Myasthenia Gravis: Practice Essentials, Background, Anatomy
Myasthenia gravis (MG) is a relatively rare acquired, autoimmune disorder caused by an antibody-mediated blockade of neuromuscular transmission resulting in skeletal muscle weakness. The autoimmune attack occurs when autoantibodies form against the nicotinic acetylcholine postsynaptic receptors at the neuromuscular junction of skeletal muscles (see the image below). [1, 2] Although the chief target of the autoimmune attack in most cases is the skeletal muscle nicotinic acetylcholine receptor (nAChR), other antigenic targets that are components of the neuromuscular junction (NMJ) have also been implicated.
Normal neuromuscular junction showing a presynapti
Normal neuromuscular junction showing a presynaptic terminal with a motor nerve ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.
Signs and symptoms
The presentation of MG has the following characteristics:
The clinical hallmark of MG is the presence of fluctuating fatigable muscle weakness that worsens with activity and improves on rest
50% to 85% of patients with MG present with ocular symptoms with or without generalized weakness
50% to 60% of patients with MG who initially present with isolated ocular involvement go on to develop generalized weakness, often within 3 years after onset of symptoms
The disease remains exclusively ocular in only 15% to 25% of patients throughout their course [1, 2]
Approximately 20% of patients with MG may present with prominent bulbar symptoms
Bulbar muscle weakness is also common, along with weakness of head extension and flexion
Limb weakness may be more severe proximally than distally
Isolated limb muscle weakness is the presenting symptom in about 5% of patients [3]
Weakness progresses from mild to more severe over weeks or months, with exacerbations and remissions
The following factors may trigger or worsen exacerbations:
Warm weather
Surgery
Immunization
Emotional stress
Menstruation
Intercurrent illness (eg, viral infection)
Tapering of immunosuppression
Pregnancy and postpartum period
Worsening of chronic medical illnesses (cardiac, renal, autoimmune, etc.)
Medication (eg, aminoglycosides, ciprofloxacin, telithromycin. clindamycin, phenothiazines, chlorpromazine, diazepam, halothane, ketamine, lidocaine, procain, non-depolarizing neuromuscular blocking agents, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, propafenone, bretylium, qunidine, calcium channel blockers, d-penicillamine, high-dose prednisone, magneisum)
The Myasthenia Gravis Foundation of America Clinical Classification divides MG into 5 main classes and several subclasses [3] :
Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal
Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity
Class IIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both
Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity
Class IIIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
Class IIIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both
Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity
Class IVa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both
Class V: Defined by the need for intubation, with or without mechanical ventilation, except when used during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.
See Clinical Presentation for more detail.
Diagnosis
The anti–acetylcholine receptor (AChR) antibody test for diagnosing MG has the following characteristics:
High specificity (up to 100% [4] )
Positive in as many as 85% of patients who have generalized MG [4]
Positive in only 50% of patients who have purely ocular MG [4]
False-positive anti-AChR antibody test results have been reported in patients with the following:
Thymoma without MG
Lambert-Eaton myasthenic syndrome
Small cell lung cancer
Rheumatoid arthritis treated with penicillamine
1-3% of the population older than 70 years
Assays for the following antibodies may also be useful:
Anti-MuSK antibody (present in about half of patients with negative results for anti-AChR antibody)
Anti-lipoprotein-related protein 4 (LRP4) antibody
Anti-agrin antibody
Antistriational antibody (present in almost all patients with thymoma and MG, as well as in half of MG patients with onset of MG at 50 years or older)
Anti-cortactin antibody
Other studies are as follows:
Plain chest radiographs may identify a thymoma as an anterior mediastinal mass
Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all cases of MG
In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG
Electrodiagnostic studies (repetitive nerve stimulation and single-fiber electromyography)
See Workup for more detail.
Management
Based on recent advances in understanding the various underlying antibodies that cause myasthenia gravis and differences in how they present clinically and their response to various therapies, it is suggested that patients with myasthenia gravis should be classified into subgroups. Subgroups are based on the profile of serum autantibodies, the age of onset, the presence or absence of thymic pathology, and the distribution of clinical weakness. [5]
Therapy for MG includes the following:
Symptomatic therapy
Anticholinesterase (AchE) inhibitors
Pyridostigmine is used for maintenance therapy [6, 7]
Neostigmine is generally used only when pyridostigmine is unavailable
Rapidly acting or short-term immunomodulating agents:
Intravenous immune globulin (IVIg)
Plasmapheresis
Prednisone is the most important immunosuppressant and provides short- and long-term benefit.
Azathioprine (AZA) is a first-line steroid-sparing agent
Mycophenolate mofetil (MMF) is also a first-line steroid-sparing agent. It is widely used and less toxic than azathioprine.
Cyclosporine (CyA) is used as a steroid-sparing agent in patients who are intolerant to azathioprine and mycophenolate mofetil.
Tacrolimus is used as a steroid-sparing agent in patients intolerant or unresponsive to AZA, MMF, or CyA.
Methotrexate is used as a steroid-sparing agent and has similar efficacy and tolerability to AZA.
Rituximab may be an effective intervention in refractory MG, both for anti-AChR and anti-MuSK-positive disease.{ref5 [6, 7, 8]
Cyclophosphamide is used in refractory/severe MG.
Emerging novel therapies targeting immunopathogenesis of MG
Eculizumab is a humanized monoclonal IgG antibody against terminal complement activity (C5b-9) preventing its depositing at the NMJ in adult patients with anti-AchR+ve gMG.
Investigational agents
Ocrelizumab, a second-generation, humanized monoclonal antibody against B-cell (anti-CD20), which appears to be better tolerated (over first-generation rituximab), is a potential consideration.
Abatacept is a cytotoxic T-lymphocyte protein 4 (CTLA-4) monoclonal antibody, which binds to CD80/CD86 and blocks both activating (CD28) and inhibitory signals (CTLA-4).
Daclizumab is a monoclonal antibody that binds to CD25 thereby antagonizing the activating effects of IL-2 on T cells.
Belimumab binds to soluble B-cell activating factor (BAFF) and reduces B-cell activation and differentiation into antibody-producing plasma cells.
Bortezomib is a protease inhibitor that has shown experimental benefit in MG. It reduced anti-AChR antibody titers, inhibited damage to the postsynaptic muscle membrane, and resulted in clinical improvement. [9]
Fc receptor modulators (FcRn–IgG) in the form of monoclonal antibody is being studied in passive and active models of rat experimental MG and shown to ameliorate symptoms and lower autantibody levels. [10]
Several human monoclonal antibodies directed against IL-17 are in development, including brodalumab (AMG 827), ixekizumab (LY2439821), and secukinumab.
Toclizumab, a humanized monoclonal antibody targeting the IL-6 receptor, is being studied as a potential therapy.
Autologous stem cell transplantation has been proposed as a therapeutic approach for refractory autoimmune disease and is based on the idea that the transplanted immune cells will be “reset” and free of autoimmune reactivity. [11]
3,4-Diaminopyridine is another symptomatic therapy with potential application in MuSK MG. Exploring use of this drug, which enhances AChR release at the motor nerve terminal, in MuSK MG is supported by preclinical models, experience with congenital MG with MuSK mutations, and case reports. [12, 13]
Tirasemtiv is a selective fast skeletal muscle troponin activator. This small molecule binds to skeletal muscle troponin, thereby sensitizing the muscle to calcium and ultimately improving muscle strength under submaximal stimulation. A study of tirasemtiv in experimental MG improved grip strength and muscle force after a single dose. [14]
Thymectomy
The Randomized Trial of Thymectomy in Myasthenia Gravis, a landmark study, has shown that trans-sternal thymectomy improves MG and even induces remission, or lessens the requirements or perhaps removes the need for prednisone and other immunosuppressants over a period of 3 years. [15]
See Treatment and Medication for more detail.
What is myasthenia gravis? Myasthenia gravis is an autoimmune disease that's categorized as a type II hypersensitivity that involves autoantibodies binding acetylcholine receptors on skeletal muscle cells. Courtesy of Osmosis.org (https://www.osmosis.org/).
Background
Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of the skeletal muscles. It is a type-II hypersensitivity immune response. The basic pathology is a reduction in the number of ACh receptors (AChRs) at the postsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies.
The reduction in the number of AChRs results in a characteristic pattern of progressively reduced muscle strength with repeated use and recovery of muscle strength after a period of rest. The ocular and bulbar muscles are affected most commonly and most severely, but most patients also develop some degree of fluctuating generalized weakness. [10] The most important aspect of MG in emergency situations is acute worsening of weakness leading to neuromuscular respiratory failure. The diagnosis of myasthenic versus cholinergic crisis and its management is also a significant challenge in emergent settings.
MG is a well-understood and well-managed disease. Pharmacologic therapy includes anticholinesterase agents, such as pyridostigmine, and immunosuppressive agents, such as corticosteroids, azathioprine, mycophenolate mofetil, tacrolimus, sirolimus, cyclosporine, cyclophosphamide, rituximab, plasmapheresis, and intravenous immune globulin (IVIg). Thymectomy has a significant role in the treatment of patients with generalized MG who are positive for acetylcholine receptor antibodies. Thymectomy becomes mandatory if a thymoma is present. Patients with MG require close follow-up care by a neurologist or neuromuscular specialist in cooperation with their primary care physician.
Anatomy
The neuromuscular junction (NMJ) serves as a transducer and amplifier to the peripheral nerve’s relatively small electrical current using a chemical signal subserved by neurotransmitter ACh. This in turn produces an electrical current of sufficient intensity and proper location such that it initiates a propagating action potential in the muscle fiber. Thus, the NMJ is considered a chemical synapse that functions as an electrical-chemical-electrical link.
In MG, autoantibodies (immunoglobulin G [IgG1]) develop against nicotinic acetylcholine postsynaptic receptors at the NMJ of skeletal muscles. [1, 2] The reasons for this development are unknown, although it is clear that certain genotypes are more susceptible. [11] To understand MG, it is necessary to become familiar with the normal anatomy and physiology of the NMJ (see the image below). A full appreciation of the normal function of the NMJ is needed to understand the principles underlying diagnostic testing and the mechanisms of therapeutic interventions.
Normal neuromuscular junction showing a presynapti
Normal neuromuscular junction showing a presynaptic terminal with a motor nerve ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.
The nerve terminal of the motor nerve enlarges at its end to form the so-called terminal bouton or terminal bulb. This bulbous nerve terminal lies within a groove or indentation along the somatic muscle fiber. The NMJ can be subdivided into 3 major areas: presynaptic region, synpatic space, and post-synaptic membrane. Disorders of neuromuscular transmission can arise from abnormalities in each of these locations.
The pre-synaptic region
Each motor neuron has an axon that branches distally to provide nerve terminals that innervate muscle fibers through the NMJ. Collectively, they are known as the motor unit. A muscle fiber is innervated by only one motor neuron with the exception of extraocular muscle fibers where single muscle fibers may receive multiple innervation. The motor nerve loses its myelin sheath as it approaches near the NMJ where it begins to divide into terminal branches. Each terminal branch of an axon, as it nears an individual muscle fiber, expands into a presynaptic terminal bouton that lies in a depression in the muscle membrane. A basement membrane overlies this terminal interface between the bouton and its muscle fiber, constituting part of the muscle end-plate. The terminal bouton has a number of subcellular components including neurotubules, neurofilaments, multiple mitochondria, and a large number of membrane-bound vesicles ranging from 300 to 500 Angstrom units in diameter, called synaptic vesicles. Each vesicle contains approximately 1 quantum of acetylcholine, which equals 10,000 molecules of acetylcholine. A single nerve terminal has approximately 200,000 synaptic vesicles. These vesicles are organized in 3 discrete groups.
The primary, or immediately available store consists of approximately 1000 quanta of ACh and are located just beneath the pre-synaptic nerve terminal membrane at specific sites called active zones. These release sites (active zones) lie directly opposite the ACh receptors (AChRs) located on the post-synaptic membrane. The primary store is available for immediate release. They behave like soldiers at the front line, ready for action.
The secondary, or mobilization store consists of approximately 10,000 quanta of ACh that can replenish the primary store after a few seconds. These behave like immediate reinforcements that become mobilized to replace the depleted primary store.
Finally, a tertiary, or reserve store of more than 100,000 quanta exists far from the NMJ in the axon and cell body. They behave like the reserves.
Voltage-gated calcium (Ca++) channels (P/Q-type) are located in the proximity of the active zones. Under the electron microscope they appear as double parallel rows of dense intramembrane particles.
The synaptic space
Located between the presynaptic region and the post-synaptic muscle membrane lies the synaptic left, which is 50–75 nm wide. It comprises the primary cleft and a number of secondary clefts (subneural clefts). The synaptic cleft is bound laterally by a basement membrane. The primary synaptic cleft has AChR concentrated at the crests of postsynaptic folds opposite the presynaptic active zones. Secondary synaptic clefts (subnerual clefts) are also a significant part of the post-synpatic membrane and located in its depth are present voltage-gated sodium channels.
