What is the classification of myasthenia gravis?

Patients with myasthenia gravis (MG) can present with a wide range of signs and symptoms, depending on the severity of the disease.

Mild presentations may be associated with only subtle findings, such as ptosis, that are limited to bulbar muscles. Findings may not be apparent unless muscle weakness is provoked by repetitive or sustained use of the muscles involved. Recovery of strength is seen after a period of rest or with application of ice to the affected muscle. Conversely, increased ambient or core temperature may worsen muscle weakness.

Variability in weakness can be significant, and clearly demonstrable findings may be absent during examination. This may result in misdiagnosis (eg, functional disorder). The physician must determine strength carefully in various muscles and muscle groups to document severity and extent of the disease and to monitor the benefit of treatment.

Another important aspect of the physical examination is to recognize a patient in whom imminent respiratory failure is imminent. Difficulty breathing necessitates urgent or emergent evaluation and treatment.

Weakness can be present in a variety of different muscles and is usually proximal and not symmetrical. Sensory examination and deep tendon reflexes are normal.

Distribution of weakness in a large cohort of patients with myasthenia gravis (n=609) (Open Table in a new window)

Weakness of the facial muscles is almost always present. Bilateral facial muscle weakness produces a “sagging and expressionless” face, and a horizontal smile. At rest, the corners of the mouth droop downward, giving the patient a look of sadness. Attempts to smile result in contraction of the medial portion of the upper lip and horizontal contraction of the corners of the mouth with loss of the natural upward curling, giving the patient's smile an appearance of a snarl (“myasthenic snarl”). Patients are unable to whistle, suck through a straw, or blow up a balloon. This often impedes bedside respiratory assessment because the lips form a poor seal around the mouthpiece of the measuring device. The frontalis muscle may be chronically contracted, giving a worried or surprised look to the patient. A unilateral frontalis ‘‘hypercontraction’’ is a clue that the lid elevators are weak on that side. Also, to compensate for ptosis, the sclerae below the limbi may be exposed secondary to weak lower lids. Mild proptosis attributable to extraocular muscle weakness also may be present. Bell’s phenomenon, which is upward rotation of the eyeballs during attempted eyelid closure, is appreciated on examination because of weakness of the orbicularis oculi muscle resulting in incomplete closure of the eyelids. Weakness of eyelid closure is seen in most patients with MG and should be specifically tested by asking patients to forcefully close their eyes while the examiner attempts to manually open the eyelids.

Typically, extraocular muscle weakness is asymmetric. The weakness usually affects more than 1 extraocular muscle and is not limited to muscles innervated by a single cranial nerve; this is an important diagnostic clue. The weakness of lateral and medial recti (more commonly involved) may produce a pseudointernuclear ophthalmoplegia, described as limited adduction of 1 eye, with nystagmus of the abducting contralateral eye on attempted lateral gaze. Pupillary responses are normal. Cogan’s lid twitch describes a brief momentary twitch seen in an eyelid that is elevated on rest. Following sustained downgaze the patient is asked to bring the eyes back up to the primary gaze position. The upper eyelid briefly overshoots resulting in exposure of the sclera between the upper limbus and upper eyelid, followed by a rapid drop to a lower position and return of ptosis of the eyelid. The “twitch” is the momentary elevation of the eyelid before it drops due to fatigue of the levator palpebrae superioris muscle. This sign is not unique to MG and may be seen in dorsal brain stem glioma and menigioma.

Weakness of palatal muscles can occur in roughly 40% of all patients. It can cause the voice to become hypophonic and assume a nasal twang. Nasal regurgitation of food (especially liquids) can occur. An inability to pucker lips or whistle, or puffing the cheeks out against resistance can be noted. As neuromuscular transmission may actually be improved by cooler temperatures, patients note cold food and liquids are easier to swallow than warm foods and liquids are.

Patients with MG who have difficulty chewing may demonstrate weakness of jaw closure due to masseter and temporalis muscle weakness. Weakness of jaw opening due to pterygoid muscle weakness, on the other hand, is rarely seen. This pattern of weak jaw closure and relatively strong jaw opening is quite typical of MG. A frequent sign of jaw weakness is that the patient holds the jaw closed with the thumb under the chin, the index finger extended up the cheek, the middle finger curled under the nose and across the philtrum, producing a studious or attentive appearance. Typically, neck flexion is weaker than neck extension in patients with MG, although occasionally patients will present with a head-drop and have severe neck extension weakness.

Certain limb muscles are involved more commonly than others (eg, upper limb muscles are more likely to be involved than lower limb muscles). In the upper limbs, deltoids and extensors of the wrist and fingers are affected most. The triceps is more likely to be affected than the biceps. In the lower extremities, commonly involved muscles include hip flexors, quadriceps, and hamstrings, with involvement of foot dorsiflexors or plantar flexors less common.

