++
The neuromuscular junction is an area of primary interest for the
anesthesiologist because it holds the key to skeletal muscle function. The
large number of nAChRs (1–10 million) in the postsynaptic muscle membrane
(the motor end-plate) is critical for maintaining normal neuromuscular
function. Under normal circumstances, only a small portion of the available
receptors must bind to acetylcholine to trigger a muscle contraction.
Therefore, there is an excess of receptors available providing a “wide
margin of safety” for muscle contraction in the event that the postsynaptic
receptors are blocked, damaged, or destroyed.
++
Neuromuscular blocking agents that interact with the nicotinic
cholinergic receptor to prevent muscle contraction are commonly
used during many surgical procedures. A large number of
receptors must be occupied by neuromuscular blocking
agents before muscle paralysis occurs. In the patient with a neuromuscular
junction defect the effects of these anesthetic agents
are markedly altered.
++
Skeletal muscle relaxation can also be produced by deep inhalational
anesthesia or by local anesthetics. The mechanism of action is different.
Inhaled anesthetics produce muscle relaxation by altering physiology of the brain and
spinal cord, as well as
the nAChRs.87 Local
anesthetics produce muscle
relaxation by their effect on voltage-dependent sodium channels on
nerve and muscle membranes.88 When a
neuromuscular junction defect is present, as is the case in the myasthenic
syndromes, the anesthesiologist must carefully choose the anesthetic agent
that will provide the greatest benefit without potentiating the skeletal
muscle weakness or causing a myasthenic crisis.
++
Myasthenia gravis (MG) is a chronic, acquired autoimmune disease caused
by antibodies that destroy or inactivate the nAChRs at the neuromuscular
junction. The antibodies specifically target the α-subunit of the
receptor in 80% of the cases of the disease. In the other 20% of the
patients (seronegative patients), autoantibodies target a muscle-specific
tyrosine kinase (MuSK).89 Weakness and easy fatigability
are the hallmark symptoms, with either discrete muscle groups affected (ie,
ocular MG), or generalized weakness with life-threatening respiratory muscle
dysfunction (ie, myasthenia crisis).90 The antibodies do
not affect the nAChRs in the autonomic nervous system or the CNS because of
differences in protein structure, therefore limiting autonomic and CNS
symptoms in the disease process.91
++
MG has a prevalence of 14 per 100,000, without an ethnic predominance.
The most common age at onset is the second and third decade in women
(childbearing age) and the sixth to seventh decade in men. Family members of
patients with MG are 1000 times more likely to have the disease than the
general population. The effects of pregnancy on MG are variable; symptoms
can remain unchanged, worsen, or improve. Of the 30–40% of patients
whose symptoms worsen with pregnancy, primigravidas usually experience
exacerbations in the first trimester. In subsequent pregnancies,
exacerbations in the third trimester and in the postpartum period are more
common.92
++
Skeletal muscles innervated by cranial nerves are especially vulnerable. In
70% of the cases, the initial complaint is diplopia, with over 90% of
the patients demonstrating extraocular muscle weakness during the course of
the disease. The vast majority will have bulbar muscle involvement
(laryngeal, pharyngeal muscles), leading to airway compromise, dysphagia,
and the increased risk of aspiration. Other signs and symptoms of the
disease include asymmetrical skeletal muscle weakness with exercise,
myocarditis (leading to cardiomyopathy, atrial fibrillation and heart
block), hypothyroidism, and isolated respiratory failure from diaphragmatic
and thoracic intercostal muscle weakness.90
++
The clinical course of the disease is marked by periods of exacerbations and
remissions. Most patients whose initial symptoms are limited to ptosis or
diplopia will develop generalized muscle weakness within the first 3
years.93 Muscle strength characteristically improves with
rest but deteriorates rapidly with exertion. The life-threatening result of
the disease is called a myasthenic crisis. It is a severe exacerbation of
weakness often associated with respiratory compromise precipitated by
menses, infection, noncompliance with treatment, or the introduction of new
medications (ie, aminoglycosides to treat infection, beta-blockers).93
++
Treatment for MG can be medical or surgical, depending on the patient's age,
the presence of a thymoma, and the extent of the disease. Medical treatment
is aimed at (1) enhancing neuromuscular transmission by
anticholinesterases, (2) suppressing the immune system with corticosteroids,
immunosuppressants (cyclosporine/azathioprine), and (3) modulating the
circulating antibody level with plasmapheresis or IVIG. Elective thymectomy
is the preferred treatment for patients with generalized MG, those younger
than 60 years of age, and in all patients with a thymoma (33% risk of
malignancy). MG patients undergoing thymectomy are twice as likely to attain
a medication-free remission and 1.7 times as likely to have an improvement
in symptoms.94 Beneficial effects of thymectomy may be
delayed for months or years, and most patients will continue to have
symptoms to a varying degree. Prior to surgery, effective immunosuppressant
therapy must be used to make the patient asymptomatic to reduce
postoperative morbidity and mortality.70
+++
Anesthetic Considerations for Patients with MG
++
Anesthetic management of the patient with MG is complicated because the
response to commonly used drugs is
variable.95,96 Cautious use of sedatives, muscle relaxants, and general
anesthetics must be considered for all patients with a diagnosis of MG.
