Ocular Myasthenia Gravis What Are the Clinical Findings in Myasthenia Gravis? Myasthenia gravis (MG) is a chronic disorder of neuromuscular transmission characterized clinically by varying degrees of weakness and fatigue of voluntary muscles. MG is caused by an acquired autoimmunity to the motor end plate and is associated with antibodies that block or cause increased degradation of acetylcholine receptors (AChRs). There is abnormal weakness in some or all voluntary muscles. The most commonly affected muscles are the levator palpebrae superioris, the extraocular muscles, the orbicularis oculi, triceps, quadriceps, and the tongue. Other voluntary muscles innervated by cranial nerves (facial, masticatory, pharyngeal, and laryngeal muscles) and cervical, pectoral girdle, and hip flexor muscles are also frequently affected. The weakness increases with repeated or sustained exertion and over the course of the day, but is improved by rest; it also may be worsened by elevation of body temperature and is often improved by cold (Engel, 1994; Weinberg, 1994). What Are the Clinical Features of Ocular Myasthenia Gravis and Generalized Myasthenia Gravis? The levator palpebrae superioris and extraocular muscles are involved initially in approximately 50 to 70% of cases, and these muscles are eventually affected in about 90% of patients. Ocular myasthenia (OM) is a form of MG confined to the extraocular, levator palpebrae superioris, and/or orbicularis oculi muscles. Approximately 50% of patients initially present with OM, but only 12 to 50% of these remain ocular (Bever, 1983; Oosterhuis, 1982). Of the 50 to 80% of patients with purely ocular symptoms and signs at onset that go on to develop generalized MG, most, but not all, develop generalized symptoms within 2 to 3 years of onset of the disorder. Bever et al performed a retrospective study and found that 226 (84%) of 269 myasthenics displayed ocular findings at onset of disease and 142 (53%) demonstrated only ocular involvement (Bever, 1983). Follow-up (average 14 years, range 1 to 39 years) of 108 patients with MG who had only ocular symptoms and signs at onset showed that 43 (40%) remained ocular and 53 (49%) became generalized. Of the 53 patients who became generalized, 44 (83%) did so within 2 years of onset of the disease. Age of onset in their patients was of prognostic significance. Patients older than 50 years of age at onset had a greater risk of generalized MG and severe complications, whereas patients who were younger at onset had a more benign outcome. In another study of 1487 myasthenic patients, 53% presented with ocular MG and 202 (4%) continued to demonstrate purely ocular involvement for up to 45 years of follow-up (mean, 17 years) (Oosterhuis, 1982). Of those patients with strictly ocular signs and symptoms during the first month after onset (40% of the 1487 patients), 66% subsequently developed clinically generalized disease; of these, 78% became generalized within 1 year after onset of symptoms and 94% within 3 years. Ptosis in MG may occur as an isolated sign or in association with extraocular muscle involvement. Evoli et al studied 48 patients with OM and noted that 10% had ptosis only, 90% had ptosis and extraocular muscle involvement, and 25% had weakness of the orbicularis oculi (Evoli, 1988). The ptosis may be unilateral or bilateral and, when bilateral, is usually asymmetric. The ptosis may be absent when the patient awakens and appear later in the day, becoming more pronounced as the day progresses. Prolonged upward gaze may increase the ptosis. Enhanced or seesaw ptosis may be demonstrated (i.e., a worsening of ptosis on one side when the opposite eyelid is elevated and held in a fixed position). Enhancement of ptosis is not specific for MG and may rarely be seen with the Lambert-Eaton myasthenic syndrome, senile ptosis, ocular myopathy, Fisher’s syndrome, and even third nerve palsy (Averbuch-Heller, 1995; Brazis, 1997; Ishikawa, 1990). During refixation (a vertical saccade) from down to the primary position, the upper eyelid may either slowly begin to droop or twitch several times before settling in a stable position (Cogan’s lid-twitch sign). This sign is characteristic, but not diagnostic, of MG (Phillips, 1997; Ragge, 1992). For example, Kao et al described two patients with fatigable ptosis due to intracranial mass lesions (hematoma and metastasis) likely causing compression of the central caudal nucleus of the dorsal midbrain (Kao, 1999). MG may also be associated with three types of eyelid retraction (Miller, 1985): (1) contralateral eyelid retraction due to bilateral excessive innervation (Hering’s law) to raise the ptotic lid; (2) brief eyelid retraction lasting only seconds following a saccade from downgaze to primary position (Cogan’s lid twitch sign); and (3) transient eyelid retraction lasting seconds or minutes after staring straight ahead or looking upward for several seconds. Involvement of extraocular muscles with MG usually occurs in association with ptosis, though not always. MG should be considered in any case of ocular motor weakness without pupil involvement because MG may mimic any pattern of neurogenic paresis. Any extraocular muscle may be selectively impaired, especially the medial rectus, and weakness characteristically increases with sustained effort (Miller, 1985; Odel, 1992; Weinberg, 1994). Myasthenia can mimic pupil-sparing third nerve palsies, superior division third nerve palsies, and fourth or sixth nerve palsies (Dehaene, 1995; Miller, 1985; Weinberg, 1994). Myasthenia may produce a false