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Myasthenia Gravis - EMEDICINE.2018.FCPS
Myasthenia Gravis - EMEDICINE.2018.FCPS
Myasthenia Gravis - EMEDICINE.2018.FCPS
Normal neuromuscular
junction showing a presynaptic terminal with a motor nerve ending in an
enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane
with multiple folds and embedded with several acetylcholine receptors.
Background
Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which
antibodies form against nicotinic acetylcholine (ACh) postsynaptic receptors at
the neuromuscular junction (NMJ) of the skeletal muscles. It is a type-II
hypersensitivity immune response. The basic pathology is a reduction in the
number of ACh receptors (AChRs) at the postsynaptic muscle membrane
brought about by an acquired autoimmune reaction producing anti-AChR
antibodies.
The reduction in the number of AChRs results in a characteristic pattern of
progressively reduced muscle strength with repeated use and recovery of
muscle strength after a period of rest. The ocular and bulbar muscles are
affected most commonly and most severely, but most patients also develop
some degree of fluctuating generalized weakness. [10] The most important
aspect of MG in emergency situations is acute worsening of weakness leading
to neuromuscular respiratory failure. The diagnosis of myasthenic versus
cholinergic crisis and its management is also a significant challenge in
emergent settings.
MG is a well-understood and well-managed disease. Pharmacologic therapy
includes anticholinesterase agents, such as pyridostigmine, and
immunosuppressive agents, such as corticosteroids, azathioprine,
mycophenolate mofetil, tacrolimus, sirolimus, cyclosporine,
cyclophosphamide, rituximab, plasmapheresis, and intravenous immune
globulin (IVIg). Thymectomy has a significant role in the treatment of patients
with generalized MG who are positive for acetylcholine receptor
antibodies. Thymectomy becomes mandatory if a thymoma is present.
Patients with MG require close follow-up care by a neurologist or
neuromuscular specialist in cooperation with their primary care physician.
Anatomy
The neuromuscular junction (NMJ) serves as a transducer and amplifier to the
peripheral nerve’s relatively small electrical current using a chemical signal
subserved by neurotransmitter ACh. This in turn produces an electrical current
of sufficient intensity and proper location such that it initiates a propagating
action potential in the muscle fiber. Thus, the NMJ is considered a chemical
synapse that functions as an electrical-chemical-electrical link.
In MG, autoantibodies (immunoglobulin G [IgG1]) develop against nicotinic
acetylcholine postsynaptic receptors at the NMJ of skeletal muscles. [1, 2] The
reasons for this development are unknown, although it is clear that certain
genotypes are more susceptible. [11] To understand MG, it is necessary to
become familiar with the normal anatomy and physiology of the NMJ (see the
image below). A full appreciation of the normal function of the NMJ is needed
to understand the principles underlying diagnostic testing and the
mechanisms of therapeutic interventions.
Normal neuromuscular
junction showing a presynaptic terminal with a motor nerve ending in an
enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane
with multiple folds and embedded with several acetylcholine receptors.
Each motor neuron has an axon that branches distally to provide nerve
terminals that innervate muscle fibers through the NMJ. Collectively, they are
known as the motor unit. A muscle fiber is innervated by only one motor
neuron with the exception of extraocular muscle fibers where single muscle
fibers may receive multiple innervation. The motor nerve loses its myelin
sheath as it approaches near the NMJ where it begins to divide into terminal
branches. Each terminal branch of an axon, as it nears an individual muscle
fiber, expands into a presynaptic terminal bouton that lies in a depression in
the muscle membrane. A basement membrane overlies this terminal interface
between the bouton and its muscle fiber, constituting part of the muscle end-
plate. The terminal bouton has a number of subcellular components including
neurotubules, neurofilaments, multiple mitochondria, and a large number of
membrane-bound vesicles ranging from 300 to 500 Angstrom units in
diameter, called synaptic vesicles. Each vesicle contains approximately 1
quantum of acetylcholine, which equals 10,000 molecules of acetylcholine. A
single nerve terminal has approximately 200,000 synaptic vesicles. These
vesicles are organized in 3 discrete groups.
The primary, or immediately available store consists of approximately 1000
quanta of ACh and are located just beneath the pre-synaptic nerve terminal
membrane at specific sites called active zones. These release sites (active
zones) lie directly opposite the ACh receptors (AChRs) located on the post-
synaptic membrane. The primary store is available for immediate release.
They behave like soldiers at the front line, ready for action.
The secondary, or mobilization store consists of approximately 10,000 quanta
of ACh that can replenish the primary store after a few seconds. These
behave like immediate reinforcements that become mobilized to replace the
depleted primary store.