The post-synaptic membrane
The post-synaptic membrane, as mentioned above, is a highly specialized area of the muscle fiber membrane, known as the end-plate. The end-plate is a convoluted structure with numerous junction folds enhancing the surface area of the post-synaptic membrane. On the crests of each junctional fold are AChR clusters aligned in proximity with an active zone on the presynaptic terminal. The basal lamina of the endplate contains the enzyme acetylcholinesterase (AChE), which are located in the troughs of the junctional folds. [16] The concentration of AChE is five- to eight-fold lower than concentration of ACh receptors, but is enough to hydrolyze most of the ACh release by the nerve terminal and prevents repeated binding of ACh to AChRs. Voltage-gated sodium channels are present in large numbers on the post-synaptic membrane and are particularly concentrated in the depths of the secondary synaptic clefts.
The acetylcholine receptor
AChR is an ionotropic ligand-gated transmembrane receptor channel. It is a quaternary glycoprotein structure with 5 subunits surrounding a central cation channel with negatively charged inner wall. In the adult or "innervated" form of AChR (2α1ß1δ1ε) and in the fetal or "denervated" form of AChR (2α1ß1δ1γ). It has a half-life of 8–11 days. [17] These subunits are homologous across different species, suggesting that the encoding genes evolved from a common ancestral gene. The AChR subunits are arranged in a circle, spanning the membrane forming a central opening that acts as an ion channel (see the image below). Each AChR subunit is composed of four transmembrane domains (M1–M4).
Acetylcholine receptor. Note 5 subunits, each with
Acetylcholine receptor. Note 5 subunits, each with 4 membrane-spanning domains forming a rosette with a central opening. The central opening acts as an ion channel.
The subunits in the AChRs are organized like barrel staves with their convexity inward or in a funnel-like fashion with the narrow end oriented to the intracellular compartment. In the center of the funnel-like portion of the AChR is a cation channel, which is contributed by the M2 and M3 domains of each subunit. Negatively charged residues located at either end of the channel allow the passage of positive ions and exclude passage of the negative ions. Ion binding sites within the channel have an important role in the passage of ions. The ACh binding sites and the main immunogenic region (MIR) are located on the protruding extracellular surfaces of alpha subunits; although in close proximity, the sites for MIR and ACh are distinctly separate. The AChR binding sites are actually located between the α1 and δ subunits and between the α2 and ε subunits. The extracellular portions of AChR extend 100 Angstrom units beyond the cell membrane. Sugars on the extracellular surface of the subunits extend outward and have complex branching patterns. On the cytoplasmic surface of the membrane are cytoskeletal components, which anchor the AChRs. The post-synaptic junctional folds are packed with AChRs (10,000 receptors/µm2) and also contain other protein subsets like MuSK, LRP4, rapsyn, integrins, ErbB receptors, N-acetylgalactosaminlyl transferase, and collagen XIII. [18, 19] Complex interactions between agrin, rapsyn, and MuSK, and LRP4 are involved in the development and maintenance of the NMJ. The clustering of AChR at the crests of the postsynaptic junctional fold is critical for normal neuromuscular transmission.
The troughs of the junctional folds have neural cell adhesion molecules (NCAM), and the voltage-gated sodium ion channels. The latter are tethered to Ankyrin G and β-spectrin, and linked to the cytoskeleton by syntrophins. [20, 21] At the endplate, rapsyn connects AChRs to each other and muscle fiber cytoskeleton via dystrophin-glycoprotein complex (DGC). The DGC contains a number of transmembrane proteins (α- and β-dystroglycan and the sarcoglycan complex). DGC also has submembrane proteins (dystrophin, utrophin, syntrophin, and dystrobrevin) and connects to the cytoskelton via F-actin and to the basal lamina via laminin.
Neureregulin produced by the NR-1 gene is a motor nerve-derived trophic factor similar to agrin. It is thought to induce accumulation of voltage-gated sodium ion channels in the depths of the synaptic clefts. It is noted that shortly after neuregulin appears at the developing NMJ, fetal AChRs containing the γ-subunit (γ-AChRs) are replaced by adult AChRs containing the ε subunit (ε-AChRs). The ε subunit is dependent on the presence of neuregulin for its continued expression at the NMJ. [18] The mature AChRs are constantly turned over by internalization and degradation and replacement by new AChRs. They are not recycled.
Pathophysiology
The following physiologic events occur in neuromuscular transmission:
A nerve action potential propagates down the axon and depolarizes the presynaptic nerve terminal.
Voltage-gage calcium channels open in response to depolarization and there is calcium influx through these channels into the nerve terminal.
Synaptic vesicles fuse with the presynaptic membrane, releasing ACh into the synaptic space.
ACh molecules bind to AChR on the post-synaptic membrane causing the the recepors to undergo conformational change, opening the ion channel.
Membrane conductance to Na+ ions increases (Na+ goes in, K+ goes out) resulting in depolarization of endplate region causing end-plate potenital (EPP).
If the EPP is sufficient to depolarize the adjacent muscle membrane to threshold, an action potential is generated in the muscle fiber. Conversely, if it is of insufficient magnitude it will not cause the muscle membrane to reach threshold, and therefore fails to generate a muscle fiber action potential.
In the resting state, there is an intermittent release of ACh molecules across the primary synaptic cleft. The ACh molecules serve as ligands and bind to the AChR on the post-synaptic membrane. Two molecules of ACh bind to the alpha subunits of the AChR, and fuse with it. The bound AChR then undergoes a 3-dimensional conformational change in the central ion channel portion of the AChR (M2, alpha-helical) opening the funnel-shaped cation channel (whose inner wall is negatively charged). This opening is very brief (about 1 ms) resulting in influx of sodium ions while simultaneously allowing potassium efflux along its opposite concentration gradient. This results in brief depolarization of the muscle membrane only at the junctional region creating a post-synaptic non-propagating depolarization called miniature endplate potentials (MEPPs).
The normal muscle fiber resting membrane potential is -80 mV (negative inside). The threshold for triggering an action potential in the muscle fiber is -50mV to -65mV. When a nerve action potential depolarizes the terminal axons, sodium ion conductance is increased and at the same time voltage-gated calcium channels (VGCCs) are activated, allowing an influx of calcium ion at the terminal portion of the axon. The entry of calcium ions is critical to the process of neuromuscular transmission (if Ca++ is removed from the extracellular space, NMJ transmission ceases). The entry of Ca++ starts a complicated interaction of many proteins including SNARE protein complex at the nerve terminal leading to facilitation of fusion of the ACh-containing vesicles with the presynaptic membrane. Consequently, the discharge of ACh occurs by exocytosis into the synaptic cleft. The greater the calcium concentration inside the presynaptic terminal, the more quanta of ACh are released into the synaptic cleft.
ACh molecules bind to the AChRs resulting in a larger depolarization of the post-synaptic membrane resulting in the endplate potential (EPP). The amplitude of EPP is normally high enough to trigger an action potential at the post-synaptic membrane. The voltage-gated sodium channels present in the depths of the secondary synaptic cleft facilitate action potential, which is propagated along the NMJ muscle membrane. When this action potential invades the transverse tubule system of the muscle, another voltage-gated calcium channel (VGCC) becomes activated causing influx of calcium ions, and triggering mechanical contraction of the muscle fiber contractile apparatus.
The action of ACh on the post-synaptic membrane is short-lived and is terminated within a few milliseconds of its release from the nerve terminal through hydrolysis by the enzyme acetylcholinesterase into acetic acid and choline. The latter is taken up by the presynaptic membrane and repackaged into new ACh molecules.
The calcium ions are normally pumped out of the terminal portion of the axon within 100 ms, so they linger for a while and maintain the axon terminal in a hyperexcitable state, enhancing the release of ACh should a second action potential depolarizes the axon within this time frame.
Safety factor
The amplitude of the EPP tends to be >60 mV above the muscle fiber resting membrane potential of -80 mV. So only 15mV is needed to reach the threshold for action potential of -65 mV. The extra 45 mV is referred as the Safety Factor. So, even if the EPP were to get smaller (e.g., 40 mV) due to repetitive contraction resulting in fatigue, the EPP would still be high to reach threshold and maintain the one-to-one relationship between the action potential of the motor axon and generation of an action potential in the muscle cell. However, if the safety factor is greatly decreased as it may occur in MG, neuromuscular transmission may become blocked.
In MG, the safety factor is reduced (i.e., baseline EPP is reduced but still above threshold). Slow RNS (3 Hz) will cause depletion of ACh quanta and may drop the EPP below threshold, resulting in the absence of a muscle fiber action potential (a phenomenon referred to as presynaptic rundown). Consequently, EPP is reduced as there are fewer AChRs for ACh molecules to bind.
In MG, there are anti-AChR-ab against AChR available at the post-synaptic folds, which become flattened or simplified by the immunopathological mechanism. This, on top of the gradual reduction of AChRs that are released with repeated use of the muscle, leads to insufficient endplate potentials (EPP), which may fall below the threshold value for generation of an action potential. The end result of this process is inefficient neuromuscular transmission. When this failure occurs at enough muscle fibers, it can manifest clinically and can be demonstrated electrophysiologically through low-frequency repetitive nerve stimulation (3 Hz RNS). However, if it occurs in only a few muscle fibers it can be detected on single-fiber electromyography (SFEMG).
Patients become symptomatic once the number of AChRs is reduced to approximately 30% of normal. The cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and usually are not affected by the disease.
The decrease in the number of postsynaptic AChRs is believed to be due to an autoimmune process whereby anti-AChR antibodies are produced and block the AChR. It causes an increase in the turnover of the AChR, and damage of the postsynaptic membrane in a complement-mediated manner.
The exact mechanism of loss of immunologic tolerance to AChR, a self-antigen, is not understood. MG can be considered a B cell–mediated disease, in that it derives from antibodies (a B cell product) against AChR. However, the importance of T cells in the pathogenesis of MG is becoming increasingly apparent. The thymus is the central organ in T cell–mediated immunity, and thymic abnormalities such as thymic hyperplasia or thymoma are well recognized in myasthenic patients.
It is thought that both the initiation and maintenance of MG occurs in a process that involves type-II hypersensitivity reactions. The production of autoantibodies implies that it is a B-cell-mediated autoimmune disorder. The intiation of the process is dependent on T-cell help. Accordingly, CD4 T cells are the main driving force in the immunopathogenesis of MG. Macrophages and dendritic cells are activated and these act as antigen-presenting cells. AChRs phagocytized by macrophages become degraded into peptide subcomponents. These are then linked to MHC-II, the molecule required for reactivity to “self-antigens.” The AChR antigenic fragment and MHC complex are transported to the surface of macrophages and dendritic cells. Specific, helper T cells, with the cooperation of CD3 complex and CD4 molecular T-cell receptor site, recognize this antigen complex. Specific receptor sites on the T-cell surface recognize cytokines secreted by the macrophage and dendritic cells. The activated helper T cells secrete interferon (IFN)-γ and interleukin (IL)-17 that stimulate B lymphocytes. The activated B lymphocytes grow and undergo clonal expansion into antibody-synthesizing plasma cells. These plasma cells secrete IgG anti-AChR antibodies that bind to the nictonic ACh-R.
Antibody response in MG is polyclonal. In an individual patient, antibodies are composed of different subclasses of IgG. In most instances, they are of IgG1 and IgG3 subclass and are directed against the main immunogenic region (MIR) on the alpha subunit. The alpha subunit is also the site of ACh binding, though the binding site for ACh is not always the same as the MIR. Binding of AChR antibodies to AChR results in impairment of neuromuscular transmission in several ways, including the following:
Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChR molecules
Causing complement-mediated destruction of junctional folds of the postsynaptic membrane
Blocking the binding of ACh to AChR
Decreasing the number of AChRs at the NMJ by simplification of the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs
Patients without anti-AChR antibodies are recognized as having seronegative MG (SNMG). These patients usually have autoantibodies (IgG4) against muscle-specific kinase (MuSK). These do not activate complement, unlike AChR-abs. MuSK plays a critical role in postsynaptic differentiation and clustering of AChRs at the NMJ to promote efficient neuromuscular transmission. MuSK autoantibodies are pathogenic and this is proven by passive transfer and active immunization studies in animals. It is likely MuSK autoantibodies disrupt the interaction between MuSK and the LRP4 and collagen Q. Patients with anti-MuSK antibodies are predominantly women, with a tendency of disease onset in the third or fourth decades. They have prominent oculobulbar weakness with dysarthria. Face and tongue atrophies have been reported in long-standing disease. It is often confused with bulbar amyotrophic lateral sclerosis (ALS). Another group has reported patients who exhibit prominent neck (dropped head syndrome), shoulder, and respiratory weakness. [12, 13] Myasthenic crises appear to be more frequent in patients with MuSK antibodies. [22, 23]
The role of the thymus in the pathogenesis of MG is not entirely clear, but 75% of patients with MG have some degree of thymus abnormality (eg, hyperplasia or thymoma). Histopathologic studies have shown prominent germinal centers. Epithelial myoid cells normally present in the thymus resemble skeletal muscle cells and possess AChRs on their surface membrane. These cells may become antigenic by molecular mimicry and unleash an autoimmune attack on the muscular endplate nicotinic AChRs.
