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Clinical manifestations of myasthenia gravis
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Clinical manifestations of myasthenia gravis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Aug 31, 2016.

INTRODUCTION — Myasthenia gravis is the most common disorder of neuromuscular transmission. It is now one of the best characterized and understood autoimmune disorders. The hallmark of the disorder is a fluctuating degree and variable combination of weakness in ocular, bulbar, limb, and respiratory muscles. Weakness is the result of an antibody-mediated, T-cell dependent immunological attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors and/or receptor-associated proteins). The diagnosis of myasthenia gravis can be established by clinical and serologic testing [1,2].

The clinical manifestations of myasthenia gravis will be reviewed here. Other aspects of this disorder are discussed separately. (See "Ocular myasthenia gravis" and "Diagnosis of myasthenia gravis" and "Differential diagnosis of myasthenia gravis" and "Pathogenesis of myasthenia gravis" and "Treatment of myasthenia gravis".)

OVERVIEW — There are two clinical forms of myasthenia gravis: ocular and generalized.

In ocular myasthenia, the weakness is limited to the eyelids and extraocular muscles. (See "Ocular myasthenia gravis".)

In generalized disease, the weakness commonly affects ocular muscles, but it also involves a variable combination of bulbar, limb, and respiratory muscles.

Patients who have detectable antibodies to the acetylcholine receptor (AChR) or to the muscle-specific receptor tyrosine kinase (MuSK) are considered to have seropositive myasthenia gravis, while those lacking both AChR and MuSK antibodies on standard assays are considered to have seronegative myasthenia. About half of patients with purely ocular myasthenia are seropositive, compared with approximately 90 percent of those with generalized disease. Another important consideration is that about 10 to 15 percent of patients with myasthenia gravis have an underlying thymoma. (See "Pathogenesis of myasthenia gravis".)

EPIDEMIOLOGY — Myasthenia gravis is a relatively uncommon disorder with an annual incidence of approximately 7 to 23 new cases per million [3-6]. The prevalence is about 70 to 320 per million [3,4,6,7]. The prevalence of the disease has been increasing since the mid-20th century [8,9]. This is thought to be due to better recognition of the condition, aging of the population, and the longer life span of affected patients.

Myasthenia gravis occurs at any age, but there tends to be a bimodal distribution to the age of onset with an early peak in the second and third decades (female predominance) and a late peak in the sixth to eighth decade (male predominance). Autoimmune juvenile myasthenia gravis accounts for approximately 10 to 15 percent of cases in North America [10,11].

In neonates, a transient form of myasthenia, called neonatal myasthenia gravis, can occur as a result of the transplacental passage of maternal antibodies that interfere with function of the neuromuscular junction. Rare, nonimmune mediated forms, collectively referred to as congenital myasthenia gravis, may be the result of mutations that adversely affect neuromuscular transmission. Neonatal and congenital myasthenia are discussed separately. (See "Neuromuscular junction disorders in newborns and infants".)

A number of reports have suggested an association of myasthenia gravis with other autoimmune diseases, including neuromyelitis optica, autoimmune thyroid disease, systemic lupus erythematosus, and rheumatoid arthritis [12-15].

CLINICAL FEATURES — The cardinal feature of myasthenia gravis is fluctuating skeletal muscle weakness, often with true muscle fatigue. The fatigue is manifest by worsening contractile force of the muscle, not a sensation of tiredness. Many clinicians think (erroneously) that fatigue without weakness is consistent with myasthenia. Patients present with complaints of specific muscle weakness and not generalized muscle fatigue.

However, patients do typically have fluctuating weakness and fatigue of the specific muscle groups affected [2]. The weakness may fluctuate throughout the day, but it is most commonly worse later in the day or evening, or after exercise. Early in the disease, the symptoms may be absent upon awakening. Often as the disease progresses, the symptom-free periods are lost; symptoms are continuously present but fluctuate from mild to severe. When present, this fluctuation in symptoms is an important feature that can distinguish myasthenia gravis from other disorders that also may present with weakness, such as myopathy or motor neuron disease.

Presenting symptoms — Although myasthenia can produce weakness in any skeletal muscle group, there are certain presentations that are quite characteristic of myasthenia gravis (table 1).

More than 50 percent of patients present with ocular symptoms of ptosis and/or diplopia [8,16,17]. Of those who present with ocular manifestations, about half will develop generalized disease within two years [16-20]. Many of the patients who present without ocular manifestations develop ptosis or diplopia at some point in the course.

About 15 percent of patients present with bulbar symptoms. These include dysarthria, dysphagia, and fatigable chewing.

Less than 5 percent present with proximal limb weakness alone.

Less common presentations include isolated neck weakness, isolated respiratory muscle weakness, and distal limb weakness.

