Myasthenia Gravis Clinical Presentation

Patients with myasthenia gravis (MG) present with painless, specific muscle weakness, and not generalized fatigue. Myasthenic weakness typically affects the extraocular, bulbar, or proximal limb muscles. Droopy eyelids or double vision is the most common symptom at initial presentation of MG, with more than 75% of patients. These symptoms progress from mild to more severe disease over weeks to months. Difficulty in swallowing, slurred or nasal speech, difficulty chewing, and facial, neck, and extremity weakness occur. ^[32] On the other hand, symptoms may remain limited to the extraocular and eyelid muscles for years. Rarely, patients with severe, generalized weakness may not have associated ocular muscle weakness.

The hallmark of MG is that muscles get weaker with repeated use. The examiner needs to establish this on the history and exam. It is important to discriminate fatigable weakness from nonspecific fatigue or somnolence. The prevalence of obstructive sleep apnea or poor sleep hygiene is higher in patients with MG; therefore, somnolence secondary to a sleep disorder may coexist with MG. ^[30] Psychosocial factors become important in assessment if a mood disorder or depression is suspected. Patients with fluctuating fatigable muscle weakness due to MG will describe weakness of a specific group of muscles that is brought on by activity and which improves with rest. In contrast, patients with generalized fatigue or exhaustion due to any number of causes will typically report generalized weakness, tiredness, or lack of energy. In myasthenia, often the complaint of weakness may be noted following exertion or at the end of the day. This often results in little detectable objective weakness at the time of examination. Maneuvers that fatigue specific muscle groups can be very useful in provoking weakness in patients. In contrast, patients with generalized fatigue or malaise do not typically display true muscle weakness with provocative maneuvers.

The general appearance of a myasthenic patient gives an impression of a person who is sleepy or with a sad-looking facial appearance caused by ptosis and facial weakness. It is often helpful to look at old photographs of the patient from earlier years, for example, by examining his or her driver’s license. Eye findings are common, with ptosis and extraocular muscle weakness occurring in more than 50% of patients at the time of presentation and in more than 90% of patients sometime during their illness. The patient who has no ptosis first thing in the morning and whose eyes are completely closed at night almost certainly has MG. Ptosis can be unilateral and, if bilateral, is usually asymmetric. Persistently symmetric ptosis is more suggestive of a myopathic etiology, especially chronic progressive external ophthalmoplegia (CPEO) or oculopharyngeal muscular dystrophy (OPMD). MG is one of few disorders that can cause complete unilateral (or rarely bilateral) ptosis or a history of ptosis alternating sides over time. Many patients describe diplopia. Milder involvement may produce blurred vision or a halo around objects. Photophobia, with worsening of either ptosis or diplopia in bright light, is not uncommon and some patients are so troubled by this that they wear dark sunglasses. Patients may give history of frequent changes in eyeglasses to correct blurry vision. Patients with LEMS rarely, if ever, present with ocular symptoms. Myasthenic weakness of the ocular muscles have been known to mimic CN III, CN IV, and CN VI nerves palsies and, rarely, an internuclear ophthalmoplegia. Unlike true CN III nerve palsies, however, MG never affects papillary function. Fixed extraocular muscle weakness may occur late in the illness, especially if untreated.

Up to 20% of patients with MG may have prominent oropharyngeal symptoms early in the disease course, including dysarthria, dysphagia, and difficulty chewing. ^[33] Weakness of palatal muscles may confer a nasal quality to the voice. Speech may become slurred (from weakness of the tongue, lips, and face), which may worsen with prolonged talking (e.g., talking on the telephone or giving a speech or presentation). Although the speech assumes a nasal intonation (from weakness of the soft palate), there is no impairment in fluency in speech.

Chewing may become difficult and often patients may actively open and close their jaw with their hands. Severe jaw weakness may cause the jaw to hang open (the patient may sit with a hand on the chin for support). Swallowing may become difficult, and aspiration may occur with fluids, giving rise to coughing or choking while drinking. Liquids are more difficult to swallow than solid food. Often, patients will complain of nasal regurgitation of liquids. Coughing, nose-blowing, or throat-clearing may be noted.

Rarely, patients with MG may present with respiratory muscle weakness without other prominent MG symptoms. ^[34] However, the vast majority of patients with respiratory muscle weakness have ocular and bulbar symptoms. Patients with diaphragmatic weakness will often have orthopnea as an early symptom. This may lead to respiratory compromise when the patient lies supine. Patients with MG and respiratory muscle weakness may report an inability to draw a full breath. They often describe their breathing as rapid and shallow, which may be misinterpreted as hyperventilation due to anxiety.

Fatigable extremity weakness in MG may affect any muscle group. Generally, it is proximal and often has an asymmetrical appearance. Characteristically, muscles are noted to weaken with repeated use, and strength improves with rest. Patients note difficulty getting up from chairs and going up and down the stairs. Patients may complain of a footdrop with prolonged walking, hip extension weakness with climbing several flights of stairs, shoulder muscle fatigue with activities that require holding their arms above their heads, and weakness of finger flexors and extensors with prolonged typing. Rarely, weakness may be very focal, affecting distal limb muscles or neck extensors selectively.

Pain, as a result of muscle aches or cramps, is commonly reported, especially in the neck. Sensory complaints are not a feature of MG; however, many patients get ulnar mononeuropathy at the elbow due to the constant attempts to hold the head up due to weakness of neck muscles.

Symptoms may worsen with exposure to extreme heat or emotional stress. Infection, systemic illness, pregnancy, the menstrual cycle, or drugs that affect neuromuscular transmission may also exacerbate myasthenia. Patients may report that they plan activities for early in the day when their strength is at its peak.

Bowel and bladder dysfunction are uncommon in MG. As MG is a disorder affecting nicotinic cholinergic receptors, dyasutonomia does not occur.

Depression may be seen from the progressive and disabling symptoms, but is not very common. Cognitive difficulties are not seen in MG.

Anti-MuSK-positive MG has several clinical characterisitics that differ from more common anti-ACh-R-positive myasthenia gravis. It occurs predominately in women with onset typically occurring in the fourth decade of life. In the United States, it is preponderant in African-American women. Patients with anti-MuSK antibodies have severe faciopharyngeal weakness with complaints of difficulty speaking and swallowing. They may have facial and tongue muscle atrophy and may mimic ALS. ^[31] Some patients have early respiratory muscle and neck weakness and present with dyspnea and neck pain. Most MuSK-positive MG patients have little or minimal associated ocular symptoms. ^[30]  Myasthenic crisis is also more common.

MGFA classification of myasthenia gravis

In May 1997, the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) formed a task force to address the need for universally accepted classifications, grading systems, and analytic methods for management of patients undergoing therapy and for use in therapeutic research trials. As a result, the MGFA Clinical Classification was created. ^[3] This classification divides MG into 5 main classes and several subclasses, as follows.

• Class I: Any ocular muscle weakness; may have weakness of eye closure. All other muscle strength is normal.
• Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity.

  • Class IIa: Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
  • Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.
• Class III: Moderate weakness affecting other than ocular muscle; may also have ocular muscle weakness of any severity

  • Class IIIa: Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
  • Class IIIb MG: Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.
• Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity.

  • Class IVa: Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
  • Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.
• Class V: Defined by intubation, with or without mechanical ventilation, except when used during routine postoperative management. Use of a feeding tube without intubation places the patient in class IVb.

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.

Provocative maneuvers used in suspected myasthenia gravis

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]

Evidence of coexisting autoimmune diseases

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.