Understanding the enigma of myasthenia gravis onset
Brief Summary of Disease
In 2018, an elderly male patient was admitted to St. Luke’s Hospital in Kilkenny, Ireland. Presenting with difficulty swallowing, hoarse voice, and an inability to move his tongue and palate following meals, he was given various differential diagnoses to discern the causes of his symptoms. Suspected disorders included amyotrophic lateral sclerosis, paraneoplastic disease, and cranial polyneuropathy. It was only after his specialists ordered serological tests to confirm the diagnosis of myasthenia gravis and prescribed the appropriate treatment that the patient began to experience gradual symptomatic relief.
Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that most commonly occurs in women younger than age 40 and men older than age 60. The age of onset categorizes the MG population into two subsets: individuals with early-onset MG (before 40 years), and late-onset MG (after 40 years).2 However, this disease has the potential to affect individuals of any age and is characterized by its sudden onset and variable symptomatic severity. Clinicians and patients often encounter challenges with the diagnosis of MG, which is rarely recognized as the cause of neuromuscular symptoms due to its similarity to other diseases.
MG affects neuromuscular connections throughout the body, resulting in skeletal muscle weakness primarily in the eyes, mouth, throat, and limbs.4 Muscles involved in eyelid movement, facial expression, chewing, talking, and swallowing are often affected. MG is both clinically and biologically heterogeneous, with the degree of resulting muscle weakness varying between individuals. However, the clinical hallmark of MG is fluctuating weakness that worsens with activity and improves with rest.3
Etiology and Pathology
The inheritance pattern of myasthenia gravis is not yet fully understood. Similar to other autoimmune disorders, familial relations are not necessarily causal in the onset of MG. It is currently understood that MG is a multifactorial disease influenced by both genetic constituents and environmental factors. 2
Although not typically inherited, population-based studies have suggested that familial factors can contribute to the development of MG. A retrospective cohort study that was conducted at clinics across North America found that 5.6% of 1032 MG patients reported a family history of MG.
5
In addition, shared environments among families are hypothesized to contribute to familial aggregation of MG. Epidemiological studies have identified low socioeconomic status, smoking at an early age, a previous infection of hepatitis virus B or C, and experiencing a postpartum period as geographically-dependent risk factors for MG.
6
Other factors that may exacerbate symptoms include emotional stress, taking certain medications, surgery, and worsening of other chronic conditions.
6
As an autoimmune disease, MG is a result of the immune system developing antibodies that disrupt the transmission of nerve impulses. In most cases, these antibodies impair cellular communication by marking the receptor for acetylcholine (ACh), an important neurotransmitter, for destruction (Figure 1). In other cases, these antibodies target muscle-specific kinase (MuSK), a protein that organizes acetylcholine receptors (AChR) on the surface of muscle cells. The abnormal presence of either of these antibodies reduces the number of AChRs available to facilitate proper signalling between nerve and muscle cells.
8
The episodic pattern of muscle weakness results from the antibody-mediated destruction of ACh receptors. Once the number of available AChRs is decreased to about 30% of normal levels, symptoms begin to progressively reappear after prolonged muscle use.
9
Due to these signalling abnormalities in MG patients, individuals periodically present with impaired muscle movement and muscle weakness.
Figure 1. The pathophysiology of MG. This depicts the destruction of AChRs by antibodies generated
by the immune system, preventing neural signal transmission.
MG in Children
Although uncommon in children, there are a few forms of MG that may occur before or during adolescence. Congenital MG is a very rare form that is inherited from a child’s parents rather than developed through autoimmunity. Babies usually inherit this type of MG from an autosomal recessive gene. As a result, symptoms appear in the baby’s first year of life and continue through their lifespan.
4
Additionally, there is a temporary form of MG known as transient neonatal MG. This is where children born to women suffering from MG exhibit symptoms during their first weeks of life. Occurring among 12-20% of babies born to mothers with MG, this form is caused by the crossing of maternal antibodies across the placenta to the fetus.
8
Similar to early-onset and late-onset MG in adults, juvenile MG delineates individuals that develop MG during childhood and adolescence. In addition, juvenile MG is an autoimmune disorder that may go in and out of remission throughout one’s life.
4
Symptoms and Prognosis
MG is characterized by the loss of control of major skeletal muscle systems. However, the wide range of affected muscle groups and fluctuating levels of severity renders it difficult to pinpoint the specific cause of a patient’s symptoms. For instance, weakness in the muscles around the eyes can result in drooping eyelids and blurry vision. Additionally, weakness in the muscles of the mouth can cause complications involving talking, eating, and swallowing. Furthermore, weakness in the diaphragm and chest wall may lead to difficulty breathing, and in more severe cases, a myasthenic crisis, in which the patient requires ventilative support until muscle strength returns.
8
Due to the constant change in symptoms and affected systems, patients may not know which specialist to see (e.g., ophthalmologists, ear, nose, and throat doctors, respirologists). Symptoms range from minimal to debilitating, leading individuals to believe that their condition is improving.
11
However, with the help of contemporary diagnostic and therapeutic procedures, individuals with MG can enjoy a relatively favourable prognosis, with a nearly normal life expectancy and mortality rates below 5%.
12
Diagnosis
When diagnosing MG, a high degree of clinical suspicion is often required to differentiate between the similarity of MG symptoms to other neurological syndromes and ageing, especially among individuals with late-onset MG. Differential diagnoses may include myocardial infarction, multiple sclerosis, and amyotrophic lateral sclerosis. Depression and certain drugs may also induce myasthenia-like syndromes.
