Myasthenia Gravis
Autoimmune Diseases

Introduction

Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. Treatment now available for MG is highly effective, although a specific cure has remained elusive.

Historical perspective

Attempts at rational treatments of MG began in the 1930s. A major step forward occurred in 1934 when had been realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine, a cholinesterase inhibitor. This parasympathomimetic alkaloid promptly improved myasthenic symptoms, making anticholinesterase drugs a staple in MG management. Was also observed that thymus pathology is common in MG patients, as first noted in the late 1800s, in 1937, a mediastinal mass was remuved from a young woman who had MG; the patient improved postoperatively. Later thymectomy has been recognized as a treatment for MG.
In 1959–1960 MG was proposed has an autoimmune disease. The Drs Jim Patrick and Jon Lindstrom confirmed it in 1973. They demonstrated that rabbits immunized with purified muscle-like AChR developed MG-like symptoms. After that seminal discovery, many studies demonstrated an autoimmune response against muscle AChR in MG and the role of anti-AChR Abs in causing the structural and functional damage of the neuromuscular junction (NMJ). These findings promoted the use of immunosuppressants in MG. In the 1970s, prednisone (it’s a glucocorticoid prodrug) and azathioprine (it’s a purine analogue immunosuppressive drug) became established treatments for MG, and plasma exchange was introduced as an effective acute treatment for severe MG, further proving that circulating factors caused MG symptoms.
Conti-Fine BM, Milani M, Kaminski HJ (2006) Myasthenia gravis: past, present, and future

Clinical features

MG is not rare, having a prevalence of at least 1 in 7500. It affects individuals in all age groups, but peaks of incidence occur in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are affected more frequently than men, in a ratio of about 3:2.

The cardinal features are weakness and fatigability of muscles. The weakness increases during repeated use (fatigue) and may improve following rest or sleep. The course of MG is often variable. Exacerbations and remissions may occur, particularly during the first few years after the onset of the disease. Remissions are rarely complete or permanent. Unrelated infections or systemic disorders often lead to increased myasthenic weakness and may precipitate “crisis”.

The distribution of muscle weakness often has a characteristic pattern. The cranial muscles, particularly the lids and extraocular muscles, are often involved early in the course of MG, and diplopia and ptosis are common initial complaints. Facial weakness produces a “snarling” expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort, as in chewing meat. Speech may have a nasal timbre caused by weakness of the palate or a dysarthric “mushy” quality due to tongue weakness. Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food. In about 85% of patients, the weakness becomes generalized, affecting the limb muscles as well. The limb weakness in MG is often proximal and may be asymmetric. Despite the muscle weakness, deep tendon reflexes are preserved. If weakness of respiration becomes so severe as to require respiratory assistance, the patient is said to be in crisis.

Classification

The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America Clinical Classification

• Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
• Class II: Eye muscle weakness of any severity, mild weakness of other muscles
  • Class IIa: Predominantly limb or axial muscles
  • Class IIb: Predominantly bulbar and/or respiratory muscles
• Class III: Eye muscle weakness of any severity, moderate weakness of other muscles
  • Class IIIa: Predominantly limb or axial muscles
  • Class IIIb: Predominantly bulbar and/or respiratory muscles
• Class IV: Eye muscle weakness of any severity, severe weakness of other muscles
  • Class IVa: Predominantly limb or axial muscles
  • Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation)
• Class V: Intubation needed to maintain airway
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Pathophysiology

Myasthenia gravis is an autoimmune channelopathy: it features antibodies (Abs) directed against the acetylcholine receptors (AChR). Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms: (a) binding and activation of complement at the NMJ; (b) accelerated degradation of AChR molecules crosslinked by Ab (a process known as antigenic modulation); and © functional AChR block.

The NMJs of MG patients contain activation fragments of complement component 3 (C3), the terminal and lytic complement component 9 (C9), and the membrane attack complex (MAC). Different lines of indirect evidence suggest that complement activation at the NMJ might be the primary cause of AChR loss and failure of neuromuscular transmission. But there are also
intrinsic complement regulators on their surface that protected themself from activation of autologous complement. These include the decay-accelerating factor (DAF or CD55), the membrane cofactor protein (MCP or CD46), and the membrane inhibitor of reactive lysis (MIRL or CD59). Anti-AChR Abs causes more severe muscle weakness in DAF-deficient.
IgG from MG patients causes antigenic modulation of muscle AChR in vivo and in vitro, it cross-linkin 2 AChR triggering a cellular signal that causes their accelerated endocytosis and degradation. If accelerated degradation is not compensated by increased AChR synthesis, it will lead to a reduction of the available AChR molecules at the NMJ and myasthenic symptoms. However, not all anti-AChR Abs cause antigenic modulation because, even though all IgG Abs have 2 antigen-binding sites, the epitope location on the AChR surface may restrict the ability of Abs to cross-link a second AChR molecule.
Functional AChR block due to Ab binding to the ACh-binding site is an uncommon pathogenic mechanism in MG that causes acute severe muscle weakness. Many MG patients have low levels of anti-AChR Abs that recognize the ACh-binding site; these might block the AChR in spite of their low concentration and contribute to acute myasthenic crises.
We know that the CD4+ T are necessary for the development of MG symptoms. In fact anti-AChR Abs are high-affinity IgGs, whose synthesis requires that activated CD4+ T cells, means MHC class II molecules, interact with B cells, resulting in low-affinity anti-AChR Abs. This triggers somatic mutations of the Ig genes, leading to synthesis of high-affinity Abs.
Differentiated CD4+ T cells are classified into subtypes based on the cytokines they secrete. Among them, Th1 and Th2 cells have different and at times opposing functions. Th1 cells secrete proinflammatory cytokines, such as IL-2, IFN-γ, and TNF-α, which are important in cell-mediated immune responses. Th2 cells secrete antiinflammatory cytokines, such as IL-4, IL-6, and IL-10, which are also important inducers of humoral immune responses.
Moreover, IL-4 stimulates differentiation of Th3 cells, which secrete TGF-β and are involved in immunosuppressive mechanisms. Both Th1 and Th2 cytokines may induce the synthesis of different Ig types. Th1 cells induce IgG subclasses that bind and activate complement efficiently whereas Th2 cells induce Ig isotypes and IgG subclasses that fix complement poorly or not at all.

