Clinical Vignette

A healthy 63-year-old man presented with a 6-week history of the gradual onset of asymmetric eyelid drooping and double vision. His ptosis and diplopia fluctuated in severity, being more noticeable later in the day. His wife noted that his speech sounded slurred near the end of the day or after he had been speaking uninterrupted for a few minutes. Neurologic examination revealed asymmetric, left worse than right, ptosis and dysconjugate eye movements in several directions of gaze with associated weakness of eye closure, neck flexion, and mild proximal limb weakness.

Nerve conduction studies and needle electromyography (EMG) demonstrated normal motor and sensory action potentials. Repetitive motor nerve stimulation testing demonstrated a 35% decrease in the ulnar compound muscle action potential (CMAP) amplitude between the first and fourth stimuli. Acetylcholine receptor (AChR) antibodies were present in significantly abnormal titers. Results of computed tomographic (CT) scanning of the mediastinum were unremarkable. Immunosuppressive and pyridostigmine bromide (Mestinon) treatments were initiated.

Etiology And Pathogenesis

The most common cause of acquired MG is the abnormal development of antibodies to immunogenic regions (epitopes) on or around the nicotinic AChR of the postsynaptic endplate region at the neuromuscular junction (NMJ) (Figs. 73-2 and 73-3). These AChR antibodies trigger immune-mediated degradation of the AChRs and their adjacent postsynaptic membrane. The loss of large numbers of functional AChRs decreases the number of muscle fibers that can depolarize during motor nerve terminal activation, resulting in a decreased generation of muscle fiber action potentials and subsequent muscle fiber contraction. Blocking of neuromuscular transmission causes clinical weakness when it affects large numbers of fibers.

Figure 73-2 Somatic Neuromuscular Transmission.

Figure 73-3 Neuromuscular Transmission.

The nicotinic AChR contains five subunits arranged radially around a transmembrane ion channel (Fig. 73-4). The antibodies generated in MG are usually directed against the alpha subunit of the AChR. These antibodies may bind at or near the acetylcholine-binding site, directly preventing acetylcholine binding, or may alter receptor function through other mechanisms, such as increased receptor degradation or complement-mediated receptor lysis.

Figure 73-4 Acetylcholine Receptor and Neuromuscular Junction.

Clinical Presentation

Myasthenia gravis is typically classified as ocular, generalized, neonatal, congenital, or drug-induced. At presentation, weakness is confined to the ocular muscles in 80% of patients. Within 1–2 years, more generalized weakness develops in 85–90% of these individuals (see Fig. 73-1). In those few patients with primary ocular MG in whom bulbar or generalized weakness do not develop during the first 2 years, further progression to generalized MG is significantly less likely although it may occur as late as 8–10 years later (these patients are classified as having ocular MG).

Fatigability is one of the most important clinical characteristics seen in MG. Typically these patients describe worsening of their symptoms late in the day or during sustained exercise. Transient improvement occurs with rest, and symptoms often progress during the day. On examination, ocular fatigability (ptosis and/or diplopia) can be demonstrated on sustained upward or lateral gaze. Generalized weakness eventually occurs in 80% of all patients with acquired MG. Cardinal symptoms include fluctuating weakness, variably affecting the ocular, bulbar, and extremity musculature. Most patients initially demonstrate asymmetric diplopia and ptosis. Pupillary responses are always normal in contrast to some other disorders of neuromuscular transmission such as botulism.

Facial weakness manifests as weakness of eye and mouth closure. Occasionally bulbar symptoms such as chewing, and swallowing weakness (dysphagia) or slurred speech (dysarthria), are the presenting complaints. Characteristically MG patients with bulbar weakness have no problem when they begin to eat their meal, but increasing difficulties develop within the same sitting, particularly as they attempt to chew foods such as meats. Typically the speech becomes soft with a nasal breathy “twang” to the voice after a few minutes of uninterrupted speaking. Respiratory muscle involvement is potentially life threatening because of the risk of respiratory failure from hypoventilation. Neck extension weakness can lead to patients having difficulty holding up their heads. Increasing proximal muscle weakness results in problems with raising the arms overhead and/or with arising from chairs or climbing stairs.

Weakness may progress during weeks or months. Long-lasting spontaneous remission rarely occurs. Occasionally, after a brief period of modest symptoms, patients with new-onset MG may have a precipitous crisis-like presentation. Exacerbations are often precipitated by hot weather (which affects the kinetics of the acetylcholinesterase enzyme system), intercurrent illness, menstruation, pregnancy, or concurrent thyrotoxicosis. Certain medications that affect NMJ function (e.g., antibiotics such as aminoglycosides) may exacerbate and even precipitate incipient MG. Myasthenic crises may cause respiratory failure, requiring assisted ventilation and treatment with plasmapheresis, intravenous immunoglobulin, and corticosteroids. For those patients already being treated with corticosteroids, a crisis is sometimes precipitated by injudicious discontinuation or rapid dosage decrease.