Respiratory muscle weakness that produces acute respiratory failure is a true neuromuscular emergency, and immediate intubation may be necessary. Weakness of the intercostal muscles and the diaphragm may result in carbon dioxide retention as a result of hypoventilation. Respiratory failure usually occurs around the time of surgery (eg, after thymectomy) or during later stages of the disease. However, it can be a presenting feature in about 14-18% of patients with MG. [33]  Weak pharyngeal muscles may collapse the upper airway. Careful monitoring of respiratory status is necessary in the acute phase of MG. Negative inspiratory force, vital capacity, and tidal volume must be monitored carefully. Relying on pulse oximetry to monitor respiratory status can be dangerous. During the initial phase of neuromuscular hypoventilation, carbon dioxide is retained but arterial blood oxygenation is maintained. This can lull the physician into a false sense of security regarding a patient’s respiratory status.

Cognition, coordination, sensation, and muscle stretch reflexes are normal in the myasthenic patient.

The following maneuvers are helpful for diagnosis of MG:

1. Sustained upgaze (60 to 180 seconds); results in fatigable ptosis in one or both eyes.

2. Manual elevation of the more ptotic lid may worsen ptosis of the contralateral eyelid, a phenomenon known as enhanced ptosis. This phenomenon is based on Herrings Law of equal innervation.

3. Sustained tight closure of the eyelids can induce fatigue of the orbicularis oculi muscles resulting in the white sclera of the eye slowly becoming apparent under the partially open eye. This is called the “peek sign.”

4. Fatigable diplopia in sustained lateral gaze (60 seconds); results in diplopia with images appearing side by side.

5. Sustained abduction of the arms (120 seconds); patient can no longer hold arms up, or weakness becomes apparent with subsequent manual testing.

6. Ask the patient to perform deep knee bends with the back straight. The patient’s palm is held in that of the examiner. An increase in pressure against the examiner’s palm while doing this maneuver is an early sign of weakness. Also, a forward lean by the patient (moving the center of gravity forward) is another sign of weakness.

7. Counting aloud (1 to 50): Enhances dysarthria (nasal, lingual, or labial) and results in dyspnea. Patient may sound relatively clear on speaking initially but will become increasingly dysarthric to the point of becoming unintelligible.

8. Weakness of the laryngeal muscles results in hoarseness. This can be elicited by asking the patient to make a high-pitched (“eeee”) sound.

9. Single breath counting aloud (1 to 20) may elicit not only dysarthria but dyspnea and gives an approximate idea of the vital capacity. Multiplying the number the patient can achieve with one breath by 100 (e.g., 20 x 100 = 2000 cc) will provide a reasonable estimate of the vital capacity.

10. Sustained elevation of leg while lying supine (90 seconds): Patient can no longer hold leg up, or weakness becomes apparent with subsequent manual testing.

11. Repeated arising from chair without use of arms (up to 20 repetitions): Fatigues after several attempts. Early/mild weakness may cause exaggerated lean-forward and ‘‘buttocks-first’’ maneuver.

The quantitative myasthenia gravis test and similar scales incorporate measures of ocular, bulbar, respiratory, and extremity strength and fatigue. Although used mostly for research trials, the quantitative myasthenia gravis test score can be used in clinical practice to follow patients during treatment. [17]

MG is an autoimmune disorder, and other autoimmune diseases are known to occur more frequently (13%–22%) in patients with MG than in the general population. Some autoimmune diseases that occur at higher frequency in MG patients are hyperthyroidism, SLE, rheumatoid arthritis, scleroderma, ulcerative colitis, Addison disease, pernicious anemia, red cell aplasia, Sjogren's syndrome, and sarcoidosis. Both acute and chronic inflammatory demyelinating polyneuropathies have been reported in patients with concurrent MG. [35, 36]

Various autoimmune channelopathies, autonomic neuropathy with and without encephalopathy concomitant with the MG and thymoma has also been reported. [37]

MG and inflammatory myopathy is seen in in 5% of cases. Most of these patients have a thymoma with or without myocarditis. Histopathology reveals a giant cell or granulomatous myositis. Elevated CK (not usually seen in MG alone) is commonly found. [38]

MG and thymoma are also reported to have been associated with acquired neuromyotonia or Isaac’s syndrome, rippling muscle disease, and stiff-person syndrome. [39, 40]

A thorough skin and joint examination may help diagnose any of these coexisting diseases. Tachycardia or exophthalmos point to possible hyperthyroidism, which may be present in up to 10-15% of patients with MG. This is important because in patients with hyperthyroidism, weakness may not improve if only the MG is treated.