Signs and symptoms of MG.
1. Introduction
The term myasthenia gravis (MG) is derived from the Greek terms my, asthenia, and gravis, which mean muscle, weakness, and severe, respectively. Myasthenia gravis is a rare potentially fatal chronic autoimmune disorder, in which circulating autoantibodies directed against components of the neuromuscular junction (NMJ) of skeletal muscles, most commonly nicotinic acetylcholine receptor (AChR) and associated protein in the postsynaptic membrane, will block neuromuscular transmission resulting in muscle weakness [1]. The muscle weakness is typically worsened with continued activity, improves on rest, and is of variable severity ranging from mild ocular muscle weakness to severe generalized muscle weakness involving the respiratory muscle with impending respiratory failure.
2. Historical perspective
The first reported case of MG could be traced to the Native American Chief Opechancanough, who died in 1664. “The excessive fatigue he encountered wrecked his constitution; his flesh became macerated; his sinews lost their tone and elasticity; and his eyelids were so heavy that he could not see unless they were lifted up by his attendants …he was unable to walk; but his spirit rising above the ruins of his body directed from the litter on which he was carried by his Indians
3. Epidemiology
The worldwide prevalence of MG is 100–200 per million population [9], affecting more than 700,000 people all over the world [10]. The prevalence rate has increased since the 1950s due to improved diagnostic precision and decreased mortality rate. It occurs in both genders, in all ages from different ethnic groups with variable prevalence and annual incidence rate from one country to another. Female-to-male ratio for incidence is 3:2 in people below the age of 30 and 1:1.5 in people more than 50 years of age. Life-threatening MG crises occur approximately in 15–20% of patients, typically within the first 2 years of diagnosis [11]. Previously, MG crises were associated with 50–80% mortality rate. Currently, the overall inpatient mortality rate of MG is 2.2%, being higher in crises (4.47%). Older age and respiratory failure were the predictors for death in MG crises [12].
4. Etiology
Myasthenia gravis is an autoimmune disease mediated by organ-specific antibody. These antibodies are present at neuromuscular junction (NMJ) and directed against nicotinic acetylcholine receptor (AChR) on the postsynaptic muscle membrane in 80–90% of patients. In 3–7%, the autoantibodies are directed against another NMJ protein, muscle-specific tyrosine kinase (MuSK). Using cell-based assay may increase the rate of detection of autoantibodies in patients with negative result by standard binding and modulating technique [13]. Patients with negative antibodies against AChR and MuSK might show positive antibodies against low-density lipoprotein receptor-related protein (LRP4) [14]. Other types of antibodies might be detected in patients with MG like agrin antibodies and antibodies to collagen Q and cortactin. These antibodies are of debatable clinical importance [15]. The reason why some patients develop these autoantibodies remains unclear. Genetic predisposition linked to human leukocyte antigen complex, single nuclear polymorphism, association with thymic hyperplasia or thymoma and abnormalities in the number and function of regulatory T and B cells are probably playing a role in the etiology of MG [16, 17, 18, 19]. Risk factors for developing MG include positive personal or family history of autoimmune disease like rheumatoid arthritis, HLA-B8, DR3, and women being less than 40 and men more than 60 years of age.
5. Pathophysiology
Normally, Ach is released in a discrete package from the motor nerve terminal at the neuromuscular junction. These Ach quanta diffuse across the synaptic cleft and bind to receptors on the folded muscle end plate membrane (Figure 1). Motor nerve stimulation will release many Ach quanta causing depolarization of muscle end plate membrane resulting in muscle contraction. In MG, Ach was released normally but its effect on the postsynaptic membrane reduced. The autoantibody against AChRs will result in the destruction of postsynaptic membrane and reduction in the number of available Ach receptors on the muscle end plate membrane (binding site for Ach), which in turn will lead to an inconsistent generation of muscular action potentials manifesting as muscle weakness (Figures 2 and 3). The process of destruction of the postsynaptic membrane is dependent on complement activation. In patients without antibodies against AChRs, a muscle-specific tyrosine kinase (MuSK), an agrin-dependent protein on muscle membrane, has been found to be the antigenic target. These autoantibodies are T-cell dependent and there is interesting differential involvement of muscle groups, especially the extraocular muscles [20].
6. Clinical presentation
Fatigable weakness, involving specific susceptible groups of muscles, is the clinical hallmark of MG. This weakness usually fluctuates from hour to hour, day to day, worsens with activity, and improves on rest. The susceptible groups of muscles include ocular, bulbar, facial, limb muscle, axial muscle, and respiratory muscle. Clinical features resulting from the involvement of the susceptible group of muscle are summarized in Table 1 [21].
