Neuromuscular Disorders, 2/E

Historically, seronegative MG referred to patients lacking AChR autoantibodies. With the discovery of MuSK autoantibodies, the concept of double seronegative MG patients was coined. As our knowledge of LPR4 MG is somewhat limited, and as LPR4 autoantibody tests are not commercially available at the time of writing this, seropositive will be used in this chapter to refer only to AChR and MuSK MG.

The incidence of MG and its serodistribution may vary with geography and/or ethnicity.¹⁰ MG has been estimated to occur in 2–10/10⁶ individuals/year in the Eastern United States and the Netherlands but up to 20/10⁶ people/year in Eastern Spain.^11–13 The prevalence is estimated to be as infrequent as 2 and as frequent as 200/10⁶ individuals.^13–24 The age of onset may also be influenced by geographical and/or ethnic differences. Juvenile onset MG is uncommon in occidental populations but may represent more than half of cases in Asian populations.²⁵ Heritable MG is rare, estimated to occur in approximately 2% of cases although the concordance rate in monozygotic twins is estimated at 40%.^23,26–28 Under the age of 40, AChR MG is almost three times more common in women. Men and women in their 40s however, are affected with equal frequency whereas in older individuals, the prevalence is greater in men at a ratio of 1.5:1.^29,30

Understanding normal and abnormal neuromuscular transmission (NMT) is relevant not only to MG but to other DNMT that may be either acquired or heritable, resulting from genetic, infectious/toxic, or paraneoplastic/autoimmune mechanisms. These mechanisms typically act individually, but be synergistic. For example, a family has been recently reported in which there appears to be synergy between genetic and autoimmune influences. Multiple family members with seropositive MG were found to have mutations in the ecto-NADH oxidase 1 gene (ENOX1), a gene expressed in both thymus and skeletal muscles.³¹ The mechanism by which this mutation, posited to predispose to autoimmunity, might cause MG remains unknown. It is thought to relate to sequence homologies between ENOX1 and the main immunogenic region (MIR) of the alpha-1 subunit of the AChR. This provides a theoretical explanation for a heritable and anatomically targeted autoimmune disorder.³²

Acquired MG typically evolves subacutely over days to months and reaches its clinical nadir within 2 years.33 The majority of patients are seropositive and usually have similar phenotypes regardless of the existence or type of autoantibody. Individual cases may have differing clinical features and natural histories, that may allow prediction of an individual serotype and different responsiveness to treatment.¹⁰ Each section of this chapter will describe the general features of the disease in its classical form associated with binding autoantibodies directed toward the AChR, and will then distinguish the differing features of other serotypes when applicable.

The natural history of myasthenia is difficult to predict in an individual patient. Information is, in a large part, derived from historical data accumulated prior to the availability of current therapeutic options.¹³ It is recognized that approximately 15–20% of Caucasian patients with initial signs and symptoms restricted to the oculomotor system will retain this restricted phenotype.³³ Ninety percent of those destined to develop generalized disease will do so within 2 years of symptom onset and a similar number will reach the nadir of their disease within a 7-year period.^13,34,35 It has been suggested, but by no means universally accepted, that immunomodulating treatment may diminish the risk of evolving into generalized disease.^36,37 Spontaneous, remissions unrelated to treatment are estimated to occur in between 10-22% of MG patients.^13,30 These remissions may occur at any time in the course of the disease. Half of the patient’s who achieve spontaneous remission, relapse within 6 months and 90% within a year.^13,30 Regarding therapeutic decisions, however, there is no apparent correlation between the existence and length of remission and maximal disease severity.¹³ Mortality statistics in MG has been undoubtedly altered by therapeutic intervention. At the turn of the twentieth century it was approximated at 70%, reduced to 23–30% by the 1950s, with contemporary estimates in the 1.2–2.2% range.^13,23,38

The diagnosis of myasthenia is clinically established by two phenotypic features, the pattern of weakness and its tendency to fluctuate. There are theories underlying the selected vulnerability of certain muscles in MG that will be addressed in the pathophysiology section. The basis for the characteristic patterns of weakness in MG remains, however, largely speculative.³⁹ It may be related to the distribution of different types of neuromuscular junctions (NMJs) in different muscles.

The fluctuating nature of myasthenic symptoms is related to the dynamic biology of the NMJ.⁴⁰ It is a quality of the disease that may be a dominant feature of the patient’s history or may be overlooked. MG patients may recognize that their symptoms may vary on a minute-to-minute, diurnal, or week-to-week basis.^41–44 For example, a patient may describe normal articulation at the onset of a telephone conversation and may have unintelligible speech 5 minutes later. Patients may observe normal eyelid position upon awakening and then develop ptosis as the day wears on. Fluctuation may not be simply diurnal and patients may have functional hardships one month that seem to improve on their own the next month without apparent explanation. Fluctuations may also occur in response to identifiable variables such as temperature, systemic infection, menses, anxiety, emotional stress, and pregnancy.^18,45–50 Myasthenic visits to emergency rooms are known to increase in frequency in early morning hours in equatorial countries where electricity and therefore air conditioning may not be available at night, making this potentially the warmest period of the day. Variability may also occur not only in the timing but in the pattern of weakness. Alternating ptosis represents the most notable example of this phenomenon. It should be emphasized that diurnal worsening of strength and stamina is not pathognomonic of MG as the weakness of any neuromuscular disease may worsen as the day goes on.

MG may also be suspected by the pattern of weakness. MG should be considered in any patient with painless weakness, particularly when the weakness is multifocal or diffuse in distribution or when weakness of ocular and bulbar muscles predominates. Asymmetry is not uncommon, particularly with ptosis. Most myasthenics will experience ptosis, diplopia, dysphagia, dysphonia, difficulty chewing, or symptoms referable to facial or neck weakness, either in isolation or in combination. Identification of weakness in muscles innervated by anatomically unrelated cranial nerves, for example, concomitant weakness of eyelid opening and eyelid closure represents a common and diagnostically useful example.

Initial symptoms restricted to ptosis or diplopia will be the presenting symptoms of MG patients in 65–85% of cases and 95% will experience oculomotor involvement at some point in their illness.^{33,37,43,51,52} Overt diplopia may be preceded by nonspecific visual blurring when ocular malalignment is minimal and insufficient to produce two distinct images. The presence of other signs and symptoms of myasthenia or the resolution of blurring the covering of either eye aids in the identification of blurring due to ocular malalignment. Other than the levator palpebrae, the medial rectus appears to be most susceptible of the extraocular muscles. Any pattern of ophthalmoparesis may occur, however, potentially mimicking an individual cranial nerve palsy or intranuclear ophthalmoplegia, or at times even producing nystagmus.^53,54,55

Facial weakness is common. Lower facial weakness may result in dysarthria or sialorrhea, or in difficulty whistling, inflating balloons, or drinking from a straw. It may also interfere with the accuracy of pulmonary function testing due to poor oral seal. Weakness of upper facial muscles is equally prevalent but less likely to be symptomatic. Occasionally, patients may complain of visual blurring due to lower lid weakness resulting in pooling of tears. Facial weakness can be easily missed if not sought for, particularly if bilateral. Patients who are affected may be unable to bury their eyelashes or maintain eye closure against resistance. They may be unable to whistle, make a kissing noise, or hold air in their distended cheeks against resistance. A “myasthenic snarl,” may occur in which the mid-portion of the upper lip elevates without elevation of the corners of the mouth during an attempted smile.

Symptoms and signs referable to jaw weakness, particularly jaw closing, occur fairly commonly in MG. Although jaw weakness may occur in other neuromuscular diseases, many of the other causes, for example, Guillain–Barré syndrome, are unlikely to have a phenotype readily confused with MG.⁵⁹ Like most neuromuscular diseases, neck flexor weakness is more common and more pronounced than neck extensors weakness in the majority but not in all MG patients. Head drop is not rare however, and may be the presenting symptom. Like other causes of head drop, posterior neck pain relieved by head support may be the most prominent symptom associated with this sign, presumably related to the stretch placed on posterior cervical muscles and ligaments by the weight of the head. Ventilatory insufficiency is a rare presenting symptom of MG but may develop in a significant percentage of patients with untreated or refractory generalized disease.^58,60 Along with dysphagia, it is undoubtedly the predominant basis for mortality in MG unrelated to complications of treatment or immobility.

Limb weakness occurs in 20–30% of affected individuals. Limb weakness preferentially affects proximal muscles.^61,62 One potential but undoubtedly partial explanation is the warmer temperature of the proximal limbs.⁶³ Typically, limb weakness occurs in concert with the signs and symptoms of oculobulbar disease. In approximately 10% of patients with limb involvement, MG may be initially restricted to distal limb muscles, with foot or finger drop being notable presentations that have been reported and that we have seen.^64–69 Again, the pattern may be focal, multifocal, or diffuse.⁴³

MUSK MG

Approximately 7–15% of all MG patients or 40% of seronegative patients with generalized MG are estimated to have MuSK autoantibodies.^{6,10,55,70–76} On average, MuSK MG patients are younger and more severely affected than their AChR MG counterparts although MuSK MG rarely if ever develops in an individual in the first decade of life.^10,77,78 Disease prevalence in MuSK MG is highest in the third and fourth decades of life in non-Asian populations. In some series, males and females are affected equally whereas in other series, females have predominated.^{73,77,79–81}

Most MuSK MG patients will have a phenotypic pattern indistinguishable from AChR MG patients. Nonetheless, there are certain clinical features that suggest an increased or decreased probability of MuSK MG.^70–88 For example, purely ocular disease is a rare MuSK MG phenotype.^{71–73,77,86,87} Patterns that suggest an increase probability of MuSK MG include persistent bulbar symptoms refractory to treatment, prominent neck, facial, and ventilatory muscle weakness and the presence of muscle atrophy in an otherwise typical MG patient, notably in the tongue.^10,72 The latter finding may render the clinical distinction from bulbar amyotrophic lateral sclerosis (ALS) more difficult.^55,77,79,88 As MuSK is known to facilitate reinnervation, it is plausible that the atrophy noted in this serotype may be related to a “denervating” effect of MuSK autoantibodies.⁸⁹ MuSK MG patients in general have more severe disease both at onset and disease nadir, are less likely to achieve complete remission with treatment, and are more likely to experience myasthenic crises than either their AChR or seronegative counterparts.^10,77–79

SERONEGATIVE MG INCLUDING PATIENTS WITH LPR4 AUTOANTIBODIES

Seronegative MG may represent up to 34% of MG patients depending on the study and the ethnic background of the cohort studied.¹⁰ In 2008, a high sensitivity assay discovered IgG1 autoantibodies in two-thirds of these seronegative MG patients.⁷ In 2011, an epitope on the LPR4 protein was found to be the target of IgG1 autoantibodies, presumably the same autoantibodies described 3 years previously.⁹ These patients, historically included in the seronegative group, represent a very small percentage of MG patients.⁸⁹ Studies to date have estimated that LPR4 autoantibodies are found in 3%, 9%, and 50% of seronegative MG patients.^9,25,90 These significant differences may represent differences between ethnicities, differences in methodology, or accuracies relevant to small sample size; the 50% figure originating from a study of only 13 patients.⁹⁰

The examination of the suspected or established MG patient includes a number of unique or relatively unique features. As ptosis is such a common manifestation of MG, documentation of the baseline upper and lid positions in relationship to the pupil is recommended prior to provocative testing and to distinguish ptosis from squinting, both of which narrow the palpebral fissure.

