptosis may not notice diplopia until their lid is elevated during their examination. Some patients
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will squint one eye shut in order to avoid diplopia. The
ophthalmoparesis may mimic or present as a comitant or incomitant strabismus, an isolated cranial nerve palsy, a gaze palsy, as an internuclear ophthalmoplegia, or as convergence insufficiency. The onset should be painless, though many patients develop headache, which is felt to be secondary to sustained muscle contraction in an attempt to elevate the lid or to fuse. Occlusion of one eye by a patch or black contact lens almost always alleviates this symptom. Pupillary dysfunction in MG has been reported in the literature, but clinically it is a rare finding. The most common reported finding has been mydriasis, anisicoria and pupillary sluggishness that improved with treatment with Tensilon or prostigmine. Fatigue of the pupillary response has also been reported (17,18). Involvement of the iris sphincter muscle is the presumed cause for these findings. SYSTEMIC SIGNS IN MG Patients with generalized MG can present with weakness and fatigability of any striated skeletal muscle group. Physical examination may reveal weakness that is generalized, apparent only in certain muscles, or present primarily after sustained effort (1). The most commonly involved muscles outside of the lids and extraocular muscles, include the facial muscles, neck flexors, triceps, and quadriceps. The limbs are usually more affected in a proximal distribution. Weakness of the jaw or pharyngeal muscles can lead to dysphagia, and weakness of the diaphragm can lead to respiratory failure. On neurological examination: Reflexes, coordination, sensation, bladder and bowel function should be unaffected in patients with presumed MG. Patients with facial muscle involvement may present with a "snarling expression", nasal speech or dysphonia. Involvement of the muscles of mastication, jaw muscles or bulbar muscles results in trouble chewing, swallowing, and again trouble with speech. Patients with severe weakness have trouble controlling their saliva, and sometimes have to manually hold their jaw to speak, or chew their food (slack jaw/hanging jaw). Proximal limb weakness is best assessed on presentation with timed forward arm abduction (5 minutes or best effort) (1). Patients may complain of difficulty with simple tasks requiring them to lift their arms, such as combing or brushing their hair, shaving or applying makeup. The clinical severity of their disease can be graded (1,3): Grade 1: focal disease Grade 2: generalized disease that is either mild or moderate Grade 3: severe generalized disease Grade 4: myasthenic crisis with life-threatening impairment of respiration Since a simple URI in patients with MG can trigger a crisis, all patients suspected of having generalized MG should undergo forced vital capacity testing (FVC), and peak respiratory force testing through a pulmonary service to rule out respiratory muscle involvement. A myasthenic patient is said to be in "crisis" when difficulty with respiration or swallowing, requiring
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assistance, occurs. Approximately 16% of myasthenics
experience crisis (19). A FVC below 1 liter usually indicates the need for ventilatory assistance. These patients are usually treated in the ICU with plasma exchange or intravenous gamma globulin (IVIG) (20-23). MANAGEMENT AND TREATMENT The suspicion of MG, whether purely ocular or systemic, requires a multi-disciplinary approach to assure appropriate work-up and treatment. The diagnosis must be established firmly before treatment is initiated because therapy entails a major commitment to medical and often surgical measures(1). As an ophthalmologist trained in neuro-ophthalmology, I always involve a neurologist, neuro-muscular specialist or neuro-immunologist early in the care of my patients who I suspect are suffering from MG. These consultants help to establish the diagnosis and evaluate the severity of the MG, and also search for associated conditions and masqueraders of myasthenia. They are also usually more comfortable and familiar with the treatment of patients who need increasing doses of anti-cholinesterase agents and prednisone or the initiation of immunosuppressive drugs such as Imuran, Cyclosporine A, Cytoxan, and CellCept (24-28). Protocol for Evaluation and Treatment of MG: Clinical suspicion Confirmation of the diagnosis with a Tensilon test (29) and/or Sleep test (30) Serology (AChR antibodies in serum) (31) Repetitive nerve stimulation (EMG) looking for a decremental response (32) CT of the chest to R/O a thymic abnormality Pulmonary function testing to assess ventilatory function Treatment / Medical treatment trials (5,33): Anticholinesterase agents: Pyridostigmine (Mestinon) 60mg Q 6 hours to 120mg Q 3hrs Occlusion therapy with patch or black contact lens for diplopia. Prism can also be tried in certain cases. Immunosuppressive agents: Prednisone 20mg QD (increase by 5mg Q 2-3 days up to 60 mg (then alternate day therapy). Caution patients that they may suffer a transient initial exacerbation. Azathioprine 50mg QD (CBC monitoring necessary) Cyclosporine 2.5mg/kg BID (serum level monitoring necessary) Thymectomy Plasmapheresis 5 exchanges over a 5-10 day period to decrease AChR antibody titers during exacerbations IVIG 1-2 gm/kg IV to downregulate autoantibody production during an exacerbation MASQUERADERS OF MG / DDX (34,35) 1. Lambert-Eaton Syndrome (LES) (35,36): Neuromuscular disease associated with carcinoma. Patients often report difficulty with walking and arising from a seated position because of weakness of their trunk and pelvic muscles. Ptosis, diplopia, and difficulty with swallowing and speaking are less
common than in MG. Other findings include decreased
reflexes, parasthesias, and autonomic dysfunction (i.e. dry mouth, constipation and erectile dysfunction). 2. Guillain-Barre Syndrome (38): An inflammatory demyelinating polyneuropathy that is usually post infectious, post surgical or following vaccination. Common features include ascending relatively symmetric limb weakness, areflexia, sensory symptoms, and oropharyngeal and facial weakness. Ptosis rare (5-10%) and does not fatigue. Diplopia secondary to ophthalmoplegia is also rare (15%). An elevated CSF protein is common. Respiratory failure is usually associated with severe limb weakness and paralysis. 3. Botulism: A presynaptic neuromuscular disorder caused by a toxin that interferes with the release of ACh at the motor terminal. Patients often present with constitutional symptoms such as nausea,
vomiting, and dysphagia. Generalized weakness of
the proximal muscles is common. Ophthalmologic findings inclu d e d ip lop ia secondary to ophthalmoplegia, poorly reactive pupils, and ptosis. 4. Bilateral midbain/brainstem lesions: Patients present ataxic, areflexic, with signs of external ophthalmoplegia. Alteration in wakefulness and coma are common. 5. Chronic progressive external ophthalmoplegia with skeletal myopathy (CPEO): This mitochondrial disorder usually presents with bilateral ptosis, followed by symmetric progressive ophthalmoplegia. Patients usually do not suffer from diplopia. Generalized skeletal muscle weakness, and facial weakness can be seen. Ataxia is seen in about 20% of patients.
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