The question of why MG affects the extraocular muscles first and predominantly remains unanswered. The answer probably has to do with type and distribution of NMJs in at least some of the muscles affected by the disease.
The distinctive features in MG, particularly the fluctuating nature of a patient's strength, is attributed to the unique pathophysiology of impaired neuromuscular transmission. This pathophysiology produces a dynamic rather than a fixed disorder as a result of the relative ease by which NMJs repair.
Etiology
MG is idiopathic in most patients. Although the main cause behind its development remains speculative, the end result is a derangement of immune system regulation. MG is clearly an autoimmune disease in which the specific antibody has been characterized completely. In as many as 90% of generalized cases, IgG to AChR is present. [14] Even in patients who do not develop clinical myasthenia, anti-AChR antibodies can sometimes be demonstrated.
Patients who are negative for anti-AChR antibodies may be seropositive for antibodies against MuSK. Muscle biopsies of these patients show myopathic features with prominent mitochondrial abnormalities, as opposed to the neurogenic features and atrophy frequently found in MG patients positive for anti-AChR. The mitochondrial impairment could explain the oculobulbar involvement in anti-MuSK–positive MG. [24]
Numerous findings have been associated with MG. For example, people with certain human leukocyte antigen (HLA) types have a genetic predisposition to autoimmune diseases. The histocompatibility complex profile includes HLA-A1, -A3, -B7, -B8, -DRw3, and -DQw2 (though these have not been shown to be associated with the strictly ocular form of MG). However, HLA genotyping is not routinely used in the evaluation of patients suspected to have MG.
Sensitization to a foreign antigen that has cross-reactivity with the nicotinic ACh receptor has been proposed as a cause of myasthenia gravis, but the triggering antigen has not yet been identified.
Various drugs may induce or exacerbate symptoms of MG, including the following:
Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and ampicillin)
Penicillamine - This can induce true myasthenia, with elevated anti-AChR antibody titers seen in 90% of cases; however, the weakness is mild, and full recovery is achieved weeks to months after discontinuance of the drug
Beta-adrenergic receptor blocking agents (eg, propranolol and oxprenolol)
Lithium
Magnesium
Procainamide
Verapamil
Quinidine
Chloroquine
Prednisone
Timolol (ie, a topical beta-blocking agent used for glaucoma)
Anticholinergics (eg, trihexyphenidyl)
Neuromuscular blocking agents (eg, vecuronium and curare) - These should be used cautiously in myasthenic patients to avoid prolonged neuromuscular blockade
Nitrofurantoin has also been linked to the development of ocular MG in 1 case report; discontinuance of the drug resulted in complete recovery.
MG induction as a side effect of cancer immunotherapy
Ipilimumab induced (anti-CTLA4) MG
PD-1, PDL-1 inhibitors
Thymic abnormalities are common: Of patients with MG, 75% have thymic disease, 85% have thymic hyperplasia, and 10–15% have thymoma. Extrathymic tumors may include small cell lung cancer and Hodgkin disease. [25, 26] Hyperthyroidism is present in 3–8% of patients with MG and has a particular association with ocular MG.
Epidemiology
The overall incidence rate of MG has been estimated at 2.1 to 5.0 per million people per year and has not changed over time. However, the prevalence rate has increased since the 1950s in keeping with the declining mortality rate in MG as well as improved diagnostic precision. Accroding to regional studies peformed since 1990, the prevalence rate ranges from approximately 7–20 per 100,000. [24, 25]
Approximately 15%–20% of patients with MG experience crisis in their lifetime, typically within the first 2 years of the diagnosis. [26]
Fifty years ago, estimates of mortality in MG crisis ranged from 50% to 80%. [27, 28, 29] Currently, the overall in-hospital mortality rate was 2.2%, being higher in MG crisis (4.47%). Older age and respiratory failure were the predictors of death.
Age-related demographics
MG can occur at any age. Female incidence peaks in the third decade of life, whereas male incidence peaks in the sixth or seventh decade. The mean age of onset is 28 years in females and 42 years in males.
Transient neonatal MG occurs in infants of myasthenic mothers who acquire anti-AChR antibodies via placental transfer of IgG. Some of these infants may suffer from transient neonatal myasthenia due to effects of these antibodies.
Most infants born to myasthenic mothers possess anti-AChR antibodies at birth, yet only 10-20% develop neonatal MG. This may be due to protective effects of alpha-fetoprotein, which inhibits binding of anti-AChR antibody to AChR. High maternal serum levels of AChR antibody may increase the chance of neonatal MG; thus, lowering the maternal serum titer during the antenatal period by means of plasmapheresis may be useful.
Sex-related demographics
Classically, the overall female-to-male ratio has been considered to be 3:2, with a female predominance in younger adults (ie, patients aged 20-30 years) and a slight male predominance in older adults (ie, patients older than 50 years). [6, 10] Studies show, however, that with increased life expectancy, males are coming to be affected at the same rate as females. Ocular MG shows a male preponderance. The male-to-female ratio in children with MG and another autoimmune condition is 1:5. MuSK myasthenia is found predominantly in women and has a peak incidence of less than 40 years of age. [30]
Race-related demographics
The onset of MG at a young age is slightly more common in Asians than in other races. [6]
The annual incidence rate of MG is higher in black women (0.01 per 1000 persons/year) compared to white women (0.009 per 1000 persons/year) and white (0.008 per 1000 persons/year) and black men (0.007 per 1000 persons/year). [31]
MG can be classified by age of onset, site or sites of involvement on the NMJ, serological status, and associated thymic pathology. This is helpful in diagnosis and management. Also, the sensitivity of diagnostic tests may very according to age of onset, specific antibodies, and whether the disease is ocular or generalized.
The vast majority of patients have MG that is immune mediated, but they are very rare congenital myasathenic syndromes that have no immune basis and where immunosuppresants must not be used.
Prognosis
Given current treatment, which combines cholinesterase inhibitors, immunosuppressive drugs, plasmapheresis, immunotherapy, and supportive care in an intensive care unit (ICU) setting (when appropriate), most patients with MG have a near-normal life span. Mortality is now 3-4%, with principal risk factors being age older than 40 years, short history of progressive disease, and thymoma; previously, it was as high as 30-40%. In most cases, the term gravis is now a misnomer.
Morbidity results from intermittent impairment of muscle strength, which may cause aspiration, increased incidence of pneumonia, falls, and even respiratory failure if not treated. [14] In addition, the medications used to control the disease may produce adverse effects.
Today, the only feared condition arises when the weakness involves the respiratory muscles. Weakness might become so severe as to require ventilatory assistance. Those patients are said to be in myasthenic crisis.
The disease frequently presents (40%) with only ocular symptoms. However, the extraocular almost always are involved within the first year. Of patients who show only ocular involvement at the onset of MG, only 16% still have exclusively ocular disease at the end of 2 years.
In patients with generalized weakness, the nadir of maximal weakness usually is reached within the first 3 years of the disease. As a result, half of the disease-related mortality also occurs during this period. Those who survive the first 3 years of disease usually achieve a steady state or improve. Worsening of disease is uncommon after 3 years.
Thymectomy results in complete remission of the disease in a number of patients. However, the prognosis is highly variable, ranging from remission to death.
Patient Education
Educate patients to recognize and immediately report impending respiratory crisis. Intercurrent infection may worsen symptoms of MG temporarily. Mild exacerbation of weakness is possible in hot weather.
The risk of congenital deformity (arthrogryposis multiplex) is increased in offspring of women with severe MG. Neonates born to women with MG must be monitored for respiratory failure for 1-2 weeks after birth. Certain immunosuppressant drugs have teratogenic potential. Discuss these aspects with women in reproductive years before beginning therapy with these drugs.
Certain medications (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, and quinidine) may exacerbate symptoms of MG; many others have been associated only rarely with exacerbation of MG. Patients should always consult a neurologist before starting any of these medications.
Myasthenia Gravis Clinical Presentation: History, Physical Examination
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History
Patients with myasthenia gravis (MG) present with painless, specific muscle weakness, and not generalized fatigue. Myasthenic weakness typically affects the extraocular, bulbar, or proximal limb muscles. Droopy eyelids or double vision is the most common symptom at initial presentation of MG, with more than 75% of patients. These symptoms progress from mild to more severe disease over weeks to months. Difficulty in swallowing, slurred or nasal speech, difficulty chewing, and facial, neck, and extremity weakness occur. [32] On the other hand, symptoms may remain limited to the extraocular and eyelid muscles for years. Rarely, patients with severe, generalized weakness may not have associated ocular muscle weakness.
The hallmark of MG is that muscles get weaker with repeated use. The examiner needs to establish this on the history and exam. It is important to discriminate fatigable weakness from nonspecific fatigue or somnolence. The prevalence of obstructive sleep apnea or poor sleep hygiene is higher in patients with MG; therefore, somnolence secondary to a sleep disorder may coexist with MG. [30] Psychosocial factors become important in assessment if a mood disorder or depression is suspected. Patients with fluctuating fatigable muscle weakness due to MG will describe weakness of a specific group of muscles that is brought on by activity and which improves with rest. In contrast, patients with generalized fatigue or exhaustion due to any number of causes will typically report generalized weakness, tiredness, or lack of energy. In myasthenia, often the complaint of weakness may be noted following exertion or at the end of the day. This often results in little detectable objective weakness at the time of examination. Maneuvers that fatigue specific muscle groups can be very useful in provoking weakness in patients. In contrast, patients with generalized fatigue or malaise do not typically display true muscle weakness with provocative maneuvers.
The general appearance of a myasthenic patient gives an impression of a person who is sleepy or with a sad-looking facial appearance caused by ptosis and facial weakness. It is often helpful to look at old photographs of the patient from earlier years, for example, by examining his or her driver’s license. Eye findings are common, with ptosis and extraocular muscle weakness occurring in more than 50% of patients at the time of presentation and in more than 90% of patients sometime during their illness. The patient who has no ptosis first thing in the morning and whose eyes are completely closed at night almost certainly has MG. Ptosis can be unilateral and, if bilateral, is usually asymmetric. Persistently symmetric ptosis is more suggestive of a myopathic etiology, especially chronic progressive external ophthalmoplegia (CPEO) or oculopharyngeal muscular dystrophy (OPMD). MG is one of few disorders that can cause complete unilateral (or rarely bilateral) ptosis or a history of ptosis alternating sides over time. Many patients describe diplopia. Milder involvement may produce blurred vision or a halo around objects. Photophobia, with worsening of either ptosis or diplopia in bright light, is not uncommon and some patients are so troubled by this that they wear dark sunglasses. Patients may give history of frequent changes in eyeglasses to correct blurry vision. Patients with LEMS rarely, if ever, present with ocular symptoms. Myasthenic weakness of the ocular muscles have been known to mimic CN III, CN IV, and CN VI nerves palsies and, rarely, an internuclear ophthalmoplegia. Unlike true CN III nerve palsies, however, MG never affects papillary function. Fixed extraocular muscle weakness may occur late in the illness, especially if untreated.
Up to 20% of patients with MG may have prominent oropharyngeal symptoms early in the disease course, including dysarthria, dysphagia, and difficulty chewing. [33] Weakness of palatal muscles may confer a nasal quality to the voice. Speech may become slurred (from weakness of the tongue, lips, and face), which may worsen with prolonged talking (e.g., talking on the telephone or giving a speech or presentation). Although the speech assumes a nasal intonation (from weakness of the soft palate), there is no impairment in fluency in speech.
Chewing may become difficult and often patients may actively open and close their jaw with their hands. Severe jaw weakness may cause the jaw to hang open (the patient may sit with a hand on the chin for support). Swallowing may become difficult, and aspiration may occur with fluids, giving rise to coughing or choking while drinking. Liquids are more difficult to swallow than solid food. Often, patients will complain of nasal regurgitation of liquids. Coughing, nose-blowing, or throat-clearing may be noted.
Rarely, patients with MG may present with respiratory muscle weakness without other prominent MG symptoms. [34] However, the vast majority of patients with respiratory muscle weakness have ocular and bulbar symptoms. Patients with diaphragmatic weakness will often have orthopnea as an early symptom. This may lead to respiratory compromise when the patient lies supine. Patients with MG and respiratory muscle weakness may report an inability to draw a full breath. They often describe their breathing as rapid and shallow, which may be misinterpreted as hyperventilation due to anxiety.
Fatigable extremity weakness in MG may affect any muscle group. Generally, it is proximal and often has an asymmetrical appearance. Characteristically, muscles are noted to weaken with repeated use, and strength improves with rest. Patients note difficulty getting up from chairs and going up and down the stairs. Patients may complain of a footdrop with prolonged walking, hip extension weakness with climbing several flights of stairs, shoulder muscle fatigue with activities that require holding their arms above their heads, and weakness of finger flexors and extensors with prolonged typing. Rarely, weakness may be very focal, affecting distal limb muscles or neck extensors selectively.
