Under normal conditions, the process of neuromuscular transmission is initiated by an action potential that depolarizes the terminal membrane of the motor nerve axon. This opens the voltage-dependent calcium channels, increasing calcium permeability which elicits the release of acetylcholine (ACh) and agrin molecules from the nerve terminal into the synaptic cleft.⁵,¹² ACh diffuses across the synapse, binds to receptors on the striated muscle, and depolarizes the postsynaptic membrane, thus producing muscle contraction.¹² The postsynaptic skeletal muscle fiber membrane (the sarcolemma) is a convoluted structure with a high density of acetylcholine receptors (AChR) at the crests of the folds and acetylcholine molecules within the clefts. To ensure successful neuromuscular transmission, normally there is a vast excess (safety margin) of released acetylcholine molecules and available postsynaptic receptors. Ultimately, the acetylcholine molecules that are released are rapidly eliminated from the synaptic cleft by the acetylcholinesterase enzyme.¹² As we shall see later, the released agrin is involved in the normal process of AChR clustering, an integral step of neuromuscular junction transmission.⁵,¹² Any disruption of the aforementioned delicate processes predisposes to failure of neuromuscular transmission, ultimately causing muscle weakness.¹²

MG is an autoimmune disorder caused by antibodies targeting the neuromuscular junction. These antibodies bind to the postsynaptic muscle end plate, attack, and destroy the postsynaptic molecules, consequently impairing signal transduction which ultimately results in muscle weakness and fatigability.⁵ Although MG is considered the archetypal example of an autoimmune disease involving the neuromuscular junction,⁴,⁵,⁶,⁷,⁸,⁹ it is an etiologically as well as an immunologically heterogeneous disease. Different autoantibody patterns, as well as the diverse clinical manifestations, may help identify the disease subgroups which include (1) early-onset MG, (2) late-onset MG, (3) muscle-specific kinase MG (MuSK⁺ MG), (4) low-density lipoprotein receptor-related protein 4 MG (LRP4 MG), (5) seronegative MG, (6) thymoma MG, and (7) OMG.⁵ In MG patients, three major antibody types predominate including (1) antibodies directed against the acetylcholine receptors (AChR), (2) antibodies directed against MuSK, and rarely (3) LRP4 antibodies, but other antibodies may be observed as well.⁵

The two major antibodies (AChR and MuSK) probably represent two distinct immunopathologic mechanisms as they are mutually exclusive and rarely manifest simultaneously in the same individual. Also, the clinical picture, the ocular findings, and thymic pathology are different.⁵,⁹,¹⁰ On the other hand, the clinical picture in patients with AChR and LRP4 antibody positivity may overlap, particularly regarding their ocular symptoms.⁵

In the great majority of MG patients, antibodies directed against acetylcholine receptors are the ones responsible for the characteristic muscle fatigability, and they can be detected with routine assays or more-sensitive cell-based assays in up to 75% to 80% of patients.⁵ Anti-AChR antibodies are usually IgG1 and IgG3 antibodies which are directed against the α-subunits (more pathogenic) or the β-subunits of the acetylcholine receptor and cause disease morbidity through three distinct mechanisms.⁵ The predominant antigenic mechanism is that they activate the complement cascade (C1), which in turn binds to the extracellular domains of the ACh receptors at the neuromuscular junction. This results in the formation of membrane attack complexes on the sarcolemmal cell membranes, which destroys the typical folds in the sarcolemma, thereby indirectly impairing signal transduction.⁵ Another less frequent mechanism for blocking the signaling pathway also exists, as AChR antibodies are bivalent and are capable of direct antigenic modulation which may result in AChR conformational changes and additional damage to the AChR function.⁵ The third and least common mechanism is that anti-AChR antibodies may directly target the acetylcholine ligand-binding site of the receptor itself without complement activation, also potentially blocking the signaling pathway.⁵ Although total AChR antibody concentration does not appear to correlate with symptom severity, fluctuations in AChR antibody levels in an individual patient have been reported to correlate with the severity of muscle weakness.⁵