Women with MG have a 15–20% chance of having a child who is affected by transient weakness, poor suck, and respiratory depression related to transplacental transfer of anti-AChR antibodies, transient neonatal MG. Usually, the infant is affected for only a few months, and management with anticholinesterase medication, such as neostigmine, is sufficient. Transient neonatal myasthenia should be differentiated from the uncommon congenital myasthenia, which is a genetic condition arising from altered NMJ structure or function.

Differential Diagnosis

Myasthenia gravis presenting with ocular or bulbar weakness may mimic other diseases of the nervous system, although usually the evaluation to confirm the diagnosis of MG is straightforward because of the characteristic presentation of MG, particularly the fluctuating and fatigable quality of pure motor manifestations that tend to develop in a “top down” sequence (i.e., first ocular, then bulbar) . In patients with initial ocular and/or bulbar weakness, multiple sclerosis or brainstem tumor may sometimes be suspected, but fatigability and fluctuation of symptoms is usually atypical for both of these disorders; however, MS patients sometimes have a component of easy fatigue. Additionally multiple sclerosis and neurologic tumors usually involve multiple neurologic nonmotor systems, such as the cerebellar system, corticospinal tract (causing hyperreflexia, Babinski signs), optic nerve and tract, urinary system, and sensory nervous systems.

The sudden development of diplopia, dysarthria, and weakness may suggest a brainstem stroke. A third nerve palsy secondary to a posterior communicating artery aneurysm or diabetes mellitus can mimic ocular MG. Thyroid orbitopathy frequently leads to diplopia mimicking ocular MG. Rarely, multiple cranial neuropathies are the presenting sign of leptomeningeal inflammatory disorders, such as sarcoidosis, tuberculosis, or fungal infections. Similarly, metastatic cancer can invade the leptomeninges and very rarely mimic MG. A brain magnetic resonance image (MRI) is particularly useful for differentiating these conditions. When bulbar dysfunction is prominent and diplopia and ptosis are absent, the bulbar presentation of amyotrophic lateral sclerosis requires consideration. The Miller Fisher variant of Guillain–Barré syndrome presents with ocular muscle paresis, mimicking MG, but is usually associated with ataxia and areflexia and often abnormal pupillary responses. The Lambert–Eaton myasthenic syndrome occasionally involves the bulbar musculature, but peripheral weakness and systemic symptoms are more prominent. Rarely, polymyositis or muscular dystrophy may present with lower bulbar weakness but diplopia and ptosis are not usually seen; however, we have seen patients with this at Lahey. EMG is helpful in differentiating between myopathies, neuropathies, and disorders of neuromuscular transmission.

Diagnostic Approach

The patient’s history and examination are the most important information directing one to a diagnosis of MG. Ancillary testing is necessary to confirm the diagnosis. Assays for antibodies to AChR are positive in approximately 85% of patients with generalized MG. Individuals with purely ocular MG have an approximately 50% incidence of positive AChR antibodies. Another 7% of patients with generalized MG have antibodies to muscle-specific tyrosine kinase (MuSK) (see Fig. 73-4). The remaining 8% of patients with generalized MG are classified as having “seronegative” generalized MG; that is, MG without a known accompanying autoantibody.

The electrodiagnostic NCS/EMG hallmark finding of MG is the presence of an electrodecremental response of the CMAP amplitude during slow (i.e., 2- or 3-Hz) repetitive motor nerve stimulation. In unaffected individuals, inherent functional reserve in neuromuscular transmission (“the safety factor”) usually enables preservation of CMAP amplitude during repetitive stimulation. However, in MG, the loss of functional AChRs can result in a decrement of 10% or more between the first and fourth CMAP amplitudes on repeated stimulation. Repetitive stimulation of peripheral nerves is usually conducted on the ulnar and spinal accessory motor nerves, and sometimes the facial nerve. Single-fiber EMG, a more technically demanding test of NMJ function, records single muscle fiber discharges. In MG, the firing interval between individual muscle fibers of the same motor unit (i.e., jitter) is often increased, and there may be intermittent blocking of neuromuscular transmission. Single-fiber EMG has a sensitivity of more than 90% in ocular and generalized MG.

Computed tomographic or MR imaging of the mediastinum is an important diagnostic test in suspected MG. Ten to 15% of MG patients have thymomas; these may be benign (75–90%) or malignant thymic tumors (Fig. 73-5). Of those patients not having thymomas, 70% have thymic lymphoid follicular hyperplasia. Anti–striational muscle antibodies are present in 90% of patients with myasthenia and thymoma.

Figure 73-5 Thymoma.