++
A thorough preoperative evaluation is necessary for the safe delivery of
anesthesia for these patients. Preoperative evaluation should include (1)
consultation with the patient's neurologist to review the course of the
patient's disease, treatment, and any recent changes in status, (2) review
of the patient's preoperative drug therapy, changes in dose or type of
medication, and response to medications as well as potential interactions
with anesthetic agents, (3) counseling the patient and the family about the
potential for postoperative mechanical ventilation.
++
Optimizing the patient's
condition preoperatively can improve
outcome. Anticholinesterase agents are usually discontinued
preoperatively unless the patient is physically dependent on them.
Preoperative plasmapheresis has been used successfully to optimize the
patient's condition and reduce perioperative morbidity and
mortality.96
++
The most important preoperative factor predicting the need for postoperative
mechanical ventilation is the degree and severity of bulbar involvement,
especially when associated with a prior history of respiratory
failure.97 Other factors that have been identified as
predictors for postoperative respiratory support include disease duration of
>6 years, concomitant pulmonary disease, peak inspiratory pressure
of –25 cm H2O, and vital capacity of <4 mL/kg.97
++
Anesthetic medications need to be used with
caution. Because of the
reduced number of nAChRs, myasthenic patients are resistant to succinylcholine.98
However, they are
exquisitely sensitive to nondepolarizing muscle relaxants.99
Short- and
intermediate-duration nondepolarizing muscle relaxants can be used with
careful titration and monitoring with a nerve stimulator. Long-acting muscle
relaxants should be avoided.
If the patient has been on pyridostigmine therapy, the response to muscle
relaxants changes. The patient will be less sensitive to
nondepolarizing muscle relaxants, the response to succinylcholine or
mivacurium will be prolonged (plasma cholinesterase effect), and reversal of
the block at the end of the case is unpredictable.98,99
++
General anesthesia has been provided with total intravenous anesthesia
(remifentanil) and high thoracic epidural, or inhaled anesthetic without
neuromuscular blockers.100 It is important to remember that these patients are
more sensitive to inhaled anesthetics (leading to a slower recovery from
anesthesia), and to the neuromuscular depressant effects of isoflurane and
halothane.100 Drugs that interfere with neuromuscular
transmission (ie, aminoglycoside antibiotics, antiarrhythmics,
beta-blockers, phenytoin) should be limited or avoided when possible. Usually, opioids are avoided or limited. During
the postoperative period, abrupt reduction in skeletal muscle strength may
occur, necessitating the need for mechanical ventilation. Diligent
postoperative monitoring in the surgical intensive care unit is therefore
necessary for the myasthenic patient.
+++
Regional Anesthesia in Patients with MG
++
Because of the numerous problems associated with perioperative
sedation, general anesthetic agents, and muscle relaxants,
regional anesthesia may be a better choice for anesthesia in the
myasthenic patient. Because local anesthetics do not directly affect the nAChRs, regional anesthesia offers greater predictability with fewer complications.