Finally, a tertiary, or reserve store of more than 100,000 quanta exists far from
the NMJ in the axon and cell body. They behave like the reserves.
Voltage-gated calcium (Ca++) channels (P/Q-type) are located in the proximity
of the active zones. Under the electron microscope they appear as double
parallel rows of dense intramembrane particles.
The synaptic space
The subunits in the AChRs are organized like barrel staves with their
convexity inward or in a funnel-like fashion with the narrow end oriented to the
intracellular compartment. In the center of the funnel-like portion of the AChR
is a cation channel, which is contributed by the M2 and M3 domains of each
subunit. Negatively charged residues located at either end of the channel
allow the passage of positive ions and exclude passage of the negative ions.
Ion binding sites within the channel have an important role in the passage of
ions. The ACh binding sites and the main immunogenic region (MIR) are
located on the protruding extracellular surfaces of alpha subunits; although in
close proximity, the sites for MIR and ACh are distinctly separate. The AChR
binding sites are actually located between the α1 and δ subunits and between
the α2 and ε subunits. The extracellular portions of AChR extend 100
Angstrom units beyond the cell membrane. Sugars on the extracellular
surface of the subunits extend outward and have complex branching patterns.
On the cytoplasmic surface of the membrane are cytoskeletal components,
which anchor the AChRs. The post-synaptic junctional folds are packed with
AChRs (10,000 receptors/µm2) and also contain other protein subsets like
MuSK, LRP4, rapsyn, integrins, ErbB receptors, N-acetylgalactosaminlyl
transferase, and collagen XIII. [18, 19] Complex interactions between agrin,
rapsyn, and MuSK, and LRP4 are involved in the development and
maintenance of the NMJ. The clustering of AChR at the crests of
the postsynaptic junctional fold is critical for normal neuromuscular
transmission.
The troughs of the junctional folds have neural cell adhesion molecules
(NCAM), and the voltage-gated sodium ion channels. The latter are tethered
to Ankyrin G and β-spectrin, and linked to the cytoskeleton by
syntrophins. [20, 21] At the endplate, rapsyn connects AChRs to each other and
muscle fiber cytoskeleton via dystrophin-glycoprotein complex (DGC). The
DGC contains a number of transmembrane proteins (α- and β-dystroglycan
and the sarcoglycan complex). DGC also has submembrane proteins
(dystrophin, utrophin, syntrophin, and dystrobrevin) and connects to the
cytoskelton via F-actin and to the basal lamina via laminin.
Neureregulin produced by the NR-1 gene is a motor nerve-derived trophic
factor similar to agrin. It is thought to induce accumulation of voltage-gated
sodium ion channels in the depths of the synaptic clefts. It is noted that shortly
after neuregulin appears at the developing NMJ, fetal AChRs containing the γ-
subunit (γ-AChRs) are replaced by adult AChRs containing the ε subunit (ε-
AChRs). The ε subunit is dependent on the presence of neuregulin for its
continued expression at the NMJ. [18] The mature AChRs are constantly turned
over by internalization and degradation and replacement by new AChRs. They
are not recycled.
Pathophysiology
The following physiologic events occur in neuromuscular transmission:
1. A nerve action potential propagates down the axon and depolarizes the
presynaptic nerve terminal.
2. Voltage-gage calcium channels open in response to depolarization and
there is calcium influx through these channels into the nerve terminal.
3. Synaptic vesicles fuse with the presynaptic membrane, releasing ACh into
the synaptic space.
4. ACh molecules bind to AChR on the post-synaptic membrane causing the
the recepors to undergo conformational change, opening the ion channel.
5. Membrane conductance to Na+ ions increases (Na+ goes in, K+ goes out)
resulting in depolarization of endplate region causing end-plate potenital
(EPP).
6. If the EPP is sufficient to depolarize the adjacent muscle membrane to
threshold, an action potential is generated in the muscle fiber. Conversely,
if it is of insufficient magnitude it will not cause the muscle membrane to
reach threshold, and therefore fails to generate a muscle fiber action
potential.
In the resting state, there is an intermittent release of ACh molecules across
the primary synaptic cleft. The ACh molecules serve as ligands and bind to
the AChR on the post-synaptic membrane. Two molecules of ACh bind to the
alpha subunits of the AChR, and fuse with it. The bound AChR then
undergoes a 3-dimensional conformational change in the central ion channel
portion of the AChR (M2, alpha-helical) opening the funnel-shaped cation
channel (whose inner wall is negatively charged). This opening is very brief
(about 1 ms) resulting in influx of sodium ions while simultaneously allowing
potassium efflux along its opposite concentration gradient. This results in brief
depolarization of the muscle membrane only at the junctional region creating a
post-synaptic non-propagating depolarization called miniature endplate
potentials (MEPPs).