Pain, as a result of muscle aches or cramps, is commonly reported, especially in the neck. Sensory complaints are not a feature of MG; however, many patients get ulnar mononeuropathy at the elbow due to the constant attempts to hold the head up due to weakness of neck muscles.
Symptoms may worsen with exposure to extreme heat or emotional stress. Infection, systemic illness, pregnancy, the menstrual cycle, or drugs that affect neuromuscular transmission may also exacerbate myasthenia. Patients may report that they plan activities for early in the day when their strength is at its peak.
Bowel and bladder dysfunction are uncommon in MG. As MG is a disorder affecting nicotinic cholinergic receptors, dyasutonomia does not occur.
Depression may be seen from the progressive and disabling symptoms, but is not very common. Cognitive difficulties are not seen in MG.
Anti-MuSK-positive MG has several clinical characterisitics that differ from more common anti-ACh-R-positive myasthenia gravis. It occurs predominately in women with onset typically occurring in the fourth decade of life. In the United States, it is preponderant in African-American women. Patients with anti-MuSK antibodies have severe faciopharyngeal weakness with complaints of difficulty speaking and swallowing. They may have facial and tongue muscle atrophy and may mimic ALS. [31] Some patients have early respiratory muscle and neck weakness and present with dyspnea and neck pain. Most MuSK-positive MG patients have little or minimal associated ocular symptoms. [30] Myasthenic crisis is also more common.
MGFA classification of myasthenia gravis
In May 1997, the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) formed a task force to address the need for universally accepted classifications, grading systems, and analytic methods for management of patients undergoing therapy and for use in therapeutic research trials. As a result, the MGFA Clinical Classification was created. [3] This classification divides MG into 5 main classes and several subclasses, as follows.
Class I: Any ocular muscle weakness; may have weakness of eye closure. All other muscle strength is normal.
Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity.
Class IIa: Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.
Class III: Moderate weakness affecting other than ocular muscle; may also have ocular muscle weakness of any severity
Class IIIa: Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
Class IIIb MG: Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.
Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity.
Class IVa: Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.
Class V: Defined by intubation, with or without mechanical ventilation, except when used during routine postoperative management. Use of a feeding tube without intubation places the patient in class IVb.
Physical Examination
Patients with MG can present with a wide range of signs and symptoms, depending on the severity of the disease.
Mild presentations may be associated with only subtle findings, such as ptosis, that are limited to bulbar muscles. Findings may not be apparent unless muscle weakness is provoked by repetitive or sustained use of the muscles involved. Recovery of strength is seen after a period of rest or with application of ice to the affected muscle. Conversely, increased ambient or core temperature may worsen muscle weakness.
Variability in weakness can be significant, and clearly demonstrable findings may be absent during examination. This may result in misdiagnosis (eg, functional disorder). The physician must determine strength carefully in various muscles and muscle groups to document severity and extent of the disease and to monitor the benefit of treatment.
Another important aspect of the physical examination is to recognize a patient in whom imminent respiratory failure is imminent. Difficulty breathing necessitates urgent or emergent evaluation and treatment.
Weakness can be present in a variety of different muscles and is usually proximal and not symmetrical. Sensory examination and deep tendon reflexes are normal.
Distribution of weakness in a large cohort of patients with myasthenia gravis (n=609) (Open Table in a new window)
Distribution of Weakness Percentage of Patients
Localized ocular 17%
Ocular and generalized 50%
Ocular and bulbar 13%
Ocular and limb 20%
Weakness of the facial muscles is almost always present. Bilateral facial muscle weakness produces a “sagging and expressionless” face, and a horizontal smile. At rest, the corners of the mouth droop downward, giving the patient a look of sadness. Attempts to smile result in contraction of the medial portion of the upper lip and horizontal contraction of the corners of the mouth with loss of the natural upward curling, giving the patient's smile an appearance of a snarl (“myasthenic snarl”). Patients are unable to whistle, suck through a straw, or blow up a balloon. This often impedes bedside respiratory assessment because the lips form a poor seal around the mouthpiece of the measuring device. The frontalis muscle may be chronically contracted, giving a worried or surprised look to the patient. A unilateral frontalis ‘‘hypercontraction’’ is a clue that the lid elevators are weak on that side. Also, to compensate for ptosis, the sclerae below the limbi may be exposed secondary to weak lower lids. Mild proptosis attributable to extraocular muscle weakness also may be present. Bell’s phenomenon, which is upward rotation of the eyeballs during attempted eyelid closure, is appreciated on examination because of weakness of the orbicularis oculi muscle resulting in incomplete closure of the eyelids. Weakness of eyelid closure is seen in most patients with MG and should be specifically tested by asking patients to forcefully close their eyes while the examiner attempts to manually open the eyelids.
Typically, extraocular muscle weakness is asymmetric. The weakness usually affects more than 1 extraocular muscle and is not limited to muscles innervated by a single cranial nerve; this is an important diagnostic clue. The weakness of lateral and medial recti (more commonly involved) may produce a pseudointernuclear ophthalmoplegia, described as limited adduction of 1 eye, with nystagmus of the abducting contralateral eye on attempted lateral gaze. Pupillary responses are normal. Cogan’s lid twitch describes a brief momentary twitch seen in an eyelid that is elevated on rest. Following sustained downgaze the patient is asked to bring the eyes back up to the primary gaze position. The upper eyelid briefly overshoots resulting in exposure of the sclera between the upper limbus and upper eyelid, followed by a rapid drop to a lower position and return of ptosis of the eyelid. The “twitch” is the momentary elevation of the eyelid before it drops due to fatigue of the levator palpebrae superioris muscle. This sign is not unique to MG and may be seen in dorsal brain stem glioma and menigioma.
Weakness of palatal muscles can occur in roughly 40% of all patients. It can cause the voice to become hypophonic and assume a nasal twang. Nasal regurgitation of food (especially liquids) can occur. An inability to pucker lips or whistle, or puffing the cheeks out against resistance can be noted. As neuromuscular transmission may actually be improved by cooler temperatures, patients note cold food and liquids are easier to swallow than warm foods and liquids are.
Patients with MG who have difficulty chewing may demonstrate weakness of jaw closure due to masseter and temporalis muscle weakness. Weakness of jaw opening due to pterygoid muscle weakness, on the other hand, is rarely seen. This pattern of weak jaw closure and relatively strong jaw opening is quite typical of MG. A frequent sign of jaw weakness is that the patient holds the jaw closed with the thumb under the chin, the index finger extended up the cheek, the middle finger curled under the nose and across the philtrum, producing a studious or attentive appearance. Typically, neck flexion is weaker than neck extension in patients with MG, although occasionally patients will present with a head-drop and have severe neck extension weakness.
Certain limb muscles are involved more commonly than others (eg, upper limb muscles are more likely to be involved than lower limb muscles). In the upper limbs, deltoids and extensors of the wrist and fingers are affected most. The triceps is more likely to be affected than the biceps. In the lower extremities, commonly involved muscles include hip flexors, quadriceps, and hamstrings, with involvement of foot dorsiflexors or plantar flexors less common.
Respiratory muscle weakness that produces acute respiratory failure is a true neuromuscular emergency, and immediate intubation may be necessary. Weakness of the intercostal muscles and the diaphragm may result in carbon dioxide retention as a result of hypoventilation. Respiratory failure usually occurs around the time of surgery (eg, after thymectomy) or during later stages of the disease. However, it can be a presenting feature in about 14-18% of patients with MG. [33] Weak pharyngeal muscles may collapse the upper airway. Careful monitoring of respiratory status is necessary in the acute phase of MG. Negative inspiratory force, vital capacity, and tidal volume must be monitored carefully. Relying on pulse oximetry to monitor respiratory status can be dangerous. During the initial phase of neuromuscular hypoventilation, carbon dioxide is retained but arterial blood oxygenation is maintained. This can lull the physician into a false sense of security regarding a patient’s respiratory status.
Cognition, coordination, sensation, and muscle stretch reflexes are normal in the myasthenic patient.
Provocative maneuvers used in suspected myasthenia gravis
The following maneuvers are helpful for diagnosis of MG:
Sustained upgaze (60 to 180 seconds); results in fatigable ptosis in one or both eyes.
Manual elevation of the more ptotic lid may worsen ptosis of the contralateral eyelid, a phenomenon known as enhanced ptosis. This phenomenon is based on Herrings Law of equal innervation.
Sustained tight closure of the eyelids can induce fatigue of the orbicularis oculi muscles resulting in the white sclera of the eye slowly becoming apparent under the partially open eye. This is called the “peek sign.”
Fatigable diplopia in sustained lateral gaze (60 seconds); results in diplopia with images appearing side by side.
Sustained abduction of the arms (120 seconds); patient can no longer hold arms up, or weakness becomes apparent with subsequent manual testing.
Ask the patient to perform deep knee bends with the back straight. The patient’s palm is held in that of the examiner. An increase in pressure against the examiner’s palm while doing this maneuver is an early sign of weakness. Also, a forward lean by the patient (moving the center of gravity forward) is another sign of weakness.
Counting aloud (1 to 50): Enhances dysarthria (nasal, lingual, or labial) and results in dyspnea. Patient may sound relatively clear on speaking initially but will become increasingly dysarthric to the point of becoming unintelligible.
Weakness of the laryngeal muscles results in hoarseness. This can be elicited by asking the patient to make a high-pitched (“eeee”) sound.
Single breath counting aloud (1 to 20) may elicit not only dysarthria but dyspnea and gives an approximate idea of the vital capacity. Multiplying the number the patient can achieve with one breath by 100 (e.g., 20 x 100 = 2000 cc) will provide a reasonable estimate of the vital capacity.
Sustained elevation of leg while lying supine (90 seconds): Patient can no longer hold leg up, or weakness becomes apparent with subsequent manual testing.
Repeated arising from chair without use of arms (up to 20 repetitions): Fatigues after several attempts. Early/mild weakness may cause exaggerated lean-forward and ‘‘buttocks-first’’ maneuver.
The quantitative myasthenia gravis test and similar scales incorporate measures of ocular, bulbar, respiratory, and extremity strength and fatigue. Although used mostly for research trials, the quantitative myasthenia gravis test score can be used in clinical practice to follow patients during treatment. [17]
Evidence of coexisting autoimmune diseases
MG is an autoimmune disorder, and other autoimmune diseases are known to occur more frequently (13%–22%) in patients with MG than in the general population. Some autoimmune diseases that occur at higher frequency in MG patients are hyperthyroidism, SLE, rheumatoid arthritis, scleroderma, ulcerative colitis, Addison disease, pernicious anemia, red cell aplasia, Sjogren's syndrome, and sarcoidosis. Both acute and chronic inflammatory demyelinating polyneuropathies have been reported in patients with concurrent MG. [35, 36]
Various autoimmune channelopathies, autonomic neuropathy with and without encephalopathy concomitant with the MG and thymoma has also been reported. [37]
MG and inflammatory myopathy is seen in in 5% of cases. Most of these patients have a thymoma with or without myocarditis. Histopathology reveals a giant cell or granulomatous myositis. Elevated CK (not usually seen in MG alone) is commonly found. [38]
MG and thymoma are also reported to have been associated with acquired neuromyotonia or Isaac’s syndrome, rippling muscle disease, and stiff-person syndrome. [39, 40]
A thorough skin and joint examination may help diagnose any of these coexisting diseases. Tachycardia or exophthalmos point to possible hyperthyroidism, which may be present in up to 10-15% of patients with MG. This is important because in patients with hyperthyroidism, weakness may not improve if only the MG is treated.
SECTIONS
Diagnostic Considerations
Myasthenia gravis (MG) can mimic other diagnoses in elderly persons and vice versa. Examples of such pathology include diagnoses such as congestive heart failure, pulmonary embolism, and acute myocardial infarction.
Differential Diagnoses
Amyotrophic Lateral Sclerosis in Physical Medicine and Rehabilitation
Basilar Artery Thrombosis
Botulism
Brainstem Gliomas
Cavernous Sinus Syndromes
Chronic Myelogenous Leukemia (CML)
Ciguatera Toxicity
Congenital Myasthenic Syndrome
Dermatomyositis
Diphtheria
Graves Disease
Guillain-Barre Syndrome
Kearns-Sayre Syndrome
Lambert-Eaton Myasthenic Syndrome (LEMS)
Miller-Fisher Syndrome
Multiple Sclerosis
Myocardial Infarction
Neurosarcoidosis
Organophosphate Toxicity
Polymyositis
Pulmonary Embolism (PE)
Tetrodotoxin Toxicity
Thyroid Ophthalmopathy
Tick-Borne Diseases
Tolosa-Hunt Syndrome
Myasthenia Gravis Workup: Laboratory Tests, Radiography, CT, and MRI, Electrodiagnostic Studies
Routine motor and sensory nerve conduction studies (NCS) must not be omitted before embarking on electrodiagnostic studies that demonstrate a defect of neuromuscular transmission. Routine NCS is done to ensure the integrity of any nerve that subsequently will be used in RNS. A decrement in RNS can be seen in other conditions (neuropathies, motor neuron disease, inflammatory myopathies) and myotonic disorders. At least one motor and sensory conduction study should be performed in an upper and lower extremity. Compound mucle action potentials (CMAP) amplitudes should be normal with only 3% to 15% showing CMAPs that are diffusely low. If CMAP amplitudes are low or borderline, repeat distal stimulation after 10 seconds of exercise to exclude a presynaptic NMJ transmission disorder such as LEMS. The routine needle EMG of distal and proximal muscles, especially weak muscles may reveal unstable or small amplitude, short duration, polyphasic motor unit potentials, with or without early recruitment. Unstable motor units represent muscle fibers that are blocked or come into action potential at varying intervals, resulting in MUAPs that change in configuration from impulse to impulse. Fibrillation potentials and other abnormal spontaneous activity are not seen in NMJ disorder, except in the case of botulism.
