Miastenia Gravis

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Rev Bras Anestesiol

2011; 61: 6: 748-763
CLINICAL INFORMATION
CLINICAL INFORMATION
Myasthenia Gravis: Two Case Reports and Review of the

Literature
Ana Laura Colle Kauling 1, Maria Cristina Simes de Almeida 2, Giovani de Figueiredo Locks, TSA 3,
Guilherme Muriano Brunharo 4
Summary: Kauling ALC, Almeida MCS, Locks GF, Brunharo GM Myasthenia Gravis: Two Case Reports and Review of the Literature.
Background and objectives: Myasthenia gravis (MG) is an autoimmune neurologic disease that affects the postsynaptic portion of the neuromuscular junction. It represents a challenge for anesthesiologists due to the diversity of disease manifestations and possibility of postoperative
respiratory complications. The objective of this study was to demonstrate the importance of adequate monitoring of the neuromuscular blockade
(NMB) due to the multiple presentations of MG.
Contents: In this paper we report two cases of patients with MG. The first patient presented with the classical sensitivity to the neuromuscular
blocker (NMB) and the second had a similar response to that of a normal patient. The literature review will be restricted to disease characteristics,
while the description of its pathophysiology will focus on its reactions to NMB.
Conclusions: We suggest that, due to the multiple presentation and treatment of MG, neuromuscular transmission monitors are fundamental
when using NMB.
Keywords: Neuromuscular Blocking Agents; Myasthenia gravis; Electromyography; Atracurium; Anesthesia, General; Monitoring, Physiologic.
2011 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Myasthenia gravis (MG) is an autoimmune neurologic disease

that affects the post-synaptic portion of the neuromuscular
junction (NMJ). Over the last years, the understanding of the
neuromuscular transmission (NMT) and nature of the disease
provided better treatment with low mortality, making the expression MG almost unjustifiable 1-5.
The precise origin of the immune response is unknown,
but thymic abnormalities almost certainly play a relevant role
in the genesis of anti-motor plate nicotinic receptor antibodies.
These antibody reactions activate the complement system,
resulting in damage to the muscular membrane and sodium
channels with significant disruption of NMT 2-8.
Despite advanced diagnostic and treatment techniques,
MG still represents a challenge to anesthesiologists, justified by the several disease manifestations and the possibility
Received from Universidade Federal de Santa Catarina (UFSC), Brazil.

1. Resident Physician of the Anesthesiology Sector of the Hospital das Clnicas da Faculdade de Medicina da Universidade de So Paulo (FMUSP)
2. Medical degree from Johannes Gutenberg Universitt Mainz, Germany; Professor of the
Departamento de Cirurgia da Universidade Federal de Santa Catarina (UFSC)
3. Anesthesiologist of Hospital Universitrio da UFSC
4. Resident Physician of the Anesthesiology Sector of the Hospital Governador Celso Ramos
Submitted on September 29, 2010.
Approved on February 21, 2011.
Correspondence to:
Dra. Ana Laura Colle Kauling
Av. Dr. Enas de Carvalho Aguiar, 155
05403000 So Paulo, SP, Brazil
E-mail: analaurakauling@gmail.com
748
of severe postoperative ventilatory complications 9,10. In the

present article we report two cases of MG patients who had
different reactions to neuromuscular blockers (NMB), and the
literature review will focus on aspects of the disease and its
pathophysiology related to reactions to NMB.
CASE REPORTS
Case 1 11
This is a 55-year old male patient, 82 kg, 167 cm, with history of MG who was admitted to undergo transternal thymectomy. He reported chronic use of prednisone 60 mg.day-1, and
pyridostigmine 180 mg.day-1, which improved his symptoms
considerably. He had no other comorbidities. Laboratory tests
and electrocardiogram were normal. Chest X-ray and tomography showed image compatible with increased thymic size.
The patient received no premedication and was referred to
the operating room on the morning of the surgery without interrupting his daily medications. In the operating room, he was
monitored with ECG on DII and V5, automatic noninvasive
measurement of blood pressure, pulse oximetry, capnography, and electromyography of the adductor pollicis muscle.
After administration of 100% oxygen by face mask, he received propofol 150 mg, and alfentanil 1,500 g. After loss
of the palpebral reflex, electromyography (Relaxograph) with
stimulating electrodes placed on the wrist, on the trajectory
of the ulnar nerve, was performed with supramaximal stimuli
every 20 seconds with frequency of 2 Hz and train-of-four
stimulus (TOF) (Figure 1).
Revista Brasileira de Anestesiologia
Vol. 61, No 6, November-December, 2011
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3:58
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MYASTHENIA GRAVIS: TWO CASE REPORTS AND REVIEW OF THE LITERATURE
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Figure 1 Electromyographic Tracing of TOF of Adductor Pollicis Muscle in a Patient with MG who Received Fractionated Doses of Cisatracurium. The lower tracing shows the response of a normal patient to the same fractionated doses of cisatracurium11. With authors and Brazilian
Society of Anesthesiologys permission.
After a short period of stabilization of the tracing, cisatracurium 0.8 mg was administered with an expressive reduction
in muscle contraction. Two additional doses of 0.4 mg were
administered before the patient was considered to have a satisfactory degree of muscle relaxation for tracheal intubation.
Anesthesia was maintained with isoflurane, nitrous oxide, and
fentanyl. At the end of the procedure, which lasted 3 hours
and 45 minutes, the T4/T1 ratio was 0.75. We decide to attempt pharmacologic reversion with neostigmine 0.05 mg.kg-1,
which was considered unsatisfactory despite the patient had
an excellent respiratory pattern. The patient was transferred to
the Intensive Care Unit intubated and on assisted ventilation,
where he remained for 2 hours with ventilatory assistance. At
the end of this period, with decurarization patterns that were
considered satisfactory (T4/T1 > 0.9), the patient was extubated. His evolution was satisfactory and he was discharged
on the sixth postoperative day.
Case 2
This is a 55-year old female patient, 64 kg, 165 cm, physical
status ASA III who was admitted for a mastectomy for breast
120
00:00
00:05
100
50
Figure 2 Electromyographic Tracing of the Adductor Pollicis Muscle in a Patient with MG who Received Initially 3.5 mg and, after 4
Minutes, 31.5 mg of Atracurium. The initial tracing did not show
muscle fatigue, and muscle relaxation was observed only with a dose
of 0.5 mg.kg-1 of atracurium.
carcinoma. On preoperative evaluation, she reported history

of diabetes mellitus and use of insulin, MG for five years and
use of valproic acid, amitriptyline, and prednisone. Her laboratorial tests, electrocardiogram, and Chest X-ray were normal.
On the morning of the surgery the patient was transferred
from the Intensive Care Unit, arriving at the operating room
awake, oriented, dyspneic, with SpO2 89%, ventilating with
oxygen by a face mask. Monitoring consisted of ECG on DII
and V5, automatic noninvasive measurement of blood pressure, pulse oximetry, capnography, electromyography (Relaxograph), and accelerometry (TOF Watch) of adductor
pollicis muscles, with one monitor on each arm.
After inhalation of 100% oxygen by a face mask for three
minutes, fentanyl 200 g and propofol 200 mg were administered. An initial dose of 3.5 mg of atracurium, complemented
to 0.5 mg.kg-1 four minutes after the initial dose, was administered. Anesthesia was maintained with sevoflurane, oxygen,
and 50% air.
After anesthetic induction, muscle contraction was verified
by electromyography of the adductor pollicis muscle through
stimulator electrodes placed on the wrist, on the trajectory
of the ulnar nerve. Evoked contraction was performed with
supramaximal stimuli every 20 seconds, frequency of 2 Hz,
with TOF stimulus (Figure 2). Simultaneously, indirect muscle
strength was recorded with an acceleration transducer placed
on the contralateral thumb. Both electromyography and accelerometry, performed before the administration of atracurium
showed no muscular fatigue.
At the end of the procedure, the patient recovered the
muscle strength spontaneously, being extubated with T4/T1
of 0.9. With the patient awake, ventilating with O2 via a face
mask, her SpO2 was above 90%.
DISCUSSION
Myasthenia gravis is a chronic autoimmune disease that usually manifests in young adults or in the elderly, being charac749
KAULING, ALMEIDA, LOCKS ET AL.
terized by weakness and fatigue of skeletal muscles due to