Management And Prognosis

Before the mid-1930s, there were no treatments for MG, and consequently the mortality rate for MG was approximately as high as 70%. The discovery and widespread use of anticholinesterase therapy (e.g., pyridostigmine) in the 1930s resulted in a dramatic reduction in mortality rate to approximately 30%. The anticholinesterase therapies work by decreasing the rate of breakdown of acetylcholine at the NMJ (Fig. 73-6). Pyridostigmine (e.g., Mestinon) is generally started at 30–60 mg orally every 6–8 hours. The dosage is titrated depending on the clinical response of the patient. Doses of more than 120 mg every 3–4 hours may cause cholinergic crisis, with paradoxically increased weakness (sometimes to a marked degree), increased salivation, abdominal cramping, diarrhea, and muscle fasciculations. Anticholinesterase therapy, however, does not treat the basic pathophysiologic process (i.e., autoimmunity), and thus, most patients with generalized MG require some form of immunosuppressive therapy.

Figure 73-6 Pharmacology of Neuromuscular Transmission.

Immunotherapy, often used in conjunction with pyridostigmine, has very substantially contributed to the reduction in MG mortality to less than 10%. Corticosteroids are the initial treatment of choice to induce remission of this autoimmune disorder. Oral prednisone is generally effective for achieving remission in MG. Some experts prefer to start patients on high-dose prednisone (e.g., 60 mg/day), whereas others prefer to start at lower doses and increase the dose until remission is achieved. The choice depends on the patient’s clinical status. For those who are acutely ill and hospitalized with careful monitoring in an intensive care unit, one can safely begin with high doses of 40–60 mg prednisone daily. In contrast, for those who have mild MG and are being treated as outpatients, one needs to start slowly with 10–20 mg daily. This is gradually increased by 10 mg every 3–4 days. When corticosteroids were first tried in patients with MG, a paradoxical worsening occurred that was severe enough to dissuade the earlier investigators from recommending corticosteroids for this disorder. It was not for another quarter century, until the autoimmune nature of MG was documented, that it was recognized that smaller doses could be safely used in an outpatient setting. After MG patients have achieved remission for 1–2 months, usually at the level of 40–80 mg daily, the prednisone dose is gradually tapered. If these patients have been on a daily dosage schedule, for example, 60 mg at remission, they can be switched to alternate-day therapy, initially decreasing the off- or low-day dose by 10-mg decrements every 2–4 weeks.

The physician and patient must monitor for the many potential side effects of prednisone that commonly occur, especially at the higher doses used in MG. Some steroid therapy complications are significant, including aseptic necrosis of the femoral head, osteoporosis, and increased likelihood of infection, diabetes mellitus, cataracts, and serious psychomotor depression.

Azathioprine (Imuran) and mycophenolate mofetil (CellCept) are other options for long-term immunotherapy in MG. These serve as steroid-sparing agents but have a significant latency for therapeutic efficacy. They cannot be substituted for corticosteroids per se but rather are introduced so that eventually steroids can be gradually decreased while long-term immunosuppression is maintained with these agents. The usual dosage for azathioprine is 100–150 mg/day. Mycophenolate mofetil is typically prescribed at 1000–1500 mg twice a day. Both azathioprine and mycophenolate mofetil have potential side effects that must be discussed with the patient. Intravenous immunoglobulin is an important therapeutic option for short-term symptomatic control in the acutely ill patient. The usual total dosage is 2.0 g/kg divided over 2–5 days. Plasma exchange removes acetylcholine receptor (or MuSK) antibodies from the blood and produces rapid but transient clinical improvement. Plasmapheresis is particularly useful during myasthenic crises or steroid-related exacerbations, in preparation for thymectomy and other surgical procedures, and occasionally as maintenance therapy in patients refractory to other therapies.

Thymectomy is recommended treatment for AChR antibody–positive patients younger than 60 years with generalized MG. However, thymectomy may not be as beneficial in patients who are MuSK antibody–positive and seronegative patients. Approximately 10–15% of patients with MG have an associated thymoma. Up to 25% of these thymomas are malignant. Both the benign and malignant entities are associated with a significant elevation of the anti–skeletal muscle antibody levels. All patients with a thymoma, regardless of their age, must undergo a thymectomy.

Respiratory failure (i.e., “myasthenic crisis”), secondary to diaphragmatic muscle weakness, is the most serious potential complication with MG. Pulmonary function should be carefully monitored in newly diagnosed patients and those experiencing disease relapses. The advent of positive-pressure and volume-controlled ventilation in 1965 was an important breakthrough in the management of MG, resulting in a substantial lowering of the mortality rate of patients with MG.

Long-term outcome in MG has improved markedly. In previous decades, up to 25% of patients died of respiratory failure within 3 years after diagnosis. However, with the widespread availability of multiple immunomodulatory therapies and the improved treatment of respiratory failure, more than 90% of patients, even those with severe generalized myasthenia, can achieve a symptom-free status within 1 year. A few patients continue to be more resistant to treatment, particularly those with the antibody-negative forms of the disease, for which therapeutic concepts are being reevaluated.