In MG, pupil function is spared although physiological anisocoria is common enough to provide a potentially confounding feature. In order to unmask or exacerbate ptosis or extraocular muscle weakness, the suspected MG patient is asked to sustain either up or lateral gaze for a minute while limiting blinking as much as possible (Fig. 25-1A–C). Drifting of lid or eyeball position is watched for. Cogan’s lid twitch is another sign thought to be a relatively specific, although not necessarily sensitive, sign in MG assessment. With this maneuver, the patient is first asked to look down and then rapidly saccade to reassume the primary position. Normally the eyelid moves synchronously with the eyeball. A positive sign is defined by the eyelid overshooting the eyeball position leading to a transient scleral exposure and upper lid oscillation.

There are special considerations in pregnant women with myasthenia, their newborn children, and children with myasthenia.93–97 In an extensive review of the literature involving 322 pregnancies in 225 myasthenic mothers, 31% of mothers had no change in their myasthenic symptoms, 28% improved, and 41% deteriorated during the pregnancy.⁹⁸ During the postpartum period, 30% had a disease exacerbation. There is a theoretical risk of transmitting IgG AChR antibodies in breast milk, although most infants have no problem with breastfeeding.

Transient neonatal autoimmune MG develops in approximately 10% of infants born to mothers with MG.^100–112 It has been reported to occur in MuSK MG.¹¹³ Maternal treatment seems to significantly lower the risk of infantile disease.¹¹⁴ Onset is usually within the first 3 days of life. The most notable features include a weak cry, difficulty feeding due to a poor suck, hypotonia, respiratory difficulty, ptosis, and diminished facial expression resulting from facial muscle weakness. The disorder is temporary in most cases, with a mean duration of about 18–20 days. In rare cases, in utero paralysis may lead to a child born with multiple joint contractures.¹¹⁴ Other than recognition and symptomatic treatment, the most important aspect of this disorder is that there appears to be no increased risk of the child developing MG in later life.

Juvenile MG represents a “subclassification” of autoimmune MG.^{96–98,115–118} It is estimated that approximately 10% of acquired (non-neonatal) autoimmune MG cases will occur before 18 years of age in occidental populations, the majority subsequent to puberty.^114,115,117 This statistic may be inflated, as some reported juvenile, seronegative cases could easily represent congenital myasthenic syndromes (CMS). The clinical features are similar to adult-onset MG, with the majority of patients initially presenting with primarily ocular symptoms.¹¹⁷ Serum AChR antibodies are present in the majority of affected children. The electrophysiologic findings are also identical to the adult form of the disease.¹¹⁸

ASSOCIATED DISORDERS

Effective management of MG requires knowledge of disorders that occur with an increased incidence in patients with MG, particularly thymic abnormalities and other autoimmune diseases which may occur separately or overlap. Thymus gland pathology is the most notorious disease association.^23,71,119 As many as 80% of patients with seropositive MG have thymic hyperplasia while approximately 12% have thymoma.^23,120–122 Hyperplasia is more common in younger patients. Thymomas occur equally in men and women and occur with the greatest frequency in middle-aged and older individuals.²³ Patients with thymoma, on average, have more severe clinical presentations and higher AChR antibody titers than their nonthymomatous counterparts. Thymic abnormalities have been documented to occur in MuSK MG but are thought to occur far less frequently.^{10,23,71,74,78,81,123} Thymic pathology, either hyperplasia or thymoma, occurs in seronegative and presumably in LPR4 MG.²³ In patients with thymoma, slightly more than half will be found to have or will develop MG.²³

Thymomas are not uniquely associated with MG and may coexist with other autoimmune disorders, other autoantibodies, and a host of other neurological and neuromuscular disorders (Fig. 25-2A,B).¹²⁴ Reported associations include granulomatous myositis, myocarditis, Isaacs’ syndrome, rippling muscle disease, limbic and cerebellar encephalitis, and autonomic neuropathy including the syndrome of intestinal pseudoobstruction.125–130 Eleven patients with a particularly severe phenotype characterized by bulbar involvement, myasthenic crises, thymoma, myocarditis, and prolonged QT electrocardiographic interval have been described associated with Kv1.4 voltage-gated potassium channel in addition to AChR-binding autoantibodies.¹²⁹

Other autoimmune diseases, most notably Hashimoto’s disease, occur with increased frequency in MG in addition to rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, red blood cell aplasia, ulcerative colitis, sarcoidosis, Addison’s disease, and hyperparathyroidism.131–135 Predictably, these disorders may occur with or without thymic abnormalities. Other neurological or neuromuscular disorders reported to coexist with MG include acute and chronic inflammatory demyelinating polyneuropathies, autonomic neuropathy (e.g., intestinal pseudoobstruction) with or without encephalopathy, Lambert–Eaton myasthenic syndrome (LEMS), acquired neuromyotonia or Isaacs’ syndrome, acquired rippling muscle disease and stiff person syndrome^{125,128,136–153} In addition, approximately 5% of patients with MG also have an inflammatory myopathy.^{137,154–157} Most of these patients also have a thymoma with or without myocarditis. The histopathology often reveals a giant cell or granulomatous myositis. Serum CK levels are usually elevated with concomitant inflammatory myopathy, which would not be expected in MG alone. It is estimated that the coexistence of other autoimmune diseases approximates 30% in AChR or in seronegative MG as opposed to MuSK MG where the prevalence of other autoimmune disease is estimated to approximate 20%.⁷¹

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of myasthenia is usually established clinically and supported by a positive response to one or more of the following tests:

• electrophysiological—repetitive nerve stimulation (RNS) or single-fiber electromyography (SFEMG)

As has been repeatedly emphasized, MG should be considered in any patient with painless weakness, occurring in a regional, multifocal, diffuse, or even a seemingly focal pattern. The likelihood of MG increases substantially with the objective demonstration of fatigable weakness, particularly in an oculobulbar distribution. Weakness may be asymmetric and occurs in the absence of fasciculations and in most cases, muscle atrophy.

Brain

Wernicke encephalopathy a

Rabies^a

Brainstem neoplasm^a

Anterior horn cell

ALS

Kennedy syndrome^a

Spinal muscular atrophy^a

Enterovirus infection^a

Root/nerve

Chronic meningitis^a

Miller Fisher syndrome^a

Diphtheria^a

Immune-mediated motor neuropathies^a

NMJ

Congenital myasthenic syndromes

Lambert Eaton myasthenic syndrome

Botulism

Tick paralysis

Muscle

Oculopharyngeal MD

Myotonic MD^a

Mitochondrial myopathy

Congenital myopathy^a

Inflammatory myopathy^a

Miscellaneous

Depression^a

Chronic fatigue^a

Dysthyroid ophthalmopathy^a

Orbital pseudotumor^a

Due to frequently overlapping phenotypes, and potentially similar electrophysiological features and pharmacological response, the most vexing of these considerations are the CMS. CMS should be seriously considered in any child, adolescent, or young adult with apparent seronegative MG. A history suggesting other involved relatives and/or consanguinity increases the probability of CMS. The CMS will be considered in more detail in the subsequent chapter.

In adults with bulbar weakness, considerations other than MG include but are not limited to the progressive bulbar palsy form of ALS, Kennedy disease, LEMS, botulism, and both acquired and hereditary myopathies. Congenital myasthenia cannot be entirely excluded from consideration as the DOK-7 and rapsyn mutations in particular may be associated with a late-onset phenotype and be readily misidentified as seronegative MG.¹⁵⁸ Most causes of multiple cranial neuropathies typically produce sensory in addition to motor symptoms but occasionally these syndromes may be motor predominant. As the presence of ptosis or ophthalmoparesis essentially excludes motor neuron disease or inflammatory myopathy from consideration, careful surveillance for these abnormalities provides valuable differential diagnostic insight. LEMS is usually dominated by symptoms referable to proximal limb muscles with prominent fatigue and symptoms of cholinergic dysautonomia, but ptosis and bulbar symptoms do occur and can make its distinction from MG challenging in some cases.^159,160 Botulism can affect children and adults and as a presynaptic disorder, can produce cholinergic dysautonomia with constipation and enlarged, unreactive pupils. Its acuity and the clinical context in which it occurs are helpful features to help distinguish it from MG. A number of inherited muscle diseases such as oculopharyngeal muscular dystrophy, mitochondrial myopathy, myotonic muscular dystrophy, and rare adult-onset cases of congenital myopathy such as centronuclear myopathy may produce oculobulbar syndromes.

As mentioned above, MG may rarely present with weakness restricted itself to limb or trunk muscles. The pattern of weakness may be predominantly proximal and symmetric or distal and asymmetric. Accordingly, the differential diagnostic considerations are broad and include anterior horn cell diseases, myopathies, neuropathies with motor predominance including some cases of inflammatory demyelinating polyneuropathy, multifocal motor neuropathy in more chronic and focal cases, as well as other forms of DNMT such as LEMS, botulism and acute organophosphate poisoning. Many of these diseases commonly have cranial nerve involvement as well. In children, SMA, congenital myasthenia, botulism, tick paralysis, and various myopathies would be the primary considerations. Poliomyelitis or other enteroviral infections would readily distinguish themselves in most cases but require consideration along with botulism and tick paralysis in any acute–subacute-onset case due to their pure motor characteristics.

PATHOPHYSIOLOGY

Successful NMT is dependent on the anatomical and physiological capabilities of the NMJ to translate and amplify a peripheral nerve action potential (NAP) into a transsynaptic chemical signal mediated by the neurotransmitter acetylcholine (ACh). Subsequently, the NMJ promotes the generation of a postsynaptic EPP, which unlike an action potential, varies in amplitude. If this EPP achieves the necessary magnitude, an action potential will be generated in the corresponding muscle fiber. This single muscle fiber action potential (SMFAP) tranduces the electrical event into a chemical and eventually mechanical event. The SFMAP promotes calcium release into the sarcoplasmic reticulum which is responsible for myofiber contraction and the generation of force.¹⁶¹ The amount of force generated is dependent on the number of motor units activated, and ultimately, the number of muscle fibers in which this sequence of events takes place.

Although DNMT are usually categorized as belonging to one of the three aforementioned anatomical domains, it would be overly simplistic to assume that all NMJs are the same, that each of the three anatomic NMJ domains develops embryologically in isolation, that any domain functions independently of the other two, or that any DNMT results solely from dysfunction of an individual domain. For example, the presynaptic configurations may differ between different NMJs in different muscles with terminal twigs having either an “en plaque” or “en grappe configuration.” The former refers to large, single contacts on each muscle fiber. It is the predominant form in most mammalian muscles. The latter array refers to multiple, smaller contact points on individual fibers. This configuration seems to correlate with the need for tonic muscle contraction and is most prevalent in nonmammalian systems, but exists in humans in extraocular muscles in particular and in the tensor tympani, stapedius, laryngeal muscles, and tongue as well.³⁹ The greater concentration of fetal-type AChR in extraocular muscles represents one hypothesis as to why these muscles appear to be disproportionately susceptible to AChBR autoantibodies and why they are relatively spared in MuSK MG.¹⁶²

In addition, AChR structure may differ between muscles as well. Muscles innervated by terminal twigs with en grappe morphologies are more likely to have fetal-type AChRs (described below) whose physiological properties may differ from their en plaque counterparts.¹ NMT also differs between different fiber types. Type 2 muscle fibers (fast twitch) have greater sensitivity to ACh than their type 1 counterparts translating to a larger safety factor in NMT. This results from larger nerve terminals, a greater average quantal content, an increased number of postsynaptic folds, and a greater density of sodium channels.^39,162 This is teleologically logical, as firing frequencies in fast twitch fibers are much higher than their slow twitch counterparts, translating to greater ACh depletion in the active zone of the presynaptic region, thereby requiring a greater safety factor in type 2 fibers to ensure uniformly successful NMT.162

Lastly, there is a significant interdependence on the three anatomical domains of the NMJ that is evident not only during synaptogenesis but in disease. Optimal postsynaptic architecture and function is very dependent on presynaptic influence.⁹⁰ As an example, acquired postsynaptic MuSK MG and the inherited synaptic form (end plate acetylcholinesterase (AChE) deficiency of CMG both have adverse effects on more than one domain of the NMJ anatomy.⁹⁰ AChE deficiency will have presynaptic effects such as reduction in quantal content and in the size of the presynaptic nerve terminal as well as a postsynaptic effect in the generation of an end plate myopathy.¹⁶³

The sequence of events in normal, successful NMT can be conceptualized as beginning with the synthesis and resynthesis of ACh in the presynaptic terminal and can be schematically followed in (Figs. 25-3 and 25-4). This is accomplished primarily by the enzyme choline acetyltransferase (ChaT) that combines acetate and choline after their reuptake into the presynaptic terminal. Synthesized ACh molecules are packaged into vesicles or quanta that exist in three separate zones; a large storage pool, a mobilization pool, and in clusters close to the presynaptic membrane referred to as the active (immediate release) zone.¹⁶⁴ Although there are non–calcium-dependent mechanisms of ACh release, the efficient function of these active zones is dependent on calcium entry into the distal motor nerve terminal. The P/Q type voltage-gated calcium channels (VGCC) integral to this process are distributed along the active zones at vesicle fusion sites on the presynaptic membrane. In response to a NAP, the presynaptic calcium concentration increases to the 100–1000 μM range.^162,165 Vesicle release occurs after a delay of approximately 100 μs following the NAP with the presynaptic calcium concentration dissipating after approximately 200 μs. As calcium channels are not fully activated by a normal NAP, the capacity to increase quantal content exists by other mechanisms not involved in normal NMT.