repetitive use 3,4,6,12-14.
Myasthenia gravis geoepidemiology shows that it is a rare
disorder with similar incidence and prevalence in the world,
except for infantile MG, which is more common in Asia 15-17.
The incidence has increased in the last decades, going from
2-5/1,000,000 to 9-21/1,000,000, but without proportional increase in mortality. The disease attacks mainly women in the
third and fourth decades of life in the proportion of 3:2 15.
Environmental and microbial agents have been suggested
for its etiology, and the association between the disease and
hepatitis C virus have been reported. Cross-reaction between
antibodies of MG patients with herpes simplex virus, besides
other virus, has been reported 18-22. Genetic predisposition for
the disease is equally important 23,24.
Whether there are predisposing factors is not established,
but in some cases the presence of infection, emotional stress,
surgeries, trauma, use of antibiotics, or pregnancy have been
related to the onset of disease manifestation 1.
Ocular and palpebral muscle involvement is at times the
only manifestation of MG with symptoms of diplopia and palpebral ptosis. These muscles have particularities that should be
mentioned: they are fatigue resistant, have high blood flow
for motor units and high mitochondrial content, therefore, they
have high metabolic rate. Motor neurons in this area are anatomically small with high discharge frequencies; some muscles have multiple innervations where the end-plate potential,
more than the action potential itself, is directly responsible
for muscle activation. This means that any reduction in endplate potential has direct repercussion on muscle contraction. The role of immature or fetal receptors on extraocular
muscle compromise in MG is controversial, but a factor that
makes them susceptible in this disease is without any doubt
the low expression of complement system regulators, making
them susceptible to muscle membrane damage by this system, which is activated by the antigen-antibody reaction 25.
Besides the compromise of palpebral muscles, the involvement of face and bulbar muscles can be incapacitating and
life-threatening 3. Table I shows the percentage of muscular
involvement in MG.
Although many aspects of MG still have no convincing explanation, there is no doubt about the immunologic character of the disease, proven by the substantial improvement of
patients with plasmapheresis 26,27. Antibodies, usually IgG1
and IgG3, are capable of activating the complement system 2.
The nature of these immunoglobulins indicates that they are
T lymphocyte-dependent and that thymic cells type ED4 help
B cells in their production 28,29. Thus, in an expressive percentage of patients, especially young ones, the thymus is abnormal 4. Despite a significant number of patients with thymic
involvement, the presence of other sites of formation of these
antibodies has been suggested, since patients are clinically
improved after thymectomy but not cured 30.
The main focus of these antibodies is, without any doubt,
the NMJ, site of many drug interactions and intoxications because in this region there is no hematologic barrier 31,32. Thus,
similar to MG, other autoimmune diseases that also interfere
750
Table I Percentage of Muscle Involvement in MG 1,2,15

Muscles
Percentage of involvement
Ocular
17%
Ocular and bulbar
13%
Mild/moderate
2%
Moderate/severe
11%
Ocular and limbs
20%
Generalized
50%
Mild
2%
Moderate
14%
Severe
15%
Requiring ventilatory assistance
11%
Death despite ventilatory assistance 8%

MG: Myasthenia Gravis.
with muscle contraction have been identified. Among them

we could mention the reaction against calcium channels in
Lambert-Eaton myasthenic syndrome and against potassium
channels in congenital neuromyotonia 2.
Most patients have anti-muscular nicotinic receptor antibodies, and there are those being considered a special subgroup
of MG. In such patients, antibodies against muscle-specific
kinase, a molecule in the proximity of the muscular nicotinic
receptor that maintains the anatomic integrity of the NMJ, are
detected 30. Note that antibodies in MG do not attack subunits
3 or 42 of the nicotinic receptors, explaining the absence
of autonomic and central nervous system symptoms 33. Finally, in 10% of patients, antibodies are not detected; however,
they have satisfactory response to plasmapheresis, and injection of plasma from these patients induces MG in animals,
suggesting that, even though antibodies are not detected by
traditional methods, there must be an antibody-producing
mechanism involved in this type of MG 3,4,13. Clinical evolution, age, involvement of human leukocyte antigen, antibodies
against nicotinic, and ryanodine receptors, besides the presence of thymic disease, help classify and predict the evolution of the disease. Myasthenia gravis classification according to clinical and laboratory aspects is presented in Tables II
and III, respectively.
To understand the pathophysiology of MG and reaction to
NMB it is important among other aspects to understand the
ways of maintaining the anatomic integrity of NMJ and muscular nicotinic receptor function when occupied by the neurotransmitter. Didactically, two important mechanisms maintain neuromuscular junction trophism. The first is the electrical
activity from the motor neuron that affects the entire muscular
surface, and the second is the involvement of molecular signals equally from axonal origin 30.
The normal electrical activity from the undivided nerve
inhibits acetylcholine receptor formation in all muscle nuclei
Table II Classification of MG According to the Ossermann Scale 34

Type I
Ocular myasthenia characterized by ptosis and diplopia
Type IIa
Slow onset, frequently ocular, with gradual evolution to skeletal musculature
Type IIb
Slow onset with dysarthria, dysphagia, and changes in mastication
Type III
Fast onset with severe bulbar and skeletal muscle fatigue with respiratory muscle compromise
Type IV
Severe MG that manifests in two years
MG: Myasthenia Gravis.
Table III Classification of MG in Subgroups 3,13,15

Subgroups
Age
(years)
HLA association
Thymic disease
Antibodies
early manifestation
< 40
DR3B8
Hyperplasia
AchR
late manifestation
> 40
DR2B7 (weak)
Normal for age
AchR, ryanodine and titin receptors*
Thymoma
Variable
Unknown
Tumor
AchR
MG with anti-AchR antibody:
AchR, ryanodine and titin receptors*

Antibody with low AchR affinity
Variable
Unknown
Some cases of
hyperplasia
Little affinity for AchR
Ocular MG
Variable
Unknown
Unknown
AchR 50%; AchR with low affinity
MuKi-MG
Variable
DR14DQ5
Normal
MuKi
Anti-AchR/MuKi antibody negative
Variable
Unknown
Not clear
Negative
E-LMS
20-60
DR3B8
No reported
VGCa++R
E-LMS scLC
> 40
Unknown
Not reported
VGCa++R
Neuromyotonia
20-60
Unknown
Maybe thymoma
VGK+R in 40%
MG: Myasthenia Gravis. AchR: acetylcholine receptor. HLA: human leukocyte antigen. DR3B8, DR7B7, DR14DQ5: subtypes of human leukocyte antigen. *titin: giant
filamentous muscular protein essential for muscular development and structure, and muscular function. MuKi: muscle-specific kinase. Ag: antigen. E-LMS : EatonLambert Myasthenic Syndrome. VGCa++R: voltage-gated calcium receptor. scLC: small-cell lung carcinoma. VGK+R: voltage-gated potassium receptor.
except in subsynaptic nuclei. The direct consequence, when

there is normal nerve activity, is the reduction in extrajunctional receptor formation and stimulation of motor plate receptor
formation. Two substances (agrin and neuregulin) mediated
by muscle-specific kinase are involved in maintaining the trophism of the motor plate. They are nerve-derived and bound
to the basement lamina 35-37. Some other forms of agrin, such
as in blood vessels, kidneys, and muscles similar to that found
in the motor plate do not lead to the formation or aggregation of acetylcholine receptors in the NMJ 30. An experimental
study 38 suggests that neuronal agrin regulates both the differentiation of the pre-synaptic region and the muscular subsynaptic region. This molecule works in the muscle subsynaptic
nucleus and induces the expression of acetylcholine receptors
and their aggregation on the surface of the muscle membrane
in the proximity of the axon terminal. Equally important in this
mechanism is the presence of rapsin. Muscle-specific kinase
is also involved on kinase receptors and neuregulin, which

also interfere in the formation of acetylcholine receptors and
their expression on the muscle membrane and sodium receptors 3,39-44. In MG, the presence of muscle-specific kinase antibodies changes these complex mechanisms that maintain
trophism and, as a result, an impoverishment of junctional
acetylcholine receptors and an increase in extrajunctional
acetylcholine receptors is observed 45, a mechanism similar
to that observed in patients whose binomial nerve-muscle is
interrupted 30.
The neuromuscular junction is a complex synapse that has
three distinct components: presynaptic axonal terminal, site
of acetylcholine synthesis and storage; synaptic cleft; and
postsynaptic membrane, where nicotinic receptors and acetylcholinesterase are located 30. Normal NMT begins when
a nerve action potential arrives to the axonal presynaptic
terminal, generating a calcium influx that penetrates in the
751
axon through specific type P and Q calcium channels, called