The normal muscle fiber resting membrane potential is -80 mV (negative
inside). The threshold for triggering an action potential in the muscle fiber is -
50mV to -65mV. When a nerve action potential depolarizes the terminal
axons, sodium ion conductance is increased and at the same time voltage-
gated calcium channels (VGCCs) are activated, allowing an influx of calcium
ion at the terminal portion of the axon. The entry of calcium ions is critical to
the process of neuromuscular transmission (if Ca++ is removed from the
extracellular space, NMJ transmission ceases). The entry of Ca++ starts a
complicated interaction of many proteins including SNARE protein complex at
the nerve terminal leading to facilitation of fusion of the ACh-containing
vesicles with the presynaptic membrane. Consequently, the discharge of ACh
occurs by exocytosis into the synaptic cleft. The greater the calcium
concentration inside the presynaptic terminal, the more quanta of ACh are
released into the synaptic cleft.
ACh molecules bind to the AChRs resulting in a larger depolarization of the
post-synaptic membrane resulting in the endplate potential (EPP). The
amplitude of EPP is normally high enough to trigger an action potential at the
post-synaptic membrane. The voltage-gated sodium channels present in the
depths of the secondary synaptic cleft facilitate action potential, which is
propagated along the NMJ muscle membrane. When this action potential
invades the transverse tubule system of the muscle, another voltage-gated
calcium channel (VGCC) becomes activated causing influx of calcium ions,
and triggering mechanical contraction of the muscle fiber contractile
apparatus.
The action of ACh on the post-synaptic membrane is short-lived and is
terminated within a few milliseconds of its release from the nerve terminal
through hydrolysis by the enzyme acetylcholinesterase into acetic acid and
choline. The latter is taken up by the presynaptic membrane and repackaged
into new ACh molecules.
The calcium ions are normally pumped out of the terminal portion of the axon
within 100 ms, so they linger for a while and maintain the axon terminal in a
hyperexcitable state, enhancing the release of ACh should a second action
potential depolarizes the axon within this time frame.
Safety factor
The amplitude of the EPP tends to be >60 mV above the muscle fiber resting
membrane potential of -80 mV. So only 15mV is needed to reach the
threshold for action potential of -65 mV. The extra 45 mV is referred as the
Safety Factor. So, even if the EPP were to get smaller (e.g., 40 mV) due to
repetitive contraction resulting in fatigue, the EPP would still be high to reach
threshold and maintain the one-to-one relationship between the action
potential of the motor axon and generation of an action potential in the muscle
cell. However, if the safety factor is greatly decreased as it may occur in MG,
neuromuscular transmission may become blocked.
In MG, the safety factor is reduced (i.e., baseline EPP is reduced but still
above threshold). Slow RNS (3 Hz) will cause depletion of ACh quanta and
may drop the EPP below threshold, resulting in the absence of a muscle fiber
action potential (a phenomenon referred to as presynaptic rundown).
Consequently, EPP is reduced as there are fewer AChRs for ACh molecules
to bind.
In MG, there are anti-AChR-ab against AChR available at the post-synaptic
folds, which become flattened or simplified by the immunopathological
mechanism. This, on top of the gradual reduction of AChRs that are released
with repeated use of the muscle, leads to insufficient endplate potentials
(EPP), which may fall below the threshold value for generation of an action
potential. The end result of this process is inefficient neuromuscular
transmission. When this failure occurs at enough muscle fibers, it can
manifest clinically and can be demonstrated electrophysiologically through
low-frequency repetitive nerve stimulation (3 Hz RNS). However, if it occurs in
only a few muscle fibers it can be detected on single-fiber electromyography
(SFEMG).
Patients become symptomatic once the number of AChRs is reduced to
approximately 30% of normal. The cholinergic receptors of smooth and
cardiac muscle have a different antigenicity than skeletal muscle and usually
are not affected by the disease.
The decrease in the number of postsynaptic AChRs is believed to be due to
an autoimmune process whereby anti-AChR antibodies are produced and
block the AChR. It causes an increase in the turnover of the AChR, and
damage of the postsynaptic membrane in a complement-mediated manner.