A small minority of MG patients (1%-10%) have monovalent antibodies to muscle-specific tyrosine kinase (MuSK) and not to the acetylcholine receptors (MUSK⁺ MG).⁵ MuSK is a protein that is concentrated in the neuromuscular junctions of skeletal muscles where it colocalizes with the densely packed acetylcholine receptors. It is responsible for AChR clustering, a key event in neuromuscular transmission,¹¹ so that MuSK plays a critical role in establishing and maintaining neuromuscular synapses.⁴,⁵ However, this interaction also requires the presence of the low-density lipoprotein receptor-related protein 4 (LRP4) and the motoneuron-secreted heparan sulfate proteoglycan agrin to co-stimulate MuSK.⁴,⁵,¹¹ MuSK is, therefore, one of the components of the agrin-mediated AChR clustering signaling cascade (agrin-LRP4- MuSK signaling).⁴,¹¹

Autoantibodies that are directed against MuSK are predominantly of the IgG4 subclass; therefore, MuSK⁺ MG belongs to the relatively new class of autoimmune diseases which are hallmarked by the predominance of IgG4 autoantibodies. In contrast to AChR antibodies that bind to complement and crosslink their antigenic target, MuSK antibodies are directly pathogenic.⁵ They act by reducing the postsynaptic density of AChRs and impairing their alignment.⁵ Of note is that the association with MuSK positivity and ocular symptoms (MuSK-OMG) is extremely rare.⁵,⁹,¹⁰ To the best of our knowledge, only nine cases of MuSK-OMG have been described in the literature so far.¹⁰ In addition, thymus pathology is also different, as the thymus is frequently involved in AChR MG, whereas in MUSK⁺ MG, it is not.⁸,¹²

A small proportion of MG patients who do not have either AChR or MuSK antibodies may possess antibodies directed against another component of the agrin-LRP4-MuSK signaling cascade, LRP4, which is a receptor for agrin that relays the signal to MuSK to initiate AChR clustering.⁵ It should be noted the prevalence of ocular symptoms and signs is similar among MG patients with either anti-AChR or anti-LRP4 antibodies, although LRP4⁺ patients usually present with milder disease and thymomas are rare.⁵

Patients who have no detectable antibodies against any of these three antigens are referred to as seronegative MG, although some of these patients may have antibodies against other cytoplasmic muscle proteins (agrin, titin, Kv1.4, ryanodine receptor antibodies, collagen Q, or contractin antibodies). However, the exact role played by these antibodies in MG pathogenesis or any relevance to diagnosis, treatment, or prognosis remains to be proven.⁵

The primary autoimmune form mentioned earlier is not the only underlying cause of MG. Thymic pathology, acute infections, and several medications may trigger or exacerbate myasthenia probably through presynaptic or even postsynaptic inhibition of acetylcholine release.¹³ Pathological thymic changes, including thymic hyperplasia (follicular or diffuse thymitis) earlier in the course of the disease, and thymomas, as well as an atrophic thymus gland (late in the disease), are seen in 80% of seropositive myasthenia patients.¹⁴ Systemic infections (viruses, bacteria, and even fungi) may also trigger a myasthenic crisis.¹⁵,¹⁶ The list of drugs inducing MG is extensive,¹² but drugs that are relevant to the current discussion are antibiotics including fluoroquinolones (ciprofloxacin and levofloxacin), macrolide antibiotics (telithromycin and azithromycin), and aminoglycosides (amikacin and gentamycin).¹³,¹⁷,¹⁸,¹⁹,²⁰ Therefore, if a patient develops an acute exacerbation of MG due to a systemic infection, the very antibiotics used to treat the infection may exacerbate the symptoms even more.¹³

The incidence of generalized MG is 5.3 per million person-years, and the estimated prevalence is 77.7 cases per million of the population.⁹ MG affects all age groups, genders, and ethnicities; however, it has a bimodal age distribution, being more prevalent both in young females (less than 30 years of age) and older males (more than 50).⁷,²¹ The exact incidence and prevalence of OMG is largely unknown, and a recent metanalysis of population-based epidemiological MG studies did not list a single study singularly concerned with OMG.⁹ But in general, OMG is considered rarer than generalized disease,²² shows a predilection for men, and appears to be more prevalent in Asian populations.⁶,²³