INTRODUCTION — Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by fluctuating weakness involving ocular, bulbar, limb, and/or respiratory muscles. The weakness is due to an antibody-mediated immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors or receptor-associated proteins). MG is the most common disorder of neuromuscular transmission.
The clinical manifestations of MG will be reviewed here. Other aspects of this disorder are discussed separately.
●(See "Pathogenesis of myasthenia gravis".)
●(See "Diagnosis of myasthenia gravis".)
●(See "Differential diagnosis of myasthenia gravis".)
●(See "Overview of the treatment of myasthenia gravis".)
●(See "Chronic immunotherapy for myasthenia gravis".)
CLASSIFICATION — The clinical manifestations of MG can vary from mild and focal weakness in some patients to severe tetraparesis with respiratory failure in others. Symptom severity may also vary substantially in an individual patient throughout the day and over the course of the condition. Classification systems stratify patients by symptoms or diagnostic findings to specify the severity of impairment and to aid with management.
●Clinical forms – There are two clinical forms of MG: ocular and generalized.
•Ocular MG – Weakness is limited to the eyelids and extraocular muscles.
•Generalized MG – Weakness involves a variable combination of ocular, bulbar, limb, and respiratory muscles.
The pathophysiology of ocular MG is the same as generalized MG, but the sensitivities of diagnostic tests and treatments can vary between these clinical forms. Many patients with ocular MG eventually progress to generalized MG, but others have a milder course that remains restricted to ocular symptoms. (See "Ocular myasthenia gravis".)
●Symptom severity – MG may be categorized by symptom severity to guide treatment decisions, determine eligibility for clinical trials, and help with prognostication. A widely used classification system from a task force of the Myasthenia Gravis Foundation of America (MGFA) stratifies patients by the extent and severity of muscle weakness (table 1) [1]. The degree of impairment progresses through successive categories from weakness that is restricted to ocular muscles, to generalized weakness also involving other muscle groups (eg, bulbar, axial, limb, or respiratory muscles), to severe weakness causing neuromuscular respiratory failure:
•Class I – Isolated ocular muscle weakness
•Class II – Mild generalized weakness involving nonocular muscles
•Class III – Moderate generalized weakness involving nonocular muscles
•Class IV – Severe generalized weakness involving nonocular muscles
•Class V – Intubation due to respiratory muscle weakness
For MG symptoms that fluctuate, the patient's most severe weakness is used to assess the MGFA clinical class.
In addition, several scoring systems have been developed to help define the severity of specific symptoms and signs in MG.
•The MG Activities of Daily Living score is used to quantify the severity of patient-reported symptoms [2]. Scoring is rated from zero to three in eight domains including talking, chewing, swallowing, breathing, teeth brushing/hair combing, ability to stand from a chair, presence of double vision, and eyelid drooping.
•The MG Manual Muscle Testing (table 2) worksheet can be used by clinicians to quantify the severity of weakness on bedside examination [3]. Muscle weakness is rated from zero (no weakness) to four (paralysis) in muscles routinely tested on patients with MG.
•The MG Composite Scale (table 3) combines patient-reported symptoms and bedside examination findings using 10 domains to help define severity of symptoms [4]. Weakness that is 50 percent of normal strength is categorized as "moderate"; any weakness that is less severe is "mild," and any weakness that is greater than moderate is "severe."
•The Quantitative MG scoring system is a detailed clinical assessment tool that may be used to help specify weakness as mild, moderate, or severe [1]. As an example, limb weakness may be rated by the duration a patient can hold an arm outstretched as mild for 1.5 to 4 minutes, moderate for 10 to 89 seconds, and severe for 0 to 9 seconds.
●Antibody status – MG is also categorized by the presence of specific autoantibodies targeting receptors at the neuromuscular junction. The role of autoantibodies in MG is discussed separately. (See "Pathogenesis of myasthenia gravis".)
EPIDEMIOLOGY — MG is a relatively uncommon disorder with an annual incidence of approximately 7 to 23 new cases per million [5-9]. The prevalence is approximately 70 to 320 per million [5,6,8,10,11]. The prevalence of the disease has been increasing since the mid-20th century, likely due to better recognition of the condition, aging of the population, and the longer life span of affected patients [12,13].