The mobilization pool is estimated to contain 300 × 10³ vesicles that can be moved readily to the active zone region.¹⁶⁸ Following vesicle fusion with the presynaptic membrane and exocytosis, ACh resynthesis and repackaging (endocytosis) take place. Experimental data suggest that the rate of resynthesis parallels the rate of ACh release under normal physiological conditions and is capable of increasing to keep pace with neuromuscular activation.¹⁷⁰

The process of ACh synthesis and resynthesis, vesicle packaging, migration, docking, and exocytotic release into the synaptic cleft is dependent on greater than 1000 functional presynaptic proteins (Fig. 25-3). Detailed description of this obviously complex system is incompletely understood and beyond the scope of this chapter. The key proteins underlying vesicular fusion with the presynaptic membrane are referred to as the SNARE protein complex (soluble NSF attachment protein receptor). Key components of the SNARE complex are synaptotagmin and synaptobrevin (bound to the vesicular membrane), and syntaxin-1 and SNAP 25 (bound to the presynaptic plasmalemma). Interaction between synaptobrevin and syntaxin-1 and SNAP 25 prime the binding and fusion process that culminates by the subsequent binding of calcium to synaptotagmin that triggers quantal release into the synaptic space.³⁹ Subsequent to its role in this process, calcium may freely diffuse away from the active sites, be removed from the nerve terminal by a coupled sodium/calcium exchange mechanism, or be sequestered in the smooth endoplasmic reticulum or mitochondria.¹⁷¹ To the best of our knowledge, there are no recognized acquired or heritable disorders related to the proteins discussed in this paragraph.

The quantal content varies in response to each NAP. Under normal circumstances, the quantal content produces an EPP that far exceeds that necessary to produce a postsynaptic muscle fiber action potential ensuring the fail-safe generation of muscle fiber action potentials with repetitive or sustained attempts at voluntary muscle activation. Although largely irrelevant to normal physiology, presynaptic release of ACh can be augmented as mentioned previously. This effect may be either pathological or therapeutic, depending on the context in which it occurs. In disorders of NMT, the EPP may be augmented by pharmacological intervention at the presynaptic terminal that either prolongs depolarization by blocking potassium channels or the duration and effect of calcium. 3,4 diaminopyridine is an example of the former and guanidine is an example of the latter.^39,162,165 In addition, autoantibodies directed at components of the presynaptic potassium channels may produce a pathological condition of muscular hyperactivity (Isaacs’ syndrome) as reviewed in Chapter 10.

Another presynaptic contribution to NMJ development in particular, and to its maintenance and function as well, is the protein agrin. Agrin, synthesized in and released from the presynapse, contributes significantly to postsynaptic differentiation and to the stabilization of end plate receptors¹⁷² This process of end plate differentiation requires interaction with a number of crucial postsynaptic proteins including LPR4, MuSK, downstream of kinase-7 (Dok7), and receptoraggregating protein at the synapse (rapsyn).⁹⁰ As will be described in this and the subsequent chapter, impaired NMT may result as a consequence of either heritable defects in many of these proteins (agrin, MuSK, rapsyn, Dok7) or in some cases autoantibodies directed against them (MuSK, LPR4).⁹⁰

The morphology of the synaptic space may be subdivided into the major or primary gap (cleft) between the nerve terminal and muscle and multiple secondary clefts formed by the postjunctional folds extending into the postsynaptic region.³⁹ This folding increases the surface area of the postjunctional membrane by 10-fold in comparison to the presynaptic membrane.^173,174 This allows for an increase in the density of AChRs/channels as described below, thereby improving the efficiency of NMT. The synaptic cleft is narrow with an average distance of 50 nm between the presynaptic membrane and the summits of the postsynaptic folds.³⁹ This narrow gap facilitates rapid NMT. Once released into the synapse, the quanta will briefly bind to and interact with ACh receptors or channels that control the ingress of cations into the muscle fibers on which the receptors are located.

ACh binding to the end plate is short-lived, due in part to diffusion away from the receptor and in large part due to catabolism by the enzyme AChE that is anchored to the basal lamina by its collagen tail, the outer layer of the postsynaptic muscle membrane.³⁹ It is encoded by the triple-stranded collagen Q gene (COLQ) which is relevant to one form of CMS that will be described in Chapter 26. Drugs that reversibly inhibit AChE are used both diagnostically (edrophonium) and therapeutically (pyridostigmine) in MG whereas irreversible anticholinesterases (organophosphates) are utilized for their toxic properties as insecticides or in warfare. There are multiple isoforms of AChE.¹⁷⁵ The primary form is AChE-S (synaptic) which is bound to the basal lamina. Other forms, AChE-E (erythropoietic) and AChE-R (read-through) do not play significant roles in ACh catalysis under normal circumstances but compensatory increases in AChR-R in response to chronic treatment with cholinesterase inhibitors may have detrimental clinical effects as described below.¹⁷⁵

ACh catalysis by AChE is one of the fastest enzymatic processes known and occurs at a rate of five ACh molecules per millisecond.¹⁷⁶ Despite this, ACh enjoys a competitive advantage as the density of AChR (15–30 K × m²) is 5–10 times greater than the molecular density of AChE (2–3 × 10³/m²).¹⁷⁷ This allows 50–75% of the quantal content to achieve successful interaction with AChR under normal circumstances.178

Temperature changes affect NMT in a variety of ways that may have both electrodiagnostic (EDX) and clinical significance.^{44,45,48,49,179,180} These effects will be addressed here as the most notable physiological effect of temperature change on NMT is on AChE. Reduced temperature slows the rate of AChE hydrolysis of ACh, prolonging the duration of EPPs by allowing ion channels to remain open for longer periods of time and enhancing end-plate responsiveness to ACh.^181,182 The net effect of cooling is to enhance NMT. Electrodiagnostically, this may diminish the probability of demonstrating a decremental response to slow repetitive stimulation. Clinically, cooling may improve function, for example, patient recognition that cold liquids are easier to swallow than warm ones.

Cooling has other non-AChE effects on the physiology of NMT. Both the duration and amplitude of the NAP at the presynaptic terminal are increased by cooling.^163–185 This may be a consequence of prolonged calcium channel open time and augmented quantal content.¹⁸⁶ Reducing the affected muscle’s temperature is known to increase the AChR’s open time as well.¹⁸² Finally, a reduction in muscle temperature leads to a lowering of the resting membrane potential, bringing it closer to threshold, allowing a myofiber action potential to be triggered with a smaller EPP. These four factors, and perhaps others as well, serve to improve NMT in response to cooling.

The organization of the postsynaptic membrane provides for efficiency in NMT (Fig. 25-4). The development and maintenance of end plate complexity is related to the proximity of nerve terminals both embryologically and during adult life and to the influence of ACh and agrin produced and released by these nerve terminals. The key anatomic structure on the end plate is the AChR receptor or channel. Each AChR channel is a glycoprotein composed of five subunits that are arranged in a manner similar to barrel staves turned inside out, resulting in a transmembrane structure with a sagittal appearance similar to the cooling tower of a nuclear power plant. In an adult, the channel consists of two α subunits with singular copies of β, δ, and ε subunits.^39,162,187 Embryologically, the AChR has a γ subunit instead of an ε subunit. The transition to an adult configuration occurs at least in part due to the trophic influence of the presynaptic nerve terminal during the innervation process. Fetal AChRs are typically downregulated during adult life but their presence may have two notable clinical influences. As mentioned above, they may persist to some degree in certain adult muscles, particularly those with en grappe nerve presynaptic morphology, and may contribute to the selected vulnerability of ocular and bulbar muscles in acquired MG. Their persistence in some forms of congenital myasthenia may allow for survival in what would otherwise be a lethal condition.

At the NMJ, AChRs preferentially reside in at the apices of the junctional folds of the muscle end plate and span the postsynaptic membrane. These channels are topographically clustered with their density estimated to approach 10,000 molecules per μm².¹⁸⁸ The density of these channels falls to approximately 10 molecules per μm² within a few microns of the end plate.^39,162 The topography of AChR channel distribution both on and within the muscle end plate is essential for optimal NMT. The placement of these channels is established embryologically and maintained during adult life through the contributions of a number of numerous proteins that are essential for the development and maintenance of channel distribution and their optimal function.¹¹⁴ The initiation of this process is through the effects of the presynaptically synthesized and released protein agrin and ACh, both of which are essential to this process. Agrin knockout mice have normal numbers of AChRs but no evidence of clustering. Agrin appears to bind postsynaptically to LRP4 which in turn results in MuSK activation.¹⁸⁹ MuSK is required not only for proper synaptogenesis, but for the stabilization and maintenance of end plates in postnatal life. Knockout MuSK mice embryos fail both to develop AChR clusters or to survive.³⁹ Deletion of MuSK in adult muscle leads to the degradation and complete loss of NMJs. MuSK reacts in turn with Dok-7 to activate certain downstream signaling pathways and with rapsyn. ACh clustering is maintained by rapsyn which directly binds with the cytoskeleton and dystrophin-glycoprotein complex, specifically through α- and β- dystroglycan.^{39,162,190,191} Despite the apparent importance of Dok-7 in this process, defects in this protein do not appear to adversely affect AChR clustering on junctional folds.¹⁶² An additional protein, neuregulin (NRG-1) also appears to play a role in the clustering of AChRs at the NMJ.^39,162

As mentioned, the AChR is a ligand-gated channel that spans the postsynaptic muscle membrane with its long axis oriented perpendicular to this membrane. It has a hydrophilic central pore with the ACh-binding site located on the extracellular surface of each subunit.¹⁹² In the resting state, the central narrow region or waist created by the apex of the convexity of all five subunits meet in opposition, effecting channel closure. Channel opening is dependent on the simultaneous binding of two molecules of ACh with each channel, which then leads to a conformational change, allowing transient opening of the channel pore and, as a result, ion movement. The agonist binding sites for ACh straddle the α/δ or α/ε (α/γ when relevant), identical to the binding site for α bungarotoxin.^114,162 They appear to be distinct from, but close to the MIR which resides on the α subunit and is the locus for AChR autoantibody binding.^114,162 The α/γ binding site appears to have the highest affinity for ACh which could in turn have relevance in regard to the selective vulnerability of certain muscles which have a greater prevalence of this channel type. Although potassium, calcium, and sodium ions are all capable of traversing the channel, sodium conductance is most dynamic due to favorable size, concentration, and electrical gradient considerations.

