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Myasthenia Gravis

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Differential Diagnosis

Myasthenia gravis (MG) is a rare autoimmune neuromuscular disorder in which the immune system attacks components of the post-synaptic neuromuscular junction (NMJ), affecting nerve-to-muscle signal transmission.1 

Symptoms

MG affects the contractility and endurance of voluntary skeletal muscles, especially the eye, bulbar, limb, and respiratory muscles. Early symptoms typically affect the eyes, neck, jaw, and face, whereas more generalized symptoms indicate disease progression. The symptoms typically worsen during repeated muscular contractions and decrease with rest.1,2

More than 50% of individuals who have MG present with ocular symptoms. These include ptosis, diplopia, ophthalmoparesis, and visual focusing problems. Bulbar symptoms include difficulty swallowing, chewing, speaking, and holding the head erect.2 

Peripheral generalized symptoms include muscle weakness and fatigue following repeated muscle contractions. The weakness interferes with walking, climbing stairs, rising from a chair, carrying, and lifting. Only approximately 5% of individuals who have MG present solely with peripheral symptoms.2 

The most serious symptoms of MG involve the respiratory system. If the muscles that control breathing become dysfunctional, a myasthenic crisis may develop, and the patient will require ventilatory support.2 

Read more about myasthenia gravis symptoms

Differential Diagnosis of MG

Many conditions can mimic MG, so that clinicians must perform a thorough diagnostic workup. 

Acute conditions with symptoms that can mimic those of MG include infections, inflammatory conditions, and vascular conditions. Infections include botulism, diphtheria, and tick-borne diseases such as Lyme disease. Acute inflammatory conditions include Guillain-Barré syndrome, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), and its variants that result in rapidly progressive or sudden muscular weakness. Acute vascular conditions that mimic MG include basilar artery thrombosis causing a brainstem infarction or ischemia, pulmonary embolism causing sudden difficulty breathing, myocardial infarction, and spinal cord infarction.3-5 

The symptoms of toxicity due to chemical substances (either natural or synthetic) and certain pharmaceuticals may mimic those of MG. Ciguatera toxicity is due to the consumption of reef fish contaminated by ciguatoxin.6 Organophosphate toxicity is caused by occupational, military, or household exposure to chemical compounds such as insecticides, nerve gases, herbicides, industrial chemicals, antihelmintics used to treat parasitic infections, and ophthalmic agents.7 Tetrodotoxin toxicity follows the consumption of incorrectly prepared puffer fish containing the neurotoxin tetrodotoxin.8 

Penicillamine-induced myasthenia develops in a small number of patients taking the drug penicillamine to treat rheumatoid arthritis or Wilson disease. The treatment of hypercholesterolemia with statins may provoke myasthenia syndrome or exacerbate existing symptoms of MG.9 

Neurological conditions in which nerve inflammation, demyelination, or lesions cause symptoms that mimic those of MG include motor neuron diseases such as amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, and multiple sclerosis (MS); Guillain-Barré syndrome; Miller-Fisher syndrome; pseudobulbar palsy caused by lesions of the corticobulbar tract; brainstem gliomas; other space-occupying lesions that compress neurological structures; osmotic demyelination; bilateral Horner syndrome; encephalopathies; and neurosarcoidosis.3,4,10,11  

Thyroid conditions that mimic MG include thyroid ophthalmopathy and Graves disease.3

Ocular disorders that mimic MG include bilateral Horner syndrome, Kearns-Sayre syndrome, Tolosa-Hunt syndrome, Miller-Fisher syndrome, and thyroid ophthalmopathy. Oculopharyngeal dystrophy affecting the bulbar muscles, cavernous sinus syndromes affecting the eyes and face, and mitochondrial diseases such as chronic progressive external ophthalmoplegia may also mimic MG.3-5

Dystrophic disorders cause muscle atrophy. Those that mimic MG include oculopharyngeal dystrophy and myotonic dystrophy.9

Muscle disorders characterized by muscle inflammation that mimic MG include dermatomyositis and polymyositis.3 

Other disorders that mimic MG include chronic myelogenous leukemia; generalized fatigue; congenital myasthenia syndromes, which are inherited myasthenic disorders affecting the synthesis of functional components of the NMJ (as opposed to acquired autoimmune MG); and Lambert-Eaton myasthenic syndrome (LEMS), which affects the pre-synaptic rather than the post-synaptic NMJ.3,5,9,12,13

Differential Diagnosis Diagnostic Tests

Serologic tests for autoantibodies allow an accurate diagnosis of MG and identification of the disease subtype. Known autoantibodies include those against acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and lipoprotein-related protein 4 (LRP-4).14

Other methods of testing involve the ice pack test and electromyography (EMG) testing. After 2 to 5 minutes of application, the ice pack test improves symptoms of ptosis and ophthalmoparesis. An EMG study called a repeated nerve stimulation (RNS) evaluation suggests MG if muscle action potentials progressively decrease in amplitude and area with repetition, indicating fatigue with repetition.14

Read more about myasthenia gravis diagnosis and testing

An accurate differential diagnosis is critical to diagnose MG so that proper treatment can be initiated immediately. Timely treatment can prevent disease progression and optimize patient outcomes. 

References

  1. Myasthenia gravis fact sheet. National Institute of Neurological Disorders and Stroke. Accessed February 13, 2022.
  2. Signs and symptoms of myasthenia gravis (MG) – diseases. Muscular Dystrophy Association. Accessed February 13, 2022. 
  3. Jowkar AA. Myasthenia gravis differential diagnoses. Medscape. Updated August 27, 2018. Accessed February 13, 2022.
  4. Myasthenia gravis. Oxford Medical Education. Accessed February 13, 2022.
  5. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2(1):44. doi:10.1186/1750-1172-2-44  
  6. Arnold TC. Ciguatera toxicity: practice essentials, pathophysiology, etiology. Medscape. Updated October 12, 2019. Accessed February 13, 2022. 
  7. Katz KD. Organophosphate toxicity: practice essentials, background, pathophysiology. Medscape. Updated December 31, 2020. Accessed February 13, 2022.
  8. Benzer TI. Tetrodotoxin toxicity: practice essentials, pathophysiology, etiology. Medscape. Updated August 9, 2021. Accessed February 13, 2022. 
  9. Bird SJ. Differential diagnosis of myasthenia gravis. Up-To-Date. Updated May 7, 2009. Accessed February 13, 2022. 
  10. Basiri K, Ansari B, Okhovat AA. Life-threatening misdiagnosis of bulbar onset myasthenia gravis as a motor neuron disease: how much can one rely on exaggerated deep tendon reflexes. Adv Biomed Res. 2015;4:58. doi:10.4103/2277-9175.151874
  11. Engstrom JW. Myasthenia gravis: diagnostic mimics. Semin Neurol. 2004;24(2):141-147. doi:10.1055/s-2004-830903
  12. Congenital myasthenic syndrome. MedlinePlus. Accessed February 13, 2022.
  13. Stickler DE. Lambert-Eaton myasthenic syndrome (LEMS): background, pathophysiology, etiology. Medscape. Updated May 23, 2019. Accessed February 13, 2022.
  14. Rousseff RT. Diagnosis of myasthenia gravis. J Clin Med. 2021;10(8):1736. doi:10.3390/jcm10081736

Reviewed by Harshi Dhingra, MD, on 2/14/2022.

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