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cerebellum (38%) Seizures
 Operative delivery
brain stem (10%) Risk of damage by
 Renal cysts (massive hemorrhage)
epidural/spinal
 Polyhydramnios
spinal cord (51%) needles or catheters
Fetal
Retina Hemangioblastomas Nil
 Preterm delivery
(60“70%)
 Intrauterine growth restriction
Kidney Hemangioblastomas (20%) Kidney dysfunction
 Increased perinatal death
Cysts
 Cardiac rhabdomyomas
Renal carcinoma Erythrocytosis
53
From King & Stamilio (2005) Adrenals Hemangioblastomas
Pheochromocytoma Severe hypertensive
response
Pancreas Hemangioblastomas (20%) Altered glucose
Anesthesiologists should be aware that patients with TS and
metabolism
neurological disease are likely to have coexisting cardiac and
Cysts
renal disease. Each parturient must be assessed on an individual
Face Hemangioblastomas Possible intubation
basis and the anesthetic tailored accordingly. Of concern is the
problems
fact that renal angiomyolipomas are present in 65% of TS
Lung Hemangioblastomas Pulmonary dysfunction
patients, and spontaneous rupture has been reported during
pregnancy.55 It is prudent, therefore, to have adequate i.v. access Pulmonary hemorrhage
Liver Hemangioblastomas Liver dysfunction
and cross-matched blood available during labor. In patients with
LAM, effective LEA in labor reduces hyperventilation and exces-
ICP ¼ intracranial pressure; CNS ¼ central nervous system
sive changes in intrathoracic pressure during contractions. An
elective instrumental delivery to avoid excessive straining during
the second stage may be preferable, especially if there is a history production.60 Although autosomal dominant inheritance occurs,
of previous nonsurgically treated pneumothorax, as the recur- there is variable expression. The responsible gene is located on
rence rate is high.56 In addition, nitrous oxide should be avoided chromosome 3p25“p26, which is a tumor suppressor gene, with
if there is evidence of noncommunicating cystic lung disease or a second, somatic mutation required for the development of the
closed pneumothorax. The presence of brain lesions (e.g. large cancer.
subependymal nodules) may cause an increase in ICP, obstruc- Maternal and fetal outcome data have been described in
tion of the ventricles and difficulty controlling seizures. It is 30 women and 56 pregnancies.61 Most pregnancies had a favor-
important to continue anticonvulsant medication, prevent able outcome, with a 96% fetal survival and 5% maternal
reductions in seizure thresholds (e.g. with adequate labor analge- morbidity. Anesthetic management has been described in par-
sia), and to avoid SAB if ICP is elevated. turients with VHL.62,63,64,65 Several of these parturients received
epidural anesthesia and there are no reports of neurological
complications.
Von Hippel-Lindau disease
Based on these few reported cases it is difficult to make firm
This rare (incidence 1 in 36 000), multisystem disease is charac- recommendations regarding anesthetic technique. Due to the
terized by a variety of benign and malignant tumors. The com- frequency of CNS involvement, elective C/S is the preferred
mode of delivery.66 Cesarean section avoids the risk of CNS
monest lesions associated with von Hippel-Lindau disease (VHL)
are hemangioblastomas (benign vascular tumors) involving hemorrhage secondary to an increase in cerebral blood pressure
the retina, adrenal glands, cerebellum, brain stem, spinal cord, associated with the expulsive efforts of labor. Although no anes-
and kidneys (see Table 8.6). 59 Other associated features include thetic method is absolutely contraindicated, management should
renal cell carcinomas (clear cell), pancreatic tumors, endolym- be tailored according to associated findings (e.g. pheochromocy-
phatic sac tumors of the middle ear, papillary cystadenomas toma, raised ICP). It can be argued that neuraxial anesthesia
of the broad ligament, and pheochromocytomas. In VHL syn- should be avoided on the grounds of asymptomatic spinal cord
drome, pheochromocytomas tend to occur in younger patients, involvement with the possibility of direct injury to a hemangio-
are often extraadrenal, and are less likely to be associated blastoma by needle or catheter. Although the spinal cord lesions
with symptoms or biochemical evidence of catecholamine are usually cervicothoracic, they may involve the lumbosacral