The nonpropagating EPP generated by the normal quantal content release typically exceeds 50 mV in amplitude, and in normal individuals, produces a propagating SMFAP in each muscle fiber stimulated.¹⁹⁵ In health there is a “safety factor”, that being an EPP whose magnitude far exceeds that which is required to depolarize the muscle fiber. A typical mammalian resting membrane potential is approximately –80 mV. The threshold for depolarization may be achieved by a change in voltage of only 10–15 mV, thus providing the three- to fourfold safety margin that normally exists in NMT transmission. The magnitude of the EPP is decreased with repetitive stimuli occurring at a frequency of 5 Hz or less, which, at least initially, deplete ACh-containing vesicles in the active zone. Because of the aforementioned safety margin however, this effect has no significance in the normal individual.

The decline in the EPP in response to “slow” repetitive stimulation will not persist indefinitely as the EPP amplitudes begin to increase after the fourth or fifth stimulus attributed to ACh arrival from the mobilization pool. Conversely, and perhaps counterintuitively, the EPP may be augmented substantially by repetitive stimuli at frequencies of 5 Hz or more. This phenomenon of post-tetanic facilitation is attributed, in large part, to enhanced quantal release related to lingering calcium effects within the presynaptic terminal. Again, this phenomenon bears no consequence in the normal individual, as MFAP occurs in each muscle fiber in response to each and every stimulus. This post-tetanic facilitation does not last indefinitely, and the EPP will begin to decline after approximately 1 minute in normal people due to declining ACh availability. This latter phenomenon is referred to as post-tetanic or postexercise exhaustion and can also be utilized as a diagnostic tool with repetitive stimulation studies in patients with suspected DNMT.^196,197 Although post-tetanic exhaustion will not result in NMT failure in normal individuals, it may do so in patients with DNMT whose safety margin for the generation of muscle fiber action potentials is compromised at baseline by disease. In all DNMT, reduction and eventual loss of the EPP safety margin by whatever means is the universal mechanism by which NMT failure and weakness are created.

In addition to the AChR channel, Nav 1.4 sodium channels are also integral to the generation of the muscle fiber action potential.¹⁶⁶ Unlike the AChR, they are clustered at the base rather than the peak of the synaptic folds.^39,175 Their density is 5–10-fold higher in the end plate than in other regions of the sarcolemma and have a greater density in type 2 than in type 1 muscle fibers.¹⁶² Sodium ingress at the NMJ facilitates the EPP generated by ACh channel opening and adds to the safety margin of NMT. Mutation of Nav 1.4 channel gene is a rare form of CMS.

The half-life of an AChR in the junctional membrane is about 8–10 days.¹⁹⁸ Under normal circumstances, there is a normal turnover of AChR which are internalized and degraded. The senescent receptors are internalized by the process of endocytosis and transported to lysosomes for degradation through an intricate network of intracellular tubules. This process is accelerated in disease as described in more detail below, being expedited by cross-linking of channels with AChR autoantibodies.¹⁶² The AChR are not recycled but are replaced by newly synthesized receptors, one reason why DNMT are more treatment responsive than other neuromuscular disorders in which damaged components are not as readily restored, even if the disease process is arrested.

Integral to the pathogenesis of ACHR MG is the reduction of AChR at the end plate as initially demonstrated by Fambrough and Drachman in 1973 through radiolabeled α-bungarotoxin techniques.³ The pathogenic AChBR autoantibodies of MG are of the IgG1 and IgG3 types and bind predominantly to the MIRs of the AChR which exist on the two alpha subunits of the channel.^{32,73,114,199–201} Once bound to the AChR, these antibodies initiate a number of irreversible processes, all of which are directed at the AChR and postsynaptic membrane. The most potent of these appears to be complement-mediated, membrane-attack complex lysis of AChR.^202,203 Resultant end plate changes not only reduce receptor number but have other anatomic consequence of physiological significance that include simplification of the normal corrugated structure of the end plate (Fig. 25-5). This not only reduces the cross-sectional area but widens the synaptic cleft, thus further reducing the probability of ACh/AChR interaction.^173,204,205 Other potential pathophysiological mechanisms include steric hindrance, with autoantibodies physically blocking ACh binding sites on adjacent channels or preventing the conformational change resulting in opening of the ion pore.²⁰⁶

The autoantibodies not only bind to the AChR but also cross-link with other antibodies.207,208 When the AChRs are cross-linked in this manner, these are reabsorbed by the postsynaptic membrane by a process known as endocytosis. This process takes place under normal circumstances but accelerates up to three times faster in the presence of AChBR autoantibodies. As a result, the normal NMJ AChR half-life of 5–10 days is dramatically reduced and the AChR population diminished.^209–211 As synthesis of new AChRs remains unchanged, there is a significant net reduction of 70–90% AChRs per NMJ.³ Although AChR MG is conceptually a disorder mediated by autoantibodies, there is a significant T-cell-mediated, CD4 lymphocyte component as well.^55,212 T lymphocytes specific to AChRs are found in patients with myasthenia.^213,214 T cell-targeted therapies hold therapeutic promise for MG.^212,215

Current knowledge suggests that MuSK MG is a disease of disordered AChR distribution as opposed to one of AChR destruction. There appears to be a good clinical pathological correlation between those muscles where clustering is impacted the most and selectively vulnerable muscles such as sternocleidomastoid, diaphragm, and masseter.⁷⁹ Histological studies of MuSK MG patients suggest that unlike AChBR MG, substantial loss of AChR content and IgG/complement does not occur.⁷⁹ Unlike AChBR autoantibodies, MuSK autoantibodies are of the IgG4 subtype and do not activate complement.^72,219 Their primary action in hampering NMT in MuSK MG appears to be fragmentation of the normal AChR clustering at the junctional peaks of the postsynaptic membrane. In addition, MuSK autoantibodies may have synaptic and presynaptic effects including impaired binding of the collagen tail of the AChE molecule and presynaptic reduction in quantal content instead of the usual compensatory increase that occurs in other forms of MG.^178,219 In fact, recent studies suggest that the primary binding site for MuSK autoantibodies is the site of interaction between MuSK and the collagen tail of AChE (ColQ) responsible for the anchoring of AChE on the basal lamina.²²⁰ This may provide an explanation for why MuSK MG patients, as will be subsequently described, uncommonly respond favorably to cholinesterase inhibitors.⁷⁹ Accordingly, MuSK MG may be eventually classified as a synaptic rather than postsynaptic disorder. Like most other postsynaptic proteins, mutation of the MuSK gene may result in rare reported cases of CMG.²²¹

LPR4 MG

The pathogenesis of LPR4 MG is incompletely understood. In support of a pathogenetic role of LPR4 autoantibodies, serum from LPR4 MG patients reduces MEPP amplitudes in mice.⁸ The preponderance of evidence suggests that LPR4 MG is an IgG1-complement–mediated disease similar to AChBR MG.^8,9,25,222 Accordingly, patients with LPR4 MG respond to immunomodulating agents in a manner similar to AChR MG patients although these two autoantibodies rarely, if ever, coexist.²⁵ In contrast, as the normal function of LPR4 involves interaction with MuSK in AChR clustering during synaptogenesis, one would predict a disease mechanism similar to MuSK MG in which complement-mediated end plate destruction does not appear to have a role. Unlike AChR MG, a small percentage of LPR4 MG patients will also harbor MuSK autoantibodies.^9,25

Transient Neonatal MG

The pathophysiology of transient neonatal myasthenia results from the passive transplacental transfer of the mother’s IgG AChR antibodies which bind to the interface of alpha and gamma subunits.¹¹⁴ The reason why this disorder does not happen with greater frequency is unknown.

No discussion of MG pathophysiology would be complete without attempting to provide a cogent explanation for the selective vulnerability of certain muscle groups and the notable asymmetries that may occur in a disease occurring as a consequence of equitable distribution of circulating autoantibodies. Two potential explanations have already been discussed: (1) differing pathophysiological mechanisms with differing autoantibodies and (2) differences in the AChR channel types in different muscles. It has also been hypothesized that the preferential involvement of the external ocular muscles may be related to the elevated temperature of the head compared to limbs. This of course, would provide an inadequate explanation for asymmetry. In the end, adequate pathophysiological explanations for the myasthenic phenotype remain elusive.^223,224

Lastly, the major gap that remains in our understanding of acquired, autoimmune MG pathogenesis is the knowledge of what initiates the disease process.³² As mentioned, Mendelian genetics appears to have a minimal causative role in acquired, autoimmune MG. We agree with those who believe that the future will identify a significant genetic role in disease susceptibility to adverse environmental influence.^23,26,31,32 The role of infectious agents such as the Epstein–Barr virus as one of these potential environmental precipitants remains uncertain.²²⁵ The thymus gland continues to occupy center stage in any MG etiology discussion.^23,226–228 One potential explanation involves the recognition that the thymus contains myoid cells and other types of stem cells that may serve as autoantigens by the expression of AChRs or AChR antigens on their surface.²³ In this same vein, AChR-specific B lymphocytes are found within the thymus gland of MG patients that are capable of generating antibodies to AChR in culture.

LABORATORY FEATURES

Diagnostic strategies in MG undoubtedly vary between clinicians and institutions due to individual bias and preference, test availability, and relevant differential diagnostic considerations in individual cases. Even in the most clinically straightforward cases, we believe that diagnostic confirmation should be obtained whenever possible, particularly if immunomodulating treatment or thymectomy is contemplated. The most sensitive test for MG is SFEMG (92–100%) followed by RNS of distal and proximal nerves (0–99%) depending on the muscle tested and whether the disease is limited or generalized in its manifestations.²²⁹ Neither modality is, however, specific for MG. AChR antibody testing is slightly less sensitive (36–94%) depending also on whether the patient has ocular or generalized disease as well as the nature of the assay utilized, but is highly specific.

SEROLOGICAL TESTING

Identification of AChR autoantibodies is the most expeditious means to confirm MG. Although there are different types of AChR autoantibodies as will be subsequently described, the AChR binding antibody is the principal pathogenic antibody tested for. It will be considered synonymous with AChR autoantibodies throughout this chapter unless otherwise specified. Typically, this is the only diagnostic test that we initially order unless there are phenotypic features that would suggest MuSK MG. As mentioned, the sensitivity is estimated at approximately 36–79% in ocular MG, 75–94% in generalized MG, and 66–93% in all MG patients.^{5,37,114,231,233} They are however, highly specific for the MG, being rarely reported as false positives in patients with other autoimmune diseases such as systemic lupus, rheumatoid arthritis, hepatitis, thymoma without MG, inflammatory neuropathy, motor neuron disease, 13% of patients with LEMS, 3% of patients with lung cancer without an apparent neurological disorder and in some asymptomatic relatives of MG patients.¹⁶⁰ We consider the diagnosis to be confirmed if these autoantibodies are present in the appropriate clinical context.