The exact mechanism of loss of immunologic tolerance to AChR, a self-
antigen, is not understood. MG can be considered a B cell–mediated disease,
in that it derives from antibodies (a B cell product) against AChR. However,
the importance of T cells in the pathogenesis of MG is becoming increasingly
apparent. The thymus is the central organ in T cell–mediated immunity, and
thymic abnormalities such as thymic hyperplasia or thymoma are well
recognized in myasthenic patients.
It is thought that both the initiation and maintenance of MG occurs in a
process that involves type-II hypersensitivity reactions. The production of
autoantibodies implies that it is a B-cell-mediated autoimmune disorder. The
intiation of the process is dependent on T-cell help. Accordingly, CD4 T cells
are the main driving force in the immunopathogenesis of MG. Macrophages
and dendritic cells are activated and these act as antigen-presenting cells.
AChRs phagocytized by macrophages become degraded into peptide
subcomponents. These are then linked to MHC-II, the molecule required for
reactivity to “self-antigens.” The AChR antigenic fragment and MHC complex
are transported to the surface of macrophages and dendritic cells. Specific,
helper T cells, with the cooperation of CD3 complex and CD4 molecular T-cell
receptor site, recognize this antigen complex. Specific receptor sites on the T-
cell surface recognize cytokines secreted by the macrophage and dendritic
cells. The activated helper T cells secrete interferon (IFN)-γ and interleukin
(IL)-17 that stimulate B lymphocytes. The activated B lymphocytes grow and
undergo clonal expansion into antibody-synthesizing plasma cells. These
plasma cells secrete IgG anti-AChR antibodies that bind to the nictonic ACh-
R.
Antibody response in MG is polyclonal. In an individual patient, antibodies are
composed of different subclasses of IgG. In most instances, they are of IgG1
and IgG3 subclass and are directed against the main immunogenic region
(MIR) on the alpha subunit. The alpha subunit is also the site of ACh binding,
though the binding site for ACh is not always the same as the MIR. Binding of
AChR antibodies to AChR results in impairment of neuromuscular
transmission in several ways, including the following:
Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus
accelerating internalization and degradation of AChR molecules
Causing complement-mediated destruction of junctional folds of the
postsynaptic membrane
Blocking the binding of ACh to AChR
Decreasing the number of AChRs at the NMJ by simplification of the
junctional folds on the postsynaptic membrane, thereby reducing the
surface area available for insertion of newly synthesized AChRs
Patients without anti-AChR antibodies are recognized as having seronegative
MG (SNMG). These patients usually have autoantibodies (IgG4) against
muscle-specific kinase (MuSK). These do not activate complement, unlike
AChR-abs. MuSK plays a critical role in postsynaptic differentiation and
clustering of AChRs at the NMJ to promote efficient neuromuscular
transmission. MuSK autoantibodies are pathogenic and this is proven by
passive transfer and active immunization studies in animals. It is likely MuSK
autoantibodies disrupt the interaction between MuSK and the LRP4 and
collagen Q. Patients with anti-MuSK antibodies are predominantly women,
with a tendency of disease onset in the third or fourth decades. They have
prominent oculobulbar weakness with dysarthria. Face and tongue atrophies
have been reported in long-standing disease. It is often confused with bulbar
amyotrophic lateral sclerosis (ALS). Another group has reported patients who
exhibit prominent neck (dropped head syndrome), shoulder, and respiratory
weakness. [12, 13] Myasthenic crises appear to be more frequent in patients with
MuSK antibodies. [22, 23]
The role of the thymus in the pathogenesis of MG is not entirely clear, but
75% of patients with MG have some degree of thymus abnormality (eg,
hyperplasia or thymoma). Histopathologic studies have shown prominent
germinal centers. Epithelial myoid cells normally present in the thymus
resemble skeletal muscle cells and possess AChRs on their surface
membrane. These cells may become antigenic by molecular mimicry and
unleash an autoimmune attack on the muscular endplate nicotinic AChRs.
The question of why MG affects the extraocular muscles first and
predominantly remains unanswered. The answer probably has to do with type
and distribution of NMJs in at least some of the muscles affected by the
disease.
The distinctive features in MG, particularly the fluctuating nature of a patient's
strength, is attributed to the unique pathophysiology of impaired
neuromuscular transmission. This pathophysiology produces a dynamic rather
than a fixed disorder as a result of the relative ease by which NMJs repair.
Etiology
MG is idiopathic in most patients. Although the main cause behind its
development remains speculative, the end result is a derangement of immune
system regulation. MG is clearly an autoimmune disease in which the specific
antibody has been characterized completely. In as many as 90% of
generalized cases, IgG to AChR is present. [14] Even in patients who do not
develop clinical myasthenia, anti-AChR antibodies can sometimes be
demonstrated.