151
2 Musculoskeletal disorders


region or even the cauda equina. As most are located in the pia
Table 8.7 Clinical classification of myasthenia gravis
mater or posterior intramedullary cord, it is prudent to scan for
such lesions prenatally. If GA is used, it is important to blunt the Type 1 Extraocular muscles involved only (10% of patients
pressor response due to tracheal intubation, as hypertensive with MG)
surges could cause CNS hemorrhage. Type 2a Mild, generalized myasthenia
No respiratory crises
Type 2b Moderate, generalized myasthenia
Myasthenia gravis
No respiratory crises
Myasthenia gravis (MG) is a chronic autoimmune disease invol- Type 3 Severe
ving the postsynaptic neuromuscular junction. The hallmarks of Acute onset, rapid deterioration (<6 months)
the disease are weakness and rapid fatigability of striated muscle Respiratory crises
with repetitive use, followed by partial recovery with rest.67 The Type 4 Severe
underlying defect is a reduction in the number of available acetyl- Slower onset (>2 years)
choline receptors (AchR) at the postsynaptic neuromuscular Respiratory crises
junction, thereby producing a compromise in the end plate
MG ¼ myasthenia gravis
potential and a reduction in the safety factor for effective synaptic
transmission. This defect is mediated by autoantibodies against
bronchoconstriction. All patients undergoing the test should
the AchR, although the factors that initiate and maintain the
be monitored with an ECG with full resuscitation equipment
autoimmune response are not fully understood. The absolute
available in case a severe cholinergic reaction occurs (e.g. sweat-
level of antiAchR antibodies correlates poorly with the disease
ing, bradycardia, hypotension, increased weakness, increased
severity, although changes in antibody levels may correlate with
respiratory secretions, and laryngospasm). The edrophonium
disease progression.
test is not specific for MG and false positives occur with other
Myasthenia gravis is the commonest disorder affecting the
disease entities such as amyotrophic lateral sclerosis, botulism,
neuromuscular junction. Prevalence of the disease appears to
Guillain-Barr´ syndrome, and end-stage renal failure. In addi-
e
be increasing, probably due to an aging population and ranges
from 12“64 cases per million (average 0.004%).68 Overall, women tion, false negatives occur with 40% of patients presenting with
eye signs alone.72 The edrophonium test can distinguish
are affected twice as often as men, and although MG can occur at
between a ˜˜myasthenic™™ and a ˜˜cholinergic™™ crisis in a patient
any age, there is a bimodal peak of incidence. The first peak, in the
on high doses of anticholinesterase medication and increasing
third decade, affects mostly women, whereas the second peak is
muscle weakness.
in the sixth and seventh decades, and affects mostly men. Familial
Repetitive supramaximal motor nerve stimulation by EMG
cases are uncommon and no consistent HLA type or genetic
inheritance pattern has been identified.69 However, ethnic differ- shows a characteristic fade in amplitude of the evoked action
potential in patients with MG. In order to increase the sensitivity
ences do occur, with Asians more likely than Caucasians to have
of the test, several muscle groups should be investigated and
type 1 MG presenting in childhood. There are some HLA associa-
tions between different ethnic groups.70 anticholinesterases should be stopped before testing. This test is
sensitive to muscle temperature, movement artifact and is less
The Osserman classification system is the most commonly
likely to be positive in patients with type 1 MG.
used clinical classification for MG (see Table 8.7). Diagnosis is
The course of the disease is highly variable but usually progres-
made on clinical grounds (i.e. fatigable muscle weakness without
sive, although exacerbations and remissions do occur. The
loss of deep tendon reflexes or other neurological symptoms),
progression of weakness in MG usually occurs in the cranial-to-
coupled with pharmacologic and electrophysiologic tests.
caudal direction: ocular-to-facial-to-lower bulbar-to-truncal-to-
Muscle weakness varies in distribution and on the time of day,
limb muscle. Exacerbations may occur spontaneously or be
with more profound weakness occurring at the end of the day.
associated with predisposing factors (see Table 8.8). Good prog-
There is no single test adequate for diagnosis and therefore
nostic indicators include female, white race, early age of onset,
clinical history and a combination of tests are used: acetylcholine
long duration of purely ocular symptoms, and spontaneous
antibody assay, edrophonium test, and electromyography
remissions lasting longer than one year.70 Some reports suggest
(EMG).71 Serum AchR binding antibodies are present in 85% of
that 40“50% of patients with type 1 (purely ocular) disease will
all MG patients, with negative results more likely in those patients
develop the generalized condition within two years.
with mild or only ocular disease. However, the use of multiple
Current treatment of MG includes enhancing neuromuscular
AchR tests (e.g. binding, blocking, modulating antibodies) may
transmission by anticholinesterase medication; suppressing the
decrease the number of seronegative MG patients. Once a muscle
immune system with corticosteroids and azathioprine; decreasing
group has been shown to weaken with exercise and improve with
circulating antibody level by plasmapheresis; or thymectomy.73,74
rest, the use of the cholinesterase inhibitor edrophonium test can
Anticholinesterases increase the amount of Ach available at the
contribute to the diagnosis of MG. Improvement in muscle
neuromuscular junction and are the first line of treatment for
strength after administration of the drug supports the diagnosis;
most patients with MG. The most commonly used anticholin-
however, due to increased muscarinic effects of acetylcholine
esterase is pyridostigmine due to its pharmacological profile (onset
(Ach), side effects may include bradycardia, asystole, and



