eMedicine Specialties > Ophthalmology > Ophthalmology for the General Practitioner

Myasthenia Gravis

Author: Shady Awwad, MD, Staff Physician, Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas
Coauthor(s): Riad Ma'luf, MD, Head, Division of Oculoplastics, Department of Ophthalmology, Clinical Assistant Professor, American University of Beirut Medical Center; Nicolas Hamush, MD, Consulting Staff, Department of Ophthalmology, Eye & Ear Hospital International, Naccache, Lebanon
Contributor Information and Disclosures

Updated: Jul 13, 2007

Introduction

Background

Myasthenia gravis (MG) is a disorder of neuromuscular transmission characterized by weakness and fatigability of skeletal muscles. The basic pathology is a reduced number of acetylcholine receptors (AChR) at the postsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies. Two major clinical forms of MG are distinguished, ocular MG and generalized MG.

Pathophysiology

When an action potential travels down a motor nerve and reaches the nerve terminal, acetylcholine (ACh) molecules are released from the presynaptic vesicles and adhere to AChR at the peaks of postsynaptic folds. Channels in the AChR open, allowing Na⁺ and other cations to enter into the muscle fiber endplate and depolarize it. The multiple depolarizations will sum up and, if large enough, trigger an action potential, which travels along the muscle fiber to produce contraction.

With every nerve impulse, the amount of ACh released by the presynaptic motor neuron normally decreases due to a temporal depletion of the presynaptic ACh stores (presynaptic rundown).

In MG, there is a reduction in the number of AChR available at the muscle endplate and flattening of the postsynaptic folds. The fewer endplate potentials produced by the yet normal amount of ACh released might fail to be translated into an action potential. The end result is an inefficient neuromuscular transmission.

This inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon results in a decremental amount of nerve fibers being activated by successive nerve fiber impulses. This explains the fatigability in the involved patients.

The decrease in number of the postsynaptic AChR is believed to be due to an autoimmune process whereby anti-AChR antibodies are produced and act to block the target receptors, increase their turnover, and damage the postsynaptic membrane in a complement-mediated manner.

Although the primary etiology remains speculative, there is increasing evidence that the thymus might play an important role. Histopathologic studies showed prominent germinal centers. Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and possess AChR on their surface membrane. These cells may become antigenic and unleash an autoimmune attack on the muscular endplate AChR by molecular mimicry.

Why the disease afflicts first and predominantly the extraocular muscles remains unanswered. It probably has to do with the physiology and antigenicity of the muscles in question.

Frequency

United States

The annual incidence is 2 cases per 1,000,000. The prevalence of MG in the United States is approximately 14 cases in 100,000.

International

Prevalence of MG in the United Kingdom is 15 cases per 100,000 population and 10 cases per 100,000 in Croatia. In Sardinia, Italy, prevalence increased from 0.75 to 4.5 cases per 100,000, respectively, for the years 1958 and 1986.

Mortality/Morbidity

In the era before corticosteroids were used for treatment, one third of patients died of the disease. With modern treatment options, MG is no more as serious at it was before, rendering the word gravis a misnomer in most cases.

Today, the only feared condition is when the weakness involves the respiratory muscles. Weakness might become so severe as to require ventilatory assistance. Those patients are said to be in myasthenic crisis.

Sex

Overall, women are affected more than men with a female-to-male ratio of 3:2. Yet, recent studies show that with increased life expectancy, males are becoming as equally affected as females. Ocular MG shows a male preponderance.

Age

MG can occur at any age but peaks in females in the fourth to fifth decade of life and in males in the sixth to seventh decade. Neonatal forms do occur but are rare. Infantile and juvenile forms have different courses than in adults.

Clinical

History

The usual initial complaint is a specific muscle weakness rather than generalized muscle weakness. The severity of the weakness typically fluctuates over hours being least severe in the morning and worse as the day progresses. It also varies over the course of weeks or months, with exacerbations and remissions.

Exposure to bright sunlight, viral illness, surgery, immunization, emotional stress, menstruation, and physical factors might trigger or worsen the exacerbations.

