eMedicine Specialties > Neurology > Neuromuscular Diseases

Myasthenia Gravis: Differential Diagnoses & Workup

Author: Aashit K Shah, MD, Associate Professor of Neurology, Wayne State University; Program Director, Clinical Neurophysiology Fellowship, Department of Neurology, Detroit Medical Center
Contributor Information and Disclosures

Updated: Jan 15, 2009

Differential Diagnoses

Other Problems to Be Considered

Botulism
Brainstem syndromes
Compressive lesions of cranial nerves
Congenital myasthenic syndromes
Mitochondrial cytopathies
Mitochondrial myopathies with or without external ophthalmoplegia
Neurasthenia
Oculopharyngeal muscular dystrophy

Workup

Laboratory Studies

Anti-acetylcholine receptor antibody

This test is reliable for diagnosing autoimmune myasthenia gravis. The result of the test for the anti-AChR antibody (Ab) is positive in 74% of patients.

• Results are positive in about 80% of patients with generalized myasthenia and in 50% of those with pure ocular myasthenia.
• Thus, the anti-AChR Ab test result is frequently negative in patients with only ocular myasthenia gravis.

False-positive anti-AChR Ab test results have been reported in cases of thymoma without myasthenia gravis and in patients with Lambert-Eaton myasthenic syndrome, small cell lung cancer, rheumatoid arthritis treated with penicillamine, and in 1-3% of the population older than 70 years.

Tindall reported AChR Ab results and their mean Ab titers in a group of patients with myasthenia gravis as shown in Table 1.⁷

Table 1: Prevalence and Titers of AChR Ab in Patients with Myasthenia Gravis

Open table in new window

Classification: R = remission, I = ocular only, IIA = mild generalized, IIB = moderate generalized, III = acute severe, IV = chronic severe.

A trend in these data suggests that the Ab titer is higher in more severe disease, although titer is not predictive of severity in an individual patient. Change in AChR Ab titer correlates with long-term improvement induced by prednisone or azathioprine. The same changes are not observed consistently in patients who undergo thymectomy. However, this is not consistent and serial antibody titer by itself is not reliable, and thus serial Ab titers by themselves are not useful clinically to judge a patient's response.

Antistriated muscle (anti-SM) Ab

This is another important test in patients with myasthenia gravis.

• It is present in about 84% of patients with thymoma who are younger than 40 years and less often in patients without thymoma.
• Thus its presence should prompt a search for thymoma in patients younger than 40 years.
• In individuals older than 40 years, anti-SM Ab can be present without thymoma.

Thyroid function tests

Thyroid function should be tested to evaluate for coexistent thyroid disease.

Anti-MuSK antibody: About half of the patients who are AChR-ab negative (seronegative myasthenia gravis) may be positive for anti–muscle-specific kinase (MuSK) antibodies. They may represent a distinct group of autoimmune myasthenia gravis, as they show some characteristics as a group that are different from AChR-positive patients.⁸

Antistriational antibodies

Serum from some patients with myasthenia gravis possesses antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections. These antibodies react with epitopes on the muscle protein titin and ryanodine receptors (RyR). Almost all patients with thymoma and myasthenia gravis and half of the late-onset myasthenia gravis patients (onset >50 y) exhibit an antibody profile with a broad striational antibody response. Striational antibodies are rarely found in AChR Ab negative patients. These antibodies can be used as prognostic determinants in myasthenia gravis; as in all subgroups of myasthenia gravis, higher titers of these antibodies are associated with more severe disease.⁹

As it is often associated with thymoma in young patients with myasthenia gravis, the presence of titin/RyR antibodies should arouse strong suspicion of thymoma in a young patient with myasthenia gravis.

Imaging Studies

• Chest radiograph
  • Plain anteroposterior and lateral views may identify a thymoma as an anterior mediastinal mass.
  • A negative chest radiograph does not rule out a smaller thymoma, in which case a chest CT scan is required.
• Chest CT scan is mandatory to identify thymoma in all cases of myasthenia gravis. This is especially true in older individuals.
• MRI of the brain and orbits should not be obtained routinely. It is helpful when the diagnosis of myasthenia gravis is not established and to rule out other causes of cranial nerve deficits. MRI can evaluate for intraorbital or intracranial lesions, basal meningeal pathology, or multiple sclerosis.

