Pathophysiology
Myasthenia gravis is essentially the disease of the neuromuscular junction. The neuromuscular
junction anatomically is composed of the presynaptic, synaptic, and post-synaptic
components. Acetyl choline (ACh) is synthesized, stored in the presynaptic nerve terminal,
and released into the synaptic clefts in quanta secondary to the actions of calcium
when an impulse arrives at the nerve terminal ([Fig. 1 ]). The acetylcholinesterase enzyme is present in these clefts that hydrolyzes the
ACh to terminate the transmission. The ACh inhibiting agents act here in improving
the clinical symptoms. The post-synaptic membrane contains the ACh receptors (AChRs),
the detailed anatomy of which can be found elsewhere.[2 ] The most common form of MG, seropositive MG, features autoantibodies ([Fig. 2 ]) which accelerate the endocytosis of the receptor or induce complement-mediated
destruction of the AChR.[3 ] About 10 to 20% of the MG patients do not demonstrate autoantibodies against the
AChR—this condition is called “seronegative MG.” These patients demonstrate antibodies
directed toward a receptor tyrosine kinase called muscle-specific kinase (MuSK). MuSKs
are required to cluster the AChRs in groups and their production is mediated by a
protein in the basement membrane called Agrin. The exact means by which Agrin activates
the MuSK is not clearly understood.[4 ]
[5 ] Though the antibodies against AChRs are produced by B cells, T cells also have a
role in this autoimmune response. T cells, specifically the CD4+ helper cells, aid
in the production and activation of the proliferation of B cells which produce immunoglobulins
against AChRs.[6 ]
[7 ]
Fig. 1 The neuromuscular junction in a healthy individual.
Fig. 2 The neuromuscular junction in an individual suffering from myasthenia gravis.
The thymus gland also plays an essential role in the pathogenesis of MG, especially
in those patients who present with thymomas. Myoid cells which are present in the
medullary region of the thymus along with the T helper cells produce antibodies against
AChRs. Any alterations in the body physiology from either genetic or viral disease
lead to tolerance induction to self-antigens and responsiveness of the lymphocytes
to alien antigens.[8 ]
[9 ]
Clinical Features and Diagnosis of Myasthenia Gravis
Presence of shifting weakness of skeletal muscle groups, which aggravates by physical
activity and improves on resting, is the hallmark of MG. In most of the cases, the
weakness is initially observed in the ocular muscles which then spreads on to bulbar
and skeletal muscles. Respiratory muscles are involved in the end which necessitates
the intensive care management of the patient.
A few tests will confirm the diagnosis of MG. The most widely used test is the edrophonium/Tensilon
test. Under close monitoring, the patient is injected with edrophonium—a short acting
acetylcholinesterase inhibitor. An objective improvement in the muscle strength primarily
the ocular muscle indicates a positive test.[10 ] An ice pack placed on the eye on the other hand improves the ptosis which is referred
to as the “ice pack” test. The ice pack test is employed in those patients where edrophonium
test is not indicated.[11 ] Electrophysiological tests can be performed for the diagnosis of MG. Single fiber
electromyography is considered to be the most effective test where action potentials
of individual nerve fibers can be identified. A delay in the second action potential
following the first indicates a positive test.[10 ] The other neurophysiological test used is the repetitive nerve stimulation study
where a nerve is repeatedly stimulated supramaximally, and a 10% decrement between
the first and the fifth stimuli is diagnostic of MG.[12 ] In all patients with confirmed MG, a computed tomography scan of the thorax has
to be done to look for thymoma.
Evaluation and Supportive Management of Myasthenia Gravis
Majority of the patients with MG without the involvement of respiratory muscles are
managed in the ward or as outpatients with specific therapies, detailed below. Weakness
of respiratory muscles and bulbar involvement require close monitoring, intensive
care, and ventilatory assistance. Inability to clear oral and bronchial secretions;
drooling of saliva; nasal voice; or choking on oral secretions indicates a severe
bulbar involvement in which case tracheal intubation is imminent for airway protection.
