Myasthenia gravis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

In 1664,Virginian Chroniclers was the first to described Myasthenia gravis. His symptoms included fatigue, heavy eyelids and weak muscle tone. In the late 1800s the name Myasthenia gravis was created and the classic symptoms of the disease were described. The autoimmune nature of this disease was first described by Simpson and Nastuck in 1959-1960. The first important step in treatment of MG occurred in 1934 by Marry Walker. She observed that the symptoms of patients with myasthenia gravis in similar to those with curare poisoning so their symptoms can improve by a cholinesterase inhibitor like physostigmine. In 1937 Blalock described an improvement in his patient after removal of the thymus and established thymectomy as one of the treatment options of MG. In 1970s the use of immunosuppressants, azathioprine and plasma exchange became more prevalent.

• The first possible patient with Myasthenia gravis, Openchancanough was first described by Virginian Chroniclers in 1664. His symptoms included fatigue, heavy eyelids and weak muscle tone.^[1]
• The other case of MG was described by an English doctor Thomas Willis. His patient had weakness and fatigue of muscles and eyelids.^[2]
• In the late 1800s the name Myasthenia gravis was created and the classic symptoms of the disease were described.^[2][3]
• The autoimmune nature of this disease was first described by Simpson and Nastuck in 1959-1960.^[4]

• The first important step in treatment of MG occurred in 1934 by Marry Walker. She observed that the symptoms of patients with myasthenia gravis in similar to those with curare poisoning so their symptoms can improve by a cholinesterase inhibitor like physostigmine.^[5]
• In 1937 Blalock described an improvement in his patient after removal of the thymus and established thymectomy as one of the treatment options of MG.^[2]
• In 1970s the use of immunosuppressants, azathioprine and plasma exchange became more prevalent.^[6][7]

The following are a few famous cases of disease name:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Myasthenia gravis may be classified into 4 sub types based on presence of autoantibodies: Pure ocular form, generalized form with anti-AChR antibodies, the forms without classical anti-AChR antibodies, neonatal MG, congenital.

Myasthenia gravis may be classified into 4 sub types based on presence of autoantibodies.

• Ocular symptoms are the initial symptom in most of the MG cases.
• In about 15 percent of these patients this initial symptom will not progress to generalized disease after 2 years and they will classify as pure ocular form of the Myasthenia gravis.
• In approximately 50 percent of these patients we can’t detect antibodies by classical assay and we need to detect them through cell-based assay.^[1]

About 85 percent of MG patients develop generalized disease with autoantibody against AchR.^[2] These antibodies are IgG1 and IgG3 subclasses which can bind to complement.^[3] Thymic abnormalities are more common in this group, especially thymic follicular hyperplasia.^[4] this subtype can be further divided into 2 groups:

• Early onset myasthenia gravis (onset of the disease before the age of 50 (EOMG)): In this group we have female predominance with the ratio of 3/1. Thymic follicular hyperplasia is more common in this group and is believed to be related to deregulation of sex hormones and their receptors on thymic cells.^[5][6]
• These patients can have other autoimmune diseases like Hashimoto’s disease.^[7]
• Late onset myasthenia gravis (onset of the disease after the age of 50 (LOMG)): Patients with this type of the disease can present with thymoma, a tumor of thymic epithelial cells.^[8] In almost 50 percent of them we can find other antibodies like anti-ryanodine antibody, anti-titin antibody and anti-striated muscle antibody.^[9] most of the patients in this group have severe symptoms like bulbar involvement.^[10]

This subtype can be further divided into 3 groups

• The form with anti-anti-MuSK antibodies: About 5 percent of MG patients, especially females has this antibody which belongs to IgG4 subclasses and cannot bind to complement.^[11][12] their symptoms are mostly sever and involves facial, bulbar and respiratory muscles but spares ocular and thymic abnormalities.^[11][13] In these patients both presynaptic and postsynaptic components of NMJ are affected and the severity of the disease is related to the amount of antibodies.^[14][15]
• The form with anti-LRP4 antibodies: About 12-50 percent of patients who seems to be seronegative for anti-AchR and MuSK, presents antibody against LRP4.^[16][17][18]
• The form with clustered AChR antibodies: 5 percent of patients with MG doesn’t have any antibodies but in 50 percent of them we can see clustered AchR with cell assay detection.^[1]

• 10-20 percent of mothers with MG may have infants who display a transient neonatal myasthenia (TNM) for few days to 3 months.
• The cause of this condition is passive transfer of antibodies to the neonate.^[19]

• Congenital form of MG follows the Mendelian pattern and is caused by an error in the genes which are expressed in the NMJ.^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Fahimeh Shojaei, M.D.