voltage-gated. They are opened whenever there is change in
membrane voltage 43. Calcium penetrates in the axon and, by
acting on calmodulin, it releases acetylcholine vesicles from
the cellular cytoskeleton. These free-vesicles move and go
to the axonal periphery in the pre-synaptic portion of the motor plate. Through mechanisms involving molecules bound to
the axonal membrane the membrane vesicle and the axonal
membrane merges leading to acetylcholine exocytosis, all
calcium-dependent mechanisms. The basement membrane
is also located in the synaptic cleft. Proteins such as collagen,
laminin, fibronectin, and perlecan on this structure are important components for efficient NMT. ColQ, a molecule similar
to collagen, connected to acetylcholinesterase, is the characteristic example of a basement membrane-bound substance
fundamental in the NMT mechanism 46.
Once released on the synaptic cleft acetylcholine molecules occupy muscular acetylcholine receptors besides other
neuronal receptors, and in special situations the extrajunctional receptors. To increase the contact area the postsynaptic membrane forms invaginations into the interior of the
muscular cell, where nicotinic receptors anchor and remain
on their crests, while sodium channels are on their deeper
portions 43,47.
The key elements of the postsynaptic region are, without

any doubt, the muscular acetylcholine receptor and calcium
molecules. Once acetylcholine molecules are bound to 1
and and 1 and subunits on the extracellular portion of the
receptor, they cause a physiologic torsion of approximately
10 degrees, especially in subunits, resulting in anatomical
modification of the pore, located in the transmembrane portion. Through the central pore, now with greater diameter,
sodium ions enter and initiate an action potential in the postsynaptic region changing membrane polarity also known as
end-plate potential 36,44,48,49. In normal adults this potential
is much higher than necessary to generate an action potential in the muscle cell, and this was called the NMT safety
factor. The action of acetylcholinesterase nullifies the effects
of acetylcholine 3,30,42. Figure 3 shows the physiologic sites
that acetylcholine binds to the muscle nicotinic receptor and
the movement of the receptor, resulting in the opening of the
central pore.
Because 17 genes encode muscle cholinergic receptors
scientists have great difficulties in determining the mutations
of these receptors 46. Thus, some functions are regulated by
more than one gene, and different mutations may result in disease with the same phenotype. This is exemplified by at least
56 mutations that cause Congenital Myasthenic Syndromes,
Figure 3 Nicotinic Receptor: Allosteric Transition Model Known as Twisted quaternary Model. In (a): lateral view of the resting and activated
receptor model. A schematic representation of the moving quaternary structure is equally demonstrated as cylinder. In (b): transmembrane area
of the resting and active models, similar to that demonstrated in (a). Reproduced with permission of Changeux JP 44 and the editor.
752

a group of diseases causing changes in NMT 46. They were

classified into presynaptic, synaptic, and postsynaptic. The
first was described in children who had normal motor plate,
but reduced size acetylcholine vesicles. This group comprises
entities with decreased number of acetylcholine molecules
released during exocytosis 46. Synaptic disorders are related
to acetylcholinesterase deficiency. This is a genetic defect of
ColQ. On chronic deficiency due to genetic mutation of this
molecule, more precisely on the 3p24.2 locus, there is a reduction in the bioavailability of acetylcholinesterase on the
synaptic cleft, and consequently excess of acetylcholine. This
leads to repetitive and persistent muscle stimulation resulting in desensitization of the motor plate nicotinic receptors.
This is a rare disease with only 17 cases described in the
literature 50. Congenital Myasthenic Syndromes classified as
postsynaptic are related to abnormalities in muscular nicotinic
receptors46. The main mutations observed are located in 1,
1, and subunits 46, so that the abnormal receptor does not
respond with physiologic movement when acetylcholine molecules bind to it, and the central pore does not allow sodium
molecules to go through 44.
Based on the mutations observed in MG, three distinct
receptor behaviors have been described. The first, called
function gain in which mutations results in slow closure of
the central pore and greater receptor affinity for acetylcholine. They are also known as slow channel syndromes 51.
Neurotransmission is compromised by the excessive cation
load that leads to the destruction of muscular invaginations
of the motor plate, receptor desensitization, and motor blockade due to depolarization 46. It is the most common type of
the disease. The second is called loss of function. In this
situation the inverse mechanism is seen, i.e., the pore clos-
es early. This type of MG is called fast channel syndrome.

The response to acetylcholine is greatly reduced despite
the increased amount of acetylcholine quantum released by
the axon. And in the third behavior there are situations in
which both changes are present 46. In all three dysfunctions
a significant compromise of the NMT is observed 43; there
are different approaches and pharmacologic responses to
treatment of MG in these three modalities of receptor reaction. Figure 4 shows the graphic representation of subunit 1
mutations in MG.
In MG, besides channel dysfunction, the architecture of
the muscle membrane is also compromised especially due
to the complement system 3,4,52. The immediate consequence
is change in the quality and speed of the end-plate potential
leading to dysfunction of the voltage-gated sodium channel.
The final result is the loss of the NMT safety factor causing muscle fatigue and weakness 5. A recent study suggested
that besides changes in the motor plate there is also more distant compromise, most precisely in the actin-myosin system
of muscle excitation/contraction. This is observed particularly
in patients with the generalized form of the disease who usually have a thymoma, which may be another contributing factor for disease symptoms 53.
Thymectomy is the characteristic situation in which the patients will undergo anesthesia. Care of MG patients is basically
focused on the preoperative use of anticholinesterase drugs,
reaction to NMB, and possible transoperative drug interactions 54,55. Factors that can lead to the need of postoperative
ventilatory assistance are equally important 56,57. Thus it has
been suggested that treatment with anticholinesterase drugs
should not be interrupted before surgery, and one should prefer regional anesthesia whenever possible 9.
Figure 4 Distribution of Mutations in MG. In (a) mutations with gain and loss of function are diffusely distributed in the extracellular and transmembrane areas of the receptor. In (b), the representation of these pathologic mutations is, according to the twisted quaternary model, located
among the subunits and rigid areas of the receptor. Reproduced with permission of Changeux JP 44 and the editor.
753
When general anesthesia is the choice, additional care

should be taken with the injection of NMB. As a rule, the reaction to muscle relaxants is unpredictable in MG patients. Regarding succinylcholine patients are often resistant to this drug
requiring larger doses to obtain maximal blockade 58. This can
be explained by the reduced number of receptors hindering the
drug from effectively depolarizing the motor plate. However, the
reaction is not always one of resistance, and patients that use
anticholinesterase drugs or those who underwent preoperative
plasmapheresis may have a potentiating effect of succinylcholine 9,55,57,50-64. The authors indicate that the effects are inversely
proportional to the activity of plasma cholinesterase 64.
Most patients seropositive or not for MG have increased
sensitivity to non-depolarizing NMB 9,56,60. The pattern of NMT
monitoring before the injection of NMB usually is of muscle
fatigue, and patients require very low doses to maintain maximum relaxation. This was seen in Case 1 (Figure 1). However, the authors observed that if before the injection of NMB the
patient does not show a pattern of fatigue after evoked stimulation, the response to and the doses of NMB will be similar to
those used in normal patients 12. This absence of fatigue was
recorded by electromyography of the pollicis adductor muscle
in Case 2, in which the response to NMB followed the pattern
of a normal patient (Figure 2).
754
Therefore, we suggest that due to the variety of response

to NMB from extreme sensitivity to conventional response,
similar to that observed in patients without MG, the monitoring
of NMT in MG mandatory, and it should be initiated before the
injection of the NMB. It has been recommended the use of a
strong stimulus, such as TOF 12,65. In addition to the information on patient response to NMB, this type of neurostimulation
is equally useful in detecting residual blockade at the end of
the procedure.
Recently, authors have reported successful reversion of
rocuronium-induced blockade by sugammadex in patients
with MG 66,67. The great advantage of this new antagonist is
the constancy of motor blockade reversion in MG patients, as
it does not depend of interactions with preoperative anticholinesterase agents 68.
To conclude, MG is defined as an autoimmune neurologic
disease that affects the postsynaptic portion of the NMJ with
involvement, in most cases, of the thymus. Due to the multiple
forms of disease presentation, treatment, and evolution, and
as a way to predict the response to NMB and its satisfactory
reversion, monitoring of the NMT with TOF during anesthesia
assessing muscle response before the administration of NMB
is recommended.