Although how the autoimmune response is initiated 
and maintained in MG is not completely understood. Has been demostrated thath MG is an acquired disease with some genetic predisposition and the hyperplastic thymus appears to play an important role in this process (The thymus is abnormal in about 75% of patients with MG)
Conti-Fine BM, Milani M, Kaminski HJ (2006) Myasthenia gravis: past, present, and future

Diagnosis

The diagnosis is suspected on the basis of weakness and fatigability without loss of reflex or impairment of sensation or other neurologic function, and it will be assess with clinical test like:

• Anticholinesterase Test:
  It use the Edrophonium. It is a drug that inhibit the enzyme AChE allow ACh to interact repeatedly with the limited number of AChRs, producing improvement in the strength of myasthenic muscles. An initial dose of 2 mg of edrophonium is given intravenously. If definite improvement occurs, the test is considered positive and is terminated. If there is no change, the patient is given an additional 8 mg intravenously. The dose is administered in two parts because some patients react to edrophonium with unpleasant side effects such as nausea, diarrhea, salivation, fasciculations, and rarely with severe symptoms of syncope or bradycardia.
  

• Electrodiagnostic Testing:
  Repetitive nerve stimulation often provides helpful diagnostic evidence of MG. Electric shocks are delivered at a rate of two or three per second to the appropriate nerves, and action potentials are recorded from the muscles. In normal individuals, the amplitude of the evoked muscle action potentials does not change at these rates of stimulation. However, in myasthenic patients there is a rapid reduction in the amplitude of the evoked responses of about 10 to 15%.
  Electrodiagnostic Testing of nerves and muscles
• Mensuration of Antia-cetylcholine Receptor Antibody:
  Anti-AChR antibodies are detectable in the serum of abuot 85% of all myasthenic patients but in only about 50% of patients with weakness confined to the ocular muscles. The presence of anti-AChR antibodies is virtually diagnostic of MG, but a negative test does not exclude the disease. The measured level of anti-AChR antibody does not correspond well with the severity of MG in different patients. Recently, antibodies to muscle-specific kinase (MuSK) have been found to be present in about 40% of AChR antibody-negative patients with generalized MG, and their presence is a useful diagnostic test in these patients. MuSK antibodies are not present in AChR antibody-positive patients or in patients with MG limited to ocular muscles. The role of these antibodies in the pathogenesis of MG is as yet uncertain. MuSK is known to participate in clustering of AChRs at neuromuscular junctions during development.

Treatment

The prognosis has improved strikingly as a result of advances in treatment. The most useful treatments for MG include:

• Anticholinesterase medications:
  It produces at least partial improvement in most myasthenic patients. In this treatment is used an anticholinesterase drugs, like oral pyridostigmine. The frequency and amount of the dose should be tailored to the patient’s individual requirements throughout the day. For example, patients with weakness in chewing and swallowing may benefit by taking the medication before meals so that peak strength coincides with mealtime. Overdosage with anticholinesterase medication may cause increased weakness and other side effects.
• Thymectomy:
  There are two type of issues: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. We will do a surgical removal of a thymoma when there is a local tumor. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, about 35% achieve drug-free remission. However, the improvement is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long-term benefit. It is the consensus that thymectomy should be carried out in all patients with generalized MG who are between the ages of puberty and at least 55 years.
• Immunosuppressive agents:
  Immunosuppression using glucocorticoids, azathioprine, and other drugs according to the relative benefits and risks for the individual patient and the urgency of treatment. It is helpful to develop a treatment plan based on short-term, intermediate-term, and long-term objectives. For the intermediate term, glucocorticoids and cyclosporine generally produce clinical improvement within a period of 1 to 3 months. The beneficial effects of azathioprine and mycophenolate mofetil usually begin after many months (up to a year), but these drugs have advantages for the long-term treatment of patients with MG. For the occasional patient with MG that is genuinely refractory to optimal treatment with conventional immunosuppressive agents, a course of high-dose cyclophosphamide may induce long- lasting (possibly permanent) benefit by “rebooting” the immune system. At high doses, cyclophosphamide eliminates mature lymphocytes, but hematopoietic precursors (stem cells) are spared, because they express the enzyme aldehyde dehydrogenase, which hydrolyzes cyclophosphamide. This procedure should be reserved for truly refractory patients and administered only in a facility fully familiar with this approach.
• Plasmapheresis:
  It has been used therapeutically in MG. Plasma, which contains the pathogenic antibodies, is mechanically separated from the blood cells, which are returned to the patient. Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in many patients. It is useful as a temporary expedient in seriously affected patients or to improve the patient’s condition prior to surgery. This treatment has the advantages of not requiring special equipment or large-bore venous access. Improvement occurs in about 70% of patients. Adverse reactions are generally not serious but include headache, fluid overload, and rarely aseptic meningitis or renal shutdown.