152
Chapter 8


Adverse effects include complications of central venous catheters
Table 8.8 Predisposing factors that exacerbate myasthenia and hypotension.
gravis Intravenous immunoglobin consists of pooled immunoglobu-
lins (specific, monoclonal antibody to B cell antigen CD 20), and
Infection
is thought to work by down-regulating the immune system.
Exertion
Improvement has been reported to occur in 75% of patients,
Menstruation
beginning within days and lasting up to eight weeks.77
Emotional stress
Thymectomy is recommended for all patients with MG that is
Acute illness
secondary to thymoma irrespective of the severity of the disease.
Pain
It is also recommended in nonthymomatous autoimmune MG, as
Excessive heat or cold
an option to increase the chance of remission or to improve
Surgery/trauma
symptoms.76 Up to 75% of MG patients have pathological
Underdosing of anticholinesterase medication
abnormalities in the thymus (85% thymic hyperplasia, 15%
Malnutrition
thymoma). The reason for improvement in MG following
Hyper-/hypothermia
thymectomy is not fully understood. However, it is known that
Drugs
cell-mediated immunity, which is expressed through the T lym-
Antibiotics (presynaptic block) “ aminoglycosides, tetracycline,
phocyte system and dependent on the thymus, plays a role in the
erythromycin
pathogenesis of MG.
Antidysrhythmics “ beta-blockers, calcium channel blockers
Magnesium (pre- and postsynaptic block)
Beta-agonists (hypokalemia)
Effect of pregnancy on myasthenia
Thyroxine
The course of MG is unpredictable during pregnancy; however,
Penicillamine (immune mechanism)
worsening of symptoms tends to occur more frequently in the first
Lithium
trimester and postpartum period.78 The effect of pregnancy on MG
Phenytoin
cannot be predicted from its course during previous pregnancies
Diuretics (e.g. furosemide [hypokalemia])
or from any feature of the maternal disease.79 Complete remission
Corticosteroids (steroid-induced myopathy)
has been described in some patients during late pregnancy.
Chloroquine
Puerperal infections increase exacerbations of MG and there-
fore should be diagnosed and treated promptly. The incidence of
Clearly the need to take one of the above drugs may take precedence
clinical exacerbations appears lower in those women who had
over the risk of worsening of myasthenia gravis symptoms.
thymectomy before pregnancy.80 Maternal mortality is more
likely in the first year of disease, and least likely after seven
years from the onset of MG. The long-term outcome of the dis-
10“15 minutes, offset four hours). A slow-release preparation is
ease is not altered by pregnancy.
available for the few patients who experience severe morning
weakness. At high doses, pyridostigmine can cause muscle weak-
Effect of myasthenia on pregnancy
ness through its effects on nicotinic receptors. However, due to
Myasthenia does not affect fertility and its reported incidence in
the use of current combined treatment therapies, high doses of
pregnancy ranges from 1:10 000 to 1:50 000.78 Women with MG
pyridostigmine are rarely required.
have an increased risk for pregnancy complications and adverse
Immunosuppressive therapy is directed at reducing the produc-
pregnancy outcomes.81 Maternal risks include respiratory failure,
tion of antibodies. Corticosteroids produce remission in 30% of
adverse drug response, myasthenic exacerbations and crisis (an
MG patients, with significant improvement in symptoms in up to
exacerbation requiring mechanical ventilation).
45% of the rest. In some patients symptoms get worse, transiently,
Perinatal mortality has been reported to be as high as 68/1000
for the first three weeks of corticosteroid therapy. Azathioprine
live births, secondary to neonatal MG and fetal anomalies. The
blocks cell proliferation and is thought to work by inhibition of T
transplacental transfer of antiAchR antibodies to the fetus may
lymphocytes. The major disadvantage of azathioprine is the pro-
be responsible for transient neonatal MG found in 10“20% of
longed time to clinical effect, and so it is used in combination with
newborns. The occurrence of neonatal MG is halved if the
corticosteroids to improve efficacy. Cyclosporine offers little
mother has had a thymectomy.81 Although there is some corre-
advantage over azathioprine, although it lowers AchR antibodies
lation between the occurrence and severity of neonatal MG and
more rapidly. In one study, the use of the immunosuppressant
high AchR antibody titers, some women without elevated AchR
mycophenolate resulted in a 73% symptom improvement in
antibodies have had babies with neonatal MG.82 All babies born
patients refractory to other treatments, and with fewer side
effects.75 to myasthenic mothers should be carefully monitored for signs
of muscle weakness. Symptoms commonly occur in the first
Plasmapheresis and i.v. immunoglobulin (IVIg) are equally
effective for treatment of MG exacerbations.76 Plasmapheresis is 12“24 hours after delivery and include poor sucking, difficulty
in feeding, generalized hypotonia, floppiness, weak Moro reflex,
thought to remove the circulating AchR antibodies, although
feeble cry, ptosis, and respiratory distress. Complete recovery is
improvement also has been reported in seronegative patients.