Rev Bras Anestesiol

2011; 61: 6: 748-763
INFORMAES CLNICAS
INFORMAES CLNICAS
Miastenia Gravis: Relato de Dois Casos e Reviso da

Literatura
Ana Laura Colle Kauling 1, Maria Cristina Simes de Almeida 2, Giovani de Figueiredo Locks, TSA 3,
Guilherme Muriano Brunharo 4
Resumo: Kauling ALC, Almeida MCS, Locks GF, Brunharo GM Miastenia Gravis: Relato de Dois Casos e Reviso da Literatura.
Justificativa e objetivos: A Miastenia Gravis (MG) uma doena neurolgica autoimune que afeta a poro ps-sinptica da juno neuromuscular. Trata-se de um desafio ao anestesiologista, pela diversidade das manifestaes da doena e pela possibilidade de complicaes ventilatrias no ps-operatrio. O objetivo deste trabalho demonstrar a importncia da monitorao adequada ao bloqueio neuromuscular (BNM) em
virtude das mltiplas formas de apresentao da MG.
Contedo: Neste artigo sero descritos dois casos de pacientes com MG um que apresentou a forma clssica de sensibilidade ao bloqueador
neuromuscular (BNM) e outro com resposta semelhante de um paciente normal. A reviso da literatura ser restrita s caractersticas da doena e a descrio de sua fisiopatologia estar voltada s reaes aos BNM.
Concluses: Como concluso, sugere-se que, em decorrncia das mltiplas formas de apresentao e de tratamento da MG, fundamental o
uso de monitores da transmisso neuromuscular quando se usa BNM.
Unitermos: ANESTESIA, Geral; BLOQUEADOR MUSCULAR, Atracrio; DOENAS, Muscular, Miastenia Gravis; MONITORAO; TCNICAS
DE MEDIO, Eletromiografia.
2011 Elsevier Editora Ltda. Todos os direitos reservados.
INTRODUO
A Miastenia gravis (MG) uma doena neurolgica auto-imune que afeta a poro ps-sinptica da juno neuromuscular
(JNM). Nos ltimos anos, a compreenso da fisiopatologia da
transmisso neuromuscular (TNM) e da natureza da doena
proporcionou melhor tratamento com baixa mortalidade, tornando o termo MG quase injustificvel 1-5.
A origem precisa da resposta imune desconhecida, mas
as anormalidades do timo certamente desempenham papel
relevante na gnese dos anticorpos contra os receptores
nicotnicos da placa motora. Essas reaes com anticorpos
suscitam ativao do sistema do complemento, que resultam, em ltima anlise, em leso da membrana muscular e
dos canais de sdio, com significativo comprometimento da
TNM 2-8.
Recebido da Universidade Federal de Santa Catarina (UFSC), Brasil.

1. Mdica residente do Servio de Anestesiologia do Hospital das Clnicas da Faculdade de
Medicina da Universidade de So Paulo (FMUSP)
2. Doutor em Medicina pela Johannes Gutenberg Universitt Mainz, Alemanha; Professor
Adjunto do Departamento de Cirurgia da Universidade Federal de Santa Catarina (UFSC)
3. Mdico Anestesiologista do Hospital Universitrio da UFSC
4. Mdico residente do Servio de Anestesiologia do Hospital Governador Celso Ramos
Submetido em 29 de setembro de 2010.
Aprovado para publicao em 21 de fevereiro de 2011.
Correspondncia para:
Dra. Ana Laura Colle Kauling
Av. Dr. Enas de Carvalho Aguiar, 155
05403000 So Paulo, SP, Brasil
E-mail: analaurakauling@gmail.com

Vol. 61, No 6, Novembro-Dezembro, 2011
A despeito das tcnicas avanadas de diagnstico e tratamento, a MG ainda um desafio ao anestesiologista, justificado pelas diversas formas de manifestao da doena e
pela possibilidade de complicaes ventilatrias graves no
perodo ps-operatrio 9,10. Neste artigo sero descritos dois
casos de pacientes com MG que apresentaram reaes diferentes aos bloqueadores neuromusculares (BNM); a reviso
bibliogrfica enfocar aspectos da doena e de sua fisiopatologia relacionados s reaes aos BNM.
RELATO DOS CASOS

Caso 1 11
Paciente masculino, 55 anos, 82 kg, 167 cm de altura, foi
internado com histria de MG para ser submetido a uma timectomia por via transesternal. Relatava uso crnico de
prednisona 60 mg.dia-1 e de piridostigmina 180 mg.dia-1, que
melhoravam sensivelmente seu quadro clnico. No apresentava outras comorbidades. Exames laboratoriais e eletrocardiograma eram normais. A radiografia e a tomografia de trax
acusaram imagem compatvel com aumento do timo.
O paciente no recebeu medicao pr-anestsica e foi
encaminhado ao centro cirrgico na manh da operao,
sem interrupo das medicaes de uso rotineiro. Na sala
de operao, foi monitorado com ECG em DII e V5, presso
arterial no invasiva com aferio automtica, oximetria de
pulso, capnografia e eletromiografia do msculo adutor do
polegar.
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Figura 1 Traado eletromiogrfico da SQE do msculo adutor do polegar em paciente com MG, que recebeu doses fracionadas de cisatracrio. O traado inferior mostra a resposta de um paciente normal s mesmas doses fracionadas de cisatracrio11. Com permisso do autor e da
Sociedade Brasileira de Anestesiologia.
Aps a administrao de oxignio a 100% por mscara facial, recebeu propofol 150 mg e alfentanil 1.500 g. Aps
a perda do reflexo palpebral, realizou-se eletromiografia
(Relaxograph) com os eletrodos estim++uladores colocados
no trajeto do nervo ulnar no punho e com impulsos supramximos a cada 20 segundos, com frequncia de 2 Hz e sequncia de quatro estmulos (SQE) (Figura 1).
Aps curto perodo de estabilizao do traado foi injetado cisatracrio na dose de 0,8 mg, havendo diminuio expressiva da contrao muscular. Duas doses adicionais de
0,4 mg foram administradas quando se considerou, ento, o
paciente em grau satisfatrio de relaxamento para intubao
traqueal. A anestesia foi mantida com isoflurano, xido nitroso e fentanil. Ao fim do procedimento de 3 horas e 45 minutos, a relao T4/T1 era de 0,75. Optou-se por tentar a
reverso farmacolgica com neostigmina 0,05 mg.kg-1, que
foi considerada insatisfatria apesar de haver excelente padro de ventilao. O paciente foi encaminhado Unidade
de Tratamento Intensivo em intubao traqueal e ventilao
assistida, onde permaneceu por duas horas em assistncia
ventilatria. Ao final desse tempo, e com padres considerados satisfatrios de descurarizao (T4/T1 > 0,9), o paciente
foi extubado. Evoluiu satisfatoriamente e teve alta no sexto
dia de ps- operatrio.
Caso 2
Paciente do sexo feminino, 55 anos, 64 kg e 165 cm, estado
fsico ASA III, internou-se para ser submetida mastectomia
por carcinoma de mama. Na avaliao pr- operatria, relatou
histria de diabetes mellitus em uso de insulina e MG conhecida h cinco anos, em uso de cido valproico, amitriptilina e
prednisona. Seus exames laboratoriais, o eletrocardiograma
e a radiografia de trax eram normais.
Na manh da cirurgia, a paciente veio encaminhada da
Unidade de Terapia Intensiva e chegou sala operatria lcida, dispneica, com valor de oximetria (SpO2) em 89%, ventilando com o auxlio de mscara facial com oxignio. A monitorao foi realizada com ECG em DII e V5, presso arterial
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no invasiva aferida automaticamente, oximetria de pulso,