On clinical examination, a patient in acute crisis will present with tachypnea, tachycardia,
sweating, accessory muscle involvement to sustain ventilation, paradoxical breathing,
drooping of the neck which indicates intense diaphragm fatigue and staccato speech
(unable to complete speaking a whole sentence in one breath).[13 ] Bedside pulmonary function tests and spirometry can be performed in clinically stable
and co-operative patients in sitting position. Single breath count test and neck flexor
strength have been shown to have good correlation with spirometry in predicting reduced
forced vital capacity (FVC).[14 ] A normal individual can count up to 50 counts after a single deep inspiration. A
count of up to 25 approximately correlates with FVC of 2 L and a count less than 15
indicates significantly less respiratory reserve.[15 ] An arterial blood gas (ABG) analysis will indicate the severity of ventilatory failure
and CO2 accumulation. However, the ABG has to be interpreted with great caution since compensatory
changes occur, and CO2 levels may be normal in a tachypneic patient.
If the clinical condition of the patient is stable with mild-to-moderate weakness
and not in overt respiratory failure, then the patient is to be managed medically
with immunosuppressive, anticholinergic, and other indicated medications under close
monitoring in the ward/high dependency unit. If the patient is demonstrating severe
muscle weakness with bulbar involvement, and/or overt respiratory failure with hypercapnia,
the risk of pulmonary aspiration is imminent or may have already occurred. Such a
patient must be immediately intubated for airway protection and ventilatory management
in the intensive care unit (ICU). In case the patient is in mild respiratory distress,
with no bulbar involvement, conscious and oriented, not overtly hypercapnic, these
patients can be given a trial of noninvasive ventilation (CPAP/BiPAP; continuous positive
airway pressure/bi-level positive air way pressure) with frequent clearing of the
oral cavity by suctioning. BiPAP has been shown to reduce both ICU and hospital stay
even in patients presenting with myasthenic crisis.[16 ] A preliminary trial showed that BiPAP may prevent tracheal intubation in patients
who present with myasthenic crisis and are not overtly hypercapnic.[17 ]
Intensive Care Management of Patients with Myasthenia Gravis
The decision to intubate and mechanically ventilate the patient should be based on
the clinical judgement of the treating physician. More than the results of the ABG,
bedside respiratory reserve measurements and vital parameters (pulse rate and BP)
take precedence. To keep matters simple, a 20/30/40 rule (FVC < 2 0 mL/kg; negative
inspiratory pressure [NIP] < 30 cm H2 O; and positive expiratory pressure [PEP] < 40 cm H2 O) can guide the decision to intubate.[18 ] Duration of mechanical ventilation is unpredictable in MG. Release from mechanical
ventilation and extubation depends on how rapidly the plasma can be cleared of autoantibodies,
and the response to anticholinergic medications and immune suppressants. Meanwhile,
the patient is to be managed according to the general principles of critical care—respiratory
care, addressing infections, and attention to nutrition along with the targeted therapy.
Early versus delayed tracheostomy is still a controversy with no clear guidelines
available at present.
Clinical improvement in muscle power can be taken as a guide to initiate weaning.