MG occurs at any age, but there tends to be a bimodal distribution to the age and sex predominance 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 MG accounts for approximately 10 to 15 percent of cases in North America [14,15]. An incidence rate of 1.6 per million with a female predominance was found in a Norwegian retrospective population-based study of juvenile MG [16].
In neonates, a transient form of myasthenia, called neonatal MG, can occur as a result of the transplacental passage of maternal antibodies that interfere with the function of the neuromuscular junction. In addition, rare, nonimmune-mediated forms, collectively referred to as congenital MG, may occur as the result of genetic variants that adversely affect neuromuscular transmission. Neonatal and congenital MG are discussed separately. (See "Neuromuscular junction disorders in newborns and infants".)
A number of reports have suggested an association of MG with other autoimmune diseases, including neuromyelitis optica, autoimmune thyroid disease, systemic lupus erythematosus, and rheumatoid arthritis [17-20]. The postpartum period was identified as a risk factor for the onset of MG in a population-based cross-sectional study in Norway and the Netherlands [21].
CLINICAL FEATURES — MG is characterized by skeletal muscle weakness that fluctuates over the course of a day. Weakness may be widespread for some patients or restricted to specific muscle groups for others.
Neuromuscular weakness — The cardinal feature of MG is skeletal muscle weakness, often with true muscle fatigue. Muscle fatigue is manifested by worsening contractile force of the muscle, not a sensation of tiredness. Fatigue without weakness is inconsistent with MG. Patients present with complaints of specific muscle weakness and not generalized muscle fatigue.
Muscle weakness may occur in any muscle but most frequently affects ocular and other bulbar muscle function more than other muscle groups. Differences in the expression and function of receptors at the neuromuscular junction of various muscles may account for the patterns of weakness characteristic for MG [22,23].
Ocular function — Ocular symptoms are the most common in MG and may include ptosis due to weakness of levator palpebral muscles and diplopia due to weakness of extraocular muscles. Symptoms are frequently asymmetric.
Pupillary function is always normal in MG, helping in the differentiation from other ocular disorders.
●Ptosis – 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. Ptosis may start unilaterally and then become bilateral or may start bilaterally and improve in one eye, resulting in unilateral ptosis. At times, it may be so severe as to occlude vision.
On examination, ptosis may be present continually or it may develop within 60 seconds of sustained upward gaze. It may also be identified by holding up the opposite eyelid with the examiner's finger (curtain sign) and may improve with testing after the application of an ice pack to the closed lid. (See "Diagnosis of myasthenia gravis", section on 'Ice pack test'.)
●Diplopia – Weakness of the extraocular muscles 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 overt diplopia is evident.
Diplopia may be identified on examination by extraocular muscle testing. For patients with mild or intermittent symptoms, diplopia may develop within 60 seconds of sustained lateral gaze. For other patients with more severe symptoms, the eyes may be misaligned at primary gaze or when the patient looks in the direction where the symptoms are most pronounced. The pattern of eye movement dysfunction often does not conform to the anatomy of one nerve or muscle. The pattern may simulate another disorder, such as an isolated oculomotor neuropathy, an internuclear ophthalmoplegia (INO), or a vertical gaze paresis.
The signs and symptoms of ocular MG are discussed in more detail separately. (See "Ocular myasthenia gravis".)
Bulbar function — Weakness of the oropharyngeal or facial expression muscles is common in generalized MG and is an important contributor to the risk of respiratory compromise due to aspiration.
●Dysarthria and dysphagia – 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.
Muscles of jaw closure may also be involved and produce (fatigable) weakness with prolonged chewing [24]. The patient may note symptoms toward the end a meal, especially when chewing something difficult like steak. When jaw weakness is present at rest, patients often use their fingers under the jaw to keep the mouth shut.
Dysphagia may be prominent in patients with dysarthria or masticatory weakness. Patients may be unable to swallow medications or consume adequate food or liquids. Severe symptoms with imminent risk of aspiration may produce a "myasthenic crisis." Nasal regurgitation, particularly of liquids, may occur due to palatal weakness. (See "Myasthenic crisis".)
On examination, the patient may develop dysarthria or hypophonia when counting aloud. Dysphagia may be identified after swallowing a cup of water by coughing or throat clearing.
●Facial expression – Muscles of facial expression 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. 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. This transverse smile may be evident on examination. The orbicularis oculi muscle may also be weak in patients with impaired facial expression and may be identified on examination when prying the eyes open during forced-eye closure.