The value of these autoantibodies is for all intents and purposes in establishing the diagnosis initially. Although titers may decline with treatment, in particular following thymectomy, it is generally held that this test cannot reliably determine disease severity, response to treatment, or to predict either remission or relapse.^55,234 Unlike many other tests used in everyday practice, mild elevations in the AChR autoantibody titer are often significant. Conversely, patients without AChR autoantibodies may have a different disease, harbor a different MG autoantibody, have seronegative MG, or on occasion have a false negative result. This latter situation may arise with testing that has been done too early, or in an individual in whom autoantibody formation has been suppressed by immunomodulating treatment or thymectomy.^233,234 For these reasons, testing prior to the initiation of immunomodulating treatment or thymectomy is ideal. As initially seronegative patients may develop autoantibodies over time, repeat testing in a recommended interval of 6 months in the appropriate clinical context may be considered.²³¹

AChR-modulating and AChR-blocking autoantibodies are also commercially available but play a less significant clinical role.^160,235 AChR modulating autoantibodies measure degradation of the AChR in cultured human myotubes.²³² Both of these autoantibodies are most likely to coexist in individuals who are AChR binding autoantibody seropositive and are unlikely to occur in isolation.^126,160,235 In one report, AChR modulating autoantibodies were found in 75% of patients with AChR binding autoantibodies but in only 5% of seronegative patients.²³² It is our practice to order these autoantibodies only in this latter population. High titers of AChR modulating autoantibodies also play a potential role in the detection of thymoma. Seventy three percent of patients afflicted with both thymoma and MG harbor AChR modulating autoantibodies producing a >90% receptor loss.125,126,142 Although this potentially justifies their use as a screening tool for thymoma detection, we preferentially rely on imaging for this purpose.

AChR-blocking autoantibodies bind to the same site as ACh or α-bungarotoxin, close to but distinct from the MIR on the extracellular domain of the ACh channel.²³² They are found in approximately half of patients with generalized MG, but in only 30% of patients with ocular disease.^160,235 In one study, these autoantibodies were found in 30% of MG patients seropositive for AChR-binding autoantibodies but in no seronegative MG patient. As a result of this insensitivity, we find AChR-blocking autoantibody testing to have limited clinical value.

It is estimated that approximately 40–70% of AChR seronegative patients will have MuSK autoantibodies.^6,73,236 Our practice is to screen for MuSK autoantibodies as a first step along with AChR-binding autoantibodies if the phenotype is suggestive of MuSK MG. We also order MuSK autoantibodies in any MG suspect who is AChR seronegative. MuSK and AChR antibodies rarely coexist.^6,73,89,237 Although somewhat controversial, there appears, unlike AChR seropositive patients, to be a correlation between anti-MuSK titers, disease severity, and treatment responsiveness, thymectomy being the notable exception.^73,79,89

Striated muscle antibodies refer to a class of antibodies directed against components of skeletal muscle including titin, the ryanodine receptor, myosin, and α-actinin.²³⁸ These are found in approximately 30% of adult patients with MG without thymoma, 24% of patients with thymoma without MG, and 70–80% of patients who have both.^126,160,239 We have had numerous experiences where the occurrence of these autoantibodies even in high titer appears to have no detectable clinical correlation. Again, we largely rely on imaging to detect thymoma, and in view of the questionable sensitivity of the test, we find their utility limited. It is reasonable however, to measure these antibodies before and after thymectomy as a failure to reduce the titer suggests incomplete resection and as an increasing striational autoantibody titer postthymectomy has been reported to herald thymoma recurrence.

We routinely obtain a thyroid stimulating hormone level as the incidence of hypo- or hyperthyroidism is fairly high in MG patients and as a failure to recognize dysthyroidism may affect treatment efficacy. It is not uncommon for other autoantibodies to coexist with MG and/or thymoma such as ganglionic (as opposed to the nicotinic found on muscle) AChR antibodies, voltage-gated potassium channel antibodies, and CRMP-5-IgG autoantibodies.^125,126,130 We do not routinely test for autoantibodies more closely related to other autoimmune diseases in MG patients unless there is clinical suspicion to do so. Antibodies directed against the Kv1.4 subunit of voltage-gated potassium channels have been described to occur in a percentage of patients with MG but not in patients with thymoma, inflammatory myopathy, or in healthy controls.¹²⁹ These were found exclusively in patients who were also AChR-binding antibody positive and are not commercially available. Their role in the diagnosis of MG, if any, has yet to be defined.

ELECTROPHYSIOLOGICAL TESTING

The role of EDX testing in MG has undoubtedly diminished in an era of readily available, affordable, and accurate serological testing. EDX provides the greatest utility in the seronegative patient where its purpose is to identify a pattern of abnormalities that support a diagnosis of a postsynaptic DNMT, in turn consistent with MG.²⁴⁰ At the same time, it attempts to identify or exclude a pattern of abnormalities suggestive of an alternative cause of painless weakness. Electrodiagnosis is used by some in MG to monitor the response to treatment but we do not find this necessary in the vast majority of patients. One uncommon use of EDX in the MG patient is to identify afterdischarges on routine motor conduction studies that would support overdosing with cholinesterase inhibitors.²⁴¹ The actual mechanics involved in the performance of repetitive stimulation of motor nerves and SFEMG are provided in Chapter 2.^218,242 In this section, we will focus on the strategies and pitfalls involved in MG EDX and its interpretation, including a summary of characteristic pattern of abnormalities.²⁴³

The EDX evaluation of a patient with suspected MG begins with routine nerve conductions. Typically we obtain, one motor and one sensory conduction from an upper and lower limb, four conductions in total. We would expect these to be normal in a postsynaptic DNMT in the absence of an alternative or additional confounding diagnosis. If the compound muscle action potential (CMAP) amplitudes are reduced in a patient with a phenotype resembling MG, a motor neuron disease or a presynaptic DNMT such as LEMS or botulism should be considered. If this occurs, we would attempt facilitation with 10 seconds of exercise followed by a second, supramaximal stimulus immediately thereafter, attempting to identify a presynaptic DNMT. We then proceed to repetitive stimulation testing at 2–3 Hz. In general, we typically study the ulnar, accessory, and facial nerves although readily adapt this menu if warranted by clinical circumstance. If possible, we start with a weak muscle, particularly if it is in the hand where the study is technically easier to perform. If there is no weakness, or the weakness is proximal, we would go straight to the accessory nerve as the best compromise between diagnostic yield and technical ease. If a patient has only ocular or bulbar weakness, we usually start with a facial muscle such as the orbicularis oculi or the nasalis.

1. Drugs that may unmask or exacerbate myasthenia gravis

a. Antiarrhythmic agents—lidocaine, quinidine, quinine, procainamide, and trimethaphan camsylate

b. Antimicrobial agents including aminoglycosides, polymyxin B, colistin, clindamycin, ciprofloxacin, netilmicin, azithromycin, pefloxacin, norfloxacin, and erythromycin

c. Corticosteroids

d. Magnesium (parenteral)

e. Neuromuscular blocking agents—depolarizing and nondepolarizing including botulinum toxin, d-tubocurarine, succinylcholine, vecuronium, pancuronium, atracurium, and gallamine

2. Drugs potentially implicated in unmasking or exacerbating myasthenia gravis

a. Anesthetics—diazepam, ketamine

b. Anticonvulsants—phenytoin, mephenytoin, ethosuximide, barbiturates, carbamazepine, and gabapentin

c. Antimicrobial agents—tetracyclines and ampicillin

d. Antirheumatics—chloroquine

e. Beta blockers—propranolol, oxprenolol, timolol, practolol, and betaxolol

f. Drugs of abuse—cocaine

g. Gastrointestinal—cimetidine

h. Miscellaneous—D–L-carnitine, tropicamide, iodinated radiographic contrast, and trihexyphenidyl

i. Ophthalmics—echothiophate

j. Psychotropic drugs—phenothiazines and lithium

3. Drugs that cause myasthenia gravis or mimic myasthenia gravis

a. D-Penicillamine

b. Alpha-interferon

c. Case reports: trimethadione, riluzole, ritonavir, chloroquine, statins, and beta-interferon

d. Tandutinib

False positives are an even larger potential pitfall in the EDX testing of an MG suspect. The most common cause of a false positive examination is undoubtedly technical, particularly with repetitive stimulation testing. Unwanted movement by either the patient or technician can result in movement of the stimulator resulting in submaximal stimulation and the appearance of a “pseudodecrement.” Unwanted movement resulting in baseline deviation is a particular problem both in large proximal muscles and in the face. The latter often occurs from grimacing in response to facial nerve stimulation and the undesired coactivation of other facial innervated muscles. Any technique that will reduce unwanted muscle contraction and movement and unwanted artifact is desirable.

To minimize the risk of a false positive interpretation, we require that all characteristics of a typical postsynaptic decremental response be fulfilled. These include: (1) a normal baseline CMAP amplitude, (2) a nadir that occurs at the fourth or fifth response of a 10-stimulus train, (3) the greatest decrease in CMAP amplitude between consecutive responses occurring between the first and second responses and (4) a steady rise in the CMAP amplitude after the fifth response that allows the CMAP amplitude to approach but not achieve that of the first response, producing a “tilted saucer,” “ski jump,” or “inverted banana” configuration (Fig. 25-6).

Two different types of abnormal motor unit action potential (MUAP) change may occur in MG. Both may be easily overlooked. Short-duration, low-amplitude MUAPs associated with early recruitment may occur. This pattern results from neuromuscular blockade and an effective reduction in the number of functional myofibers within a given motor unit, analogous to what may occur with myopathies.^251,252 Small MUAPs have been reported in MuSK MG as well, also consistent with a reduced number of normally functioning muscle fibers per motor unit resulting from either NM blockade, muscle fiber loss, or muscle fiber atrophy.

A more sensitive and valuable needle EMG tool is the demonstration of MUAP variability (instability) (Fig. 25-7). MUAP variability is the analog of clinical weakness and fatigue, a decremental response with repetitive stimulation, and blocking on SFEMG. It represents NMT failure of one or more single-fiber components to the MUAP that is typically intermittent, resulting in constant variation in the size, shape, and sound produced by an isolated MUAP. Unstable MUAPs are readily identified by the trained ear, and visualized with the use of a trigger and delay line. Their value is to provide evidence of abnormal NMT in muscles not easily studied by repetitive stimulation without necessarily undergoing the rigor of the SFEMG examination.

In patients with ocular MG, repetitive stimulation of a distal upper extremity nerve yields positive results in up to 35% of patients. Adding a proximal nerve increases the yield slightly to 45%. Patients who are MuSK antibody positive tend to have both a lesser incidence estimated at 60% and a lesser degree of decrement in limb muscles compared to other MG populations.^73,78,81 A higher yield of abnormal decrement will be found in facial muscles in the anti-MuSK patient population.²⁵⁹ Estimates of incidence of abnormal decrement in these patients range from 25% to 50% in limb muscles as opposed to 50–85% in facial muscles.^77,82

The EDX assessment of children with suspected MG is analogous to adults. In normal infants, the limited data available suggest that with stimulation rates between 1 and 2 Hz, there is no alteration in the CMAP.^260–262 Repetitive stimulation at rates between 2 and 5 Hz yields variable results, with some normal infants demonstrating a decrement and others revealing no change. In summary, premature infants and some term infants will have a reduced NMJ reserve capacity, especially at the higher rates of stimulation. Repetitive stimulation can be performed and interpreted confidently in term infants as long as this caveat is kept in mind.

The electrical findings in transient neonatal MG are analogous to those found in adults.101,263 A decremental CMAP response is typically demonstrable at low rates of stimulation, which can be minimized with postactivation excitation (20–50 Hz repetitive stimulation) and augmented with postactivation exhaustion (repetitive trains of 2–5 Hz stimulation performed at 30 seconds to 1 minute intervals over a protracted period). Frequently, a decrement occurring at high rates of stimulation occurs as well, depending on the severity of the disease.