Group of muscle | Clinical features |
---|---|
Ocular muscle | Fluctuating ptosis and/or diplopia |
Bulbar muscle | Dysarthria, painless dysphagia, dysphonia, and masticatory weakness |
Facial muscle | Facial weakness, inability to close eye firmly, drooling of saliva |
Axial muscular | Flexion or extension of the neck |
Limb muscle | Weakness involving the arms more than legs |
Respiratory muscle | Labor breathing, orthopnea, dyspnea, and respiratory failure |
The most common initial presenting feature of MG is ocular muscle involvement presenting as fluctuating ptosis and/or diplopia, with or without generalized weakness, in about 85% of cases [22]. The absence of ocular involvement makes the diagnosis difficult. In 50–60% of patients with isolated ocular involvement, progression to generalized weakness occurs within 2 years of the onset. The second most common presenting feature is bulbar muscle involvement manifesting as dysphagia, dysarthria, dysphonia, or difficulties in chewing, occurring in about 15% of cases [23]. A life-threatening respiratory muscle involvement, requiring immediate therapeutic action might occur on rare occasions. Patients with MG usually experience a variable course with intermittent worsening of symptoms precipitated by viral infection, surgery, warm weather, immunization, emotional stress, pregnancy, chronic diseases, or medications. Progression to maximum severity usually occurs with the first 2 years of onset and spontaneous long-term remission might occur in up to 10–20% of patients [22]. About 10–20% of infants born to mothers with symptomatic or asymptomatic MG present soon after birth with transient neonatal MG. It occurs as a result of transplacental passage of antibodies against NMJ receptors. The most common presenting features are hypotonia and poor feeding that resolve usually within the first months after birth [24].
7. Clinical classifications
Myasthenia gravis is classified clinically into five classes and several subclasses according to MG foundation of American clinical classification, see Table 2 [25].
Class | Clinical description |
---|---|
Class 1 | Any eye muscle weakness, possible ptosis, all other muscles’ strength is normal |
Class 2 2a 2b | Mild weakness of other muscles; may have eye muscle weakness of any severity Predominantly limb or axial muscles weakness or both Predominantly oropharyngeal or respiratory muscle weakness or both |
Class 3 3a 3b | Moderate weakness of other muscles; may have eye muscle weakness of any severity Predominantly limb or axial muscle weakness or both Predominantly oropharyngeal or respiratory muscle weakness or both |
Class 4 4a 4b | Severe weakness of other muscles; may have eye muscle weakness of any severity Predominantly limb or axial muscle weakness or both Predominantly oropharyngeal or respiratory muscle weakness or both; use of feeding tube without intubation |
Class 5 | Intubation needed to maintain airway |
8. Diagnosis
The diagnosis of MG might be difficult and easily missed, because of the rarity of the condition and hence unfamiliarity to physicians. Furthermore, fluctuations of muscle weakness may add to the perplexing presentation. Once MG is suspected, the following test can be requested:
8.1 Serological tests
Anti-AchR has about 100% specificity, 85% sensitivity in patients with generalized MG, and 50% sensitivity in pure ocular variety [26]. False positive results may occur in patients with thymoma without MG, small cell lung cancer, rheumatoid arthritis treated with penicillamine, and rarely in people over 70 years of age. Other serological tests include anti-MuSK antibody (positive in 50% of myasthenic patients with negative anti-AchR), anti-agrin antibody, anti-lipoprotein-related protein 4 (LRP4) antibody, antistriational antibody (present in all myasthenic patients with thymoma), and anti-cortactin antibody.
8.2 Neurophysiological studies
These studies are commonly used to detect defects in neuromuscular transmission in patients with MG. Repetitive nerve stimulation and single-fiber electromyography are the most commonly used tests. Repetitive nerve stimulation can detect 75 and <50% of generalized and ocular MG patients, respectively. On the other hand, single-fiber electromyography can detect defects in neuromuscular transmission in 95–99% of myasthenic patients and a negative result can exclude the diagnosis [27].
8.3 Radiological studies
Chest X ray, CT scan, and MRI might be recommended to evaluate patients with anterior mediastinal mass and suspected thymoma, and also to exclude brain and orbit mass lesion inducing cranial nerve palsies in ocular MG.
8.4 Pharmacological tests
In MG, the number of AChRs at the NMJ is low due to inhibition by the autoantibody. The result is decrease in the number of interaction between Ach (release from motor nerve terminals) and its receptors on postsynaptic muscle membrane of NMJ. The Ach is metabolized by Ach esterase (AChE) enzyme. Therefore, inhibition of this enzyme will increase the Ach concentration at the NMJ and hence improve the chance of interaction between the Ach and its receptors. Edrophonium test is based on the clinical improvement of muscle weakness in myasthenic patients after intravenous administration of short-acting Ach esterase inhibitor, Edrophonium (Tensilon). Double blinding of both the patient and the examiner increases the validity of the test [28].