capnografia, eletromiografia (Relaxograph) e acelerometria
(TOF Watch) dos msculos adutores do polegar, sendo instalado um monitor em cada brao.
Aps a inalao de oxignio a 100% por mscara facial
por trs minutos, a paciente recebeu fentanil 200 g e propofol 200 mg. A dose inicial de atracrio foi de 3,5 mg, posteriormente complementada para 0,5 mg.kg-1 aps quatro minutos
da dose inicial. A anestesia foi mantida com sevofurano, oxignio e ar em 50%.
Aps a induo, a contrao muscular foi aferida por eletromiografia do msculo adutor do polegar, atravs de eletrodos estimuladores instalados no trajeto do nervo ulnar no
punho. A contrao evocada foi realizada com impulsos supramximos a cada 20 segundos, frequncia de 2 Hz, com
SQE (Figura 2). Simultaneamente, foi registrada a fora muscular de forma indireta, com transdutor de acelerao instalado no polegar contralateral ao que estava sendo registrado
com EMG. Tanto a eletromiografia quanto a acelerometria,
realizadas antes da administrao do atracrio, no demonstraram fadiga muscular.
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em paciente com MG que recebeu inicialmente 3,5 mg e, aps quatro minutos, 31,5 mg de atracrio. O traado inicial no evidencia
fadiga muscular, e o relaxamento muscular s se deu com dose de
0,5 mg.kg-1 de atracrio.
MIASTENIA GRAVIS: RELATO DE DOIS CASOS E REVISO DA LITERATURA
Ao final do procedimento, a paciente recuperou a funo

muscular espontaneamente e foi extubada com T4/T1 em
0,9. A SpO2, com a paciente lcida ventilando com mscara
facial com 5 L de O2, mostrava valores superiores a 90%.
DISCUSSO
A MG uma doena auto-imune crnica que se manifesta
usualmente em adultos jovens ou em idosos e caracterizada por fraqueza e fadiga dos msculos esquelticos de uso
repetitivo 3,4,6,12-14.
A geo-epidemiologia da MG mostra que se trata de uma
doena rara, de incidncia e prevalncia similares no mundo, exceto para MG infantil, que mais comum na sia 15-17.
A incidncia aumentou nas ltimas dcadas e passou de
2-5/1.000.000 para 9-21/1.000.000, porm sem haver aumento proporcional na mortalidade. A doena acomete, predominantemente, mulheres nas terceira e quarta dcadas na
proporo de 3:2 15.
Como etiologia, tem-se sugerido influncia ambiental e de
agentes microbianos, e h relatos de casos da associao
da doena com o vrus da hepatite C. Ainda possvel registrar reaes cruzadas entre os anticorpos de pacientes com
MG com o vrus do herpes simplex, alm de outras doenas
virais 18-22. Igualmente importante a predisposio gentica
para a doena 23,24.
No est claramente estabelecido se h fatores precipitantes da MG, mas em alguns casos, presena de infeco,
estresse emocional, cirurgias, traumas, uso de antibiticos ou
gestao tm sido relacionados ao incio das manifestaes
dessa doena 1.
O envolvimento dos msculos extra-oculares e das plpebras , por vezes, a nica manifestao da MG, com sintomas de diplopia e ptose palpebral. Esses msculos apresentam particularidades que podem ser citadas: so resistentes
fadiga, tm alto fluxo sanguneo para as unidades motoras
e possuem contedo mitocondrial farto, portanto apresentam
alto ndice metablico. Os neurnios motores dessa regio
so anatomicamente pequenos e as frequncias de disparo
so altas; alguns msculos possuem inervao mltipla, onde
o potencial final de placa, mais do que o potencial de ao em
si, responsvel direto pela ativao muscular. Isso significa
que qualquer reduo do potencial final de placa repercute
diretamente na contrao muscular. O papel dos receptores
imaturos ou fetais no comprometimento dos msculos extraoculares na MG ainda motivo de controvrsia, mas um fator
que os torna suscetveis nessa doena , sem dvida, a baixa expresso dos reguladores do sistema do complemento,
o que os torna vulnerveis leso da membrana muscular
por esse sistema, ativada pela reao antgeno-anticorpo 25.
Alm do comprometimento dos msculos palpebrais, o envolvimento de msculos da face e bulbares pode ser incapacitante, impondo risco vida do paciente 3. O percentual de
acometimento muscular na MG est apontado na Tabela I.
Embora muitos aspectos da MG ainda permaneam sem
explicao convincente, no h dvida acerca do carter imuRevista Brasileira de Anestesiologia
Tabela I Percentual de Acometimento Muscular na MG

Msculos
1,2,15
Percentual de acometimento
Ocular
17%
Ocular e bulbar
13%
Leve/moderado
2%
Moderado/intenso
11%
Ocular e de membros
20%
Generalizada
50%
Leve
2%
Moderado
14%
Intenso
15%
Com necessidade da AV.
11%
Morte apesar da AV.
8%
MG: Miastenia Gravis; AV: Assistncia Ventilatria.
nolgico da doena, comprovado pela melhora substancial

dos pacientes com a plasmaferese 26,27. Os anticorpos so
usualmente do tipo IgG1 e IgG3, capazes de ativar o sistema
do complemento 2. A natureza dessas imunoglobulinas indica
que so dependentes de linfcitos T, e que clulas do timo
do tipo ED4 auxiliam clulas B em sua produo 28,29. Assim,
em um percentual expressivo de pacientes, principalmente
os jovens, o timo est anormal 4. A despeito de haver um
nmero significativo de pacientes com envolvimento do timo,
sugere-se a existncia de outros stios de formao desses
anticorpos, porque a timectomia melhora clinicamente os pacientes, mas no os cura da doena 30.
O foco principal desses anticorpos sem dvida a JNM,
local de muitas interaes medicamentosas e intoxicaes,
pois nessa regio no h barreira hematolgica 31,32. Assim,
a exemplo da MG, tambm tem sido identificada uma srie
de outras doenas auto-imunes que igualmente interferem
na contrao muscular. Dentre elas, pode-se citar a reao
contra os canais de clcio na sndrome miastnica de Lambert-Eaton e contra os canais de potssio na neuromiotonia
congnita 2.
A maioria dos pacientes apresenta anticorpos contra os
receptores nicotnicos musculares e h ainda aqueles que
esto sendo considerados como um subgrupo especial de
MG. Nesses, so detectados anticorpos contra a cinase
especfica para os msculos, uma molcula localizada nas
proximidades do receptor nicotnico muscular e que atua na
manuteno da integridade anatmica da JNM 30. Interessante observar que os anticorpos na MG no agridem, nos
receptores nicotnicos, as subunidades 3, nem as 42, o
que explica a ausncia de sintomas autonmicos e sobre o
sistema nervoso central 33. Por ltimo, em 10% dos pacientes
no se detectam anticorpos, porm esses respondem satisfatoriamente plasmaferese e a injeo de plasma desses
pacientes em animais de experimentao induz neles o aparecimento de MG, sugerindo que, mesmo sem a deteco de
anticorpos por mtodos tradicionais, deve igualmente haver
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um mecanismo de anticorpognese envolvido nessa forma

de MG 3,4,13. Evoluo clnica da doena, idade, envolvimento
do antgeno leucocitrio humano, positividade para anticorpos contra os receptores nicotnicos da placa motora e de
rianodina, alm da presena de doena do timo, auxiliam na
classificao e na previso da evoluo da doena. A classificao da MG conforme aspectos clnicos e laboratoriais
figuram nas Tabelas II e III, respectivamente.
Para a compreenso da fisiopatologia da MG e das reaes aos BNM importante, entre outros aspectos, o entendimento das formas de manuteno da integridade anatmica
da JNM e do funcionamento do receptor nicotnico muscular,
quando da ocupao do neurotransmissor.
Didaticamente, pode-se expor que, basicamente, so dois
os mecanismos mais importantes que mantm o trofismo da
juno nervo e msculo. O primeiro a prpria atividade eltrica provinda do neurnio motor, que atua em toda a superfcie do msculo; o segundo diz respeito ao envolvimento de
sinais moleculares igualmente de origem axonal 30.
A atividade eltrica normal provinda do nervo ntegro inibe
a formao de receptores de acetilcolina em todos os ncleos
musculares, exceto nos subsinpticos. A consequncia direta, quando h uma atividade normal do nervo, a diminuio da formao de receptores extrajuncionais e o estmulo
formao de receptores da placa motora. No que tange ao
envolvimento de molculas na manuteno do trofismo da
placa motora, podem-se citar, em importncia, as aes de
duas substncias agrina e neuregulina, mediadas pela cinase especfica para os msculos, anatomicamente localizada nas proximidades dos receptores nicotnicos musculares.
As duas primeiras molculas provm do nervo e ligam-se
lmina basal 35-37. Algumas outras formas de agrina semelhantes encontrada na placa motora, como as dos vasos
sanguneos, rins e msculos, no levam formao nem ao
agrupamento de receptores de acetilcolina na JNM 30. Estudo
em laboratrio 38 sugere que a agrina neuronal regula tanto a
diferenciao da regio pr-sinptica quanto da regio subsinptica muscular. Essa molcula atua no ncleo subsinptico
do msculo e induz tanto a expresso de receptores de acetilcolina quanto o respectivo agrupamento desses receptores
na superfcie da membrana muscular nas proximidades do
terminal axnico. Igualmente importante nesse mecanismo
Tabela II Classificao da MG segundo a Escala de Ossermann 34