Patients who are negative for anti-AChR antibodies may be seropositive for
antibodies against MuSK. Muscle biopsies of these patients show myopathic
features with prominent mitochondrial abnormalities, as opposed to the
neurogenic features and atrophy frequently found in MG patients positive for
anti-AChR. The mitochondrial impairment could explain the oculobulbar
involvement in anti-MuSK–positive MG. [24]
Numerous findings have been associated with MG. For example, people with
certain human leukocyte antigen (HLA) types have a genetic predisposition to
autoimmune diseases. The histocompatibility complex profile includes HLA-
A1, -A3, -B7, -B8, -DRw3, and -DQw2 (though these have not been shown to
be associated with the strictly ocular form of MG). However, HLA genotyping
is not routinely used in the evaluation of patients suspected to have MG.
Sensitization to a foreign antigen that has cross-reactivity with the nicotinic
ACh receptor has been proposed as a cause of myasthenia gravis, but the
triggering antigen has not yet been identified.
Various drugs may induce or exacerbate symptoms of MG, including the
following:
Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin,
and ampicillin)
Penicillamine - This can induce true myasthenia, with elevated anti-AChR
antibody titers seen in 90% of cases; however, the weakness is mild, and
full recovery is achieved weeks to months after discontinuance of the drug
Beta-adrenergic receptor blocking agents (eg, propranolol and oxprenolol)
Lithium
Magnesium
Procainamide
Verapamil
Quinidine
Chloroquine
Prednisone
Timolol (ie, a topical beta-blocking agent used for glaucoma)
Anticholinergics (eg, trihexyphenidyl)
Neuromuscular blocking agents (eg, vecuronium and curare) - These
should be used cautiously in myasthenic patients to avoid prolonged
neuromuscular blockade
Nitrofurantoin has also been linked to the development of ocular MG in 1
case report; discontinuance of the drug resulted in complete recovery.
MG induction as a side effect of cancer immunotherapy
o Ipilimumab induced (anti-CTLA4) MG
o PD-1, PDL-1 inhibitors
Thymic abnormalities are common: Of patients with MG, 75% have thymic
disease, 85% have thymic hyperplasia, and 10–15% have thymoma.
Extrathymic tumors may include small cell lung cancer and Hodgkin
disease. [25, 26] Hyperthyroidism is present in 3–8% of patients with MG and has
a particular association with ocular MG.
Epidemiology
The overall incidence rate of MG has been estimated at 2.1 to 5.0 per million
people per year and has not changed over time. However, the prevalence rate
has increased since the 1950s in keeping with the declining mortality rate in
MG as well as improved diagnostic precision. Accroding to regional studies
peformed since 1990, the prevalence rate ranges from approximately 7–20
per 100,000. [24, 25]
Approximately 15%–20% of patients with MG experience crisis in their
lifetime, typically within the first 2 years of the diagnosis. [26]
Fifty years ago, estimates of mortality in MG crisis ranged from 50% to
80%. [27, 28, 29] Currently, the overall in-hospital mortality rate was 2.2%, being
higher in MG crisis (4.47%). Older age and respiratory failure were the
predictors of death.
Age-related demographics
MG can occur at any age. Female incidence peaks in the third decade of life,
whereas male incidence peaks in the sixth or seventh decade. The mean age
of onset is 28 years in females and 42 years in males.
Transient neonatal MG occurs in infants of myasthenic mothers who acquire
anti-AChR antibodies via placental transfer of IgG. Some of these infants may
suffer from transient neonatal myasthenia due to effects of these antibodies.
Most infants born to myasthenic mothers possess anti-AChR antibodies at
birth, yet only 10-20% develop neonatal MG. This may be due to protective
effects of alpha-fetoprotein, which inhibits binding of anti-AChR antibody to
AChR. High maternal serum levels of AChR antibody may increase the
chance of neonatal MG; thus, lowering the maternal serum titer during the
antenatal period by means of plasmapheresis may be useful.
Sex-related demographics
In May 1997, the Medical Scientific Advisory Board (MSAB) of the Myasthenia
Gravis Foundation of America (MGFA) formed a task force to address the
need for universally accepted classifications, grading systems, and analytic
methods for management of patients undergoing therapy and for use in
therapeutic research trials. As a result, the MGFA Clinical Classification was
created. [3] This classification divides MG into 5 main classes and several
subclasses, as follows.
Class I: Any ocular muscle weakness; may have weakness of eye
closure. All other muscle strength is normal.