Myasthenia gravis is a neuromuscular disease caused by an autoimmune reactions. The main problem in this disease is the abnormal transmission of nerve impulses to muscle fibers in NMJ. Genes involved in the pathogenesis of Myasthenia gravis include: The Major Histocompatibility Complex, the CHRNA1 Locus, the PTPN22 Gene, the FCGR2 Locus and the CTLA4 Locus.

• In the nerve terminals of alpha motor neurons, there are lots of vesicles containing ACh.
• When the action potential reaches the synaptic end, voltage gated Ca channels will open and trigger the release of these vesicles. ACh will diffuse into synaptic cleft and binds to AChR.
• The action of ACh will end with the work of AChE.
• ACh receptors consist of 5 subunits and are transmembrane proteins.
• There are other proteins which help AChR clustering and signal transduction including MuSK. It is the receptor of a protein named agrin. When these two bind to each other, the result is maintaining the clustering of AChRs.^[1][2][3]

• Myasthenia gravis is a neuromuscular disease caused by an autoimmune reactions.
• The main problem in this disease is the abnormal transmission of nerve impulses to muscle fibers in NMJ.^[2] In the nerve terminals of alpha motor neurons, there are lots of vesicles containing ACh. When the action potential reaches the synaptic end, voltage gated Ca channels will open and trigger the release of these vesicles. ACh will diffuse into synaptic cleft and binds to AChR. The action of ACh will end with the work of AChE. ACh receptors consist of 5 subunits and are transmembrane proteins. There are other proteins which help AChR clustering and signal transduction including MuSK. It is the receptor of a protein named agrin. When these two bind to each other, the result is maintaining the clustering of AChRs.^[1][2][3]

• Not all of the MG patients share the same auto antibodies. One of these autoantibodies is antibody against AChR. They will destruct AChR by 3 mechanisms.
  • First they will activate the complement system.
  • Second they will increase the degradation of AChR by Ab binding and third by blocking AChR’s function.^[4]
• The other type of autoantibody in MG patients are antibody against MsUK protein (muscle-specific receptor tyrosine kinase).^[2][5]

• AChR antibodies are IgG1 and IgG3 and can bind to complement and activates them, but in contrast antibodies against MuSK are IgG4 and cannot activate complement system.^[6][7][8]
• The function of the MuSK starts with the binding of agrin and LRP4. Activated MuSK cause recruitment and clustering of AChRs.^[9][10][11]

• There are a group of MG patients which are seronegative for both AChR and MuSK antibodies.^[12]
  • About 50 percent of them turn out to be positive for clustered AChR antibodies after cell-based immunofluorescence. ^[8][13][14]
  • The other half may be positive for other antibodies including antibody against LRP4 (which are IgG1)^[15], cortactin (which help AChR clustering)^[16], ryanodine receptor, titin, myosin, alpha actin, rapsyn and gravin.^[17][18][19]
• Other than B cells, T cells have a role in the pathology on MG too. They will not act as the effector cells but stimulate B cells to produce more antibodies.^[20]
  • The role of T cells: There are two kinds of CD4+ T cells, Th1 and Th2. Th1 cells produce IL-2, IFN-γ and TNF- α which are proinflammatory cytokines and stimulate cell-mediated immune responses. Th2 cells produce IL-4, IL-6 and IL-10 which are anti-inflammatory cytokines and stimulate humoral immune response. In the blood of MG patients we have anti-AChR Th1 cells against which can induce B cells to produce high-affinity anti-AChR antibodies. Based on this fact treatment against Th1 cells can improve MG symptoms.^[21][22][23]

Genes involved in the pathogenesis of Myasthenia gravis include:

