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Myasthenia Gravis

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Comorbidities

Myasthenia gravis (MG) is an antibody-complement-mediated T-cell-dependent autoimmune disease that manifests as fatigue due to muscle weakness. The disease is associated with antibodies against acetylcholine receptor (AchR), muscle-specific kinase (MuSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane of the neuromuscular junction.1 

Thyroid disease, systemic lupus erythematosus, and rheumatoid arthritis are the most frequent comorbidities. Cardiomyositis and subclinical cardiac dysfunction have been reported in cases of thymoma MG and late-onset MG, however, these conditions do not pose a significant risk. Although lymphomas and a few other cancers have been documented with a slightly higher frequency, autoimmune MG does not appear to be a separate cancer risk factor.2 

Autoimmune Diseases

Autoimmune comorbidities are conditions that are immunologically mediated and occur before, during, or after the diagnosis of MG. In patients with MG, the majority of autoimmune conditions emerge more frequently. The most common is autoimmune thyroiditis, followed by systemic lupus erythematosus and rheumatoid arthritis. Myasthenia gravis is seen in 0.2% of diagnosed cases of autoimmune thyroid disease. Pernicious anemia, psoriasis, systemic vasculitis, and other conditions have also been identified.1-3 The prevalence of autoimmune comorbidity differs with MG subgroups. People with early-onset MG are substantially more likely to develop a second autoimmune disease than those with late-onset MG.2 

Cardiovascular Diseases

In MG with giant cell myocarditis, the heart muscle has been considered as a potential source of inflammation. Stress cardiomyopathy, neurogenic cardiac stunning, cardiac conduction abnormalities, and pericarditis are all manifestations of cardiac involvement. These are particularly common in elderly individuals and patients with severe MG. Antibodies against striated muscles (anti-titin, anti-ryanodine, and anti-Kv 1.4 antibodies) have been documented.4 Cardiomyositis tends to be more common in MG than in other autoimmune conditions. Antibodies produced in MG against antigens outside the neuromuscular junction react with the heart muscle. Antibodies of this type have been found in patients with thymoma and late-onset MG, the same groupings in which clinical cardiomyositis has been documented.2 The prevalence of arterial hypertension (AH) in patients with MG has been noted. Individuals with MG and AH visited the emergency room more frequently and had more myasthenic crises (MC) than MG patients without AH. One of the most important risk factors for cardiovascular disease is dyslipidemia. Although steroids are a risk factor for dyslipidemia, the existence of dyslipidemia in those who do not take steroids appears to be an independent factor linked to MG.3

Cancers 

In Taiwan and Denmark, large registry-based population studies have yielded mixed results. The overall cancer incidence was found to be increased by a ratio of 1.4 in 2614 Taiwanese patients with MG. Lymphoma, breast cancer, and lung cancer were all more common in the MG group.2 

Thymoma 

Thymoma MG accounts for roughly 15% of all MG cases. Antibodies to titin and ryanodine receptors (RyR) are present in 95% of thymoma MG cases and 50% of late-onset MG cases (MG onset ≥50 years), and they are linked to severe disease and considered predictors of thymoma MG outcomes.5,6 Although there is a strong link between thymoma and MG, thymoma is also linked to an elevated risk of other autoimmune diseases. Patients with thymoma are more likely to develop blood cytopenias, hypogammaglobulinemia, polymyositis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M component, and skin changes), neuromyotonia, and autoimmune encephalitis, which are uncommon in patients with MG.7 

Nervous System Disorders

Depression and anxiety are common among MG patients, along with reduced health-related quality of life. Amyotrophic lateral sclerosis (ALS) is a neurological disease with a proclivity for inflammation. Concurrent AChR antibody-positive MG and ALS have been reported in many case studies.2 

Respiratory Diseases

Respiratory insufficiency is a severe danger in MG due to skeletal muscle weakening. Because of the fatigue in MG, a rapid deterioration of respiratory function is possible. The most common trigger of significant respiratory muscle weakness is infection, particularly of the respiratory tract.2 

Diabetes Mellitus 

Many studies have described an association between diabetes mellitus (DM) and MG. A study identified DM in 20% of patients with MG, which is almost 3 times higher than the rate of the general population (7%). Patients with MG and DM had a later onset age, a greater rate of MC, more emergency room visits, a higher mean dose of pyridostigmine (PDM) (410 vs 337 mg/day, p 0.006), a higher mean dose of prednisone (PDN) (52 vs 45 mg/day, p 0.029), and more frequent azathioprine (AZA) (54 vs 39%) (p 0.041) administration than those without DM.3 

Ptosis

Extraocular muscle weakness in MG is characterized by fluctuating double vision and ptosis.8 Ocular MG manifests clinically as weakness in the extraocular muscles, levator, and orbicularis oculi. Ptosis and diplopia are the earliest signs of the disease in more than half of MG patients. In 50% to 80% of these cases, the patient develops generalized disease. Within the first 2 years of ocular symptoms, the majority of ocular MG cases (90%) progress to a generalized form.9 

References 

  1. Misra UK, Kalita J, Singh VK, Kumar S. A study of comorbidities in myasthenia gravis. Acta Neurol Belg. 2020;120(1):59-64. doi:10.1007/s13760-019-01102-w
  2. Gilhus NE, Nacu A, Andersen JB, Owe JF. Myasthenia gravis and risks for comorbidity. Eur J Neurol. 2015;22(1):17-23. doi:10.1111/ene.12599
  3. Diaz BC, Flores-Gavilán P, García-Ramos G, Lorenzana-Mendoza NA. Myasthenia gravis and its comorbidities. J Neurol Neurophysiol. 2015;6(5):1-5.
  4. Sivadasan A, Alexander M, Aaron S, et al. Comorbidities and long-term outcomes in a cohort with myasthenic crisis: experiences from a tertiary care center. Ann Indian Acad Neurol. 2019;22(4):464-471. doi:10.4103/aian.AIAN_197_19
  5. Romi F. Thymoma in myasthenia gravis: from diagnosis to treatment. Autoimmune Dis. 2011;2011:474512. doi:10.4061/2011/474512
  6. Kumar R. Myasthenia gravis and thymic neoplasms: a brief review. World J Clin Cases. 2015;3(12):980-983. doi:10.12998/wjcc.v3.i12.980
  7. Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-2581. doi:10.1056/NEJMra1602678
  8. Toyka KV. Ptosis in myasthenia gravis: extended fatigue and recovery bedside test. Neurology. 2006;67(8):1524. doi:10.1212/01.wnl.0000240069.24338.c8
  9. Nair AG, Patil-Chhablani P, Venkatramani DV, Gandhi RA. Ocular myasthenia gravis: a review. Indian J Ophthalmol. 2014;62(10):985-991. doi:10.4103/0301-4738.145987

Reviewed by Debjyoti Talukdar, MD, on 2/15/2022.

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