Class II: Mild weakness affecting other than ocular muscles; may also
have ocular muscle weakness of any severity.
o Class IIa: Predominantly affecting limb, axial muscles, or both. May
also have lesser involvement of oropharyngeal muscles.
o Class IIb: Predominantly affecting oropharyngeal, respiratory
muscles, or both. May also have lesser or equal involvement of limb,
axial muscles, or both.
Class III: Moderate weakness affecting other than ocular muscle; may
also have ocular muscle weakness of any severity
o Class IIIa: Predominantly affecting limb, axial muscles, or both. May
also have lesser involvement of oropharyngeal muscles.
o Class IIIb MG: Predominantly affecting oropharyngeal, respiratory
muscles, or both. May also have lesser or equal involvement of limb,
axial muscles, or both.
Class IV: Severe weakness affecting other than ocular muscles; may also
have ocular muscle weakness of any severity.
o Class IVa: Predominantly affecting limb, axial muscles, or both. May
also have lesser involvement of oropharyngeal muscles.
o Class IVb: Predominantly affecting oropharyngeal, respiratory
muscles, or both. May also have lesser or equal involvement of limb,
axial muscles, or both.
Class V: Defined by intubation, with or without mechanical ventilation,
except when used during routine postoperative management. Use of a
feeding tube without intubation places the patient in class IVb.
Physical Examination
Patients with MG can present with a wide range of signs and symptoms,
depending on the severity of the disease.
Mild presentations may be associated with only subtle findings, such as
ptosis, that are limited to bulbar muscles. Findings may not be apparent
unless muscle weakness is provoked by repetitive or sustained use of the
muscles involved. Recovery of strength is seen after a period of rest or with
application of ice to the affected muscle. Conversely, increased ambient or
core temperature may worsen muscle weakness.
Variability in weakness can be significant, and clearly demonstrable findings
may be absent during examination. This may result in misdiagnosis (eg,
functional disorder). The physician must determine strength carefully in
various muscles and muscle groups to document severity and extent of the
disease and to monitor the benefit of treatment.
Another important aspect of the physical examination is to recognize a patient
in whom imminent respiratory failure is imminent. Difficulty breathing
necessitates urgent or emergent evaluation and treatment.
Weakness can be present in a variety of different muscles and is usually
proximal and not symmetrical. Sensory examination and deep tendon reflexes
are normal.
Distribution of weakness in a large cohort of patients with myasthenia gravis
(n=609) (Open Table in a new window)
Percentage of
Distribution of Weakness
Patients
Differential Diagnoses
Amyotrophic Lateral Sclerosis in Physical Medicine and Rehabilitation
Basilar Artery Thrombosis
Botulism
Brainstem Gliomas
Cavernous Sinus Syndromes
Chronic Myelogenous Leukemia (CML)
Ciguatera Toxicity
Congenital Myasthenic Syndrome
Dermatomyositis
Diphtheria
Graves Disease
Guillain-Barre Syndrome
Kearns-Sayre Syndrome
Lambert-Eaton Myasthenic Syndrome (LEMS)
Miller-Fisher Syndrome
Multiple Sclerosis
Myocardial Infarction
Neurosarcoidosis
Organophosphate Toxicity
Polymyositis
Pulmonary Embolism (PE)
Tetrodotoxin Toxicity
Thyroid Ophthalmopathy
Tick-Borne Diseases
Tolosa-Hunt Syndrome
Laboratory Tests
The serum titer of the acetyl-choline receptor antibodies does not correlate
with disease severity. Their value is mainly in the initial diagnosis, or in the
case of modulating antibodies as a potential marker for thymoma. Unlike anti-
AChR-abs, there appears to be a correlation between anti-MuSK titers,
disease severity, and the application of immunomodulatory therapy. [41]
Anti–acetylcholine receptor antibody
About half of the patients with negative results for anti-AChR Ab (seronegative
MG) may have positive test results for antibody to muscle-specific kinase
(MuSK), a receptor tyrosine kinase that is essential for neuromuscular junction
development. [46] These patients may represent a distinct group of autoimmune
MG, in that they show some collective characteristics that are different from
those of anti-AChR–positive patients. [17]
Anti-MuSK–positive individuals tend to have more pronounced bulbar
weakness and may have tongue and facial atrophy. They may have neck,
shoulder and respiratory involvement without ocular weakness. They are also
less likely to respond to acetylcholine esterase (AChE) inhibitors, and their
symptoms may actually worsen with these medications. [47, 35]
Anti-lipoprotein-related protein 4 (LRP4) antibody
Dosage regimen 1:
Rituximab 1 gm IV on day 1 and day 14
Further rituximab doses depend on whether CD19 count has returned to
normal (usually at 6 months)
Rituximab 1 gm IV once at 6 months, if indicated
Dosage regimen 2:
Rituximab 375/m2 IV every 12 weeks for 48 weeks
Prednisone 60 mg daily until minimal manifestation state, then taper to 10
mg every 4 weeks
Often patients are started on prednisone in the outpatient setting when their
MG is mild. The strategy here is to increase the dose gradually until
symptoms resolve or minimal manifestation status is achieved. Initially,
patients are started on prednisone 20 mg daily and the dose is increased by 5
mg every 3–5 days until symptoms resolve. Patients are usually kept on the
dosage that achieved minimal manifestation state for a month, then the dose
is gradually tapered (no faster than 5 mg every 2 weeks down to a dose of 20
mg daily, and then by 2.5 mg every two weeks). [5, 54]
MG induction as a side effect of cancer immunotherapy with checkpoint
inhibitors (PD-1, PD-L1, and CTLA-4) is described to rapidly progress to
myasthenic crisis and must be aggressively treated by discontinuation of
immunotherapy with the checkpoint inhibitors and initiation of high-dose
steroids along with IVIg or plasmapheresis.