8.5 Ice pack test
This debatable test uses the fact that cooling might improve neuromuscular transmission. It is mainly used by ophthalmologists to assess improvement in ptosis and diplopia in myasthenic patients [29].
9. Treatment
The severity of symptoms in patients with MG will determine the strategy of the treatment using the many therapeutic options available. According to MG foundation of American clinical classification (Table 2), MG can be divided into three categories: mild (classes 1 and 2), moderate (class 3), and severe (classes 4 and 5). The available therapeutic options include:
9.1 Pharmacologic therapy
The cornerstone for the treatment of MG is the administration of reversible cholinesterase (AChE) inhibitor, pyridostigmine, which is more effective in patients with generalized and ocular MG and less effective in patients with positive anti-MuSK antibody. In those patients with poor response to pyridostigmine, steroid and immunosuppressive agents should be considered [30, 31, 32].
9.2 Immunosuppressive agent
All types of MG respond to corticosteroid (prednisone and prednisolone) in terms of improvement of muscle strength. Furthermore, corticosteroid may prevent progression of the disorder from ocular to generalized MG [30, 33]. Patients who do not respond to corticosteroid or who cannot tolerate it are candidates for immunosuppressive agents using azathioprine (they are first-line agents and can be used with corticosteroid), cyclosporine, methotrexate, mycophenolate mofetil, or tacrolimus [32]. Recently, promising results are shown by two monoclonal antibodies, rituximab and eculizumab. The use of rituximab in refractory MG may show clinical improvement and reduction for the need of corticosteroid and therapeutic plasma exchange [34].
9.3 Therapeutic plasma exchange (TPE)
It is the procedure by which the patient’s plasma is removed and replaced by fresh plasma or albumin. This will lead to the removal of autoantibody against AChRs, leading to short-term improvement of NMJ transmission and hence muscular strength. It is useful as an acute treatment in patients with severe generalized MG, refractory MG, myasthenia crises, and as maintenance therapy in patients with juvenile MG [35].
9.4 Intravenous immunoglobulin (IVIG)
The mechanism of action of IVIG is complex and may involve inhibition of cytokines and complement deposition, competition with autoantibodies, interference with binding of Fc receptor on macrophages and immunoglobulin receptor on B cells, and interference with antigen recognition by sensitized T cells [36]. It is used as an acute treatment in patients with severe generalized MG and MuSK-MG, as a maintenance therapy in patients with refractory and juvenile MG, and in myasthenia crises [1].
9.5 Thymectomy
Myasthenic patients commonly have thymic abnormalities. Patients with generalized MG have thymic hyperplasia in 85% and thymoma in 10–15% of cases. Those patients are usually anti-AChR antibody positive. Thymectomy is indicated for all patients with thymoma and for patients aged 10–55 years who have generalized MG but without thymoma. In fact, thymectomy is proposed as first – line therapy in most patients with generalized MG. Thymectomy not indicated in patients with antibodies to MuSK, LRP4, or agrin antibodies because the thymic pathology is different from the more common type of MG characterized by seropositivity to AChR, and also it is not indicated in patients with ocular MG during the first 2 years after diagnosis because the possibility of spontaneous remission [2].
10. Prognosis
With the recent advances in the management of MG in both supportive intensive care and specific therapeutic options, most patients enjoy normal or near normal life span. The mortality rate is about 3–4% and the risk factors for death include a short history of a progressive disease, age more than 40 years, and thymoma. Morbidity in MG results from intermittent muscle weakness, which may result in aspiration pneumonia, difficult breathing, and even respiratory failure requiring ventilator assistance and in possible side effects of medications used in the treatment.
References
- 1.
Kernich CA. Patient and family fact sheet. Myasthenia gravis: Maximizing function. The Neurologist. 2008; 14 (1):75-76 - 2.
Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: Past, |present, and future. The Journal of Clinical Investigation. 2006; 116 (11):2843-2854 - 3.
Marsteller HB. The first American case of myasthenia gravis. Archives of Neurology. 1988; 45 :185-187 - 4.
Pascuzzi RM. The history of myasthenia gravis. Neurologic Clinics. 1994; 12 :231-242 - 5.
Wilks S. On cerebritis, hysteria and bulbar paralysis, as illustrative of arrest of function of the cerebrospinal centres. Guy's Hospital Reports. 1877; 22 :7-55 - 6.
Walker MB. Case showing the effect of prostigmin on myasthenia gravis. Proceedings of the Royal Society of Medicine. 1935; 28 :759-761 - 7.
Nastuk WL, Strauss AJ, Osserman KE. Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis. The American Journal of Medicine. 1959; 26 :394-409 - 8.
Simpson JA. Myasthenia gravis, a new hypothesis. Scottish Medical Journal. 1960; 5 :419-436 - 9.