• The Major Histocompatibility Complex: In genetic etiology of most of the autoimmune diseases including MG, MHC genes play the most important role.^[24]
• The CHRNA1 Locus: The translation product of this gene is the alpha subunit of AChR, which is the target of many autoantibodies in myasthenia gravis patients.^[25]
• The PTPN22 Gene: This gene is responsible for producing an intracellular protein phosphatase PTPN22. The impaired binding of this protein to protein tyrosine kinase Csk occurs as a result of a missense polymorphism which replace arginine with tryptophan. Activity of PTPN22 will increase and inhibits T cell activation and interleukin 2 production which leads to predisposition to autoimmunity.^[26][27]
• The FCGR2 Locus: Some studies investigated the relationship between polymorphism of FC receptors gene and MG and suggested that R arginine variant in type 2 (FCGR2) can be related to this disease.^[28][29]
• The CTLA4 Locus: This gene is known to be responsible for many autoimmune diseases.^[30]

Conditions associated with Myasthenia gravis include:

• Thymus abnormalities:
  • Thymus abnormalities including thymic hyperplasia and thymoma are very common in myasthenia gravis and thymectomy is one of the treatment of this disease.^[31][32]

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Myasthenia gravis may be caused by thymus abnormalities, genetic and environment.

Myasthenia gravis may be caused by:

• Thymus abnormalities:
  • Thymus abnormalities including thymic hyperplasia and thymoma are very common in myasthenia gravis and thymectomy is one of the treatment of this disease.^[1][2]
  • In thymus, we have myoid cells which present intact AChR on their surface. On the other hand thymic epithelial cells produce AChR subunits which activate helper T cells. These T cells attack AChR on the myoid cells and the cascade of antibody production and complement activation will begin.^[3][4][5]

• Genetic:
  • The Major Histocompatibility Complex: In genetic etiology of most of the autoimmune diseases including MG, MHC genes play the most important role.^[6]
  • The CHRNA1 Locus: The translation product of this gene is the alpha subunit of AChR, which is the target of many autoantibodies in myasthenia gravis patients.^[7]
  • The PTPN22 Gene: This gene is responsible for producing an intracellular protein phosphatase PTPN22. The impaired binding of this protein to protein tyrosine kinase Csk occurs as a result of a missense polymorphism which replace arginine with tryptophan. Activity of PTPN22 will increase and inhibits T cell activation and interleukin 2 production which leads to predisposition to autoimmunity.^[8][9]
  • The FCGR2 Locus: Some studies investigated the relationship between polymorphism of FC receptors gene and MG and suggested that R arginine variant in type 2 (FCGR2) can be related to this disease.^[10][11]
  • The CTLA4 Locus: This gene is known to be responsible for many autoimmune diseases.^[12]

• Environment:
  • Drugs: Drugs such as D-penicillamine^[13], fludarabine^[14], lithium carbonate^[15] and botulinum toxin^[16] can induce MG, and drugs such as curare, aminoglycosides, macrolides, fluoroquinolones, quinine, quinidine, procainamide, magnesium salts, calcium channel blockers, beta blockers, iodinated contrast agents and statins can worsen MG.^[17][13]
  • Infections: Infections such as hepatitis C^[18], HSV^[19], EBV^[20], CMV^[21], HTLV1^[22] and west Nile virus^[23] are suggested to have a relationship with myasthenia gravis disease.
  • Trauma: Few reports suggest that MG can appear after cardiothoracic bypass surgery and insulting the remaining thymus.^[24][25]

Less common causes of [disease name] include:

• [Cause1]
• [Cause2]
• [Cause3]

• [Disease name] is caused by a mutation in the [gene name] gene.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Differential diagnosis for Myasthenia gravis includes: adult Botulism, infant Botulism, guillian-Barre syndrome, eaton lambert syndrome, electrolyte disturbance, organophosphate poisoning, tick paralysis, tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosisand myositis.

Myasthenia gravis should be differentiated from other causes of muscle weakness, hypotonia and flaccid paralysis. The differentials include the following:^{[1][1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The incidence of Myasthenia gravis is approximately 7-23 new cases per year. The prevalence of Myasthenia gravis is approximately 70-320 per million and increasing since 20^th century. The age of onset in Myasthenia gravis follows a bimodal distribution. The early type (before age of 50) is female predominant and the late type (after age of 60) is male predominant. Between the age of 50-60 there is no significant different between male and female. Some studies demonstrated that the incidence, prevalence and the severity of this disease is higher in African/Americans.

