Myasthenia Gravis: Clinical Manifestations

Myasthenia gravis is seen in all age groups, with a bimodal distribution, affecting younger adults in their 20s and 30s (with a female predominance) and older adults in their 60s and 70s (slight male predominance). The annual incidence is 10 to 20 new cases per million, and the prevalence is 150 to 200 per million.

The two major clinical forms of autoimmune myasthenia gravis are ocular and generalized. Transitory myasthenia gravis may also occur in infants born to myasthenic mothers—so-called neonatal myasthenia (a cause of the floppy baby syndrome) brought about by transplacental maternal antibodies. Myasthenia may also be congenital and nonimmune in character, presenting in infancy and childhood with ocular weakness, and resulting from a genetically determined defect at the neuromuscular junction (see Plate 11-11).

CLINICAL PICTURE

The cardinal feature of myasthenia gravis—the one that helps distinguish it from other neuromuscular disorders—is fluctuating weakness. The degree of weakness often varies throughout the day, typically most pronounced later in the day or evening and often mild in the morning after a period of rest, that is, diurnal.

More than 50% of patients initially present with ocular weakness, with complaints of double vision and lid droop. If there is bulbar and facial muscle involvement, patients experience difficulty chewing, speaking, swallowing, and effecting facial expressions. Neck extensors and flexors often become involved, causing head-drop. Limb weakness has a predilection for the shoulder and hip girdle muscles and the proximal muscles of the arms and legs so that difficulties washing and drying hair or climbing stairs are commonly reported complaints. Shortness of breath is a sign of diaphragmatic weakness and may herald respiratory insufficiency, leading to respiratory failure, and ultimately the life-threatening situation of “myasthenic crisis” that requires mechanical ventilation.

On physical examination, ocular involvement is revealed by (1) ptosis, which may be unilateral or bilateral and may worsen (or be unmasked) during the course of sustained (>60 seconds) upgaze, and (2) extraocular muscle weakness (sparing the pupil), the patient noting binocular diplopia or blurry vision. Facial weakness is typically characterized by both an inability to bury the eyelashes with forced eye closure and the “myasthenic snarl.” In the latter, there is weakness of the orbicularis oris and inability to turn the corners of the mouth upward when the patient is asked to smile. This manifestation leads to a “smile” that is transverse and appears almost angry. Patients may also develop jaw weakness (with difficulty in keeping the jaw closed); changes in speech (nasal quality from palatal weakness or low quality/hypophonic); neck extensor weakness, causing the head to be propped up using the hand under the chin; and proximally predominant arm and leg weakness.

DIFFERENTIAL DIAGNOSIS

Disorders that may be confused with ocular myasthenia gravis, which cause ptosis and/or diplopia, include thyroid ophthalmopathy, myotonic dystrophy, oculopharyngeal muscular dystrophy, chronic progressive external ophthalmoplegia, and brainstem pathology. Conditions that mimic generalized myasthenia gravis include motor neuron disease, myopathy, and Lambert-Eaton myasthenic syndrome. In most instances, however, these disorders are recognized by their distinctive clinical and laboratory features, and unlike myasthenia gravis, these do not demonstrate true fatigability with diurnal fluctuating weakness.

DIAGNOSIS

Testing for autoantibodies specifically directed against the acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) are the MG diagnostic studies of choice; when positive, none of the other studies subsequently mentioned are usually required. The one drawback to these studies is that they are not immediately available in the acutely ill patient. Acetylcholine receptor antibodies (AChRAbs) are found in 90% of patients with generalized myasthenia gravis and 50% of patients with purely ocular involvement. These antibodies, which are able to fix complement, originate in hyperplasic germinal centers of the thymus gland and bind to the acetylcholine receptors. The binding of antibody to receptors—each divalent immunoglobulin G (IgG) antibody cross-linking two receptor molecules—triggers a cascade of events resulting in loss of skeletal muscle postsynaptic ACh receptors. This is related to the effects of the terminal portion, that is, membrane attack complex of the complement cascade, leading to loss and simplification (marked reduction of surface area) of the postsynaptic membrane.

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