An FVC > 15 mL/kg, NIP > 20 mL/kg, and a PEP > 40 mL/kg indicate a possible successful
weaning process.[18 ]
[19 ] Similarly, a patient demonstrating an FVC > 25 mL/kg, NIP > 40 mL/kg, and PEP >
50 mL/kg may be considered a suitable candidate for extubation. Clinically, a good
cough reflex and improvement in the neck flexor power facilitating a sustained neck
lift indicate good resolution in weakness of the bulbar muscles, and extubation in
these patients may be successful.[20 ]
Atelectasis, decreased FVC, and acidosis are important predictors of reintubation.[21 ] About one-fourth of the extubated patients get reintubated.[21 ]
[22 ] Reintubated patients tend to spend a longer time in the ICU. Early decision to intubate
and tracheostomy, high-quality chest physiotherapy, frequent change in positioning,
and early mobilization from the bed during off ventilator hours can aid in preventing
reintubation.[23 ]
Occasionally, we come across patients who do not respond to plasmapheresis or anticholinesterases
and weakness continues to persist. Steroid-induced myopathy is a possibility in such
patients. Gradual tapering and cessation of steroids will improve the clinical condition.[24 ]
[25 ]
Specific Management of Myasthenia Gravis
Several specific treatments are available for the management of MG. However, significant
variation in the treatment is noted because good-quality randomized controlled trials
of MG therapies are rare and generalizability of the available evidence is difficult
due to the heterogeneous nature of the disease. Hence, experts and societies have
developed treatment statements and clinical practice guidelines by consensus to guide
clinicians on multipronged approach to MG management.[26 ]
[27 ] The limitations of treatment statements are that the recommendation depends on the
constituents of the expert panel and also needs updating every few years with availability
of new evidence.[28 ]
Following are the classes of specific treatment options for medical management of
MG.
Acetylcholinesterase inhibitors (pyridostigmine and neostigmine)
Corticosteroids (prednisolone)
Plasma exchange (PLEX)
Intravenous immunoglobulin (IVIG)
Immunosuppressants (azathioprine, rituximab, cyclosporine, mycophenolate mofetil,
methotrexate, tacrolimus)
Acetylcholinesterase Inhibitors
As a first-line therapy for mild MG, acetylcholinesterase inhibitors slow down the
degradation of acetylcholine and prolong their effect on the neuromuscular junction
providing symptom benefits. Pyridostigmine administered orally has a rapid onset of
action (< 30 minutes) and the action lasts for 3 to 4 hours. The effective dose ranges
from 30 to 90 mg every 4 to 6 hours. Neostigmine is used intramuscularly along with
anticholinergic drugs to reduce its side effects (excessive secretions, bradycardia)
as 0.5 to 1 mg every 4 to 6 hours under close monitoring. When treatment with these
drugs alone fails, immunosuppressant drugs are considered.[29 ]
Corticosteroids
Prednisone is the most commonly used drug which leads to significant improvement in
three-fourth of patients with ocular or generalized MG. The effective dose depends
on the severity of symptoms. Patients with mild-to-moderate symptoms need approximately
20 to 40 mg/day of drug while those with severe symptoms may require up to 1 mg/kg/day.
During the initial 1 to 2 weeks, approximately 50% of patients may develop worsening
of weakness. Therefore, high-dose regimen is initiated in the hospital along with
PLEX or IVIG. Otherwise, outpatient dose-escalation strategy is followed till target
dose is achieved over several weeks. Tapering of the dose is initiated after a significant
improvement in symptoms is established for 1 to 2 months. Tapering by 5 to 10 mg/month
is preferred, with slower withdrawal once 30 mg/day dose is reached. The maintenance
dose thereafter is approximately 5 mg/day. Side effects such as weight gain, cushingoid
features, easy bruising, cataracts, glaucoma, hypertension, diabetes, dyslipidemia,
and osteoporosis should be closely monitored. Calcium (1.5 g/day) and vitamin D (400–800
IU/day) should be supplemented and those at risk of osteoporosis should also receive
a bisphosphonate. Other immunosuppressants, which have delayed onset of action, should
be added early in the treatment to either replace or reduce corticosteroid dose and
reduce its long-term adverse effects.[30 ]
Rapid Onset Immune Therapies
Rapid-onset immune therapies such as IVIG and PLEX ([Table 1 ]) are first-line therapies for worsening MG or myasthenic crisis, described as respiratory
failure from bulbar or diaphragmatic muscle weakness mostly provoked by infection,
surgery, or medications. Rapid treatment effects make them useful as a short-term
rescue therapy for rapidly worsening symptoms or as a preparation for surgery. IVIG
and PLEX are equally effective for the treatment of moderate-to-severe MG with regard
to functional outcomes and quality of life scores at 14 and 28 days.[31 ] The choice between PLEX and IVIG is, therefore, based on the mechanism of action,
efficacy, adverse effects, cost, and availability. PLEX is preferred in myasthenic
crisis as it has a relatively faster onset of action then IVIG. However, if expertise
is lacking, IVIG should be used. For disabling but non–life-threatening symptoms,
IVIG may be preferred.[32 ]
Table 1
Immune-modulating drugs for MG based on timing of onset and duration of action
Onset of action
Duration of action
Drugs
Abbreviations: IVIG, intravenous immunoglobulin; MG, myasthenia gravis; PLEX, plasma
exchange.