The incidence of Myasthenia gravis is approximately 7-23 new cases per year.^[1][2][3][4]

The prevalence of Myasthenia gravis is approximately 70-320 per million and increasing since 20^th century.^[1][2][4][5]

The age of onset in Myasthenia gravis follows a bimodal distribution. The early type (before age of 50) is female predominant and the late type (after age of 60) is male predominant. Between the age of 50-60 there is no significant different between male and female.^[6]

Some studies demonstrated that the incidence, prevalence and the severity of this disease is higher in African/Americans.^[7][8]  

• The majority of [disease name] cases are reported in [geographical region].

• [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]

Myasthenia gravis (MG) is a complex autoimmune disease of the neuromuscular junction in which disease risk reflects interaction between genetic susceptibility, demographic factors, thymic disease, immune dysregulation, environmental exposures, and drug-related triggers. Genetic susceptibility, including HLA associations and other inherited risk loci, is discussed in the genetics microchapter. This section focuses on clinically relevant risk factors for MG onset, drug-induced MG, and factors that may precipitate MG exacerbation or myasthenic crisis.

MG demonstrates a characteristic sex-dependent distribution that varies by age of onset. Early-onset MG, usually defined as onset before age 50 years, is more common in women. Late-onset MG is slightly more common in men, and very-late-onset MG demonstrates a clearer male predominance.^[1][2] This age-sex pattern is clinically important because late-onset MG in older men is increasingly recognized and may be underdiagnosed when fatigable weakness is attributed to frailty, stroke, pulmonary disease, or medication adverse effects.

Age at onset is both a classification feature and a risk modifier. Contemporary epidemiologic studies suggest that the incidence and prevalence of MG have increased over recent decades, particularly among older adults, likely because of improved recognition, better diagnostic testing, population aging, and longer survival.^[1] A large contemporary cohort reported peak incidence in older age groups, including patients aged 70-74 years.^[2]

In the Swedish nationwide GEMG study, smoking at disease onset was associated with increased risk of early-onset MG, with a stronger association in AChR-antibody-positive early-onset MG.^[3] Use of Swedish snuff, a high-nicotine smokeless tobacco product, was also associated with increased early-onset MG risk.^[3] These findings suggest that nicotine exposure may be a subtype-specific risk factor rather than a uniform risk factor across all MG phenotypes.

The Swedish nationwide GEMG study reported an inverse association between alcohol consumption and MG risk, particularly in late-onset MG.^[3] This finding is observational, may be affected by residual confounding or reverse causality, and should not be interpreted as a recommendation to consume alcohol for MG prevention.

Respiratory infections are common triggers of MG exacerbation and myasthenic crisis.^[4] Specific infectious agents have been investigated as possible triggers for MG onset, including Epstein-Barr virus, human papillomavirus, and poliovirus; however, a systematic review concluded that evidence for a causal relationship between specific pathogens and MG onset remains limited.^[14] During the COVID-19 pandemic, MG worsening was reported in a substantial proportion of infected patients, supporting the clinical importance of respiratory infection prevention and early management in established MG.^[15]

Stress-related disorders are associated with increased risk of autoimmune diseases broadly, but MG-specific evidence for stress as an independent cause of MG onset is limited.^[16] In established MG, chronic stress, depression, and personality-related stress vulnerability have been associated with relapse risk and symptom burden in observational studies.^[17][18]

Approximately 15% of patients with MG have another autoimmune disease, most often in early-onset MG and thymic hyperplasia.^[5] A Danish nationwide case-control study found that patients with MG were more likely than matched controls to have another autoimmune disease before or after MG diagnosis.^[6]

Commonly associated autoimmune diseases include:

• Autoimmune thyroid disease, including Graves disease and autoimmune thyroiditis
• Systemic lupus erythematosus
• Pernicious anemia
• Rheumatoid arthritis
• Neuromyelitis optica, especially aquaporin-4 antibody-associated disease

The presence of one autoimmune disease should increase clinical suspicion for additional autoimmune disease when symptoms are compatible. Thyroid disease is particularly relevant because ocular thyroid disease may mimic ocular MG and because thyroid dysfunction may worsen fatigue or weakness.