Tipo I
Miastenia ocular caracterizada com ptose e diplopia
Tipo IIa
Incio lento, frequentemente ocular, com evoluo gradativa para musculatura esqueltica
Tipo IIb
Incio lento, com disartria, disfagia e alteraes da mastigao
Tipo III
Incio rpido, com fadiga grave de msculos bulbares e esquelticos, com comprometimento dos msculos da respirao
Tipo IV
MG grave que se manifesta em dois anos
MG: Miastenia Gravis.
Tabela III Classificao da MG segundo Subgrupos 3,13,15

Subgrupos
Idade
(anos)
Associao com ALH
Doena do Timo
Anticorpos
manifestao precoce
< 40
DR3B8
Hiperplasia
RAcol
manifestao tardia
> 40
DR2B7(fraco)
Normal para idade
RAcol, Receptor de rianodina e de titina*
Timoma
Varivel
Desconhecido
Tumor
-RAcol
MG com Ac RAcol:
RAcol, Receptor de rianodina e de titina*

Ac com baixa afinidade RAcol
Varivel
Desconhecido
Alguns casos de
hiperplasia
Pouca afinidade contra RAcol
MG ocular
Varivel
Desconhecido
Desconhecido
RAcol 50% ; RAcol com baixa afinidade
CeMu-MG
Varivel
DR14DQ5
Normal
CeMu
Ac negativo RAcol/CeMu
Varivel
Desconhecido
No esclarecido
Negativo
SME-L
20-60
DR3B8
No relatado
RCa++VD
SME-L com CPcp
> 40
Desconhecido
No relatado
RCa++VD
Neuromiotonia
20-60
Desconhecido
Talvez timoma
RK+VD em 40%
MG: Miastenia Gravis. Ac: anticorpos. RAcol: receptor de acetilcolina. ALH: antgeno leucocitrio humano. DR3B8, DR7B7, DR14DQ5: subtipos de antgeno leucocitrio humano. *titina: protena muscular filamentosa gigante, essencial para desenvolvimento, estrutura e funo muscular. CeMu: cinase especfica do msculo.
Ag: antgeno. SME-L: Sndrome miastnica de Eaton-Lambert. RCa++VD: receptor de clcio voltagem-dependente. CPcp: carcinoma pulmonar de clulas pequenas.
RK+VD: receptor de potssio voltagem-dependente.
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a presena de rapsina. O segundo mecanismo de envolvimento da cinase especfica para os msculos sobre os
receptores de cinases e neuregulina, que tambm interferem
tanto na formao de receptores de acetilcolina e de sua expresso na membrana muscular como nos receptores de sdio 3,39-44. Na MG, a presena de anticorpos contra a cinase
especfica para os msculos altera todos esses mecanismos
complexos de manuteno do trofismo e, como resultado,
evidenciam-se um empobrecimento de receptores de acetilcolina juncionais e um aumento de receptores de acetilcolina
extrajuncionais 45, mecanismo semelhante ao que ocorre em
pacientes cuja atividade eltrica do binmio nervo-msculo
est interrompida 30.
A JNM uma sinapse complexa, que apresenta trs componentes distintos: o terminal axnico pr-sinptico local de
sntese e armazenamento da acetilcolina, a fenda sinptica e
a membrana ps-sinptica, onde se localizam os receptores
nicotnicos e a acetilcolinesterase 30. A TNM normal tem incio
quando um potencial de ao nervoso chega ao terminal axnico pr-sinptico, gerando um influxo de clcio que penetra
no axnio atravs de canais de clcio especficos do tipo P
e Q, ditos voltagem-dependentes. Assim, eles so abertos
quando h alteraes da voltagem da membrana 43. O clcio
penetra no axnio e, ao atuar sobre a calmodulina, libera as
vesculas de acetilcolina do citoesqueleto celular. As vesculas livres movimentam-se e dirigem-se periferia do axnio,
na poro pr-sinptica da placa motora. Atravs de mecanismos que envolvem as molculas ligadas membrana do
axnio, ocorre a fuso da membrana da vescula com a membrana axonal e exocitose de acetilcolina, todos mecanismos
clcio-dependentes. Na fenda sinptica localiza-se tambm a
membrana basal. Nessa estrutura, existem protenas como:
colgeno, laminina, fibronectina e perlecam, importantes
componentes para uma eficiente TNM. O exemplo caracterstico de substncia ligada membrana basal e fundamental
no mecanismo da TNM a ColQ, uma molcula similar ao
colgeno, que se mantm ligada acetilcolinesterase 46.
Uma vez liberadas na fenda sinptica, molculas de acetilcolina ocupam receptores de acetilcolina musculares, alm
de outros neuronais e, em situaes especiais, os extrajuncionais. Com o objetivo de aumentar a rea de contato, a
membrana ps-sinptica forma uma srie de invaginaes
para o interior da clula muscular, onde os receptores nicotnicos ancoram-se e permanecem em suas cristas, enquanto os canais de sdio assumem as pores mais profundas
delas 43,47.
Os elementos-chave da regio ps-sinptica so, sem dvida, o receptor muscular de acetilcolina e as molculas de
clcio. Uma vez que as molculas de acetilcolina ligam-se
entre as subunidades 1 e e 1 e na poro extracelular do receptor, provocam fisiologicamente um movimento
de toro de aproximadamente 10 graus, principalmente das
subunidades , o que resulta em modificao anatmica do
poro localizado na poro transmembrnica. Atravs do poro
central, agora ento com dimetro maior, h entrada de ons
sdio que, alterando a polaridade da membrana, do incio
a um potencial de ao na regio ps-sinptica, tambm
conhecido como potencial de placa 36,44,48,49. Esse potencial,