++
Epidural anesthesia has been used in myasthenic patients. High
thoracic epidural with either total intravenous anesthesia or a balanced
general anesthesia provides excellent anesthesia for the MG patient
undergoing thymectomy.101,102
++
In the pregnant patient with MG, epidural anesthesia has been used
successfully to reduce the physical and emotional stress that may potentiate
a crisis.103 Many of the drugs used to treat the disease are continued during
pregnancy to avoid a crisis, but these may have an effect on platelet
function and number. Prior to placing a central neuraxial block, it is
important to obtain a coagulation profile as well as a platelet
count.103 Amide local anesthetics may be a better choice
than ester local anesthetics because the metabolism of amides is not
dependent on cholinesterase activity.103
++
Very little data are available on the use of peripheral nerve blocks in the
patient with MG.
The
successful use of a paravertebral block for inguinal hernia surgery,
infraclavicular block for a dislocated elbow, and various central neuraxial
blocks for surgery on the lower extremities have been
reported.104,105
++
Interscalene blocks should be avoided in patients with
bulbar or respiratory compromise because the phrenic nerve can be blocked during the procedure. Infraclavicular or axillary blocks in selected cases will provide
anesthesia for the upper extremity without compromising respiratory
function. Isolated digital nerve blocks for injuries to the fingers, hand,
wrist, or ankle are excellent methods for providing anesthesia without
involving other muscle groups. Lumbar plexus blocks
should probably be avoided in patients with
dysfunctional platelet function. The anesthesiologist should be prepared for
the possibility of epidural spread causing a more profound motor block.
Femoral, popliteal sciatic, and ankle blocks are effective blocks for
surgery on the lower extremities. Reduced doses of sedatives and opioids
during block placement are necessary due to the sensitivity of the
myasthenic patient to these medications.
+++
Lambert–Eaton Myasthenic Syndrome
++
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease
in which autoantibodies target voltage-gated calcium channels.106 Sixty-six
percent of the cases are associated with carcinomas (usually small cell
carcinomas of the lung), but the symptoms of LEMS may precede the discovery
of the cancer by as much as 5 years. The autoantibodies are directed at
calcium channels in the tumor, but because of antigenic similarity, they
cross-react with calcium channels at the presynaptic neuromuscular junction
responsible for the release of acetylcholine. Consequently, acetylcholine
release is reduced.106
++
The typical patient is a male, smoker, 50–70 years of age, who presents
with slowly progressive proximal muscle weakness and fatigue that affects
gait and the ability to stand and climb stairs.106 Muscle pain and paresthesias
can occur, although the sensory examination is usually normal. Over 75%
of the patients with LEMS have symptoms of autonomic dysfunction, including
dry mouth, constipation, blurred vision, orthostatic hypotension, and
impotence.106 Ocular and bulbar symptoms (ptosis, dysphagia, diplopia) are less
prominent than in MG, but may occur in up to 30% of the patients. Unlike
in MG, exercise improves strength.106
++
Treatment of LEMS is geared toward identification and treatment of the
underlying neoplasm, medications that enhance neuromuscular transmission,
and alteration of the autoantibodies. Early and successful treatment of the
lung cancer usually results in clinical improvement.70,107
Treatment includes 3,4-diaminopyridine (enhances acetylcholine release by
blocking potassium channels), pyridostigmine (inhibits acetylcholinesterase,
resulting in more available acetylcholine), immunosuppresants,
plasmapheresis or IVIG.107
++
Medications that interfere with neuromuscular transmission can worsen the
symptoms of LEMS should be avoided. These include aminoglycoside
antibiotics, beta-blockers, neuromuscular blocking agents, quinidine, and
iodinated contrast agents.107
+++
Anesthetic Considerations
++
Patients with LEMS are sensitive to the effects of both depolarizing
and nondepolarizing muscle relaxants. Therefore, doses of these drugs should
be reduced.108 Neuromuscular function should be carefully assessed with a nerve
stimulator. Because the syndrome is difficult to diagnose, it may be
unmasked perioperatively when the patient demonstrates prolonged paralysis
after receiving the usual dose of neuromuscular
blockers.108 In patients with LEMS, antagonism with
anticholinesterases may be inadequate.108 The possibility
of postoperative mechanical ventilation must be considered. Because of the
autonomic dysfunction related to the syndrome, hemodynamic instability may
occur with inhaled anesthetics.108 Anticipating and preparing for orthostatic
changes is prudent.
+++
Regional Anesthesia for Patients with Lems
++
LEMS is a rare disease, much less common than MG.
Literature regarding the use of regional anesthesia in these patients is absent. Given the complications
associated with general anesthesia, selective nerve blocks may be advantageous in specific cases.