Phillips LH. The epidemiology of myasthenia gravis. Seminars in Neurology. 2004; 24 :17-20 - 10.
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis. Neurology. 2016; 87 (4):419-425 - 11.
Liu CJ, Chang YS, Teng CJ, et al. Risk of extrathymic cancer in patients with myasthenia gravis in Taiwan: A nationwide population-based study. European Journal of Neurology. 2012; 19 (5):746-751 - 12.
Alshekhlee A, Miles JD, Katirji B, Preston DC, Kaminski HJ. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology. 2009; 72 (18):1548-1554. DOI: 10.1212/WNL.0b013e3181a41211 - 13.
Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: Beyond diagnosis? Expert Review of Clinical Immunology. 2012; 8 (5):427-438 - 14.
Higuchi O, Hamuro J, Motomura M, et al. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Annals of Neurology. 2011; 69 (2):418-422 - 15.
Cossins J, Belaya K, Zoltowska K, et al. The search for new antigenic targets in myasthenia gravis. Annals of the New York Academy of Sciences. 2012; 1275 :123-128 - 16.
Giraud M, Vandiedonck C, Garchon HJ. Genetic factors in autoimmune myasthenia gravis. Annals of the New York Academy of Sciences. 2008; 1132 :180-192 - 17.
Renton AE, Pliner HA, Provenzano C, et al. A genome-wide association study of myasthenia gravis. JAMA Neurology. 2015; 72 (4):396-404 - 18.
Hohlfeld R, Wekerle H. The role of the thymus in myasthenia gravis. Advances in Neuroimmunology. 1994; 4 (4):373-386 - 19.
Vander Heiden JA, Stathopoulos P, Zhou JQ , et al. Dysregulation of B cell repertoire formation in myasthenia gravis patients revealed through deep sequencing. Journal of Immunology. 2017; 198 (4):1460-1473 - 20.
Hughes BW, Moro De Casillas ML, Kaminski HJ. Pathophysiology of myasthenia gravis. Seminars in Neurology. 2004; 24 :21-30 - 21.
Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: Emerging clinical and biological heterogeneity. Lancet Neurology. 2009; 8 (5):475-490 - 22.
Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle & Nerve. 2008; 37 :141-149 - 23.
Grob D. Course and management of myasthenia gravis. Journal of the American Medical Association. 1953; 153 :529-532 - 24.
Hassoun M, El Turjuman U, Chokr I, Fakhoury H. Myasthenia gravis in the neonate. NeoReviews. 2010; 11 (4):e200-e205. DOI: 10.1542/neo.11-4 e200 - 25.
Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: Recommendations for clinical research standards. Task force of the medical scientific advisory board of the myasthenia Gravis foundation of America. The Annals of Thoracic Surgery. 2000; 70 (1):327-334 - 26.
Padua L, Stalberg E, LoMonaco M, Evoli A, Batocchi A, Tonali P. SFEMG in ocular myasthenia gravis diagnosis. Clinical Neurophysiology. 2000; 111 (7):1203-1207 - 27.
Katirji B, Kaminski HJ. Electrodiagnostic approach to the patient with suspected neuromuscular junction disorder. Neurologic Clinics. 2002; 20 :557-586, viii - 28.
Phillips LH 2nd, Melnick PA. Diagnosis of myasthenia gravis in the 1990s. Seminars in Neurology. 1990; 10 (1):62-69 - 29.
Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscular Disorders. 2006; 16 (7):459-467 - 30.
Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. European Journal of Neurology. 2010; 17 (7):893-902 - 31.
Gilhus NE, Owe JF, Hoff JM, Romi F, Skeie GO, Aarli JA. Myasthenia gravis: A review of available treatment approaches. Autoimmune Diseases. 2011; 2011 :847393 - 32.
Saperstein DS, Barohn RJ. Management of myasthenia gravis. Seminars in Neurology. 2004; 24 (1):41-48 - 33.
Benatar M, Kaminski H. Medical and surgical treatment for ocular myasthenia. Cochrane Database of Systematic Reviews. 2012; 12 :CD005081 - 34.
Nowak RJ, Dicapua DB, Zebardast N, Goldstein JM. Response of patients with refractory myasthenia gravis to rituximab: A retrospective study. Therapeutic Advances in Neurological Disorders. 2011; 4 (5):259-266 - 35.
Kumar R, Birinder SP, Gupta S, Singh G, Kaur A. Therapeutic plasma exchange in the treatment of myasthenia gravis. Indian Journal of Critical Care Medicine. 2015; 19 (1):9-13 - 36.
Eng H, Lefvert AK, Mellstedt H, Osterborg A. Human monoclonal immunoglobulins that bind the human acetylcholine receptor. European Journal of Immunology. 1987; 17 :1867-1869