Fast
Short (days to weeks)
PLEX, IVIG
Intermediate
Intermediate (weeks to months)
Corticosteroids, cyclosporine, cyclophosphamide, methotrexate
Slow
Prolonged (months to years)
Thymectomy, azathioprine, rituximab, mycophenolate
Intravenous Immunoglobulin
Intravenous Immunoglobulin is obtained from pooled blood donors and contains purified
immunoglobulin G (IgG). The exact mechanism by which it acts is unclear but likely
involves blockade of Fc receptors on macrophages, reduced complement activation, and
reduced production of antibodies and cytokines. The usual dose of IVIG is 2 g/kg (0.4
g/kg/day) over 2 to 5 days. Improvement in symptoms is observed by 1 week and the
effect lasts for several weeks in more than 50% of patients. Common side effects of
IVIG include chills, fever, headache, and serious, rarer side effects include stroke,
leukopenia, renal dysfunction, and aseptic meningitis.[32 ] Presence of cardiac disease may warrant IVIG whereas IVIG may not be appropriate
in renal dysfunction.
Plasma Exchange
Plasma Exchange involves apheresis where circulating immunoglobulins, complement,
immune complexes, cytokines and other inflammatory mediators are removed. The normal
course involves exchange of approximately 1 to 1.5 times the blood volume, performed
on alternate days over five to six sittings. Daily small volume PLEX is performed
in those with expected large fluid shifts. Improvement in symptoms is observed in
majority of patients (especially MuSK-antibody positive MG) within few days and lasts
for approximately 3 months. Adverse effects related to PLEX include paresthesias (citrate-induced
hypocalcemia), hypotension (from large fluid shifts), arrhythmias, nausea, chills,
hypoproteinemia, dyselectrolytemia, and peripheral edema. Complications from central
venous catheter (CVC) for PLEX include thrombosis, bacteremia, pneumothorax, and thrombophlebitis.[32 ] Literature reports PLEX to be costlier than IVIG, largely from the need for increased
staff, CVC placement and care, longer treatment course, and management of complications.
However, in India, PLEX remains a significantly cheaper option than IVIG.
Azathioprine
The effect of azathioprine begins 6 to 12 months after initiation and reaches a peak
after 1 to 2 years. More than 90% of patients improve with azathioprine alone or with
concurrent prednisone.[33 ] With 2 to 3 mg/kg/day dose, most patients can be weaned off prednisolone and yet
maintain remission for few years. The common side effects include nausea, vomiting,
and malaise, while the less common side effects are hematologic and liver function
abnormalities and pancreatitis. Monthly monitoring of blood cell counts and liver
function during the initial 6 months and less frequently during later stages is desirable.