Neck and limb strength — Neck extensor and flexor and limb muscles weakness may be found in some patients with generalized MG. The weight of the head may overcome weakened extensors, particularly late in the day, producing a "dropped-head syndrome" [25]. Posterior neck muscles may ache due to the added effort in keeping the head up with the weakened extensors.
The pattern of limb weakness in MG is typically proximal and the arms tend to be more often affected than the legs. In addition, wrist and finger extensors and foot dorsiflexors may also be involved. Predominantly distal presentations of otherwise typical MG are uncommon but have been reported in case series [26].
Neck weakness can be assessed on examination by head dropping during attempts to hold the head against gravity or manual resistance applied on the head. Limb weakness may be measured by limitations in holding the arm or leg against gravity.
Respiratory function — Weakness of the muscles of respiration produces the most serious symptoms in MG. Respiratory muscle weakness that leads to respiratory insufficiency and impending 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. Myasthenic crisis with neuromuscular respiratory failure may be the initial presentation of MG in some patients [27]. (See "Myasthenic crisis".)
Several medications can increase weakness in MG and should be avoided or used with great caution (table 4). (See "Overview of the treatment of myasthenia gravis", section on 'Avoidance of drugs that may exacerbate myasthenia'.)
Respiratory function can be assessed by measuring forced vital capacity and maximal inspiratory pressure (also known as negative inspiratory force). (See "Overview of pulmonary function testing in adults", section on 'Pulmonary function tests' and "Tests of respiratory muscle strength", section on 'Maximal inspiratory and expiratory pressure'.)
Fluctuation of weakness — Patients typically have fatigable weakness of the specific muscle groups affected [28]. 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 and apparent only later in the day. As the disease progresses, the symptom-free periods may be lost; symptoms are continuously present but fluctuate from mild to severe. When present, this fluctuation in symptoms is an important feature that can distinguish MG from other disorders that also may present with weakness, such as myopathy or motor neuron disease.
CLINICAL COURSE
Presenting symptoms — Although MG can produce weakness in any skeletal muscle group, certain characteristic presentations of MG are more common than others (table 5) [12,29,30]:
●Isolated ocular symptoms of ptosis and/or diplopia are the presenting features in more than 50 percent of patients.
●Bulbar presentation occurs in approximately 15 percent of patients. Symptoms may include dysarthria, dysphagia, and/or fatigable chewing.
●Proximal limb weakness without other symptoms is the presenting symptom in less than 5 percent of patients.
●Other presentations are rare, including distal limb predominating weakness, isolated neck weakness, or isolated respiratory muscle weakness.
Progression — Early in the disorder, the symptoms may be episodic, with asymptomatic intervals lasting hours, days, or even weeks. Over time, the manifestations typically worsen and become more persistent.
The progression of MG to maximal severity typically peaks within a few years of disease onset. In a case series from the United States of 1976 patients with MG, the maximum extent of weakness was reached within two years in 82 percent of patients [12]. 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 [31].
New symptoms frequently develop in the weeks or months following the initial presentation for patients with isolated initial symptoms. Many patients with symptoms initially restricted to ocular dysfunction eventually develop weakness in other muscle groups [29]. Similarly, patients who present without ocular manifestations frequently develop ptosis or diplopia at some point in the course [30].
For those who present with isolated ocular symptoms, an important question is whether symptoms will progress to generalized MG. Approximately 80 percent of patients (45 to 60 percent in most studies) "generalize" by two to three years [12,29,30,32-34]. There are no factors that predict which patients who present with ocular disease will develop generalized MG. Autoantibody and electrodiagnostic testing to assess subclinical generalized involvement do not reliably predict which patients will develop generalized MG. In one small study of patients with ocular disease, an abnormal single-fiber electromyography (EMG) of a limb muscle was not predictive of subsequent development of generalized MG, although a normal single-fiber EMG was associated with a tendency for involvement to remain purely ocular (82 percent likelihood) [34].
Clinical stages — Many clinicians feel that there are three stages to the disease, although these have been altered considerably by modern immunotherapy.
●Active phase – An active phase characterized by the most fluctuations and the most severe symptoms typically occurs in the five to seven years after onset. Most myasthenic crises occur in this early period.
●Stable phase – The active phase 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.