Thymoma is present in approximately 10-20% of patients with MG, and approximately 30% of patients with thymoma develop MG.^[7][8] Thymoma-associated MG is typically AChR-antibody-positive, generalized, and clinically more severe than purely ocular MG.^[7] WHO type B1 and B2 thymomas have been associated with higher likelihood of MG association.^[19]

A small proportion of patients with thymoma may develop new-onset MG after thymectomy. Preoperative AChR antibody positivity or higher AChR antibody titers may identify patients at increased risk for post-thymectomy MG.^[8]

Drug-induced MG should be distinguished from medication-triggered worsening of established MG. Drug-induced MG refers to de novo autoimmune MG or MG-like disease occurring after exposure to a medication, whereas medication-triggered worsening reflects impaired neuromuscular transmission or immune activation in a patient with known or subclinical MG.^[9]

Immune checkpoint inhibitors may cause de novo MG or unmask preexisting MG. The estimated frequency of MG among patients treated with PD-1 inhibitors is 0.12-0.2%, with median onset approximately 4 weeks after ICI initiation.^[20] ICI-associated MG is clinically important because of its severity: bulbar involvement occurs in approximately 75%, respiratory failure in approximately 45-65%, concurrent myositis in approximately 37-51%, and concurrent myocarditis in approximately 8-16%. Mortality ranges from approximately 28% to 38% across systematic reviews, with respiratory failure as the most common cause of death. AChR antibodies are elevated in approximately 58-66% of tested patients; MuSK antibodies have not been detected in ICI-induced MG.^[10][21]

Patients with suspected ICI-associated MG should be evaluated for overlap with myositis and myocarditis, including creatine kinase, aldolase, troponin, and electrocardiogram when clinically appropriate.^[22]

D-penicillamine, used historically for rheumatoid arthritis and Wilson disease, can induce MG, usually with AChR antibodies and rarely with concurrent MuSK antibodies.^[23] D-penicillamine-induced MG is often reversible after drug discontinuation, although immunotherapy may be required in some patients.^[24][25]

Interferons and selected tyrosine kinase inhibitors have been reported to induce or unmask MG, but the evidence is less robust than for immune checkpoint inhibitors and D-penicillamine.^[9]

Medication review is essential in all patients with known or suspected MG. The following medications may worsen MG or precipitate exacerbation. Risk varies by drug, dose, route, baseline MG severity, respiratory reserve, and availability of alternatives.

Myasthenic crisis is respiratory failure caused by MG-related weakness. Approximately 15-20% of patients with MG experience crisis at least once.^[4][33][34]

Common triggers include:

• Infection, especially upper respiratory infection, bronchitis, pneumonia, and sepsis
• Exposure to drugs that impair neuromuscular transmission
• Recent surgery, trauma, or perioperative exposure to neuromuscular blocking agents
• Pregnancy or the postpartum period
  • Exacerbation of MG occurs in approximately 19-50% of pregnancies, most commonly in the first trimester, with postpartum exacerbations in approximately 27%. Myasthenic crisis occurs in approximately 6.4% of women with MG during pregnancy and approximately 8.2% in the postpartum period.^[29][35]
  • A Swedish nationwide cohort study found no increased risk of MG hospitalization during pregnancy itself, but the postpartum period was associated with increased risk of prolonged MG admissions.^[36]
• Intravenous magnesium exposure in pregnant patients with MG
• Rapid tapering, discontinuation, or inadequate dosing of immunotherapy
• High-dose corticosteroid initiation in high-risk patients
• Vaccination, rarely reported as a temporal trigger; in most patients with MG, the benefits of recommended vaccination generally outweigh the risk of disease worsening^[4]
• No identifiable trigger, which occurs in approximately 30-40% of crises^[4]

Risk factors for crisis include prior crisis, prominent oropharyngeal weakness, severe generalized symptoms, MuSK antibody positivity, thymoma, and reduced respiratory reserve.^[4]

• Do not assume MG is primarily a disease of young women. Late-onset MG is increasingly common and often affects older men.^[2]
• Do not prescribe fluoroquinolones, macrolides, aminoglycosides, magnesium, or neuromuscular blocking agents without checking for MG history and assessing respiratory reserve.^[9]
• Do not give telithromycin to patients with MG. Telithromycin is contraindicated in MG and is no longer commercially available in the United States.^[7][26]
• Do not overlook ICI-associated MG in patients receiving cancer immunotherapy who develop ptosis, diplopia, dysphagia, dysarthria, dyspnea, or proximal weakness.^[10]
• Do not treat suspected ICI-associated MG as an isolated neurologic adverse event without evaluating for concurrent myositis and myocarditis.^[22]
• Do not start high-dose corticosteroids in severe generalized or bulbar MG without a monitoring plan, because early transient worsening may precipitate crisis.^[4]
• Do not rely on stress as a stand-alone explanation for MG onset; the evidence is stronger for stress as a disease activity modifier than as an independent causal risk factor.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There is insufficient evidence to recommend routine screening for Myasthenia gravis.