The following 2 studies are commonly performed:
Repetitive stimulation of a muscle at 2-3 Hz, also known as repetitive nerve stimulation (RNS)
Single-fiber electromyography (SFEMG), aimed at evaluating neuromuscular block, jitter, and fiber density
SFEMG is more sensitive than RNS in assessing MG. However, SFEMG is technically more difficult and much more dependent on the experience and skill of the testing physician. Consequently, RNS is the most frequently performed neurophysiologic test of neuromuscular transmission.
Repetitive nerve stimulation
RNS is abnormal in more than 50% to 70% of patients with generalized MG but are often normal in patients with purely ocular form of MG. During low-frequency (1-5 Hz) RNS, the locally available acetylcholine (ACh) becomes depleted at all neuromuscular junctions (NMJs), and less is therefore available for immediate release. This results in smaller excitatory postsynaptic potentials (EPSPs).
In patients without MG, all EPSPs exceed the threshold to generate an action potential (ie, there is a safety factor). No change in the summated compound muscle action potential (CMAP) is noted. In patients with MG, the number of AChRs is reduced, lowering the safety factor. During RNS, some EPSPs may not reach threshold, which means that no action potential is generated. This results in the decrement in the amplitude of the CMAP.
In patients with myasthenia gravis, this decremental response usually has a maximum decrement at the fourth or fifth response, followed by a tendency toward repair (see the image below). A stimulation rate of 1-5 per second should result in a 10% or more decrease in amplitude by the fourth or fifth action potential; any decrement over 10% is considered abnormal. The most common employed stimulation rate is 3 Hz.
Repetitive nerve stimulation at frequency of 2 Hz
Repetitive nerve stimulation at frequency of 2 Hz showing increasing decrement in amplitude of compound muscle action potential up to fourth response (42% amplitude loss), after which it stabilizes.
Patients with MG rarely have a decreased response in a clinically normal muscle. Thus, testing a proximal weak muscle gives a better yield than testing a unaffected distal muscle, even if the latter is technically easier. Testing a facial muscle (eg, the orbicularis oculi) is useful because most patients suffer from eyelid weakness or ptosis. RNS results are less likely to be positive in patients with ocular MG. Facial RNS is especially important to perform in suspected anti-MuSK MG due to much higher facial and bulbar involvement than a limb muscle.
Factors affecting results
Several factors can affect RNS results. Lower temperatures increase the amplitude of the CMAPs. Patients with MG may report clinically significant improvement in cold temperatures, and they typically report worsening of ptosis in bright sunlight or on a warm day. Therefore, maintaining a constant and perhaps higher-than-ambient temperature during RNS testing is important to bring out abnormalities of NMJ function. The temperature of the skin overlying the tested muscle should be at least 34°C.
Administration of AChE inhibitors before testing may mask the abnormality and consequently should be avoided for at least 1 day beforehand (even longer for long-acting agents).
Factors related to tetanic contraction may also affect RNS findings. A tetanic contraction of muscle is followed by 2 distinct phases:
Post-exercise facilitation or repair of decrement, occurring for the first 2 minutes after tetanic contraction
Post-exercise exhaustion, lasting an additional 15 minutes after posttetanic potentiation
During post-exercise facilitation, accumulation of calcium inside the terminal axon causes enhanced mobilization and release of ACh, which overcomes the reduced number of AChRs at the NMJ and thus leads to larger EPSPs with additional recruitment of muscle fibers, resulting in a larger CMAP. In MG, this potentiation may normalize RNS results.
In the post-exercise exhaustion phase, the NMJ is less excitable, and even fewer EPSPs reach threshold. Thus, some patients with an equivocal abnormality on RNS during the resting phase may show clear-cut abnormalities during the post-exercise exhaustion phase.
Tetanic contraction of the muscle can be achieved by applying electrical stimulation to the nerve at a rate of 50 per second for 20-30 seconds. However, this is painful. Voluntary contraction of the muscle for 10 seconds at the maximum force can achieve the same goal without discomfort and is preferred. This principle is utilized in RNS studies. If on slow RNS (3 Hz) there is no significant decrement (< 10%) on RNS at baseline, the patient should peform maximual voluntary contraction of the muscle being tested for 1 minute. This is followed by RNS immediately and at 1-minute intervals for the next 4 minutes, looking for a >10% CMAP decrement that results from post-exercise exhaustion. If at any time, either at baseline or following exercise, a significant decrement (>10%) develops, the patient should perform a brief 10 seconds of maximum voluntary contraction of the muscle being tested. Immediately following this maneuver, slow RNS is performed looking for an increment in the CMAP that suggests post-exercise facilitation or “repair” of decrement. This finding should be demonstrated in at least two nerves for the definite diagnosis of a neuromuscular transmission defect.
It is useful to get a baseline RNS on patients who are clinically and have serological positive status for MG. Typically, these patients who are initially weak will on slow RNS (3Hz) demonstrate significant decrement (>10%). When such patients who are on treatment return later at some point with worsening of symptoms, a normal RNS (showing no decrement) may be helpful in ruling out worsening of weakness due to myasthenia.
Single-fiber electromyography
SFEMG provides the most sensitive measure of myasthenia gravis. A normal SFEMG of a clinically weak muscle effectively rules out the diagnosis of MG.
A concentric needle electrode and other monopolar and bipolar needle electrodes can record single motor unit potentials, but they cannot discriminate individual muscle fibers within the motor unit. The single-fiber needle used in SFEMG, which has a small recording surface, allows recording from individual muscle fibers.
SFEMG is capable of determining jitter (ie, variability of the time interval between the action potentials of 2 single adjacent muscle fibers in the same motor unit) and fiber density (ie, number of single-fiber action potentials within recording radius of the needle). Increased jitter (with or without impulse blocking) and normal fiber density are suggestive of a neuromuscular fiber transmission defect (see the image below).
Single-fiber electromyography showing so-called ji
Single-fiber electromyography showing so-called jitter phenomenon (second action potential wave group).
Myasthenia Gravis Treatment & Management: Approach Considerations, Pharmacologic Therapy, Management of neonatal myasthenia gravis
Approach Considerations
Even though no rigorously tested treatment trials have been reported and no clear consensus exists on treatment strategies, myasthenia gravis (MG) is one of the most treatable neurologic disorders. Several factors (eg, severity, distribution, rapidity of disease progression) should be considered before therapy is initiated or changed. Treatment regimens are individualized depending on the severity of the myasthenia (MGFA class), patient age, serology status, thymic pathology, concurrent medical issues, patient and physician preference and physician experience.
In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG. Definitions were developed for goals of treatment, minimal manifestation status (MMS), remission, ocular MG, impending crisis, crisis, and refractory MG. Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. [53]
MGFA Task Force defined goals of treatment of MG to achieve Minimal Manifestation Status (MMS) or better, with no more than grade 1 Common Terminology Criteria for Adverse Events (CTCAE) medication side effects. Operational definitions were set as follows:
Definition of remission: The patient has no symptoms or signs of MG. Weakness of eyelid closure is accepted, but there is no weakness of any other muscle on careful examination. Patients taking cholinesterase inhibitors (ChEIs) every day with reasonable evidence to support symptomatic benefit are therefore excluded from this category.
MMS: The patient has no symptoms or functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of remission have mild weakness.
CTCAE grade 1 medication side effects: asymptomatic or only mild symptoms; intervention not indicated.
Definition of ocular MG (based on dysfunction due to MG at a specified point in time, and not dependent upon the duration of disease): MGFA Class I: Any ocular muscle weakness. May have weakness of eye closure. Strength in all other facial, bulbar, and limb muscles is normal. (It is recognized that some patients report fatigue when strength testing is normal. The physician should use clinical judgment in attributing fatigue to generalized MG in the absence of objective nonocular weakness).
Definition of impending myasthenic crisis: Rapid clinical worsening of MG that, in the opinion of the treating physician, could lead to crisis in the short term (days to weeks).
Definition of manifest myasthenic crisis (the concept of crisis focuses on the clinical implications—it represents a serious, life-threatening, rapid worsening of MG and potential airway compromise from ventilatory or bulbar dysfunction): MGFA Class V: Worsening of myasthenic weakness requiring intubation or noninvasive ventilation to avoid intubation, except when these measures are employed during routine postoperative management (the use of a feeding tube without intubation places the patient in MGFA Class IVB).
Definition of refractory MG: Unchanged or worse after corticosteroids and at least 2 other immunosuppressant agents, used in adequate doses for an adequate duration, with persistent symptoms or side effects that limit functioning, as defined by patient and physician
Pharmacologic therapy includes anticholinesterase medication and immunosuppressive agents, such as corticosteroids and nonsteroid immunosuppressants like azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, sirolimus, rituximab, cyclophosphamide, and other immunomodulatory therapies that include plasmapheresis, and intravenous immune globulin (IVIg).
Plasmapheresis and thymectomy are also employed to treat MG. They are not traditional medical immunomodulating therapies, but they function by modifying the immune system. Thymectomy is an important treatment option for MG, especially if a thymoma is present. A cardiothoracic surgeon should be consulted whenever thymectomy is contemplated as part of treatment.
MG is a chronic disease that may worsen acutely over days or weeks (and on rare occasions, over hours). Treatment requires scheduled reevaluation and a close doctor-patient relationship. Patients with MG require close follow-up care in cooperation with the primary care physician.
Intubation and intensive care unit (ICU) transfer usually are reserved for patients in myasthenic crisis with respiratory failure. Rapid respiratory failure may occur if the patient is not monitored properly. Patients should be watched very carefully, especially during exacerbation, by measuring negative inspiratory force and vital capacity.
Pharmacologic Therapy
Acetylcholine esterase (AChE) inhibitors and immunomodulating therapies are the mainstays of treatment.
Pyridostigmine is used for symptomatic treatment only. It does not treat the underlying disease.
In the mild form of the disease, AChE inhibitors are used initially. These agents include pyridostigmine and neostigmine. Pyridostigmine is used for maintenance therapy. [6, 7] Neostigmine is generally used only when pyridostigmine is unavailable. Edrophonium is primarily but rarely used as a diagnostic tool to predict the response to longer-acting cholinesterase inhibitors (see Workup). [43]
AChE inhibitors have a wide variability in the effective dose, depending on the severity and current activity of the disease and the presence of other factors that influence cholinergic transmission (eg, certain antibiotics, antidysrhythmic medications, and impaired renal function). [7, 18] Most patients are able to titrate the dosage of their medication to control disease symptoms, but severe exacerbations can occur in patients with previously well-controlled disease. [7]
Pyridostigmine dose should be adjusted as needed based on symptoms. The ability to discontinue pyridostigmine can be an indicator that the patient has met treatment goals and may guide the tapering of other therapies. Corticosteroids or IS therapy should be used in all patients with MG who have not met treatment goals after an adequate trial of pyridostigmine.
Most patients with generalized MG require additional immunomodulating therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids.
The corticosteroid regimen should be tailored according to the patient’s overall improvement. The lowest effective dose should be used on a long-term basis. Because of the delayed onset of effects (3–4 months), steroids are not recommended for routine use in the emergency department (ED). Patients who are taking long-term moderate or high doses of steroids may have suppressed adrenal function and may require stress doses (eg, hydrocortisone 100 mg IV in an adult) during acute exacerbations. [7]
Once patients achieve treatment goals (MMS or remission), the corticosteroid dose should be gradually tapered. In many patients, continuing a low dose of corticosteroids long-term can help to maintain the treatment goal.
Limited evidence from randomized, controlled trials (RCTs) suggests that corticosteroid therapy provides a short-term benefit in MG; this supports the conclusions of previous observational studies, as well as expert opinion. A systematic review found no clear difference between steroids and IVIg or azathioprine; however, further trials are indicated because of the flaws in the trials reviewed. [19]
Nonsteroidal immunosuppressant agents (AZA, MMF, MTX, CyA, etc.) should be used alone when corticosteroids are contraindicated or refused. A nonsteroidal IS agent should be used initially in conjunction with corticosteroids when the risk of steroid side effects is high based on medical comorbidities. A nonsteroidal immunosuppressant agent should be added to corticosteroids when the steroid side effects, deemed significant by the patient or the treating physician; when a response to an adequate trial of corticosteroids is failed; or the corticosteroid dose cannot be reduced due to symptom relapse.