SFEMG is the most sensitive and least specific of EDX testing procedures for MG.²⁶⁴ It can be performed either voluntary activation of a tested muscle or by electrical stimulation of a motor nerve branch innervating that muscle. Either method has its benefits and drawbacks. One strength of stimulated SFEMG is that it is less reliant on patient cooperation than voluntary SFEMG, making it the technique of choice in infants, an elderly person who may not be able to steadily sustain a minimal level of muscle activation, or any potentially uncooperative individual.^265–269 Stimulated SFEMG is typically faster to perform than voluntary SFEMG, providing an additional advantage. Its major disadvantage occurs when a muscle rather than nerve fiber is stimulated leading to a falsely reduced jitter value. Both voluntary and stimulated SFEMG are specialized techniques that many electromyographers do not receive training in. One benefit of SFEMG, stimulated or voluntary, is that it allows access to muscles frequently affected in MG not accessible to repetitive stimulation. The major benefit of SFEMG, however, and the one that translates to its high diagnostic sensitivity is its ability to detect abnormalities in NMT prior to development of overt NMT failure.

As described in Chapter 2, SFEMG assesses NMT by comparing the discharge intervals of two or more SMFAPs belonging to the same MUAP. This is technically accomplished by limiting the recording radius of the EMG needle. Historically, this was accomplished both by increasing the low frequency filter settings of the EMG machine and by using a special needle with a very limited recording radius. These needles are, however, expensive and reusable, necessitating sterilization after each use as well as periodic sharpening. For practical reasons, many institutions now use disposable, concentric needles which are adequate surrogates providing acceptable accuracy if attention is paid to detail during performance and interpretation.^270–273

Two parameters are typically measured in the SFEMG assessment of a suspected MG patient. Jitter refers to the variation in the interval between the two single-muscle fiber action potentials mentioned above. Because of the normal variation in EPP amplitude, jitter is a property of normal muscle, typically lying in the 15–45 μs range depending on age and the muscle studied.^274,275 It becomes abnormal only when it is either smaller or in the case of MG, larger than normal (Fig. 25-8A,B). Increased jitter reflects abnormal or delayed, not failed NMT. As a result, abnormal jitter does not translate to weakness. With an increase in jitter values to 80 μs or above, however, NMT becomes tenuous and begins to intermittently fail. As a result, blocking, the equivalent of a decremental response to repetitive stimulation, motor unit instability, and clinical weakness, becomes manifest (Fig. 25-8B).

SFEMG is abnormal in 77–100% of patients, depending on disease severity and the number and distribution of muscles tested.252,276–280 Specifically, the sensitivity of SFEMG is estimated at 97% if both a limb and a facial muscle are studied.²⁶³ SFEMG abnormalities are found in the frontalis or orbicularis oculi in 87–99% of patients with oculobulbar weakness.²⁶⁴ Studying the frontalis as opposed to a limb muscle will increase diagnostic yield from the 22–66% to the 54–100% range in all MG patients.^276,278 SFEMG abnormalities, like every other aspect of MG, can be patchy. We have observed instances while recording three SMFAPs belonging to the same motor unit where jitter is markedly increased in one pair while normal in the other. As a quantitative reflection of this, one study of 433 potential pairs from 32 patients with MG revealed normal jitter in 9%, increased jitter in 38%, and abnormal jitter with blocking in 53% of the potentials.^252,277 Although jitter measurements improve following successful treatment,^{276,281–283} jitter abnormalities may persist even in those in clinical remission.^276,284 As in “slow” repetitive stimulation, SFEMG abnormalities in patients with MuSK MG are more likely to be found in facial or proximal muscles rather than in distal limb muscles such as the extensor digitorum communis, with a lower yield in limb muscles in general than expected in other MG populations.^75,86

Historically, regional applications of both ischemia and d-tubocurarine curare were used in addition to “slow” repetitive stimulation, in an effort to increase diagnostic yield in MG. As these are cumbersome and potentially risky maneuvers, SFEMG represents the preferred EDX alternative in most EMG laboratories where “slow” repetitive stimulation is nondiagnostic.

PHARMACOLOGICAL TESTING

The sensitivity of edrophonium testing in MG is reported to be 86% for ocular and 95% for generalized MG.288 Like repetitive stimulation, an abnormal test signifies abnormal NMT but does not define a singular disease. False positive responses have been reported in LEMS, ALS, CMS, botulism, Guillain–Barré syndrome, dysthyroid ophthalmopathy, and brainstem tumors.^37,289–292 Edrophonium testing is reported to have less utility in MuSK MG with a reported sensitivity of 50–70%.^78,82

Edrophonium testing is not without risk. Historically, these were office-based procedures, performed without incident in most cases. Some patients would experience transient, disquieting but ultimately harmless symptoms such as nausea, vomiting, increased tearing, lacrimation, fasciculations, borborygmi, and eructation. Rarely however, serious reactions including bradycardia or heart block may occur. For consideration of patient safety, these tests are now routinely performed in monitored settings with individuals who are trained in resuscitation with adequate resources including parenteral atropine available.

Pathological changes in the thymus are found in >80% of patients with MG, detectable by imaging in many cases. In approximately 50% of those with MG, the histology will be that of lymphoreticular hyperplasia.293 In the minority estimated at between 10–30%, either a benign low-grade thymoma of the thymic epithelium may be encountered, or on occasion an invasive thymoma.²³ Although chest x-ray may detect thymic enlargement from either hyperplasia or thymoma, either computerized tomography or magnetic resonance provide better resolution and are preferable studies. Although the thymus is typically located in the anterior mediastinum, it may be found ectopically in the neck or other regions of the chest.^293,294 In normal individuals, the CT appearance of normal thymus is homogeneous with attenuation characteristics similar to muscle, decreasing in size with age as fatty replacement takes place. The gland loses its appearance as a discreet structure somewhere between ages 25 and 40.²⁹³ With MR, the normal childhood thymic appearance is also homogeneous with signal characteristics somewhere between muscle and fat. In addition to these features, a normal thymus gland is also characterized by its size and shape. A focal abnormality of the contour of the gland suggests an underlying neoplasm.

With thymic hyperplasia, the CT attenuation properties are normal. In slightly more than half of cases, the gland will appear abnormal because of its enlargement or in some cases, a focal mass.²⁹³ MR characteristics are similar with gland enlargement but with normal signal characteristics. With thymoma, CT typically identifies sharply demarcated round or lobulated masses, commonly associated with low attenuation components that represent cysts, hemorrhage or necrosis (Fig. 25-2A,B). Calcifications occur and do not distinguish between invasive and noninvasive tumors.²⁹³ Thymomas may enhance with iodinated contrast but the benefit is likely outweighed by the risk of an allergic response or a myasthenic exacerbation.²⁹⁵

The MR appearance of thymoma is also that of a gland incorporating a round, oval, or lobulated mass.²⁹³ Signal intensity is low on T1-weighted images similar to that of muscle and relatively high signal intensity with T2-weighting. T2-weighted images may also define a lobulated structure characteristic of thymoma. One potential advantage of MR over CT in the evaluation of thymoma is the identification of characteristics suggestive of invasive thymoma such as obliteration of the adjacent fat planes.²⁹³ Thymic abnormalities in patients with anti-MuSK antibodies are uncommon and typically minimal when they occur.⁷⁷ This point is emphasized in a study of 167 patients with thymoma.¹²⁶ Of the 92 who had MG, only one was seropositive for MuSK antibodies.

Recently, the bright tongue sign has been reported in ALS patients, representing fatty replacement of the genioglossus muscle demonstrable with MR imaging. This finding is not unique to ALS and has been reported in MuSK MG patients, in keeping with the muscle atrophy that can be seen in some of these patients, and providing another potentially confounding feature in the distinction of MG from bulbar ALS.⁸⁹

HISTOPATHOLOGY

Presumably, the majority of muscle biopsies performed in MG patients is done inadvertently in seronegative individuals with phenotypes that mimic myopathy. Muscle biopsy has no role in the majority of MG patients and much of what we know about myasthenic muscle histology comes from postmortem specimens.²⁹⁶ These reports need to be interpreted with caution. Although MG is a systemic disease, described abnormalities often existed in limb muscles whereas the majority of these patients had oculobulbar phenotypes. Consequently, the abnormalities described are not necessarily disease-related.²⁹⁶ Conversely, if muscle biopsy were to be performed, consideration of a false negative result should be given in view of sampling error and the patchy nature of the disease. Interpretation of historical publications of muscle histology in MG should be made with the knowledge that many preceded the availability of contemporary histochemical analysis. Lastly, interpretation of muscle histology in MG should be made with consideration of the effects from potential coexistence of other disorders that occur with increased frequency in MG such as dysthyroidism or autoimmune muscle disease.

The findings on light microscopic analysis of MG muscle are nonspecific. The muscle may be normal in appearance.²⁹⁶ When abnormal, the most common findings are type 1 fiber predominance, mild fiber type grouping, or type 2 fiber atrophy.^296,297 Focal interstitial inflammatory infiltrates, historically referred to as lymphorrhages, are not uncommon, and have been described predominantly within proximity of necrotic fibers, blood vessels, and muscle end plates (Fig. 25-9).^296–299 Histological features of myopathy are not a characteristic feature of myasthenic muscle.²⁹⁶

Ultrastructural abnormalities are more evident in MG. Immunoelectron microscopy of the postsynaptic membrane region in patients with myasthenia demonstrates IgG and complement precipitation on the membrane, a widened synaptic space, reduced postsynaptic membrane complexity with fewer postjunctional folds, and decreased numbers of AChRs. Many of the remaining AChRs are bound with IgG.^{173,203–205,301} In contrast, the presynaptic portion of the NMJ appears completely normal.

There has been some historical concern pertaining to potential adverse structural effects on muscle in response to chronic or excessive anticholinesterase exposure.¹⁷⁶ In animals, degeneration of postsynaptic folds has been described. SFEMG studies have suggested increased fiber density in patients treated with anticholinesterase medications, suggested of denervation and reinnervation and consistent with some of the histological findings described above. In addition, prolonged exposure to anticholinesterases leads to an overexpression of the AChE-R isoform. Overexpressed AChE-R in transgenic mice leads to myopathic muscle changes including atrophic and vacuolated muscle fibers as well as neurogenic muscle changes.³⁰² The clinical relevance of these observations is uncertain, given the relatively minor histological findings reported in patients largely studied in an era when anticholinesterase medications were the primary therapy for MG, commonly used in large doses for prolonged periods of time.

Although relevant to myasthenia, the histological abnormalities of the thymus gland are beyond the scope of this chapter. The reader is referred to an excellent review of the thymus gland in myasthenia for more detailed information on this subject.²³

TREATMENT

Managing a myasthenic patient requires consideration of numerous variables. Patient age, gender, comorbidities, concurrent medication, patient functional expectations, serotype, clinician experience and preference, treatment availability and cost, and whenever available, an evidence-based perspective all require consideration in treatment decisions. Many excellent reviews are available that address these options and strategies.^38,55,303 The ideal of a fully evidence-based therapeutic approach is hampered by the lack of adequate studies. This impediment is multifactorial. MG is a relatively uncommon disease with multiple treatment options, many of which are considered effective, if imperfectly so. In support of this perception of therapeutic efficacy is the previously mentioned mortality statistics which unequivocally demonstrate an improvement in MG care over the course of the last century.^13,23,38 The strategies suggested in this chapter represent our approach, based in part on the teaching of our mentors and in part our personal experience, heavily blended with guidance from the literature. Our approach is intended to provide guidance and is not intended to be dogmatic or inflexible in its application.