153
2 Musculoskeletal disorders



Table 8.9 Equivalent dosages of anticholinesterase medication

Drug Duration of action Intravenous dose Intramuscular dose Oral dose

Pyridostigmine 4“6 hours 1“2 mg 1“2 mg 30“60 mg
Neostigmine 2“3 hours 0.5 mg 1.5 mg 15 mg

Physostigmine is not used as it crosses the blood“brain barrier and causes central stimulation.
Pyridostigmine is preferred anticholinesterase as it has less muscarinic side effects than neostigmine.



expected in less than eight weeks in 90% and by 16 weeks in the
Table 8.10 Associated problems in patients with myasthenia
other 10% of babies.83 Anticholinesterase drugs and ventilatory
gravis
support may be necessary in some cases. The perinatal death
rate due to fetal anomalies is significantly higher than in the Bulbar/oropharyngeal ! pooling of secretions and
Muscle
normal population. Severe birth defects were observed in 3.9% saliva ! respiratory obstruction and aspiration
weakness
of the 127 newborns of MG mothers compared with 1.9% in a Respiratory ! difficulty in clearing secretions !
control group.84 respiratory failure
Associated Thymus hyperplasia (75%), thymoma (10“25%) and
Obstetric management conditions other malignancies
This high-risk pregnancy should encompass a multidisciplinary Thyroid disease (3“15%)
approach involving obstetrician, anesthesiologist, pediatrician, Systemic lupus erythematosus (2%)
and neurologist. The key to prenatal management includes Rheumatoid arthritis (4%)
increased rest, prompt treatment of infection, proper titration of Ankylosing spondylitis
medication, alertness for exacerbations, and avoidance of predis- Crohn disease
posing factors (see Table 8.8).78 Myasthenia gravis therapy for Hypertension
parturients should be chosen after evaluating the severity of the Diabetes mellitus
disease against possible fetal side effects. No fetal problems have Myocarditis ! cardiomyopathy, dysrhythmias
been attributed to anticholinesterase medications, since they do Seizures
not cross the placenta readily. The fetal risks of immunosuppres-
sant drugs are listed in Chapter 22. Plasmapheresis and IVIg have
been used safely in pregnancy, mainly for short-term manage- Hypermagnesemia causes neuromuscular blockade by inhibit-
ment of exacerbations.76 ing the release of Ach, reducing the depolarizing action of Ach at
During pregnancy, dosage adjustments of medications are fre- the end plate and depressing muscle fiber membrane excitability.
quently necessary due to the physiological changes of expanded Therefore, magnesium sulfate (MgSO4) should not be used in
plasma volume, increased renal excretion, and hepatic stasis. patients with severe MG (for tocolysis or preeclampsia), and if
This may be compounded by erratic gastrointestinal absorption, considered in mild MG should be used with great caution.
especially when nausea, vomiting, or increased bulbar involvement Maternal deaths in MG parturients have occurred from the use
are present. Anticholinesterases may have to be administered of MgSO4 for preeclampsia.
parenterally during the first trimester if emesis is an issue. Most myasthenic mothers can safely breast feed. However, it
Parenteral administration avoids the problem of variable gastric may be prudent to avoid breast feeding in symptomatic neonates,
absorption and should minimize breakthrough symptoms caused as AchR antibodies can potentially pass into the breast milk and
by subtherapeutic levels (see Table 8.9). enhance neonatal MG. Breast-feeding should also be avoided in
If thymectomy is deemed necessary, it should be planned prior those mothers taking azathioprine and mycophenolate mofetil.
to conception, as there is no advantage in incurring the added
Anesthetic management
operative risk during pregnancy even though thymectomy has
been performed successfully during the first trimester. Some of the problems facing the anesthesiologist are listed in
Most parturients can deliver vaginally although one study Table 8.10. It is important to perform an extensive, early evaluation
reported a higher number of C/S in women with MG.81 of the patient. Particular importance should be paid to onset, dura-
Myasthenia does not affect the first stage of labor because the tion, severity (especially bulbar and respiratory muscle involve-
uterus consists of nonstriated muscle. However, during the sec- ment), disease treatment, and associated diseases (see Table 8.11).
ond stage, striated muscles are required and instrumental An EKG should be obtained because there are reports of focal
delivery may be required due to fatigue.79 Neostigmine, given myocardial necrosis in some MG patients. Preoperative lung func-
intramuscularly or i.v., is preferred despite its shorter half-life, tion testing may identify patients at particular postoperative risk.
as pyridostigmine may cause a sterile abscess at the injection site. Women with a forced vital capacity < 40 ml/kg or 2.9 L are more
Corticosteroids should be continued and supplemental doses likely to require prolonged respiratory support. Optimizing their
condition will decrease the risk of surgery and improve outcome.85
may be required during labor or instrumental delivery.