There is insufficient evidence to recommend routine screening for Myasthenia gravis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Natural history: The age of onset before age of 50 is female predominant and after age of 60 is male predominant. Between the age of 50-60 there is no significant different between male and female. About 50 percent of patiens have ptosis and diplopia as their presenting sign. Complications: Complications from the treatment of myasthenia gravis such as: Glucocorticoids, azathioprine, cyclosporine, tacrolimus, cyclophosphamide, plasmapheresis, intravenous immune globulin and myasthenia crises (Respiratory failur). The prognosis of myasthenia gravis depends on: Disease duration at diagnosis, disease severity and the age of onset.

• The age of onset in Myasthenia gravis follows a bimodal distribution. The early type (before age of 50) is female predominant and the late type (after age of 60) is male predominant. Between the age of 50-60 there is no significant different between male and female.^[1]
• About 50 percent of patiens have ptosis and diplopia as their presenting sign. Ptosis is usually asymmetrical. The direction and degree of diplopia may change in a MG patients because of fatigable ocular motor paresis.^[2]
• The hallmark of myasthenia symptoms is Fluctuating weakness of specific muscles in limbs, bulbar, ocular and respiratory system which get worse with activity or using the muscle.^[3][4][5]
• Other signs and symptoms include: Gaze paralysis ^[6], Photophobia ^[7], Facial weakness ^[8], Orbicularis oculi weakness ^[9], tongue weakness, chewing problems and dysphagia ^[10][11], Respiratory problems ^[12], Limbs muscles weakness ^{[13][14][15][16]}, Fatigue ^[17], Pelvic floor weakness ^[18][19].

• In 15 percent of MG patients the symptoms remain in the area of palpebrae superioris, orbicularis oculi and oculomotor muscles and other symptoms of generalized disease doesn’t occur in them. This kind of myastehnia is OMG (ocular myasthenia gravis).^{[20][21][22][23]}

Complications that can develop as a result of myasthenia gravis are:

• Complications from the treatment of myasthenia gravis: the side effects of drugs we use in the treatment of myasthenia gravis can become very serious and reduce the quality of life in these patients:
  • glucocorticoids: Skin thinning and purpura^[24], Cushingoid appearance and weight gain^[25], cataracts and glaucoma^[26], ischemic heart disease and heart failure^[27], gastritis, ulcer formation, and gastrointestinal bleeding^[28], menstrual irregularities in women and low fertility in both men and women^[29][30] and psychiatric and cognitive symptoms.^[31]
  • Azathioprine: macrocytosis (increased MCV) and malignancies such as non-hodgkin lymphoma.^[32][33]
  • Cyclosporine: nephrotoxicity^[34], tremor, nausea, myalgias, gingival hyperplasia, hypertrichosis and malignancies such as squamous cell skin cancer and lymphoma.^[35]
  • Tacrolimus: the side effects of this drug include hyperglycemia, hypomagnesemia, paresthesias and tremor.^[36]
  • Cyclophosphamide: anorexia, nausea and vomiting, leukopenia, alopecia and hemorrhagic cystitis and it can also increase the risk of malignancies.^[37][38]
  • plasmapheresis: infection and thrombosis.^[39]
  • intravenous immune globulin: headache, dizziness, chills, fluid retention, aseptic meningitis, acute renal failure, anaphylaxis and thrombosis.^[40][41]

• Myasthenia crises (Respiratory failur): because of respiratory muscle weakness, MG patients may experience crises in which the respiratory weakness is so severe that may result in intubation.^[42]
• since the myasthenia is a chronic disease,most of the Complications that can develop as a result of this disease, may be equal to disease symptoms.

The prognosis of myasthenia gravis depends on:

• Disease duration at diagnosis: If the symptoms last less than 1 year, the patient has a 25 percent chance of going into remission by 10 years.^[43]
• Disease severity^[43]
• The age of onset: Younger patients seems to have better chance for remission than older ones.^[43] Patients more than 50 years old are more prone to myasthenia crises like respiratory failure.^[21]

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