internuclear ophthalmoplegia (Ito, 1997), the one-and-a-half syndrome (Bandini, 2001), horizontal or vertical gaze palsy (Miller, 1985), divergence paresis (Lepore, 1999), double elevator palsy, and complete external ophthalmoplegia. MG may also be associated with abnormalities of saccadic eye movements (Miller, 1985) including (1) hypermetric saccades; (2) hypometric saccades that begin with normal velocity but ultimately show a decrease in velocity (intersaccadic fatigue) and undershoot the target; (3) small, jerky, quivering eye movements; and (4) gaze-evoked nystagmus. Patients with MG often have weakness of the orbicularis oculi muscles. In some cases, a “peek sign” may occur. In an attempt to sustain forceful eye closure, the orbicularis oculi may fatigue, resulting in the patient “peeking” through the partially opened palpebral fissure. Lower eyelid ectropion may occur in myasthenic patients, and become especially noticeable as the day progresses (Miller, 1985). Finally, although abnormalities of pupillary function and accommodation have been described in MG, this dysfunction is not clinically significant (Miller, 1985; Weinberg, 1994). In a study of 25 children with MG, more than half had had ocular symptoms (Mullaney, 2000). Generalization occurred in 5 of the 14 patients; ocular progression to systemic involvement developed on average in 7.8 months (range 1 to 23 months). Long-term permanent damage to the extraocular muscles as a result of juvenile MG is rare. What Studies Are Suggested to Diagnosis Ocular Myasthenia Gravis? The diagnosis of OM is based on the clinical history and exam (fatigue, rest or sleep test), pharmacologic testing (e.g., Tensilon), serologic testing (e.g., antibody testing), and electrophysiology (e.g., electromyography [EMG]). EMG investigations include study of the decremental response, conventional needle EMG, and single-fiber recordings. In some instances, in vitro microelectrode studies of neuromuscular transmission and ultrastructural studies of the neuromuscular junction may be required to establish the diagnosis (Engel, 1994). In general, microelectrode and ultrastructural studies are reserved for patients with generalized MG and are not discussed here. The diagnosis of OM should be considered in any patient with ptosis and/or ocular motor weakness without pupillary involvement. Weakness and fatigue confined to the extraocular muscles or lids combined with orbicularis oculi paresis is especially suggestive of OM. Significant clinical involvement of the pupil, eye pain or headaches, proptosis, visual loss, or involvement of trigeminal sensation are not seen in MG. What Studies Are Used in the Pharmacologic Testing for Ocular MG? A positive Tensilon (edrophonium hydrochloride) or Prostigmin (neostigmine methyl-sulfate) test is usually, but not always, indicative of ocular myasthenia. The improvement of extraocular muscle function should be quantified with prisms, a Hess screen, or the Lancaster red-green test (Coll, 1992). Ptosis tends to respond better to anticholinesterases than does ophthalmoparesis (Miller, 1985). Evoli studied 43 OM patients with both ptosis and diplopia and found that Tensilon relieved only the ptosis in 15 (35%) patients (Evoli, 1988). False-positive responses to anticholinesterases have been described with brainstem and parasellar tumors, aneurysms, metastasis to the orbital apex, multiples sclerosis, Lambert-Eaton myasthenic syndrome, poliomyelitis, Guillain-Barré syndrome, motor neuron disease, botulism, orbital myositis, congenital ptosis, snake bites, diabetic sixth nerve palsy, and dermatomyositis (Miller, 1985; Ragge, 1992; Shams, 2002; Straube, 1990; Weinberg, 1994). In most of these reports, the correct diagnosis was evident by associated neurologic signs and symptoms. Moorthy et al, however, described eight cases originally diagnosed as having MG in whom an intracranial lesion instead of, or in addition to, MG was later identified (Moorthy, 1989). Four of these patients probably had both MG and an intracranial lesion, but the other four had only intracranial lesions with clinical “pseudo-myasthenic” features, including fatigable weakness, Cogan’s lid twitch sign, and positive Tensilon or Prostigmin tests. Three had pupil-sparing third nerve palsies and one had a third nerve palsy associated with a sixth nerve palsy. These authors suggested that patients with clinical features consistent with MG restricted to the ocular or cranial muscles should be carefully evaluated for intracranial lesions using computed tomography (CT) or magnetic resonance imaging (MRI). We do not routinely perform neuroimaging on all patients with OM (class IV, level C). Miller suggests that it is advisable to rule out an intracranial lesion by CT or MR imaging in all patients with isolated, unilateral, pupil-sparing ophthalmoparesis even when the diagnosis of MG seems assured by a positive Tensilon or Prostigmin test or other studies (Miller, 1985) (class IV, level C). A negative Tensilon or Prostigmin test does not rule out MG (Evoli, 1988; Miller, 1985; Weinberg, 1994). For example, Spector and Daroff noted negative responses to Tensilon in 2 of 11 (18%) OM and in 6 of 21 (29%) of patients with both OM and generalized MG (Spector, 1976). Paradoxical responses to Tensilon may also occur in OM patients, including paresis of previously nonparetic muscles and increased eye misalignment due to further weakening of paretic muscles. What Nonpharmacologic Testing Is Helpful in the Diagnosis of Myasthenia Gravis?
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