Ocular muscles — Weakness of the eyelid muscles can lead to ptosis, the degree of which can be quite variable throughout the day. It may switch from one eye to the other over time. The ptosis may start bilaterally and improve in one eye, resulting in unilateral ptosis. In addition, ptosis may start unilaterally and then become bilateral. At times, it may be so severe as to occlude vision.

The extraocular muscles are also often involved. This produces binocular diplopia that disappears when the patient closes or occludes one eye. It may be horizontal or vertical. At the onset, this is sometimes sensed as intermittent periods of blurred vision before the diplopia is evident.

On examination, eye movements are often weak in a pattern that does not conform to the anatomy of one nerve or muscle. They may also be weak in a pattern that simulates another disorder, such as an isolated oculomotor neuropathy, an internuclear ophthalmoplegia (INO), or a vertical gaze paresis. The pupils are always spared in myasthenia gravis, helping in the differentiation from other disorders. The ptosis may increase with sustained upward gaze or by holding up the opposite eyelid with the examiner's finger (curtain sign).

The signs and symptoms of ocular myasthenia gravis are discussed in more detail separately. (See "Ocular myasthenia gravis".)

Bulbar muscles — Muscles of jaw closure are often involved and produce weakness with prolonged chewing (fatigable chewing) [21]. The patient frequently notes that this occurs half-way through a meal, especially when chewing something difficult like steak. When jaw weakness is present at rest, the patients often use their fingers under the jaw to keep the mouth shut.

Oropharyngeal muscle weakness produces dysarthria and dysphagia. The quality of speech sounds nasal when there is weakness of the palatal muscles, or it may be of low intensity (hypophonic). These symptoms often worsen with prolonged speech. Dysphagia may be prominent; the patient may be unable to swallow medications or consume adequate food or liquids. Imminent risk of aspiration may produce a "myasthenic crisis." Nasal regurgitation, particularly of liquids, may occur due to palatal weakness. (See "Myasthenic crisis".)

Facial muscles — Facial muscles are frequently involved and make the patient appear expressionless. Family members may notice that the patient has "lost his or her smile" as a result of weakness of the orbicularis oris muscle. This transverse smile may be evident on examination. When attempting to smile, the patient may produce the "myasthenic sneer," where the mid-lip rises but the outer corners of the mouth fail to move. Orbicularis oculi weakness is often easily identified on examination when prying the eyes open during forced-eye closure.

Neck and limb muscles — Neck extensor and flexor muscles are commonly affected. The weight of the head may overcome the extensors, particularly late in the day, producing a "dropped head syndrome." Posterior neck muscles may ache due to the added effort in keeping the head up with the weakened muscles.

Involvement of the limbs in myasthenia produces predominantly proximal weakness similar to other muscle diseases. However, the arms tend to be more often affected than the legs. In addition to proximal muscles, wrist and finger extensors and foot dorsiflexors are often involved. Predominantly distal presentations of otherwise typical myasthenia can occur, as shown in 6 of 84 patients in one prospective series [22].

Respiratory muscles — Involvement of the muscles of respiration produces the most serious symptoms in myasthenia gravis. Respiratory muscle weakness that leads to respiratory insufficiency and pending respiratory failure is a life-threatening situation called "myasthenic crisis." It may occur spontaneously during an active phase of the disease or may be precipitated by a variety of factors including surgery, infections, certain medications, or tapering of immunosuppression. (See "Myasthenic crisis".)

A number of medications can increase weakness in myasthenia and should be avoided or used with great caution (table 2 and table 3). (See "Treatment of myasthenia gravis", section on 'Drugs that may exacerbate myasthenia'.)

Clinical course — Early in the disorder, the symptoms are often transient in many patients, with hours, days, or even weeks free of symptoms. The symptoms may even remit spontaneously for weeks or longer. However, the manifestations typically worsen and are more persistent. New symptoms often develop weeks or months later.

The progression of myasthenia gravis usually peaks within a few years of disease onset. In a case series from the United States of 1976 patients with myasthenia gravis, the maximum extent of weakness was reached within two years in 82 percent of patients [8]. In another retrospective study of 1152 patients in Italy, the maximum extent of the disease was seen by three years of onset in 77 percent [23].

Of those who present with ocular manifestations, an important question is whether they will develop generalized disease. About 50 percent of patients (45 to 60 percent in most studies) "generalize" by two years [16-20]. There are no factors that predict which patients who present with ocular disease will develop generalized myasthenia. The presence of AChR antibodies, a decremental response to repetitive nerve stimulation studies, or abnormal single-fiber electromyographic (EMG) studies of a limb muscle do not predict spread. In one study of patients with ocular disease, an abnormal single fiber EMG of a limb muscle was not predictive of subsequent development of generalized myasthenia, although a normal single fiber EMG was associated with a tendency for involvement to remain purely ocular (82 percent likelihood) [20]. Of those who will develop generalized myasthenia, virtually all do so by two to three years, although there are uncommon exceptions.