Other medications that are used to treat more difficult cases include azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly. [20, 21, 44]
The mainstay of therapy is still azathioprine, usually after an initial dose of corticosteroids. Cyclosporine A and occasionally methotrexate and cyclophosphamide are used for severe cases, while tacrolimus is under investigation. [45] No evidence-based studies fully prove the usefulness of AChE inhibitors, corticosteroids, and other immunosuppressive agents in improving ocular symptoms. In addition, the effect of corticosteroids and azathioprine on the progression to generalized MG is still uncertain. [48]
To date, most of the studies on immunomodulatory therapy have had few participants and have found it difficult to assess the efficacy of the addition of immunosuppressive therapy to the previous regimens of corticosteroids and AChE inhibitors. Furthermore, most of the RCTs were short-term and did not evaluate long-term usage of these drugs. As a result, good RCT data on the use of immunosuppressive agents as monotherapy or dual therapy with steroids are absent. [49]
However, limited evidence indicates that cyclosporine and cyclophosphamide improve symptoms in MG and decrease the amount of corticosteroid usage. The more common drugs used in MG, such as azathioprine and tacrolimus, show no clear benefit in use. [49]
For nonsteroidal immunosuppressant agents, once treatment goals have been achieved and maintained for 6 months to 2 years, the IS dose should be tapered slowly to the minimal effective amount. Dosage adjustments should be made no more frequently than every 3–6 months.
The danger of tapering too soon. Tapering of immunosuppressant drugs is associated with risk of relapse, which may necessitate upward adjustments in dose. The risk of relapse is higher in patients who are symptomatic, or after rapid taper. It is usually necessary to maintain some immunosuppression for many years, sometimes for life.
PLEX and IVIg are appropriately used as short-term treatments in patients with MG with life-threatening signs such as respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction; when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations. The choice between PLEX and IVIg depends on individual patient factors (e.g., PLEX cannot be used in patients with sepsis and IVIg cannot be used in renal failure) and on the availability of each. Both are equally effective in the treatment of severe generalized MG, but the efficacy of IVIg is less certain in milder MG or in ocular MG. Also expert consensus suggests that PLEX is more effective and works more quickly than IVIg.
Impending MG crisis requires hospital admission and close observation of respiratory and bulbar function in an intensive care unit for management. When the FVC declines to < 15 mL/kg or negative inspiratory pressure (NIF) is < 30 cm H2O, intubation is recommended for airway protection. Mechanical ventilation is initiated to reduce the work of breathing, and improve ventilation. PLEX and IVIg are used as short-term treatment for impending and manifest myasthenic crisis. It is good practice to start corticosteroids or other immunosuppressant agents at the same time when starting PLEX or IVIg to achieve a sustained clinical response. PLEX is discontinued if 2 weeks pass without a meaningful response. While the patient is intubated, pyridostigmine is avoided to minimize secretions.
A treatment strategy using the following regimen for refractory MG, or MG presenting in crisis is as follows:
Do 5 PLEX sessions.
Start azathioprine (AZA)
IV methylprednisolone at dose of 500-1000 mg daily for 5 days may be used, followed by 0.8 mg/kg IV daily until patient is capable of taking medications by mouth. Start prednisone at 60 mg PO daily for 2 weeks, then 50 mg PO daily for 2 weeks, then 40 mg PO daily for a month. This is followed by a slow taper by 5 mg per month to reach 20 mg/day. Around this time (6 months), the imuran (AZA) reaches therapeutic efficacy ("kicks in"). From then on, taper prednsione 2.5 mg per month while monitoring for worsening of myasthenia symptoms. Goal is to achieve prednisone 5–7.5 mg PO daily or 10 mg every other day (no significant side effects if continued on this dose).
Although the steroids may initially worsen the patient’s myasthenia symptoms, it is not an issue as the patient is in the ICU setting and intubated. It is hypothesized that corticosteroids have a mild neuromuscular blocking properties that precede their immunomodulatory beneficial effects.
The use of IVIg as maintenance therapy can be considered for patients with refractory MG or for those in whom immunosuppressant agents are relatively contraindicated.
Although cholinergic crises are now rare, excessive ChEI cannot be completely excluded as a cause of clinical worsening. ChEIs like pyridostigmine can cause an increase of airway secretions, which may exacerbate breathing difficulties during a crisis.
Rituximab has emerged as a potentially effective therapeutic option for treatment of MG when first- and second-line immunotherapy fails. Patients with MuSK-MG appear to respond well to corticosteroids and to many steroid-sparing immunosuppressant agents, particularly rituximab. It is a chimeric monoclonal antibody that targets the CD20 angtigen found on subsets of the B-cell lineage. CD20 is expressed by all mature B cells but not on the pre-B or differentiated plasmablasts and plasma cells. Apart from showing significant clinical improvement, rituximab also allowed for tapering and even discontinuation of other immunsuppressants in both AChR and MuSK MG patients. However, relapses are known to occur on stopping rituximab.
Rituximab regimens
Dosage regimen 1:
Rituximab 1 gm IV on day 1 and day 14
Further rituximab doses depend on whether CD19 count has returned to normal (usually at 6 months)
Rituximab 1 gm IV once at 6 months, if indicated
Dosage regimen 2:
Rituximab 375/m2 IV every 12 weeks for 48 weeks
Prednisone 60 mg daily until minimal manifestation state, then taper to 10 mg every 4 weeks
Often patients are started on prednisone in the outpatient setting when their MG is mild. The strategy here is to increase the dose gradually until symptoms resolve or minimal manifestation status is achieved. Initially, patients are started on prednisone 20 mg daily and the dose is increased by 5 mg every 3–5 days until symptoms resolve. Patients are usually kept on the dosage that achieved minimal manifestation state for a month, then the dose is gradually tapered (no faster than 5 mg every 2 weeks down to a dose of 20 mg daily, and then by 2.5 mg every two weeks). [5, 54]
MG induction as a side effect of cancer immunotherapy with checkpoint inhibitors (PD-1, PD-L1, and CTLA-4) is described to rapidly progress to myasthenic crisis and must be aggressively treated by discontinuation of immunotherapy with the checkpoint inhibitors and initiation of high-dose steroids along with IVIg or plasmapheresis.
Aminoglycoside antibiotics inhibit ACh release from nerve terminals by competing with Ca++. Administration of calcium salts overcomes this effect.
Transient neonatal MG, in which MG is transmitted vertically from an affected mother to her fetus, occurs in 10-30% of neonates born to myasthenic mothers. It may occur any time during the first 7-10 days of life, and infants should be monitored closely for any signs of respiratory distress.
The syndrome of neonatal myasthenia is caused by transplacental transfer of maternal autoantibodies against the acetylcholine receptor (AChR). Infants affected by this condition are floppy at birth, and they display poor sucking, muscle tone, and respiratory effort. They often require respiratory support and intravenous (IV) feeding, as well as monitoring in a neonatal ICU. As the transferred maternal antibodies are metabolized over several weeks, symptoms abate and the infants develop normally.
Treatment with cholinesterase inhibitors is effective in this age group as well. However, the dosage must be carefully titrated to the clinical effect.
Complications
Long-term immunomodulating therapies may predispose patients with MG to various complications. Long-term steroid use may cause or aggravate osteoporosis, cataracts, hyperglycemia, weight gain, avascular necrosis of hip, hypertension, opportunistic infection, and other complications. Long-term steroid use also increases the risk of gastritis or peptic ulcer disease. Patients on such therapy should take an H2 -blocker or antacid as well.
Some complications are common to any immunomodulating therapy, especially if the patient is on more than 1 agent. These would include infections such as tuberculosis, systemic fungal infections, and Pneumocystis carinii pneumonia. The risk of lymphoproliferative malignancies may be increased with chronic immunosuppression. Immunosuppressive drugs may have teratogenic effects.
Initial deterioration in weakness before improvement is a common and serious concern within the first 3 weeks of immunomodulatory therapy; this potential complication warrants initiation of high doses in a supervised setting.
Excessive use of cholinesterase inhibitors can result in a cholinergic crisis. Other immunosuppressive medications increase the incidence of opportunistic infections, renal insufficiency, and hypertension.
Plasmapheresis
Plasmapheresis (plasma exchange) is believed to act by removing circulating humoral factors (ie, anti-AChR antibodies and immune complexes) from the circulation. It is used as an adjunct to other immunomodulatory therapies and as a tool for crisis management. Like IVIg, plasmapheresis is generally reserved for myasthenic crisis and refractory cases. Improvement is noted in a couple of days, but it does not last for more than 2 months.
Plasmapheresis is an effective therapy for MG and is often the initial treatment of choice in myasthenic crisis. Also, it is used to optimize control in preparation for surgery. Improvement in strength may help to achieve rapid postoperative recovery and to shorten the period of assisted ventilation. Long-term regular plasmapheresis on a weekly or monthly basis can be used if other treatments cannot control the disease.
Complications are primarily limited to complications of intravenous (IV) access (eg, central line placement) but also may include hypotension and coagulation disorders (though less commonly). Patients will need careful monitoring of fibrinogen and may need FFB if fibrinogen levels drop to less than 150 mg/dL prior to the next pheresis. There is a risk of hypocalcemia, central-line-associated bloodstream infection (CLABSI), thrombocytopenia, thromboembolism, and heparin-induced thrombocytopenia.
ACE inhibitors must be stopped 24 hrs before treatment and until treatment is completed.
Plasmapheresis is given as 250 mL/Kg total divided every other day over 5-6 exchanges. The onset of action is 1-7 days with maximal effect in 1-3 weeks.
Thymectomy
Thymic abnormalities are common in patients with MG. Of patients with generalized MG, 85% have thymic hyperplasia, and 10-15% have thymoma. Thymic pathology in early-onset generalized MG is invariably thymic hyperplasia. These patients invariably are anti-AChR-ab positive.
There is evidence that resident cells in the thymus, including myoid cells and epithelial cells, express various subunits of AChR, including the α subunit. Additional factors found uniquely in hyperplastic MG thymus include increased expression of chemokines that attract immigrant CD4+ T and B cells; the presence of nAChR-reactive B and CD4+ T cells and anti-AChR antibody-secreting plasma cells; cytokines that can facilitate B cell activation, differentiation, and survival; and possibly decreased CD4+ CD25+ regulatory T cell function. [55]
An extended trans-sternal thymectomy is standard of care and is indicated for all patients with thymoma and for patients aged 10-55 years without thymoma but who have generalized MG. Patients with thymomas almost always have anti-AChR-ab and so one must look carefully for thymoma in late-onset patients with anti-AChR-ab positive status. Removal of thymoma is essential to prevent local dissemination and systemic metastases. In late onset patient with MG and thymoma, thymectomy probably does not change the course of MG. Thymectomy has been proposed as a first-line therapy in most patients with generalized myasthenia. [52] In patients who have myasthenia gravis like symptoms but who are seronegative order a CT of chest regardless, to check for thymic pathology, since a small percentage of these patients may subsequently seroconvert to anti-AChR-ab positive status.
In ocular MG, thymectomy should be delayed at least 2 years to allow for spontaneous remission or the development of generalized MG. Whether thymectomy is to be performed for prepubescent patients or patients older than 55 years is still controversial. Reports tend to encourage surgical treatment for the latter group.
Thymectomy is not recommended in patients with antibodies to muscle-specific kinase (MuSK), because of the typical thymus pathology, which is very different from the more common type of MG characterized by seropositivity for AChR antibodies. [53] Current evidence also does not support an indication for thymectomy in patients with LRP4, or agrin antibodies.
Thymectomy may be considered in patients with generalized MG without detectable AChR antibodies if they fail to respond adequately to immunosuppressant therapy, or to avoid/minimize intolerable adverse effects from immunosuppressant therapy. [56]
Patients often experience some transient worsening of symptoms early in the postoperative period. Improvement usually is delayed for months or years. Complete removal of thymic tissue is widely considered to be of the utmost importance, on the grounds that any small remnant might lead to recurrence.
Thymectomy may induce remission. This occurs more frequently in young patients with a short duration of disease, hyperplastic thymus, more severe symptoms, and a high antibody titer, although a high titer of antibody is not consistently linked to better outcome. [57]
Remission rate increases with time: at 7-10 years after surgery, it reaches 40-60% in all categories of patients except those with thymoma. In the absence of a thymoma, 85% of patients experience improvement, and 35% of these patients achieve drug-free remission. In a study by Nieto et al, the rate of remission in the presence of thymic hyperplasia was 42% compared to 18% in patients with thymoma. [55]
As there is a long delay in onset of beneficial effect of thymectomy for MG, an elective procedure should be performed when the patient is stable and deemed safe to undergo a procedure where postoperative pain and mechanical factors can limit respiratory function.