One management consideration is disease serotype. AChR and seronegative MG are largely considered to have overlapping but non-identical phenotypes and treatment responsiveness. Reports suggest that seronegative MG patients respond better to most treatment modalities than either MuSK or AChR MG but less well to thymectomy than AChBr disease.^71,80,304 In general, the weight of existing evidence suggests that MuSK MG is a more severe disease, less treatment responsive, and requires in part a different therapeutic strategy.^10,71 Cholinesterase inhibitors are thought to be ineffective and may worsen the disease. Current thinking suggests that thymectomy has a limited role in MuSK MG unless thymoma is identified, an extremely rare occurrence.^{71,73,77,83,123} Steroids may or may not be effective.⁷⁸ Expert opinion indicates that MuSK MG responds to other immunomodulating therapies.^{73,74,80,81,82,305,306–308} Intravenous immunoglobulin (IVIG) may work in some cases of MuSK MG patients refractory to other modalities.^308,311 We and others have been impressed with rituximab in refractory MG, both AChR-MG and MuSK-MG.^310–313 With LPR4 MG, a distinct therapeutic strategy has not been developed. Current strategy is to treat it identically to traditional AChR MG.

Therapeutic strategies in MG include attempts to treat the disease symptomatically (cholinesterase inhibitors, noninvasive positive pressure ventilation, percutaneous gastrostomy), remove a potential contributor to disease pathogenesis (thymectomy), suppress components of disease immunopathogenesis (immunomodulation through the use of drugs, IVIG, or PLEX), prevent when possible and address when necessary potential exacerbating factors (e.g., avoidance of drugs with neuromuscular blocking properties, treating intercurrent infections and comorbidities such as dysthyroidism), and potentially prevent the escalation from mild to more severe disease. In that regard, it has been suggested that corticosteroids may reduce the conversion frequency of purely ocular to generalized disease.36,37 Although we frequently treat disabling ocular symptoms refractory to pyridostigmine with immunomodulating agents, we do not do so routinely with the goal of reducing the probability of disease generalization.

In general, our philosophy is to treat the patient, not the disease. We attempt to achieve an optimal sense of patient well-being and function, while at the same time considering what an acceptable level of risk might be. This would include consideration of both probability and magnitude of potential side effects. Along those lines, we do not dogmatically adhere to historical therapeutic recommendations such as avoidance of thymectomy in patients >65 years of age or in patients with ocular myasthenia. The reluctance to thymectomize older individuals (without thymoma) is based largely on the atrophic nature of the gland in older individuals. We are unaware of any evidence that supports either decreased efficacy or increased procedural risk based on chronological age alone. Similarly we would consider thymectomy or immunosuppression in a pyridostigmine-resistant individual with limited ocular disease if their visual morbidity significantly interfered with their vocation or quality of life.^314–316 Our management strategies are summarized at the end of this section.

SYMPTOMATIC TREATMENT

Although most patients will not adequately respond to peripheral cholinesterase inhibitors alone, they are frequently used as the initial treatment. This practice evolves from the consideration of their cost and favorable side effect profile. In patients with minor morbidity, they may suffice as the sole treatment. Pyridostigmine is the drug of choice as it has a more favorable duration of action and side effect profile than other drugs of its class. The initial oral dose is typically 15–60 mg three times a day. In a patient with dysphagia, it is typically prescribed 30–60 minutes before meals. We rarely use more than 240 mg a day as higher doses are commonly associated with adverse rather than beneficial effect. If the patient does not achieve the desired therapeutic effect by 360 mg per day, it is our experience that they are unlikely to benefit by further dose escalation. It is also important to recognize that the beneficial effects of pyridostigmine may wane with time if autoimmunity remains unchecked, with unabated destruction of motor end plates resulting in depletion of ACh binding sites. For these reasons, we typically initiate immunomodulating therapy if 240 mg of daily pyridostigmine (60 mg every 6 hours) does not achieve or maintain the desired effect. As we tend to avoid large anticholinesterase doses, cholinergic crisis is a disorder of largely historical interest in our experience.

There are different peripheral cholinesterase inhibitors with different delivery models. Neostigmine can be given parenterally at a dose of 7.5–15 every 4–6 hours and may be the drug of choice for intramuscular delivery.³⁰³ Pyridostigmine is also available in a 180 timespan capsule, utilized primarily for treatment of nocturnal symptoms. The timespan formulation is rarely used diurnally due to its variable absorption.³⁸ It is also available in a liquid form (12 mg/ml) and in a parenteral form that can be used in patients who cannot or should not swallow. It is important to be aware that the parenteral dose pyridostigmine is 1/30th to 1/60th of its oral counterpart. The most common side effects are related to the gastrointestinal tract such as abdominal discomfort, nausea and diarrhea. As these symptoms are related to muscarinic, not nicotinic side effects, they may be treated with anticholinergic drugs without adversely affecting the beneficial effects on nicotinic NMT.

The role of parenteral pyridostigmine is primarily in the treatment of MG patients undergoing elective surgery during the period where their oral intake is prohibited. We are less likely to use it during myasthenic crisis in an intubated patient as its potential beneficial effect may be outweighed by increased secretion production as an unwanted side effect.³⁸ Pyridostigmine by itself will rarely, if ever, prevent myasthenic crises or rescue patients from it once it occurs.

Noninvasive positive pressure ventilation has a limited but important role in the management of MG patients. It is used to delay or avoid intubation in a patient with imminent crisis, to help wean a patient from invasive ventilation recovering from crisis, or to treat sleep-disordered breathing when present, which MG patients, like all neuromuscular patients, are susceptible to.³¹⁷ Percutaneous gastrostomy is virtually never required in MG due to the typical efficacy and relative rapid onset of available MG treatments in restoring functional swallowing and minimizing aspiration risk. We have encountered rare MG patients who have received percutaneous gastrostomy as a result of diagnostic delay, for example, for an anterior cervical osteophyte misidentified as the cause of dysphagia, the gastrostomy tube subsequently removed once effective swallowing was restored.

Symptomatic treatments may be used locally as well. Lid crutches for the treatment of ptosis may be tried but is in our experience rarely tolerated. Topical naphazoline, a sympathomimetic drug with preferential α2 activity, has been reported to provide a marked response in 30% and a worthwhile benefit in an additional 40% of MG patients with ptosis.³¹⁸ Presumably, the drug acts on the sympathetically innervated lid elevator, Müller’s muscle.

Thymectomy

The American Academy of Neurology Practice Parameter that reviewed 21 published level II studies of nonthymomatous thymectomy in MG patients found that patients undergoing thymectomy were 1.7 times as likely to improve, 1.6 times as likely to become asymptomatic, and twice as likely to attain medication-free remission.³²² The apparent benefits of thymectomy are often delayed with a median time to achieve complete stable remission judged to be in the 17–20 month range.³²² Current beliefs are that the benefits of thymectomy are greatest if performed within 3 years of initial symptoms.³⁸ The neuromuscular community awaits the results of an international prospective trial intended to identify the frequency and magnitude of thymectomy benefit in MG patients.^323–325

Response appears to vary by thymectomy technique and disease serotype. Historically, remission rate is thought to increase proportionately to the extent of thymic removal, and a transcervical, transsternal “complete” thymectomy is thought to provide the greatest chance of achieving this goal.²⁹⁴ We acknowledge however, that more recent data suggest similar efficacy with less invasive techniques such as video-assisted thoracoscopic surgery.^326,327

There is a consensus that all patients with thymoma should have thymectomy to minimize the risk of the morbidity and potential mortality of local invasion, or the smaller risk of disseminated metastasis. It is generally held that MG in patients with thymoma are less responsive to thymectomy in comparison to MG patients with thymic hyperplasia.³⁸

Immunomodulating Treatment

Details pertaining to specific immunomodulating treatments have been provided in Chapter 4. This chapter will focus on specific principles and practices related to the management of the MG patient.

Prior to the initiation of any immunomodulating agent, we attempt to exclude any indolent infectious disease such as tuberculosis or strongyloidiasis that may become symptomatic with treatment. We attempt to identify patients at increased risk because of potential prior exposure to these diseases (e.g., someone who has emigrated from a country where strongyloidiasis is endemic) and liberally obtain skin and serological testing, quantiferon gold assessments and chest x-rays. With corticosteroid use, we obtain baseline bone density determinations and vitamin D levels. All patients on corticosteroids are advised to take calcium carbonate (approximately 1000 mg/day) and vitamin D (approximately 2000 IU/day) supplements. There is an increased risk of symptomatic osteoporosis and pneumocystis in patients treated with corticosteroids or other immunomodulating drugs. Bisphosphonate prophylaxis of glucocorticoid-induced osteopenia has been shown to reduce adverse effects on bone density but has equivocal results regarding reducing the rate of bone fracture.³²⁸ Studies provide varying results depending on patient gender, prophylactic drug utilized and dose chosen. We do not routinely provide pneumocystis prophylaxis as we are unaware of any literature that provides adequate guidance regarding risk and risk reduction relevant to the number and type of immunomodulating agents that are used.

Corticosteroids are estimated to benefit 80–90% of myasthenic patients, typically within 2 weeks with maximum benefit occurring on average within 3 months and within 6 months in all patients destined to respond.^38,329–332

There are two approaches commonly used in treating patients with corticosteroids. Regardless of the dosage used, the prednisone is typically prescribed as a single morning dose, attempting to mimic the normal physiological diurnal variation of endogenous glucocorticoids as much as possible. Unfortunately, again there is no literature to support any one approach being more effective than the others.

The first approach is the start low, go slow approach advocated by the Johns Hopkins group.⁴⁴ We typically use this in patients with ocular myasthenia or mild generalized MG. In such cases, we usually initiate prednisone at 20 mg daily with instructions for the patient to increase the dose by 5 mg every 5–7 days as needed to control their symptoms up to a total daily dose of 1.0 mg/kg. We have patients stay on whatever the effective dosage is for one month before slowly tapering down by 5 mg a month to 20 mg daily and then by 2.5 mg every month until we find the lowest possible dose that controls their disease. The downside of this start low, go slow approach is that it takes longer from initiation of steroids to see an effect and does not guarantee avoidance of corticosteroid exacerbation.³⁰⁵

The second approach is to start patients on high dose daily prednisone (e.g., 0.75–1.0 mg/kg) at onset. The benefit of this approach is that patients usually improve faster. The downside is that approximately 10–15% of myasthenics who are started on high-dose prednisone may experience an initial decline in strength during the first week or so.^{330,332–334} For this reason, we usually reserve this approach to patients with moderate-to-severe MG who are or who will be hospitalized. The mechanism of the exacerbation is not clear. It would appear to be related to NMT as opposed to adverse nerve or muscle effect as it is associated with worsening of the decremental response to repetitive stimulation if employed.³³⁴ This weakness tends to dissipate even with continued use of high steroid dosage. It is also possible that the apparent worsening represents situational bias. That is, the patients who are started on high dose prednisone most often have newly diagnosed or progressive MG. The worsening of the MG may be because of the progression of the disease itself and not the addition of the steroids.

Mycophenolate is attractive both for its ease of use and relatively benign side effect profile for an immunomodulating drug. Although the two randomized, blinded, clinical trials reported in 2008 failed to demonstrate a benefit, this may have been a consequence of trial design (studies too short in duration for a response to occur).^340,341 A retrospective study demonstrating a therapeutic benefit after 6 months would support this contention.³⁵¹ Alternatively, the concurrent small prednisone dose, 20 mg daily, that patients received in both the treatment and placebo arm in the MSG study suggests efficacy from this drug that might have masked a potential benefit from mycophenolate. We, as well as others, believe it to be an effective, well-tolerated drug in some patients.