em adultos normais, muito maior do que o necessrio para
a gerao de potencial de ao na clula muscular, e isso foi
conceituado como fator de segurana da TNM. O trmino
do efeito da acetilcolina dado pela ao da acetilcolinesterase 3,30,42. Os stios fisiolgicos de ligao da acetilcolina no
receptor nicotnico muscular e a movimentao deste, resultando na abertura do poro central, esto representados na
Figura 3.
A grande dificuldade dos cientistas em determinar as mutaes dos receptores colinrgicos musculares que 17 genes codificam esses receptores 46. Assim, algumas funes
so reguladas por mais de um gene e diferentes mutaes
podem resultar em doenas com o mesmo fentipo. Isso
exemplificado por, no mnimo, 56 mutaes que causam as
denominadas Sndromes Miastnicas Congnitas, como so
agrupadas essas doenas que cursam com alteraes da
TNM 46. Elas foram classificadas em pr-sinpticas, sinpticas e ps-sinpticas. As primeiras foram descritas em crianas, que mostraram placa motora normal, mas vesculas de
acetilcolina de tamanho reduzido. Ainda nesse grupo, esto
as entidades que cursam com a diminuio do nmero de
molculas de acetilcolina liberadas quando da exocitose 46.
As denominadas sinpticas esto relacionadas deficincia
de acetilcolinesterase. Esse um defeito gentico da ColQ, j
anteriormente citada. Na deficincia crnica por mutao gentica dessa molcula, mais precisamente no locus 3p24.2,
h diminuio da biodisponibilidade da acetilcolinesterase na
fenda e, como consequncia, excesso de acetilcolina. Ocorre, ento, uma estimulao repetitiva e persistente do msculo, que resulta, por fim, na dessensibilizao dos receptores
nicotnicos da placa motora. Trata-se de uma doena muito rara, com apenas 17 casos descritos na literatura 50. As
Sndromes Miastnicas Congnitas classificadas como pssinpticas esto relacionadas a anormalidades do receptor
nicotnico muscular 46. As principais mutaes registradas
esto localizadas nas subunidades 1, 1 e 46, de forma
que o receptor anormal no responde com movimentao fisiolgica quando h ligao das molculas de acetilcolina, e
o poro central no permite a passagem adequada de molculas de sdio 44.
Na dependncia das mutaes observadas na MG, so
descritos trs comportamentos distintos do receptor nicotnico muscular. O primeiro foi denominado de ganho de funo, onde as mutaes resultam em fechamento lento do
poro central e maior afinidade do receptor pela acetilcolina.
So tambm conhecidas como sndromes do canal lento 51.
A neurotransmisso est comprometida pela carga excessiva de ctions, que leva destruio das invaginaes musculares da placa motora, dessensibilizao do receptor e
ao bloqueio motor por despolarizao 46. a forma mais comum da doena. A segunda disfuno denominada perda de funo. Nessa situao, ocorre o mecanismo inverso, ou seja, o poro se fecha precocemente. Essa forma de
MG recebeu a denominao de sndrome do canal rpido.
A resposta acetilcolina est muito reduzida, a despeito do
aumento do quantum de acetilcolina liberado pelo axnio.
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Canal de on fechado
Canal de on aberto
Figura 3 O receptor nicotnico: modelo de transio alostrica, denominado Modelo quaternrio torcido. Em (a): o modelo do receptor em
estado de repouso e em estado ativo em viso lateral. Uma representao esquemtica da estrutura quaternria em movimento est igualmente
demonstrada em forma de cilindros. Em (b): a rea transmembrnica dos modelos em repouso e no estado ativo, a exemplo do demonstrado em
(a). Reproduzido de Changeux JP 44 com permisso do autor e da editora.
E, por ltimo, h situaes em que ambas as alteraes esto presentes 46. Em todas as trs disfunes, observa-se
comprometimento significativo da TNM 43; para essas trs
modalidades de reao do receptor h diferentes abordagens
e respostas farmacolgicas no tratamento da MG 44. Na Figura 4, esto representadas graficamente as mutaes na MG
na subunidade 1.
Na MG, alm da disfuno de canal, tambm est comprometida a arquitetura da membrana do msculo, principalmente por ao do sistema do complemento 3,4,52. A consequncia imediata a alterao da qualidade e da velocidade
do potencial de placa, levando disfuno dos canais de
sdio voltagem dependente. O resultado final a perda do
Fator de segurana da TNM, provocando fadiga e fraqueza musculares 5. Estudo recente sugere que, alm das alteraes na placa motora, h tambm comprometimento mais
a distncia, precisamente no sistema actina-miosina de
excitao/contrao muscular. Isso observado, particularmente, nos pacientes com a forma generalizada da doena,
que costumam apresentar-se com timoma, o que pode ser
mais um dos fatores que contribuem para a sintomatologia
da doena 53.
A timectomia a situao caracterstica em que o paciente ser submetido a uma anestesia. Os cuidados com o
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paciente portador de MG esto basicamente focados no uso

de medicaes anticolinestersicas no pr-operatrio, na reao aos BNM e em possveis interaes medicamentosas no
perodo transoperatrio 54,55. Igualmente importantes so os
fatores que podem levar necessidade de assistncia ventilatria no ps-operatrio 56,57. Assim, sugere-se que a terapia
com anticolinestersicos no deve ser interrompida antes da
operao e a anestesia regional deve ser preferida sempre
que possvel 9.
Quando a anestesia geral for a escolha, cuidados adicionais devem ser tomados com a injeo de BNM. De forma
geral, pode-se dizer que a reao aos relaxantes musculares
no paciente com MG imprevisvel. No que tange succinilcolina, na maioria das vezes, os pacientes mostram-se resistentes, exigindo doses maiores para se obter um bloqueio
mximo 58. A explicao est embasada no nmero reduzido de receptores, o que resulta na dificuldade de a droga
efetivamente despolarizar a placa motora. No entanto, nem
sempre a reao de resistncia, e pacientes que utilizam
anticolinestersicos ou que fizeram plasmaferese no properatrio podem apresentar um efeito de potencializao da
succinilcolina 9,55,57,59-64. Os autores apontam que os efeitos
so inversamente proporcionais atividade da colinesterase
plasmtica 64.
Ganho de funo
Ganho ou perda
de funo
Perda de funo
Figura 4 Distribuio das mutaes na MG. Em (a) as mutaes com ganho e perda de funo esto distribudas difusamente, na rea extracelular e transmembrnica do receptor. Em (b), a representao dessas mutaes patolgicas esto, de acordo com o Modelo quaternrio torcido,
situadas entre as subunidades e reas rgidas do receptor. Reproduzido de Changeux JP 44 com a permisso do autor e da editora.
A maioria dos pacientes soropositivos ou no para MG

mostra-se com sensibilidade aumentada aos BNM adespolarizantes 9,56,60. Assim, o padro de monitorao da TNM antes
da injeo do BNM geralmente de fadiga muscular e os
pacientes necessitam de doses muito pequenas para manter
um relaxamento mximo. Este foi o exemplo do Caso no 1
(Figura 1). No entanto, autores observaram que, se antes da
injeo de BNM o paciente no apresenta o padro de fadiga
estimulao evocada, a resposta e as doses de BNM sero
iguais s de um paciente normal 12. Essa ausncia de fadiga
foi registrada por eletromiografia do msculo adutor do polegar no Caso no 2, em que a resposta ao BNM seguiu o padro
de um paciente normal (Figura 2).
Assim, sugere-se que, pela variedade de respostas aos
BNM, desde extrema sensibilidade at uma resposta convencional, semelhante observada em pacientes sem MG,
torna-se mandatria a monitorao da TNM na MG, que deve
ser sempre iniciada antes da injeo do relaxante. Recomenda-se, para tanto, o uso de estmulo de forte intensidade,
como SQE (TOF: train-of-four) 12,65. Alm da informao do
comportamento do paciente ao BNM escolhido pelo anestesiologista, essa forma de neuroestimulao igualmente til
na deteco do bloqueio residual no final do procedimento.
Recentemente, autores registram em pacientes com MG
sucesso na reverso do bloqueio induzido por rocurnio com
o sugammadex 66,67. A grande vantagem no uso desse novo
antagonista a constncia na reverso do bloqueio motor
nos pacientes com MG, pois no depende de interaes com
anticolinestersicos usados no tratamento pr-operatrio 68.
Como concluso, a MG definida como uma doena
neurolgica auto-imune que afeta a poro ps-sinptica da
JNM, cursando, na maioria dos casos, com envolvimento do

timo. Em decorrncia das mltiplas formas de apresentao,
de tratamento e de evoluo da doena, e como forma de
prever a reao ao BNM e sua satisfatria reverso, sugerese, na anestesia, a monitorao da TNM com a SQE, com a
aferio da resposta muscular antes da injeo do BNM.
REFERNCIAS / REFERENCES
1.
Grob D, Brunner N, Namba T et al. Lifetime course of myasthenia