Robotic thymectomy
A robotic minimally invasive approach to thymectomy has been used. [58] In a review of 100 consecutive patients who underwent left-sided robotic thymectomy for MG, Marulli et al demonstrated the safety and efficacy of this procedure. No deaths or intraoperative complications occurred. On 5-year clinical follow-up, 28.5% of patients had complete stable remission, and 87.5% showed overall improvement. Remission was significantly more likely in patients with preoperative Myasthenia Gravis Foundation of America class I to II MG. [59]
MGFA classification of thymectomy
Over the years, many different techniques have been employed to perform thymectomy. Although it is generally believed that complete removal of thymic tissue is better (see above), this is not an established fact. There is no consensus as to whether one technique is superior to another in achieving benefit or minimizing risks.
The Myasthenia Gravis Foundation of America (MGFA) has proposed a classification scheme for thymectomy, which is primarily based on techniques described in various published reports. [3]
The MGFA thymectomy classification is as follows:
T-1 transcervical thymectomy – Basic; extended
T-2 videoscopic thymectomy - Classic or VATS (video-assisted thoracic surgery) thymectomy; VATET (video-assisted thoracoscopic extended thymectomy)
T-3 transsternal thymectomy – Standard; extended
T-4 transcervical and transsternal thymectomy
Randomized trial of thymectomy in MG
Trans-sternal thymectomy has been known to improve MG in many anecdotal case reports and has been adopted as an effective way to manage the disease and even induce remission or lessen the requirements or perhaps remove the need of prednisone and other immunosuppressants.
Randomized Trial of Thymectomy in Myasthenia Gravis is a landmark study. This is the first randomized trial of thymectomy in MG. The cohort of patients who were involved in the trial had generalized MG and were acetylcholine receptor antibody positive. Patients who entered the study were between the ages of 18 and 65 years, and none could have a duration of MG based on their historical presentations that exceeded 5 years. Patients were randomized one to one to thymectomy plus prednisone or to prednisone alone. They could go on prednisone as long as they did not exceed a dosage of 50 mg a day. Other immunosuppressants were excluded. The intervention was an extended trans-sternal thymectomy in order to get as much thymic tissue as possible. The primary outcome was tiered and included both outcomes of the disease based on QMG score and prednisone dose. The outcome was that not only was the prednisone requirement less in the thymectomy group, but there was a better outcome in patients who underwent thymectomy. Also, the requirement of azathioprine was reduced in the thymectomy patients. Therefore, over a period of 3 years, thymectomy was associated with more favorable clinical outcomes with respect to requirements for prednisone and azathioprine therapy, the number of symptoms and the distress level related to immunosuppressive agents, and the need for hospitalization to manage disease exacerbations. [58]
An upper age limit for extended transternal thymectomy is not determined. Patients with an upper age limit of 65 years without significant medical comorbid conditions can be considered for thymectomy.
Phrenic nerve injury resulting in diaphragmatic paralysis and paresis of recurrent laryngeal nerve were some known complications.
Diet and Activity
Patients with MG may experience difficulty chewing and swallowing because of oropharyngeal weakness. It may be difficult for the patient to chew meat or vegetables because of masticatory muscle weakness. If dysphagia develops, it is usually most severe for thin liquids because of weakness of pharyngeal muscles. To avoid nasal regurgitation or frank aspiration, liquids should be thickened.
Educate patients about the fluctuating nature of weakness and exercise-induced fatigability. Patients should be as active as possible but should rest frequently and avoid sustained physical activity. Patients are instructed to begin an aerobic exercise program.
Patients are instructed to start a low-sodium, low-carbohydrate, high-protein diet to prevent excessive weight gain.
Pregnancy and Myasthenia Gravis
In an review of literature involving 322 pregnancies in 225 myasthenic mothers, 31% had no change in their myasthenic symptoms, 28% improved, and 41% deteriorated during pregnancy.{Plauche WC. Myasthenia gravis in mother and their new-borns. Clin Obstet Gynecol 1991;34:82-99}. Of the pregnant myasthenic mothers, 30% had exacerbation of the disease in the post-partum period. In general, pyridostigmine and, if needed, prednisone are used, whereas other immunomodulating agents are avoided if possible beause of teratogenic concerns.
Current information indicates that azathioprine and cyclosporine are relatively safe in expectant mothers who are not satisfactorily controlled with or cannot tolerate corticosteroids. Current evidence indicates that mycophenolate mofetil and methotrexate increase the risk of teratogenicity and are contraindicated during pregnancy. (These agents previously carried Food and Drug Administration [FDA] Category C (cyclosporine), D (azathioprine and mycophenolate mofetil), and X (methotrexate) ratings.) The FDA has recently discontinued this rating system, and replaced it with a summary of the risks of using a drug during pregnancy and breastfeeding, along with supporting data and relevant information to help health care providers make prescribing and counseling decisions. Although this statement achieved consensus, there was a strong minority opinion against the use of azathioprine in pregnancy. Azathioprine is the nonsteroidal immunosuppressant of choice for MG in pregnancy in Europe but is considered high risk in the United States. This difference is based on a small number of animal studies and case reports.
PLEX or IVIg are useful when a prompt, although temporary, response is required during pregnancy.
Pregnant women with myasthenia gravis should be considered high-risk pregnancies and followed closely by an obstetrician, neonatologist, and a neuromuscular clinician. Planning for pregnancy should be instituted well in advance to allow time for optimization of myasthenic clinical status and to minimize risks to the fetus. Magnesium sulfate is avoided if possible if preeclampsia develops due to its neuromuscular blocking properties. It is preferable to give regional anesthesia for delivery and cesarean section.
All babies born to myasthenic mothers should be examined for evidence of transient myasthenic weakness, even if the mother’s myasthenia is well controlled, and should have rapid access to neonatal critical care support.
Chest CT without contrast can be performed safely during pregnancy, although the risks of radiation to the fetus need to be carefully considered. Unless there is a compelling indication, postponement of diagnostic CT until after delivery is preferable.
Juvenile Myasthenic Gravis
It is estimated that approximately 10% of non-neonatal autoimmune MG cases that are acquired will occur before the age of 18 years, and the majority occur subsequent to puberty. The mean age of onset ranges from 7 to 14 years. All features are identical with adult myasthenia gravis, except age. [57] Children with acquired autoimmune ocular MG are more likely than adults to go into spontaneous remission. Thus, young children with only ocular symptoms of MG can be treated initially with pyridostigmine. Immunotherapy can be initiated if goals of therapy are not met. Children are at particular risk of steroid side effects, including growth failure, poor bone mineralization, and susceptibility to infection, due in part to a delay in live vaccinations. It is recommended that for long-term treatment with corticosteroids use of the lowest effective dose to minimize side effects is acceptable. Maintenance PLEX or IVIg as alternatives to immunosuppressant agents in JMG is also recommended.
IVIg
IVIg is given as 400 mg/kg daily for 5 days (2 g/kg total).
Onset of action: 1-2 weeks with maximal effect: 1-3 weeks.
Benefit can last for 3-5 weeks.
The effect of IVIg variable and slower in onset when compared to PLEX.
The dose is spreading over more days in patients with renal disease (Cr >1.4), diabetes mellitus, congestive heart failure, and in elderly.
Advantages: Noninvasive. Pretreatment with NS 250 mL; Tylenol and Benadryl can mitigate complications.
Disadvantages: Risk of hypersensitivity with IgA deficiency (should check IgA levels before starting), aseptic meningitis, headache, chills, myalgias, transient hypertension, fluid overload, acute tubular necrosis, hyperviscosity syndrome (stroke, MI, cryoglobulinemia, monoclonal gammopathy, high lipoproteins, or preexisting vascular disease). Benefits last only a few weeks.
Myasthenia Gravis Medication: Anticholinesterase Inhibitors, Corticosteroids, Immunomodulators, Immune Globulins, Monoclonal Antibodies, Beta2 Agonists, Anticholinergic agents
Class Summary
Anticholinesterase inhibitors interfere with the degradation of acetylcholine (ACh) by AChE, thereby increasing the amount of ACh available at the neuromuscular junction (NMJ) and increasing the chance of activating the acetylcholine receptors (AChRs). Any medication that increases the activity of the AChRs can have an effect on MG.
AChE inhibitors continue to be used as first-line treatment of MG. The improvement is usually partial and frequently decreases after many weeks to months of treatment. Besides, these agents are not as beneficial for ocular MG as for generalized MG. Hence, they often are complemented (and sometimes replaced) with immunosuppressive therapy.
Pyridostigmine acts in smooth muscle, the central nervous system (CNS), and secretory glands, where it blocks the action of ACh at parasympathetic sites. An intermediate-acting agent, it is preferred in clinical use to the shorter-acting neostigmine bromide and the longer-acting ambenonium chloride. It starts working in 30-60 minutes; effects last 3-6 hours.
Individualize the dose; MG does not affect all skeletal muscles similarly, and all symptoms may not be controllable without adverse effects. In critically ill or postoperative patients, administer the drug intravenously (IV).
In the United States, pyridostigmine is available in 3 forms: 60-mg scored tab, 180-mg timespan tablet, and 60-mg/5 mL syrup. Dose should not typically exceed 600 mg a day in adults and 7 mg/kg in children. Dosing half hour before meals may help in swallowing and reduce the risk of aspiration. The effects of the timespan tablet last 2.5 times longer. The timespan form is a useful adjunct to regular pyridostigmine for nighttime control of myasthenic symptoms. The absorption and bioavailability of the timespan tablet vary among subjects. It should be used only at bedtime, and patients need close monitoring for cholinergic adverse effects.
Patients can develop cholinergic side effects secondary to the accumulation of ACh at muscarinic and nicotinic receptors. Muscarinic side effects include nausea, vomiting, abdominal cramping, diarrhea, increased oral and bronchial secretions, bradycardia, and sometimes confusion or psychosis. When patients develop significant side effects, pretreatment with anticholinergic medications is recommended (eg, propantheline, glycopyrrolate, or diphenoxylate with atropine) 30 minutes before taking pyridostigmine.
Neostigmine inhibits the destruction of ACh by AChE, thereby facilitating the transmission of impulses across the NMJ. It is a short-acting AChE inhibitor that is available in an oral form (15 mg tablet) and a form suitable for IV, intramuscular (IM), or subcutaneous (SC) administration. Its half-life is 45-60 minutes. It is poorly absorbed from the gastrointestinal (GI) tract and should be used only if pyridostigmine is unavailable. Individualize the dose for all patients.
Edrophonium is primarily used as diagnostic tool to predict the response to longer-acting cholinesterase inhibitors. Like other cholinesterase inhibitors, it decreases the metabolism of ACh, increasing the cholinergic effect at the NMJ. It was used in the past to distinguish between cholinergic and myasthenic crisis. If IV edrophonium resultsed in worsening of symptoms, the increased weakness in patients is probably due to overdosing the anticholinesterase medication. If weakness, on the other hand, improves following edrophonium, the weakness is due to the underlying MG.
Corticosteroids
Class Summary
Corticosteroids are anti-inflammatory and immunomodulating agents used to treat idiopathic and acquired autoimmune disorders. They were among the first immunomodulating agents used to treat MG and still are used frequently and effectively. They are typically used in moderate or severe cases that do not respond adequately to AChE inhibitors and thymectomy. Long-term treatment with corticosteroids is effective and may induce remission or cause marked to moderate improvement in most patients.
Transient worsening might occur initially; clinical improvement then shows after 2-4 weeks with maximal effect in 5-6 months. These agents are usually given over 1 or 2 years before tapering is begun. Remissions are noted in 30% and marked improvement in 40%.
Corticosteroids act in both ocular MG and generalized MG. They can be combined with other immunosuppressive medications for better effect with lesser dose and shorter duration of administration. Pulsed IV steroids might be beneficial in refractory patients.
Prednisone is most commonly used corticosteroid in the United States. Some experts believe that the long-term administration of prednisone is beneficial, but others use the drug only during acute exacerbations to limit the adverse effects of chronic steroid use.
Prednisone is effective in decreasing the severity of MG exacerbations by suppressing the formation of autoantibodies. However, clinical effects often are not seen for several weeks. Significant improvement, which may be associated with a decreased antibody titer, usually occurs in 1-4 months. An alternate-day regimen may minimize adverse effects. A trial of steroid withdrawal may be attempted, but most patients on long-term corticosteroid therapy relapse and require re-institution of steroids.
Chronic administration of corticosteroids is associated with numerous serious side effects. The risk of infection, diabetes mellitus, hypotension, glaucoma, osteoporosis, steroid myopathy, and aseptic necrosis of the joints are some examples. It is prudent to obtain chest X-ray, PPD skin test, and a detailed history of exposure to tuberculosis, strongyloides, or other organisms that may grow as a result of the chronic administration of corticosteroids. Measurement of DEXA at baseline and every 6-12 months while the patient is on corticosteroids is recommended. If the bone density shows evidence of osteopenia or osteoporosis, calcium supplementation (1 g/day), vitamin D (400-800 IU daily), and biphosphonates are started prophylactically for steroid-induced osteoporosis. Prophylactic treatment with histamine-H2 receptor blockers are usually not required.