We have had positive experiences with other immunomodulating agents, typically prescribed in those patients who have had inadequate or adverse responses to pyridostigmine, corticosteroids, azathioprine, and/or mycophenolate. In view of their side effect profiles, uncertainty of benefit, monitoring requirements or cost considerations, we tend to use cyclosporine,^352–356 tacrolimus,^357–367 cyclophosphamide,^368–371 and rituximab^{305–307,310–313,372–374} as third-line treatment agents. We also use methotrexate as third-line agent while awaiting the results of a large randomized, double-blind trial. As mentioned above, rituximab, cyclophosphamide, and cyclosporine have been specifically, albeit anecdotally, reported to benefit MuSK MG patients.^{305,307,356,369} We have used rituxan in either two or four infusions over the course of 1 month and found it to be quite effective in refractory MuSK and AChR patients (Chapter 4). In our experience, the response to rituximab is durable and often exceeds a year of more before tretreatment is required. We have had a limited experience with sirolimus and remain uncertain regarding its efficacy. We reserve cyclophosphamide for patients’ refractory to other aforementioned treatments.

As the specter of opportunistic infection and neoplasm exists in all patients treated with long-term immunomodulating agents, we give consideration to gradual withdrawal of these agents in any patient who has been in a stable, apparent remission for 2 years or more. It is our impression that many MG patients will have mild, asymptomatic, residual weakness of eye closure despite otherwise excellent disease control. We do not consider this finding to represent a contraindication to attempted weaning from immunomodulating therapy. Given the statistical uncertainty of risk versus benefit, this decision is heavily influenced by patient perspective. We have been successful in this approach in a number of individuals, with or without thymectomy, although are uncertain whether this represents the effect of treatment or the natural history of the disease.

IVIG 98,116,375–385 and PLEX^{381,384,386–398} are considered to be effective treatments for MG.^{381,384,393,399–402} Their therapeutic support however, has not been without controversy. Historically, many neurologists have considered PLEX superior to IVIG.³⁹³ IVIG, however, has been demonstrated to benefit MG patients in a prospective randomized trial whereas no analogous PLEX study has been conducted.³⁷⁷ In addition, IVIG has been suggested to be particularly effective in the treatment of MuSK MG.^{73,77,308,309,403} As a result, American Academy of Neurology guidelines have identified IVIG as “probably effective and should be considered” in contrast to PLEX where “there is insufficient evidence to support or refute the use of plasma exchange” in MG.^385,390 The latter position generated a considerable editorial response from the journal’s readership including many individuals recognized for their expertise in MG management.³⁹⁷ These critics aptly pointed out that PLEX was penalized due to its competitive disadvantage, that is, the unlikelihood of a class 1 study of PLEX in MG ever being conducted. A subsequently published head-to-head class 1 study reinforced the opinion that PLEX performed slightly better than IVIG, although both treatments were found to be statistically equivalent relative to both the degree of efficacy and the number of MG patients that benefitted from their use.^399,402

We primarily use IVIG and PLEX in two situations, to avert or treat myasthenic crisis or to “tune up” an MG patient with residual weakness prior to thymectomy.⁴⁰⁴ This is done hoping to minimize the risk of postoperative complications such as aspiration or prolonged ventilator dependency.⁴⁰⁰ Typical algorithms involving five infusions or exchanges are used for each. Due to the cost, lifestyle inconvenience and in some cases risk (e.g., need for central venous access in PLEX), we tend to avoid chronic treatment with these two modalities unless other therapeutic options are precluded.

Their greatest benefit of IVIG and PLEX is their relatively rapid onset of action, often within days.^381,401 Both are costly although IVIG may enjoy a cost advantage, particularly in the hospitalized patient as it can characteristically be completed in a shorter period of time resulting in a potentially shorter length of stay. PLEX has been reported to have a 90% efficacy in one retrospective study and 65% in a prospective one.^396,399 IVIG has been reported to achieve a significant benefit in 69% of patients.³⁹⁹ Exchange can be successfully accomplished in an outpatient setting through peripheral access in the majority of patients. Peripheral versus central venous access minimizes risk, particularly that of a serious risk.³⁹⁶ One additional potential drawback of PLEX is the need to coordinate its timing in relation to immunomodulatory drug administration.

Other novel treatments for MG have been suggested, all intended to address adverse effects while sparing beneficial aspects of immune surveillance.²¹⁵ One such attempt that appears to have been successful in an in vitro rat model of autoimmune myasthenia is vaccination with cytoplasmic epitopes of the ACh subunits. The intended strategy is to deflect the potentially destructive aspects of autoimmunity away from the extracellular domains of these ACh subunits that the disease targets.⁴⁰⁵ A second strategy is the development of synthesized anti-sense RNA molecules that target the gene expression of the AChE-R isoform. By doing so, NMT is augmented and potential adverse effects of increased AChE-R levels on muscle that may result from chronic anticholinesterase use are avoided.²¹⁵ Another apparent successful in vitro strategy is to utilize genetically engineered dendritic cells to present AChR epitopes. The intent here is to specifically kill the T cells responsible for the initiation of the autoimmune response.²¹² The engineering of monoclonal antibodies that target specific components of disease-specific autoimmunity represents an additional strategy. Blocking of complement activation by eculizumab that is currently being studied in clinical trial is one such strategy. The C5 complement inhibitor rEV576 has also been utilized.⁴⁰⁶ The tumor necrosis factor alpha blocker etanercept was reported in a small trial to have modest efficacy.⁴⁰⁷ Allogenic hematopoietic stem cell transplantation has been utilized successfully in one case.⁴⁰⁸

Special Circumstances

The treatment of MG in children and adolescents provides a number of additional challenges.^{96–98,115–117} In adolescents with MG, we attempt to avoid corticosteroids and other immunomodulating drugs if possible in view of the adverse effects on growth and the concern for the suspected increased risk of neoplasm over a patient’s lifetime. Avoidance in adolescent females is of particular concern due to the potential teratogenicity in future pregnancies. We are uncertain of the potential for teratogenicity resulting from immunomodulating drug exposure in males. We have been very supportive of thymectomy in the adolescent female population in the hope of achieving drug-free remission during the patient’s reproductive years. Removal of the thymus in children does not appear to have any deleterious effect on immune system development.³³³ In a large retrospective series of 149 patients with juvenile MG, 85 patients had a thymectomy while 64 patients were managed medically.⁹⁷ In the thymectomy group, 82% of patients improved, while 48% went into remission compared to a 63% improvement rate and a 34% remission rate in the patients who are nonthymectomized.⁹⁷ In another retrospective series of 79 patients with juvenile MG, 65 patients (82%) underwent thymectomy. Of the patients who were thymectomized, remission occurred in 60% compared to 29% in the nonthymectomized group.⁹⁶ Neither of these studies controlled for baseline severity or concomitant medical treatment, thus the role of thymectomy in juvenile MG like adults remaining unproven.³²²

Regarding management, cholinesterase inhibitors have been used anecdotally without apparent harm. There appears to be little, if any, risk of unwanted stimulation of the myometrium. Magnesium, potentially used for the treatment of pregnancy-related hypertension, is optimally avoided in a pregnant MG patient. There are theoretical concerns that PLEX may adversely affect pregnancy by unwanted effects on hormonal levels, potentially increasing the risk of premature delivery.⁴⁰⁹ The risks of IVIG during pregnancy are largely unknown. Of the immunomodulating treatment options, corticosteroids are probably the safest although they do pose a slightly increased risk of fetal cleft lip and of premature rupture of the membranes.⁴⁰⁹ As a general rule, although successful pregnancies have been accomplished under their influence, other immunomodulating drugs are avoided prior to conception and during pregnancy if at all possible.

Prevention and Treatment of Potential Exacerbating Factors

The effects of pregnancy on MG have already been described. Intercurrent infections and other coexisting autoimmune diseases if uncontrolled are both believed to aggravate MG. Drugs remain the most noteworthy category of influences that aggravates, and in some cases even causes, MG (Table 25-3).

Monitoring

We monitor our patient’s treatment response primarily through clinical assessment. We feel that in most cases, it is at least as effective and undoubtedly more efficient and cost-effective than other testing modalities. As mentioned in Chapter 1, hand-held dynamometry can be a very effective tool for this purpose. As mentioned, monitoring autoantibody titers has little or no role other than potentially assessing the efficacy of thymectomy or monitoring for thymoma reoccurrence. Although electrophysiological parameters can be utilized as an indicator of treatment responsiveness, we find them to be unnecessary in the vast majority of cases. We tend to use them only in confounding situations, that is, attempting to separate myasthenic weakness from that of another potential cause. Cost, time expenditure, and patient comfort are factors that dissuade us from their routine use in patient monitoring. Again, in the spirit of treating the patient, not the disease, electrophysiological monitoring may be too sensitive and potentially lead to excessive treatment. As an example, increased jitter in an asymptomatic muscle is not an indication for treatment initiation or modification.

Assessment scales designed specifically for MG have been used both to stage disease severity, to accurately monitor response to treatment, and to assess quality of life in MG patients.^410,411 They are, to the best of our knowledge, utilized more as clinical research tools rather than assessment tools routinely used in the clinic. The Osserman scale is primarily a staging tool.¹⁸ Adult MG is subdivided into Group 1 (ocular: 15–20%), Group 2A (mild generalized: 30%), Group 2B (moderately severe generalized: 20%), Group 3 (acute fulminating: 11%), and Group 4 (late severe: 9%). In Europe, the myasthenic muscle score (MMS) developed in 1983 is the preferred metric for determining efficacy in MG clinical trials.⁴¹² It is a 100-point scale that assesses trunk as well as oculobulbar, limb and muscle strength. In the United States, the quantified MG score (QMS), also initially proposed in 1983 and later modified, is the preferred instrument. It is a 39-point scale that has considerable overlap with the MMS although it incorporates ventilatory muscle strength and does not address trunk strength beyond neck flexors.^412–414

Thymectomy is offered to virtually every patient with thymoma, unless comorbidities negate any reasonable chance of benefit. We also offer thymectomy to the majority of adolescents and adults with generalized myasthenia without MuSK autoantibodies assuming that they are strong enough and otherwise healthy enough to safely undergo this treatment. We do so based upon the anecdotal belief that it will increase the probability of future drug-free remission. As a general rule, we do not offer this treatment initially, allowing the patient the opportunity to accept and adapt to their diagnosis. By the same token, based again on the anecdotal suggestion that the efficacy of thymectomy wanes in patients with longstanding MG, we typically offer this option within the first two years of disease if possible.

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CHAPTER 25

Autoimmune Myasthenia Gravis

CLINICAL FEATURES

MUSK MG

SERONEGATIVE MG INCLUDING PATIENTS WITH LPR4 AUTOANTIBODIES

MG IN SPECIFIC POPULATIONS

ASSOCIATED DISORDERS

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

PATHOPHYSIOLOGY

MuSK MG

LPR4 MG

Transient Neonatal MG

LABORATORY FEATURES

SEROLOGICAL TESTING

ELECTROPHYSIOLOGICAL TESTING

PHARMACOLOGICAL TESTING

IMAGING

HISTOPATHOLOGY

TREATMENT

SYMPTOMATIC TREATMENT

Thymectomy

Immunomodulating Treatment

Special Circumstances

Prevention and Treatment of Potential Exacerbating Factors

Monitoring

REFERENCES

CHAPTER 25Autoimmune Myasthenia Gravis

CLINICAL FEATURES

MUSK MG

SERONEGATIVE MG INCLUDING PATIENTS WITH LPR4 AUTOANTIBODIES

MG IN SPECIFIC POPULATIONS

ASSOCIATED DISORDERS

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

PATHOPHYSIOLOGY

MuSK MG

LPR4 MG

Transient Neonatal MG

LABORATORY FEATURES

SEROLOGICAL TESTING

ELECTROPHYSIOLOGICAL TESTING

PHARMACOLOGICAL TESTING

IMAGING

HISTOPATHOLOGY

TREATMENT

SYMPTOMATIC TREATMENT

Thymectomy

Immunomodulating Treatment

Special Circumstances

Prevention and Treatment of Potential Exacerbating Factors

Monitoring

REFERENCES

CHAPTER 25

Autoimmune Myasthenia Gravis