Aminoglycoside antibiotics inhibit ACh release from nerve terminals by
competing with Ca++. Administration of calcium salts overcomes this effect.
Management of neonatal myasthenia gravis
Transient neonatal MG, in which MG is transmitted vertically from an affected
mother to her fetus, occurs in 10-30% of neonates born to myasthenic
mothers. It may occur any time during the first 7-10 days of life, and infants
should be monitored closely for any signs of respiratory distress.
The syndrome of neonatal myasthenia is caused by transplacental transfer of
maternal autoantibodies against the acetylcholine receptor (AChR). Infants
affected by this condition are floppy at birth, and they display poor sucking,
muscle tone, and respiratory effort. They often require respiratory support and
intravenous (IV) feeding, as well as monitoring in a neonatal ICU. As the
transferred maternal antibodies are metabolized over several weeks,
symptoms abate and the infants develop normally.
Treatment with cholinesterase inhibitors is effective in this age group as well.
However, the dosage must be carefully titrated to the clinical effect.
Complications
Long-term immunomodulating therapies may predispose patients with MG to
various complications. Long-term steroid use may cause or aggravate
osteoporosis, cataracts, hyperglycemia, weight gain, avascular necrosis of
hip, hypertension, opportunistic infection, and other complications. Long-term
steroid use also increases the risk of gastritis or peptic ulcer disease. Patients
on such therapy should take an H2 -blocker or antacid as well.
Some complications are common to any immunomodulating therapy,
especially if the patient is on more than 1 agent. These would include
infections such as tuberculosis, systemic fungal infections, and Pneumocystis
carinii pneumonia. The risk of lymphoproliferative malignancies may be
increased with chronic immunosuppression. Immunosuppressive drugs may
have teratogenic effects.
Initial deterioration in weakness before improvement is a common and serious
concern within the first 3 weeks of immunomodulatory therapy; this potential
complication warrants initiation of high doses in a supervised setting.
Excessive use of cholinesterase inhibitors can result in a cholinergic crisis.
Other immunosuppressive medications increase the incidence of opportunistic
infections, renal insufficiency, and hypertension.
Plasmapheresis
Plasmapheresis (plasma exchange) is believed to act by removing circulating
humoral factors (ie, anti-AChR antibodies and immune complexes) from the
circulation. It is used as an adjunct to other immunomodulatory therapies and
as a tool for crisis management. Like IVIg, plasmapheresis is generally
reserved for myasthenic crisis and refractory cases. Improvement is noted in a
couple of days, but it does not last for more than 2 months.
Plasmapheresis is an effective therapy for MG and is often the initial treatment
of choice in myasthenic crisis. Also, it is used to optimize control in
preparation for surgery. Improvement in strength may help to achieve rapid
postoperative recovery and to shorten the period of assisted ventilation. Long-
term regular plasmapheresis on a weekly or monthly basis can be used if
other treatments cannot control the disease.
Complications are primarily limited to complications of intravenous (IV) access
(eg, central line placement) but also may include hypotension and coagulation
disorders (though less commonly). Patients will need careful monitoring of
fibrinogen and may need FFB if fibrinogen levels drop to less than 150 mg/dL
prior to the next pheresis. There is a risk of hypocalcemia, central-line-
associated bloodstream infection (CLABSI), thrombocytopenia,
thromboembolism, and heparin-induced thrombocytopenia.
ACE inhibitors must be stopped 24 hrs before treatment and until treatment is
completed.