Procedures

• Electrodiagnostic studies can demonstrate a defect of neuromuscular transmission in 2 ways.
  • The first is by repetitive stimulation of a muscle at 2-3 Hz, also known as repetitive nerve stimulation (RNS).
  • The second is by performing single-fiber electromyography (SFEMG) and evaluating neuromuscular block, jitter, and fiber density.
  • SFEMG is more sensitive than RNS in myasthenia gravis. However, SFEMG is technically more difficult and much more dependent on the experience and skill of the testing physician.
  • Thus RNS is the most frequently performed neurophysiological test of neuromuscular transmission.
• Single-fiber electromyography: A concentric needle electrode or other monopolar and bipolar needle electrodes record single motor unit potentials, but cannot discriminate individual muscle fibers within the motor unit.
  • The single-fiber needle, which has a small recording surface, allows recording from individual muscle fibers.
  • It can determine jitter (ie, variability of the interpotential interval between 2 or more single muscle fibers of the same motor unit) and fiber density (ie, number of single-fiber action potentials within recording radius of the needle).
  • The following findings are suggestive of NMF transmission defect: increased jitter (with or without impulse blocking) and normal fiber density.
  • Examination of a weak muscle by SFEMG is more useful than RNS in demonstrating abnormal neuromuscular transmission. In generalized myasthenia gravis, results of SFEMG of the extensor digiti communis (EDC) are abnormal in 87% of patients. Examination of a second muscle raises the sensitivity to 99%.
  • In ocular myasthenia gravis, examination of the frontalis muscle is more useful than examination of the EDC, since frontalis findings are abnormal in almost 100% of patients; only approximately 60% of EDC findings are abnormal.
  • Treatment with AChR inhibitors does not normalize SFEMG.
  • SFEMG findings are abnormal in almost 100% of patients, while RNS findings are abnormal in only 44-65%.
• Repetitive nerve stimulation (RNS): During low-frequency RNS (1-5 Hz), the locally available ACh becomes depleted at all NMJs, and less is available for immediate release. This results in smaller EPSPs.
  • In patients without myasthenia gravis, all EPSPs exceed the threshold to generate an action potential (ie, safety factor). No change in the summated compound muscle action potential (CMAP) is noted.
  • In patients with myasthenia gravis, the number of AChRs is reduced, lowering the safety factor. During RNS, some EPSPs may not reach threshold and no action potential is generated. This results in the decrement in the amplitude of the CMAP.
  • In patients with myasthenia gravis, this decremental response usually has a maximum decrement at the fourth or fifth response and then a tendency toward repair, as shown below.
    • 
      

      

      A typical recording of compound muscle action potentials with repetitive nerve stimulation at low frequency in a patient with myasthenia gravis. Note the gradual decline in the amplitude of the compound muscle action potential with slight improvement after the fifth or sixth potential.

      [ CLOSE WINDOW ]

      

      A typical recording of compound muscle action potentials with repetitive nerve stimulation at low frequency in a patient with myasthenia gravis. Note the gradual decline in the amplitude of the compound muscle action potential with slight improvement after the fifth or sixth potential.

  • Any decrement over 10% is considered abnormal.
  • Patients with myasthenia gravis rarely have a decremental response in a clinically normal muscle. Thus, testing a proximal weak muscle gives a better yield than testing a technically easier unaffected distal muscle. Testing a facial muscle (orbicularis oculi) is useful since most patients suffer from eyelid weakness or ptosis.
  • The most common employed stimulation rate is 3 Hz.
  • Several factors can affect RNS results.
    • Lower temperature increases the amplitude of the CMAPs. Patients with myasthenia gravis may report clinically significant improvement in cold temperatures. Typically they report worsening of ptosis in bright sunlight or on a warm day. Therefore maintaining a constant and perhaps higher-than-ambient temperature during RNS testing is important to bring out abnormalities of NMJ function. Temperature of skin overlying the tested muscle should be at least 34°C.
    • Administration of AChE inhibitors prior to the testing may mask the abnormality and should be avoided for at least 1 day prior to testing (even longer for long-acting agents).
  • Posttetanic potentiation and posttetanic exhaustion
    • A tetanic contraction of muscle is followed by 2 distinct phases: for the first 2 minutes after tetanic contraction, posttetanic potentiation occurs; this is followed by posttetanic exhaustion, which lasts an additional 15 minutes.
    • During posttetanic potentiation, accumulation of calcium inside the terminal axon causes enhanced mobilization and release of ACh, which overcomes the reduced number of AChR at the NMJ and results in larger EPSPs with additional recruitment of muscle fibers, resulting in a larger CMAP.
    • In myasthenia gravis, this potentiation may normalize RNS.
    • In the posttetanic exhaustion phase, the NMJ is less excitable and even fewer EPSPs reach threshold. Thus, some patients with an equivocal abnormality on RNS during resting phase may show clear-cut abnormality during the posttetanic exhaustion phase.
    • Tetanic contraction of the muscle can be achieved by electrical stimulation of the nerve at a rate of 50 per second lasting for 20-30 seconds. However, this is painful. Voluntary contraction of the muscle for 10 seconds at the maximum force can achieve the same goal without discomfort and is preferred.
• Pharmacological testing (edrophonium or Tensilon test) for the diagnosis of myasthenia gravis
  • In patients with myasthenia gravis, the number of AChR at the NMJ is low. This results in a decreased number of interactions between ACh and its receptor. ACh released from motor nerve terminals is metabolized by AChE.
  • Pharmacological inhibition of AChE increases ACh concentration at the NMJ, improving the chance for interactions between ACh and its receptor. Edrophonium (Tensilon) is a short-acting AChE inhibitor that improves muscle weakness in patients with myasthenia gravis.
  • Evaluate weakness (eg, ptosis, partial or complete ophthalmoplegia, and forced hand grip) before and after administration of Tensilon. Blinding of both the examiner and the patient increases the validity of the test.
  • Sinus bradycardia due to excessive cholinergic stimulation of the heart is a serious complication. An ampule of atropine should be available at the bedside or in the clinic room while performing the test.
  • To perform the test, a test dose of 0.1 mL of 10 mg/mL edrophonium solution is administered. If no response and no untoward effects are noted, remainder of the drug (0.9 mL) is injected.
  • While interpreting this test, it is important to remember that these drugs can improve weakness in diseases other than myasthenia gravis, such as amyotrophic lateral sclerosis, poliomyelitis, and some peripheral neuropathies.

Histologic Findings

Lymphofollicular hyperplasia of thymic medulla occurs in 65% of patients with myasthenia gravis; thymoma, in 15%.

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