Patients with thiopurine methyltransferase gene deficiency (1 in 300 people) should
not receive azathioprine in view of life-threatening bone marrow suppression.[34 ]
Mycophenolate Mofetil
There is contrasting evidence for the efficacy of mycophenolate mofetil in MG. However,
this drug is well tolerated with a few side effects. At 1 to 3 g/day, significant
improvement in symptoms and remission with steroid dose reduction was noted.[35 ] However, a later trial failed to demonstrate beneficial effect of 2 g/day mycophenolate
when administered for 36 weeks.[36 ] Common side effects include nausea, diarrhea, leukopenia, and infections necessitating
frequent blood counts monitoring during the therapy. Major fetal malformations are
reported with mycophenolate use during pregnancy.[30 ]
Cyclosporine
Cyclosporine has relatively faster onset of action (1–2 months) among nonsteroidal
immunosuppressant drugs. A 5 mg/kg/day dose with 100 to 150 ng/mL serum level is generally
recommended. Due to significant renal, hepatic, and hematologic toxicity and major
drug interactions, its use is decreasing.[30 ]
Methotrexate
Methotrexate is a selective inhibitor of dihydrofolate,[29 ] and its steroid-sparing effect is reported to be similar to that of azathioprine.[37 ] However, a recent RCT found no steroid sparing benefit with oral methotrexate 20
mg/week in patients with generalized MG during the 12-month study period.[38 ]
Rituximab
Rituximab is a monoclonal antibody against B cell membrane marker CD20. It is found
to be efficacious in generalized MG refractory to other immunosuppressants,[39 ] especially for MuSK antibody-positive disease. The standard dose is 375 mg/m2 /week for 4 consecutive weeks. Common side effects include depletion in peripheral
B cells (within 2 weeks), flushing, and chills (with first dose) and susceptibility
for infections.[30 ]
Cyclophosphamide
Cyclophosphamide is an alkylating agent that reduces B and T cell proliferation. The
commonly used regimen is six cycles of intravenous cyclophosphamide (0.75 g/m2 ) every 4 weeks followed by oral immunosuppression.[40 ] Though effective, potentially serious side effects limit its use to patients who
are refractory to other immunotherapies.[30 ]
Tacrolimus
Tacrolimus is a macrolide immunosuppressant which inhibits the production of interleukin-2.
The dose used for MG along with conventional treatment is 3 to 5 mg/day (0.1 mg/kg/day)
for 6 to 36 months. The adverse effects are mild and most commonly include increase
in hemoglobin A1C level and neutrophil count and transient alterations in renal and
liver function tests. Tacrolimus with adequate treatment duration might have steroid-sparing
effect in the management of MG without major side effects.[41 ]
Leflunomide
Leflunomide is an immunosuppressant that blocks pyrimidine nucleotide biosynthesis.
A pilot study in 15 patients demonstrated good tolerance and efficacy with leflunomide
20 mg for corticosteroid-dependent MG which resulted in significant lowering of corticosteroid
dose by 6 months.[42 ]
Surgical Management: Thymectomy
Thymectomy should be considered for patients with thymoma. If thymectomy is not possible,
chemo-radiotherapy may be considered to relieve symptoms and prevent local invasion.
For patients without thymoma, thymectomy may be beneficial in younger (< 60 years)
patients with generalized MG. Medication-free remission and symptom-free state are
high after thymectomy, though this may take several years.[43 ]
The optimal timing of thymectomy is not clear; however, thymectomy is recommended
during the initial 3 years of diagnosis.[44 ] The response rate from thymectomy is similar for both AChR antibody-positive and
seronegative patients.
New Drugs Undergoing Evaluation
Rozanolixizumab (UCB7665) is an antihuman neonatal Fc receptor monoclonal antibody
aimed at reducing IgG levels. It is currently in phase II trial for MG treatment.
Efgartigimod (ARGX-113), Fc receptor monoclonal antibody, demonstrated clinical improvement
in 75% of patients with MG over a 6-week study period compared with 25% improvement
in placebo in the recently concluded phase II trial with reduction in IgG levels and
good tolerance. Monarsen (EN101) is an antisense oligonucleotide which reduces the
production of acetylcholinesterase enzyme.[45 ]
Conclusion
Though mortality from myasthenic crisis has become very rare, morbidity still exists.
Better understanding of the pathophysiology and advancement in therapeutic interventions
have further been able to contain the morbidity. Even then the time to clinically
significant remission of the disease is variable. In the intensive care setting, aggressive
pulmonary care, good nutritional support, early intubation/tracheostomy, judicious
weaning, and extubation decisions along with specific targeted therapy will improve
the outcomes and reduce hospital stay in MG patients.