10
Because clinical presentations can vary greatly between individuals, appropriate neurological tests are required to ensure an expedient diagnostic process. This importance is highlighted in the case of the patient in St. Luke’s Hospital, where treating his symptoms of uncoordinated swallowing and tongue weakness prevented the need for an invasive and distressing gastrostomy procedure.
1
In the case of many other MG patients, multiple tests often need to be ordered to make the correct diagnosis. During a physical examination, a patient’s medical and family history is taken to evaluate the need for genetic testing. MG is typically diagnosed through the detection of anti-AChR or anti-MuSK antibodies in the blood. About 80-85% of MG patients test positive for the former, and 5-10% for the latter.
12
However, additional support for the diagnosis of MG may be needed. Patients may be given pharmacological treatments for MG that improve acetylcholine signalling, which drastically improves muscle weakness in many cases.
4
Alternatively, in nerve conduction studies, electrical impulses are repeatedly applied to a nerve to stimulate muscle contraction. Compared to healthy individuals, the muscles of MG patients fatigue more easily in response to stimulation. Electromyograms involve inserting an electrode into a muscle to record electrical activity resulting from muscle contractions. Abnormal muscle activity may be detected through the analysis of the electrical signals.
13
Current Research into Treatments for MG
Although there is no cure for MG, symptom management allows patients to lead near-normal lives. Common therapeutic interventions include the use of anticholinesterases, which prevent acetylcholine breakdown to ensure signal transmission can occur.
3
There are limitations to pharmacological treatments as they only treat the symptoms, not the underlying causes.
10
As a result, many patients eventually require corticosteroids or immunosuppressants, which work to limit antibody production and prevent the immune system from attacking AChR and MuSK.
3
In recent times, performing a thymectomy, an operation to remove the thymus gland, is becoming a more viable option for patients seeking a long-term treatment option. About 75% of individuals with MG have an abnormally large or overactive thymus, which is believed to play a pathogenetic role in MG.
8
Although the specific role of the thymus has not been discerned, in some cases, a thymectomy reduced the need for immunosuppressants for over 3 years or even induced remission.
7
Based on available evidence, a thymectomy is not recommended for patients with late-onset MG, those with ocular symptoms only, or anti-MuSK MG, where the thymus has no pathogenetic significance.
14
Although a thymectomy is an established and recommended treatment for defined subgroups of MG, electing to undergo surgery should be made on a selective basis as it may not improve symptoms for every patient.
Laura Li
Relevant Resources
The Myasthenia Gravis Society of Canada functions as an MG advocacy group and support organization. Its mission is to provide individuals with MG with access to support programs, to educate patients, families, and medical providers about MG, and to fundraise for further research. They publish monthly newsletters online aiming to keep members up to date on current research, advice on coping with the disease, and stories from other individuals who have been diagnosed.
References
1. Marshal M, Mustafa M, Crowley P, McGovern R, Ahern E, Ragab I. Misdiagnosis of myasthenia gravis presenting with tongue and palatal weakness. Oxf Med Case Reports. 2018;2018(8). doi:10.1093/omcr/omy052
2. Zagoriti Z, Kambouris ME, Patrinos GP, Tzartos SJ, Poulas K. Recent advances in genetic predisposition of myasthenia gravis. BioMed Research International. doi:10.1155/2013/404053
3. Myasthenia Gravis Fact Sheet. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Myasthenia-Gravis-Fact-Sheet
4. Myasthenia gravis. Department of Neurology. Published August 18, 2020. https://www.columbianeurology.org/neurology/staywell/
myasthenia-gravis
5. Green JD, Barohn RJ, Bartoccion E, et al. Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America. BMJ Open. 2020;10(9):e037909. doi:10.1136/bmjopen-2020-037909
6. Liu F-C, Kuo C-F, See L-C, Tsai H-I, Yu H-P. Familial aggregation of myasthenia gravis in affected families: a population-based study. Clinical Epidemiology. doi:10.2147/CLEP.S146617
7. Jowkar A, Lorenzo N. Myasthenia Gravis: Practice Essentials. Medscape. Published August 27, 2018. https://emedicine.medscape.com/article/1171206-overview
8. Myasthenia gravis. MedlinePlus Genetics. Published August 18, 2020. https://medlineplus.gov/genetics/condition/myasthenia-gravis/
9. Zagaria MA. Late-onset myasthenia gravis: fatigability and fluctuating weakness. U.S. Pharmacist. Published January 19, 2017. https://www.uspharmacist.com/article/lateonset-myasthenia-gravis-fatigability-and-fluctuating-weakness
10. Diseases - MG - Causes/Inheritance. Muscular Dystrophy Association. Published December 18, 2015. https://www.mda.org/disease/myasthenia-gravis/causes-inheritance
11. Stein B. Why is myasthenia gravis so difficult to diagnose? HCPLive. Published March 2, 2018. https://www.hcplive.com/view/why-is-myasthenia-gravis-so-difficult-to-diagnose
12. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44. doi:10.1186/1750-1172-2-44
13. How to diagnose myasthenia gravis. Conquer Myasthenia Gravis. 2020. https://www.myastheniagravis.org/about-mg/diagnosis/
14. Gilhus NE. Advances in the treatment of myasthenia gravis. Future Neurology. 2012;7(6):701-708. doi:10.2217/fnl.12.73
Cite This Article:
Li L., Patel M. & Chau J. Understanding the enigma of myasthenia gravis onset Illustrated by C. Qian. Rare Disease Review. September 2021.