Plasmapheresis is given as 250 mL/Kg total divided every other day over 5-6
exchanges. The onset of action is 1-7 days with maximal effect in 1-3 weeks.
Thymectomy
Thymic abnormalities are common in patients with MG. Of patients with
generalized MG, 85% have thymic hyperplasia, and 10-15% have thymoma.
Thymic pathology in early-onset generalized MG is invariably thymic
hyperplasia. These patients invariably are anti-AChR-ab positive.
There is evidence that resident cells in the thymus, including myoid cells and
epithelial cells, express various subunits of AChR, including the α subunit.
Additional factors found uniquely in hyperplastic MG thymus include increased
expression of chemokines that attract immigrant CD4+ T and B cells; the
presence of nAChR-reactive B and CD4+ T cells and anti-AChR antibody-
secreting plasma cells; cytokines that can facilitate B cell activation,
differentiation, and survival; and possibly decreased CD4+ CD25+ regulatory
T cell function. [55]
An extended trans-sternal thymectomy is standard of care and is indicated for
all patients with thymoma and for patients aged 10-55 years without thymoma
but who have generalized MG. Patients with thymomas almost always have
anti-AChR-ab and so one must look carefully for thymoma in late-onset
patients with anti-AChR-ab positive status. Removal of thymoma is essential
to prevent local dissemination and systemic metastases. In late onset patient
with MG and thymoma, thymectomy probably does not change the course of
MG. Thymectomy has been proposed as a first-line therapy in most patients
with generalized myasthenia. [52] In patients who have myasthenia gravis like
symptoms but who are seronegative order a CT of chest regardless, to check
for thymic pathology, since a small percentage of these patients may
subsequently seroconvert to anti-AChR-ab positive status.
In ocular MG, thymectomy should be delayed at least 2 years to allow for
spontaneous remission or the development of generalized MG. Whether
thymectomy is to be performed for prepubescent patients or patients older
than 55 years is still controversial. Reports tend to encourage surgical
treatment for the latter group.
Thymectomy is not recommended in patients with antibodies to muscle-
specific kinase (MuSK), because of the typical thymus pathology, which is
very different from the more common type of MG characterized by
seropositivity for AChR antibodies. [53] Current evidence also does not support
an indication for thymectomy in patients with LRP4, or agrin antibodies.
Thymectomy may be considered in patients with generalized MG without
detectable AChR antibodies if they fail to respond adequately to
immunosuppressant therapy, or to avoid/minimize intolerable adverse effects
from immunosuppressant therapy. [56]
Patients often experience some transient worsening of symptoms early in the
postoperative period. Improvement usually is delayed for months or years.
Complete removal of thymic tissue is widely considered to be of the utmost
importance, on the grounds that any small remnant might lead to recurrence.
Thymectomy may induce remission. This occurs more frequently in young
patients with a short duration of disease, hyperplastic thymus, more severe
symptoms, and a high antibody titer, although a high titer of antibody is not
consistently linked to better outcome. [57]
Remission rate increases with time: at 7-10 years after surgery, it reaches 40-
60% in all categories of patients except those with thymoma. In the absence
of a thymoma, 85% of patients experience improvement, and 35% of these
patients achieve drug-free remission. In a study by Nieto et al, the rate of
remission in the presence of thymic hyperplasia was 42% compared to 18% in
patients with thymoma. [55]
As there is a long delay in onset of beneficial effect of thymectomy for MG, an
elective procedure should be performed when the patient is stable and
deemed safe to undergo a procedure where postoperative pain and
mechanical factors can limit respiratory function.
Robotic thymectomy
Over the years, many different techniques have been employed to perform
thymectomy. Although it is generally believed that complete removal of thymic
tissue is better (see above), this is not an established fact. There is no
consensus as to whether one technique is superior to another in achieving
benefit or minimizing risks.
The Myasthenia Gravis Foundation of America (MGFA) has proposed a
classification scheme for thymectomy, which is primarily based on techniques
described in various published reports. [3]
The MGFA thymectomy classification is as follows:
T-1 transcervical thymectomy – Basic; extended
T-2 videoscopic thymectomy - Classic or VATS (video-assisted thoracic
surgery) thymectomy; VATET (video-assisted thoracoscopic extended
thymectomy)
T-3 transsternal thymectomy – Standard; extended
T-4 transcervical and transsternal thymectomy
Neostigmine (Bloxiverz)
Edrophonium (Enlon)
Cyclophosphamide
Rituximab (Rituxan)
Eculizumab (Soliris)
Ipratropium (Atrovent)
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