●Remission phase – Most patients improve with treatment and reach a third phase, in which remission may occur, with the patient free of symptoms on immunotherapy, or sometimes even off medications entirely. Approximately 10 percent of patients with generalized MG do not achieve (pharmacologic) remission and are categorized as having refractory MG.
Some patients in remission may have persistent fixed deficits (eg, facial weakness, limb weakness, ptosis) that do not fluctuate and are not responsive to therapies. These chronic symptoms may be due to complement-mediated damage of the post-synaptic muscle membrane and tends to occur late in the course of the disease. (See "Pathogenesis of myasthenia gravis".)
Prognosis — The prognosis of MG varies by symptom severity and response to treatment. Patients with severe or refractory symptoms, including those hospitalized for myasthenic crisis, are at higher risk for complications compared with those with mild or nonbulbar symptoms.
Factors associated with worse prognosis in patients with MG include [35-39]:
●Frequent exacerbations ("brittle" MG)
●Severe bulbar symptoms
●Myasthenic crisis
●Presence of thymoma
●Onset at age >50 years
Although data are limited, MG may be associated with increased mortality. In a population-based study from Denmark, overall mortality was significantly increased for subjects with acetylcholine receptor-antibody-seropositive MG compared with matched controls from the general population (mortality rate ratio 1.41, 95% CI 1.24-1.60) [35]. However, other contemporary studies have not found an increased mortality rate, perhaps due to better disease management with the increasing availability of effective immunotherapies [40].
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
●Clinical subtypes – There are two clinical forms of myasthenia gravis (MG) (see 'Classification' above):
•Ocular MG – Weakness is limited to the eyelids and extraocular muscles.
•Generalized MG – Symptoms involve a variable combination of ocular, bulbar, limb, and/or respiratory muscles.
●Disease classification – MG may be classified clinically according to the extent or severity of muscle weakness. The degree of impairment progresses through successive categories from weakness that is restricted to ocular muscles, to weakness involving other muscle groups (eg, bulbar, axial, limb, or respiratory muscles), to neuromuscular respiratory failure (table 1 and table 3). (See 'Classification' above.)
●Muscle weakness – MG is characterized by skeletal muscle weakness that fluctuates over the course of a day and may be prominent in or restricted to specific muscle regions (table 1 and table 2). (See 'Clinical features' above.)
•Ocular symptoms – Ocular symptoms are the most common in MG and may include ptosis due to weakness of levator palpebral muscles and diplopia due to weakness of extraocular muscles. (See 'Ocular function' above.)
•Bulbar symptoms – Weakness of the oropharyngeal muscles produces dysarthria and/or dysphagia and is an important contributor to the risk of respiratory compromise due to aspiration. Weakness of facial expression muscles may make the patient appear expressionless. (See 'Bulbar function' above.)
•Neck and limb weakness – Neck extensor and flexor and limb muscles weakness may be found in some patients with generalized MG. The weight of the head may overcome weakened extensors, producing a "dropped-head syndrome." Limb weakness in MG is typically proximal, similar to other muscle diseases. (See 'Neck and limb strength' above.)
•Respiratory symptoms – Weakness of the muscles of respiration produces the most serious symptoms in MG. Respiratory muscle weakness that leads to respiratory insufficiency and impending 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 (table 4), or tapering of immunosuppression. (See 'Respiratory function' above and "Myasthenic crisis".)
●Fluctuation of symptoms – The weakness of the specific muscle groups affected typically fluctuates, being mild or absent early in the day and most commonly worse later in the day or evening or after exercise. (See 'Fluctuation of weakness' above.)
●Presenting symptoms – MG can produce weakness in any skeletal muscle group, but characteristic presentations of MG are common (table 5). (See 'Presenting symptoms' above.)
●Progression – Early in the disorder, the symptoms may be episodic, with asymptomatic intervals lasting hours, days, or even weeks. Over time, the manifestations typically worsen and become more persistent. New symptoms frequently develop in the weeks or months following the initial presentation for patients with isolated initial symptoms. The progression of MG to maximal severity typically peaks within a few years of disease onset. (See 'Progression' above.)
●Prognosis – The prognosis of MG varies by symptom severity and response to treatment. Inadequate symptom control, myasthenic crisis, older age at diagnosis, and thymoma are associated with poor outcome. (See 'Prognosis' above.)