• Ophthalmic symptoms
  
  
  • Of the patients, 75% initially complain of ocular disturbance, mainly ptosis and diplopia. Eventually, 90% of patients with MG develop ocular symptoms. About 50% of patients will present solely with ocular symptoms, and about 50-60% of these patients will progress to develop generalized disease.
  • Ptosis may be unilateral or bilateral, and it may shift from eye to eye.
• Nonophthalmic symptoms
  
  
  • Oropharyngeal muscle disturbances come second in presentation, with 15% of patients first experiencing difficulty in swallowing, talking, and chewing.
  • Limb and trunk weakness is the initial complaint of 10% of patients. Yet, 85% of patients with MG develop a generalized weakness also affecting the limb muscles.
  • MG can involve the respiratory muscles and can lead to respiratory failure. This can sometimes be the first presentation of the disease. Qureshi et al showed that out of 51 patients with MG and respiratory failure, 7 (14%) had no previous diagnosis of MG.¹

Physical

• Ptosis
  
  
  • Ptosis can be unilateral or bilateral.
  • The ptosis is usually most prominent upon sustained upward gaze (see Media file 1) or repeated eyelid closure.
  • In cases of unilateral ptosis, the contralateral lid may assume a ptotic position upon occluding the eye with the ptosis or lifting the ptotic lid with a finger (Herring phenomenon).
  • The lid twitch sign described by Cogan can be elicited by having the patient change gaze from the downward position to the primary position.² The lid will be seen to overshoot in a twitch before gaining its initial ptotic position (see Media file 2). A recent study, however, has questioned the validity of such a sign, as its sensitivity and specificity were shown to be relatively low.³
  • A subtle lid flutter is occasionally encountered.
• Extraocular muscle involvement
  
  
  • Extraocular muscle involvement does not follow a certain pattern. However, the superior rectus and/or the medial rectus are commonly involved (see Media file 1).
  • Isolated inferior rectus palsy is rare, but, when present, it raises the suspicion of MG since it is extremely rare to be encountered otherwise.
  • The spectrum of affection stretches from isolated muscle palsies to total external ophthalmoplegia.
  • Any acquired ocular motility disturbance with or without ptosis, but normally reacting pupils, should raise the clinical suspicion of MG.
• Orbicularis involvement
  
  
  • Orbicularis involvement consistently is present when ocular symptoms are reported.
  • Weakness in forceful closure of the eyes against resistance is present.
• Pupils and ciliary muscles: Traditionally, pupils and ciliary muscles were believed not to be involved, although recent studies suggest the contrary, notably in a case analysis by Cooper and coworkers.⁴
• Weakness in facial, oropharyngeal, limbal, and trunk muscles, without any other sign of neurologic deficit, such as sensory loss, change in deep tendon reflexes, or muscle atrophy
  
  
  • Facial weakness frequently imparts a snarling expression upon attempted smiling. Speech may have a nasal quality.
  • Upper extremities fatigue is demonstrated best by having patients sit with arms stretched in front of them. Lower extremities fatigue is tested by stepping up and down over a footstool. Grip strength is measured best by a dynamometer.
• Fatigability: Patients show incremental weakness upon repeating the motor power test over and over.

Causes

The main cause behind the development of MG remains speculative. The end result is a derangement in the immune system regulation. Associated findings with MG are many.

• Anti-AChR antibodies are present in most but not all patients with MG.
• Thymic enlargement: Of patients with MG, 75% have thymic disease, 85% have thymic hyperplasia, and 10-15% have thymoma.
• Histocompatibility complex profile
  
  
  • Human leukocyte antigens B8, DRw3, and DQw2
  • These were not shown to be associated with the strictly ocular form of the disease.
• Autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), may be associated with MG.
• Extrathymic tumors may include small cell lung cancer and Hodgkin disease.
• Hyperthyroidism is present in 3-8% of patients with MG and especially is associated with ocular MG.
• Drugs
  
  
  • D-penicillamine can induce true myasthenia with elevated anti-AChR antibody titers. However, the weakness is mild, and full recovery is achieved weeks to months after discontinuation of the drug.
  • Nitrofurantoin has been linked to the development of ocular MG in one case report. Discontinuation of the drug also resulted in complete recovery.
  • Aminoglycosides, polymyxins, and many other drugs are associated with MG.

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