154
Chapter 8


Depolarizing and nondepolarizing muscle relaxants (NDMR)
Table 8.11 Relevant assessment of the patient with have been safely administered, although in altered doses.
myasthenia gravis Because there are fewer Ach receptors in MG patients, succinyl-
choline, which acts by depolarizing the neuromuscular junction,
History Tests
may not effectively depolarize the end plate. This may result
Difficulties: chewing, Hemoglobin
in ˜˜resistance™™ to the effective dose (ED95 ¼ 2.6 ‚ normal)91 and
swallowing Urea and electrolytes
an increased incidence of phase II block. Because the dose of
May have decreased nutritional
succinylcholine commonly administered to normal patients
intake
(1“1.5 mg/kg) represents three to five times the ED95, it is likely
Difficulties: coughing, clearing Chest radiograph (? chronic
this ˜˜resistance™™ is not clinically significant.92 Anticholinesterases
secretions aspiration)
decrease plasma cholinesterase activity and may cause a delay
Difficulties: clear/loud speech Bulbar problems
in hydrolysis of succinylcholine and potentiation of neuro-
Dyspnea: rest/exercise Arterial blood gases
muscular block. Plasmapheresis may decrease the amount of
Pulmonary function tests
circulating plasma cholinesterase producing a similar effect.
(e.g. vital capacity)
Myasthenic patients are more sensitive to NDMR. Dosing
Cardiac symptoms Electrocardiogram
should start at about one-tenth of the usual recommended
Thyroid dysfunction symptoms Thyroid function tests
doses and agents with short or intermediate half-life should be
Neurologic symptoms Full neurologic examination
used (e.g. atracurium, vecuronium). Because mivacurium is
Medication side effects
metabolized by pseudocholinesterase its use is relatively contra-
indicated. The abnormal response to muscle relaxants also is seen
in patients with localized ocular disease or in patients during
Regional anesthesia is the preferred method of analgesia for
remission.93 Reversal of neuromuscular block may be sponta-
labor and delivery86,87,88,89 since it avoids opioid-induced respira-
neous to avoid drug reactions or small doses of neostigmine
tory depression and allows flexibility should operative delivery be
(0.5 mg) may be given. Patients undergoing GA should be
necessary. Regional anesthesia is favored for C/S unless the

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