BP monitoring, periodic eye exam to check for glaucoma and cataracts is recommended. Fasting blood glucose, serum potassium levels should be periodically checked. Potassium may be supplemented if the patient becomes hypokalemic.
High dose steroids and lack of physical activity can lead to type 2 muscle fiber atrophy with proximal muscle weakness. Distinction from myasthenic weakness is important and is challenging. Patients who become weaker during a prednisone taper, and show craniobulbar, and upper extremity muscle weakness, and demonstrate worsening of their decremental response on RNS are more likely to experience worsening of their myasthenia gravis symptoms. In contrast, patients who are continued on high doses of corticosteroids, normal RNS, and other evidence of steroid induced toxicity (i.e., Cushingoid features), increasing leg weakness, or have type 2 muscle fiber atrophy could benefit from physical therapy and steroid dose reduction.
Methylprednisolone may be used in place of prednisone in patients who are intubated and in those unable to tolerate oral intake. It decreases inflammation by suppressing the migration of polymorphonuclear (PMN) leukocytes and reversing increased capillary permeability.
Immunomodulators
Class Summary
MG is an autoimmune disease, and immunomodulatory therapies have been used for these disorders since introduction of steroids. Although no rigorous clinical trials have established the efficacy of immunomodulatory therapies in MG, several uncontrolled trials and retrospective studies support use of such therapies. The therapies used in MG include prednisone, azathioprine, IV immunoglobulin (IVIg), plasmapheresis, and cyclosporine.
Azathioprine is an imidazolyl derivative of 6-mercaptopurine (6-MP). Many of its biological effects are similar to those of its parent compound. Both compounds are eliminated rapidly from the blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or 6-MP is detectable in urine 8 hours after being taken.
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. The mechanism whereby it affects autoimmune diseases is unknown. It works primarily on T cells, suppresses hypersensitivities of the cell-mediated type and causing variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses.
Azathioprine is the second most commonly used immunosuppressive medication in MG. It is reserved for patients with either steroid failure or unacceptable effects from prolonged steroid use. Furthermore, it can be used for steroid-sparing effects to lower steroid doses. One drawback is that it works very slowly; it may require 12-18 months to exert its therapeutic effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow the white blood cell (WBC) count to drop below 3000/µL or the lymphocyte count to drop below 1000/µL.
Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.
Administer 2-3 mg/kg PO daily or BID; begin with a low initial dose. Maximal effect is 1-2 years.
The disadvantage of using this product is that it increases the risk of eoplasia, immunosuppression, pancytopenia, pancreatitis, and hepatotoxicity.
It is not for use in pregnant patients.
The drug causes flu-like symptoms, bone marrow suppression, and LFTs abnormalities. About 10% of patients do not tolerate the drug.
Check TPMT (thiopurine methyltransferase) enzyme activity. If the individual is homozygous for TPMT (1:300), do not give azathioprine as these individuals are unable to metabolize azathioprine and may have myelosuppression. Heterozygous individuals for TPMT are given azathioprine in smaller doses and monitored carefully.
Not to be used with allopurinol as the combination can result in bone marrow suppression and liver toxicity. Concurrent administration of allopurinol can increase azathioprine toxicity by interfering with its metabolism by xanthine oxidase, an important degradative pathway. Reduce azathioprine dose by as much as 75% in patients who take allopurinol.
Perform a CBC to check WBC for the first few months of starting treatment. Azathioprine is a useful and generally well-tolerated agent in MG. The usual dosage is 2-3 mg/kg/day. Approximately 5-10% of individuals have idiosyncratic reaction with fever, nausea, and vomiting, sometimes accompanied by eosinophilia or increased hepatocellular enzymes at the initiating dose. Obtain a baseline CBC and differential, platelet count, and LFTs (ALT, AST, and ALP). If the patient is not already receiving corticosteroids, obtain an anergy panel, including a PPD, and check that a recent x-ray film has been taken.
Therapy starts with 50 mg/day for 5 days, blood tests are checked, and the dosage is increased by 50 mg/day every 5 days, with blood tests checked before each increase. After reaching 150 mg/day, increase 25 mg/day every 5 days, checking the blood studies. At 2 to 2.5 mg/kg/day, observe the patient for 3-4 months. If the patient has not started to show clinical improvement and an increase in red blood cell (RBC) mean cell volume (MCV; increase in MCV of >100 fL is a useful indicator of a therapeutic dose, in the absence of concomitant iron deficiency), increase dose again by 25 mg/day to 3 mg/kg/day.
CBC and LFTs are monitored every 2 weeks for several months, until a stable dose of azathioprine is achieved. Patients who have been receiving a stable dose for greater than 2 years and who have shown no signs of toxicity can be monitored 2 to 3 times per year. Upward adjustment of dose or signs of toxicity require returning to weekly monitoring and going through the same cycle.
Macrocytosis is not an indication of discontinuation of therapy. WBC 3-4K/mm3 is a safe endpoint. If WBC falls <2.5K/mm3 or the absolute neutrophil count is less than 1000/mm3, azathioprine should be briefly discontinued, then reintroduced at a lower dose. Leukopenia can present within a week or as late as 2 years after intiating azathioprine. This measure cannot be used in patients receiving prednisone, because of the steroid-induced leukocytosis. In that situation, an absolute lymphocyte count of 5-10% is an appropriate target. If LFTs show transaminases trend upwards of 2-3 times of normal values, the medication is held. This can be typically seen within a month of starting the medication. Side effects that may respond to lowering of the dose or dividing the daily dose to twice or three times a day include epigastric distress, nausea and vomiting, stomatitis, oral thrush, increased susceptibility to infections, marrow suppression, or increase in hepatocellular or obstructive liver chemistries. The majority of patients benefit from the drug and tolerate it long term (years). Generally, leucopenia reverses within 1 month and hepatotoxicity usually takes several months to resolve.
Very little evidence has shown an increased incidence of neoplasm from azathioprine in the doses generally used in MG. The major disadvantage of azathioprine is the delay in therapeutic effect; it takes 3-4 months to see a clinical effect, and it may take more than 12 months for maximal effect.
An adequate therapeutic trial with azathioprine should last at least 1-2 years, since the lag to onset of effect may range from 3-12 months, and the point of maximum benefit may be delayed 1-3 years.
Cyclosporine A is an 11-amino acid cyclic peptide that is a natural product of fungi. It acts on T-cell replication and activity. It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.
Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin (IL)–2 and subsequent recruitment of activated T cells. It has about 30% bioavailability, but there is marked individual variability. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.
Cyclosporine A suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.
Cyclosporine A is used as a second-line immunosuppressive agent and has been shown effective in patients with MG in prospective, double-blind, placebo-controlled clinical trial. This agent does have some significant adverse effects (more serious than those of azathioprine), which usually preclude its use as first-line immunosuppressive therapy. However, in patients who are at high risk for adverse steroid effects, it can be used as initial therapy. The onset of action is within a few weeks to months, similar to that of prednisone.
Administer 2.5-4 mg/kg/day divided BID with a fat-containing meal or snack.
The onset of action for this agent is 2-4 months with optimum effect to be observed in 7 months.
The advantage of this product is that it is a steroid-sparing immunosuppression; not cytotoxic but selectively immunomodulatory.
Disadvantages include increased risk of neoplasia, skin malignancy, HTN, renal failure, immunosuppression, hepatotoxicity, seizures, PRES (posterior reversible encephalopathy syndrome), increased ICP, and tremor. It also has a broad range of interactions with many drugs.
Metabolized in liver CYP450 system, and excreted in bile; potentiates risk of necrotizing myopathy or myoglobinuria due to lovastatin, which also depends on biliary excretion. It is lipid soluble.
Corticosteroids increase plasma cyclosporine levels.
MG improvement noted in about 2 weeks, with maximal improvement by 4 months, correlating with reduction in AChR antibody levels.
Monitor plasma cyclosporine trough levels every 3 weeks until stable, then monthly. Trough levels are measured in the morning 12 hours after last dose. Trough levels should be maintained between 100–200 ng/mL. Decrease dose if Cr rises above 1.4 times the baseline level.
Common side effects include HTN, PRES (posterior reversible encephalopathy syndrome), and nephrotoxic (especially elderly). Facial hirsutism, GI disturbances, headache, tremor, convulsions, and hepatotoxicity are related to drug levels and are reversible with dose reduction. When used concurrently, NSAIDs will potentiate cyclosporine nephrotoxicity.
Cyclophosphamide is an alkylating agent that interferes with cell proliferation. It is more effective against B cells than against T cells, which makes it a good choice in an antibody-mediated disease such as MG. Because of potential for serious side effects (ie, gastrointestinal upset, bone marrow toxicity, alopecia, hemorrhagic cystitis, teratogenicity, sterilization, and increased risk of infections and secondary malignancies), it is usually reserved for more severe cases where more routinely used immunotherapy has failed because of lack of efficacy or intolerable adverse effects.
Mycophenolate mofetil, a derivative of mycophenolic acid (MPA), blocks the de novo pathway of guanosine nucleotide synthesis by inhibiting the activity of inosine monophosphate dehydrogenase and thus inhibiting de novo purine synthesis. Both T and B lymphocytes are highly dependent upon the de novo pathway, whereas other cells use the purine salvage pathway of nucleotide synthesis. As a result, MPA selectively inhibits lymphocyte activity.
Mycophenolate mofetil has been shown to be effective in MG and is recommended as a steroid-sparing immune modulator.
The starting dose is 250 mg PO BID for 5 days, then 500 mg PO BID for 5 days, then 1 g PO BID
Its onset of action is 2-4 months with maximal effect observed at 5-6 months.
The advantage to using this agent is that it acts through steroid-sparing immunosuppression.
The disadvantages include increased risk of lymphoma, immunosuppression, teratogenicity risk, pancytopenia, GIB, renal failure, acute ILD, and HTN. It may also cause nausea, diarrhea, abdominal pain, fever, leukopenia, and edema.
Mycophenolate mofetil is an immunosuppressive drug with a mode of action similar to azathioprine. Its major advantage is that its effect seems to be limited to lymphocytes. Thus, although lymphocytes may be reduced in function and number, there is no effect on liver function tests and no effect on either RBC or PMN counts. Several uncontrolled studies have reported efficacy, and some also suggest that mycophenolate mofetil has a quicker mode of onset than azathioprine, particularly at 1 g BID.
Begin with 500 mg BID, and if the drug is tolerated, increase the dose to 1 g bid after 4 weeks. If diarrhea occurs, try 1 to 1.5 g/day. Other side effects include gastrointestinal hemorrhage and perforation; increased susceptibility to infections is a consideration with all of these agents, particularly in combination with corticosteroids. Neutropenia is generally associated with doses of 2 g/day or greater. Mycophenolate mofetil eventually may replace azathioprine as the first-line immunosuppressive drug in patients with MG, but further studies are required.
Monitor blood tests weekly for the first month of treatment, twice monthly for the second and third months, and then monthly thereafter.
It is used sometimes as an adjuvant drug in combination with cyclosporine and prednisone. It is the preferred drug for elderly myasthenics.
Methotrexate is not used frequently in myasthenia gravis, although it may be effective. It has an earlier onset of action compared to azathioprine. It may be initiated orally at 7.5 mg/week given in three divided doses 12 hours apart. It is gradually increased by 2.5 mg a week up to 25 mg/week as necessary. Major side effects include alopecia, stomatitis, interstitial lung disease, teratogenicity, oncogenicity, risk of infection, pulmonary fibrosis, renal, liver, and bone marrow toxicities. Doses of over 50 mg a week are rarely used for MG as this may require leukovorin rescue. Patients are given folate along with methotrexate.
Immune Globulins
Class Summary
Immunoglobulins are commonly used in admitted patients and rarely administered in the emergency department (ED).
IVIg is recommended for MG crisis, in patients with severe weakness poorly controlled with other agents, or in lieu of plasma exchange at a dose of 1 g/kg. IVIg is effective in moderate or severe MG worsening into crisis but does not exhibit value in mild disease. Data do not support or exclude a role for IVIg in chronic MG. The use of IVIg in a seronegative patient is not supported by the literature.
High-dose IVIg successfully treats MG, though the mechanism of action is unknown. It is used in crisis management (eg, myasthenic crisis and the perioperative period) instead or in combination with plasmapheresis. Like plasmapheresis, it has a rapid onset of action, but the effects last only a short time.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules, antigens). This binding is very versatile and can mimic, block, or cause changes to enact precise mechanisms (eg, bridging molecules, replacing or activating enzymes or cofactors, immune system stimulation).
In October 2017, the FDA approved eculizumab for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AchR) antibody-positive. Approval was based on data from the phase 3, multicenter, randomized, double-blind, placebo-controlled REGAIN study that randomized 62 patients to eculizumab and 63 to placebo. Patients were randomly assigned (1:1) to either IV eculizumab or IV matched placebo for 26 weeks. The primary efficacy endpoint for gMG was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at week 26. Treatment with eculizumab showed a statistically significant difference in the mean change from baseline to week 26 in MG-ADL total scores (–4.2 points vs. –2.3 points). [60]