Most clinicians feel that there are three stages to the disease, although these have been altered considerably by modern immunotherapy.

There is an active phase with the most fluctuations and the most severe symptoms that occurs in the five to seven years after onset. Most myasthenic crises occur in this early period.

This is typically followed by a more stable second phase. In this phase, the symptoms are stable but persist. They may worsen in the setting of infection, medication taper, or other perturbations.

In many patients, this is followed by the third phase, in which remission may occur, with the patient free of symptoms on immunotherapy, or even off medications entirely.

Although data are limited, myasthenia gravis may be associated with increased mortality. In a population-based study from Denmark, overall mortality was significantly increased for subjects with AChR-antibody-seropositive myasthenia gravis compared with matched controls from the general population (mortality rate ratio 1.41, 95% CI 1.24-1.60) [24].

DIAGNOSIS — The diagnostic approach to myasthenia is focused on confirming the clinical diagnosis established by the history and typical examination findings described above. Bedside tests (the Tensilon test and the ice pack test) are easy to perform and are sensitive, but they have major limitations due to concerns about excess false-positive results with these techniques. Confirmation by these tests alone is unwise.

More reliable laboratory methods that aid in the confirmation are serologic tests for autoantibodies and electrophysiological studies (repetitive nerve stimulation studies and single-fiber EMG). The diagnostic sensitivity of these studies also varies considerably depending on whether the patient has ocular or generalized disease.

The diagnosis and differential diagnosis of myasthenia gravis are discussed in detail separately. (See "Diagnosis of myasthenia gravis" and "Differential diagnosis of myasthenia gravis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Myasthenia gravis (The Basics)")

SUMMARY

Myasthenia gravis is a relatively uncommon disorder. However, it is the most common disorder of neuromuscular transmission. Age of onset is characterized by an early peak in the second and third decades (female predominance) and a late peak in the sixth to eighth decade (male predominance). (See 'Epidemiology' above.)

About 10 to 15 percent of those with myasthenia gravis have an underlying thymoma. (See 'Overview' above.)

The cardinal feature of myasthenia gravis is fluctuating skeletal muscle weakness, often with true muscle fatigue. The fatigue is manifest by worsening contractile force of the muscle. (See 'Clinical features' above.)

There are two clinical forms of myasthenia gravis: ocular and generalized. In ocular myasthenia, the weakness is limited to the eyelids and extraocular muscles. In generalized disease, the weakness may also commonly affect ocular muscles, but it also involves a variable combination of bulbar, limb, and respiratory muscles. (See 'Overview' above.)

More than 50 percent of patients present with ocular symptoms of ptosis and/or diplopia. Of those who present with ocular manifestations, about half will remain purely ocular. About 15 percent of patients present with bulbar symptoms. These include fatigable chewing, dysphagia, and dysarthria. Less than 5 percent present with proximal limb weakness alone. (See 'Presenting symptoms' above.)

Eyelid muscle weakness can lead to ptosis that can vary throughout the day. Extraocular muscle weakness produces binocular diplopia that disappears when the patient closes or occludes one eye. (See 'Ocular muscles' above.)

Muscles of jaw closure are often involved and produce weakness with prolonged chewing. Oropharyngeal muscle weakness produces dysarthria and dysphagia. (See 'Bulbar muscles' above.)

Facial muscles are frequently involved and make the patient appear expressionless. (See 'Facial muscles' above.)

Neck extensor and flexor muscles are commonly affected. The weight of the head may overcome the extensors, producing a "dropped head syndrome." Involvement of the limbs produces predominantly proximal weakness similar to other muscle diseases. Predominantly distal presentations of otherwise typical myasthenia can occur. (See 'Neck and limb muscles' above.)

Involvement of the muscles of respiration produces the most serious symptoms in myasthenia gravis, such as respiratory insufficiency and pending respiratory failure, called "myasthenic crisis." (See 'Respiratory muscles' above.)

Early in the disorder, the symptoms of myasthenia gravis are often transient in many patients, with hours, days, or even weeks free of symptoms. New symptoms often develop weeks or months later. The maximal extent of the disease is seen in 77 percent of patients by three years of onset. (See 'Clinical course' above.)

The diagnostic approach to myasthenia gravis is focused on confirming the clinical diagnosis established by the history and examination findings. The diagnosis and differential diagnosis of myasthenia gravis is discussed in detail separately. (See "Diagnosis of myasthenia gravis" and "Differential diagnosis of myasthenia gravis".)

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REFERENCES

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