gravis. Muscle Nerve, 2008;37:141-149.
2. Meriggioli MN, Sanders DB Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol, 2009;8:475490.
3. Vincent A Autoimmune disorders of the neuromuscular junction.
Neurol India, 2008;56:305-313.
4. Lang B, Vincent A Autoimmune disorders of the neuromuscular
junction. Curr Opin Pharmacol, 2009;9:336-340.
5. Ruff RL, Lennon VA How myasthenia gravis alters the safety factor
for neuromuscular transmission. J Neuroimmunol, 2008;201-202:1320.
6. Lang B, Vincent A Autoantibodies to ion channels at the neuromuscular junction. Autoimmun Rev, 2003;2:94-100.
7. Pasnoor M, Wolfe GI, Nations S et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve,
2009;41:370-374.
8. Provenzano C, Marino M, Scuderi F et al. Anti-acetylcholinesterase
antibodies associate with ocular myasthenia gravis. J Neuroimmunol,
2009;218:102-106.
9. Blobner M, Mann R Anesthesia in patients with myasthenia gravis.
Anaesthesist, 2001;50:484-493.
10. Souza Neto D, Mdolo N Miastenia Gravis: implicaes anestsicas. Rev Bras Anestesiol, 1993;43:373-382.
11. Almeida MCS Uso de Bloqueadores Neuromusculares em Pacientes com Miastenia Gravis. Relato de dois casos. Rev Bras Anestesiol,
2001;51:133-140.
761
12. Mann R, Blobner M, Jelen-Esselborn S et al. Preanesthetic trainof-four fade predicts the atracurium requirement of myasthenia gravis
patients. Anesthesiology, 2000;93:346-350.
13. Romi F, Gilhus NE, Aarli JA Myasthenia gravis: clinical, immunological, and therapeutic advances. Acta Neurol Scand, 2005;111:134141.
14. Meriggioli MN Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci, 2009;26:94-108.
15. Meyer A, Levy Y Geoepidemiology of myasthenia gravis. Autoimmun Rev, 2009;9:A383-386.
16. Chiu HC, Vincent A, Newsom-Davis J et al. Myasthenia gravis:
population differences in disease expression and acetylcholine receptor antibody titers between Chinese and Caucasians. Neurology,
1987;37:1854-1857.
17. Phillips LH The epidemiology of myasthenia gravis. Semin Neurol,
2004;24:17-20.
18. Ercolini AM, Miller SD Role of immunologic cross-reactivity in neurological diseases. Neurol Res, 2005;27:726-733.
19. McGuire LJ, Huang DP, Teoh R et al. Epstein-Barr virus genome in thymoma and thymic lymphoid hyperplasia. Am J Pathol,
1988;131:385-390.
20. Mori M, Kuwabara S, Nemoto Y et al. Concomitant chronic inflammatory demyelinating polyneuropathy and myasthenia gravis following cytomegalovirus infection. J Neurol Sci, 2006;240:103-106.
21. Lalive PH, Allali G, Truffert A Myasthenia gravis associated
with HTLV-I infection and atypical brain lesions. Muscle Nerve,
2007;35:525-528.
22. von Herrath MG, Fujinami RS, Whitton JL Microorganisms and
autoimmunity: making the barren field fertile? Nat Rev Microbiol,
2003;1:151-157.
23. Roxanis I, Micklem K, Willcox N True epithelial hyperplasia in the
thymus of early-onset myasthenia gravis patients: implications for immunopathogenesis. J Neuroimmunol, 2001;112:163-173.
24. Giraud M, Beaurain G, Yamamoto AM et al. Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies. Neurology, 2001;57:1555-1560.
25. Kaminski HJ, Li Z, Richmonds C et al. Complement regulators in
extraocular muscle and experimental autoimmune myasthenia gravis.
Exp Neurol, 2004;189:333-342.
26. Lennon VA, Lambert EH Myasthenia gravis induced by monoclonal
antibodies to acetylcholine receptors. Nature, 1980;285:238-240.
27. Newsom-Davis J, Pinching AJ, Vincent A et al. Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange. Neurology, 1978;28:266-272.
28. Protti MP, Manfredi AA, Straub C et al. Immunodominant regions for
T helper-cell sensitization on the human nicotinic receptor alpha subunit in myasthenia gravis. Proc Natl Acad Sci U S A, 1990;87:77927796.
29. Wang ZY, Okita DK, Howard Jr. J, et al. T-cell recognition of muscle
acetylcholine receptor subunits in generalized and ocular myasthenia
gravis. Neurology, 1998;50:1045-1054.
30. Naguib M, Brull SJ Update on neuromuscular pharmacology. Curr
Opin Anaesthesiol, 2009;22:483-490.
31. Ellison M, Feng ZP, Park AJ et al. Alpha-RgIA, a novel conotoxin
that blocks the alpha9alpha10 nAChR: structure and identification of
key receptor-binding residues. J Mol Biol, 2008;377:1216-1227.
32. Saez-Briones P, Krauss M, Dreger M et al. How do acetylcholine receptor ligands reach their binding sites? Eur J Biochem, 1999;265:902910.
33. Vernino S, Adamski J, Kryzer TJ et al. Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology, 1998;50:1806-1813.
34. Osserman KE, Genkins G Studies in myasthenia gravis: review
of a twenty-year experience in over 1200 patients. Mt Sinai J Med,
1971;38:497-537.
35. Ngo ST, Noakes PG, Phillips WD Neural agrin: a synaptic stabiliser.
Int J Biochem Cell Biol, 2007;39:863-867.
36. Brejc K, van Dijk WJ, Klaassen RV et al. Crystal structure of an
ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature, 2001;411:269-276.
762
37. Poo MM Neurotrophins as synaptic modulators. Nat Rev Neurosci,

2001;2:24-32.
38. Nitkin RM, Smith MA, Magill C et al. Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J Cell Biol,
1987;105:2471-2478.
39. Mossman S, Vincent A, Newsom-Davis J Myasthenia gravis without
acetylcholine-receptor antibody: a distinct disease entity. Lancet,
1986;1:116-119.
40. Fuhrer C, Sugiyama JE, Taylor RG et al. Association of musclespecific kinase MuSK with the acetylcholine receptor in mammalian
muscle. EMBO J, 1997;16:4951-4960.
41. Wallace B scFvs get down to basics: how MuSK makes synapses.
Nat Biotechnol, 1997;15:721-722.
42. Naguib M, Flood P, McArdle JJ et al. Advances in neurobiology
of the neuromuscular junction: implications for the anesthesiologist.
Anesthesiology, 2002;96:202-231.
43. Hughes BW, Kusner LL, Kaminski HJ Molecular architecture of the
neuromuscular junction. Muscle Nerve, 2006;33:445-461.
44. Changeux JP, Taly A Nicotinic receptors, allosteric proteins and medicine. Trends Mol Med, 2008;14:93-102.
45. Lindstrom JM Acetylcholine receptors and myasthenia. Muscle Nerve, 2000;23:453-477.
46. Celesia GG Disorders of membrane channels or channelopathies.
Clin Neurophysiol, 2001;112:2-18.
47. Catterall WA From ionic currents to molecular mechanisms: the
structure and function of voltage-gated sodium channels. Neuron,
2000;26:13-25.
48. Sine SM, Engel AG Recent advances in Cys-loop receptor structure
and function. Nature, 2006;440:448-455.
49. Unwin N Refined structure of the nicotinic acetylcholine receptor at
4A resolution. J Mol Biol, 2005;346:967-989.
50. Ohno K, Brengman J, Tsujino A et al. Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail
subunit (ColQ) of the asymmetric enzyme. Proc Natl Acad Sci USA,
1998;95:9654-9659.
51. Croxen R, Newland C, Beeson D et al. Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome.
Hum Mol Genet, 1997;6:767-774.
52. Vincent A, Beeson D, Lang B Molecular targets for autoimmune
and genetic disorders of neuromuscular transmission. Eur J Biochem,
2000;267:6717-6728.
53. Nakata M, Kuwabara S, Kawaguchi N et al. Is excitation-contraction coupling impaired in myasthenia gravis? Clin Neurophysiol,
2007;118:1144-1148.
54. Nocite J Miastenia Gravis e Anestesia. Rev Bras Anestesiol,
1990;40:443-448.
55. Baraka A, Wakid N, Mansour R et al. Effect of neostigmine and
pyridostigmine on the plasma cholinesterase activity. Br J Anaesth,
1981;53:849-851.
56. Naguib M, el Dawlatly AA, Ashour M et al. Multivariate determinants
of the need for postoperative ventilation in myasthenia gravis. Can J
Anaesth, 1996;43:1006-1013.
57. Baraka A Anaesthesia and myasthenia gravis. Can J Anaesth,
1992; 39: 476-486
58. Eisenkraft JB, Book WJ, Mann SM et al. Resistance to succinylcholine in myasthenia gravis: a dose-response study. Anesthesiology,
1988;69:760-763.
59. Naguib M, Sari-Kouzel A, Ashour M et al. Myasthenia gravis and
pipecuronium--report of two cases. Middle East J Anesthesiol,
1992;11:381-390.
60. Itoh H, Shibata K, Nitta S Sensitivity to vecuronium in seropositive and seronegative patients with myasthenia gravis. Anesth Analg,
2002;95:109-113.
61. Kim JM, Mangold J Sensitivity to both vecuronium and neostigmine
in a sero-negative myasthenic patient. Br J Anaesth, 1989;63:497500.
62. Nilsson E, Meretoja OA Vecuronium dose-response and maintenance requirements in patients with myasthenia gravis. Anesthesiology,
1990;73:28-32.
63. Smith CE, Donati F, Bevan DR Cumulative dose-response curves

for atracurium in patients with myasthenia gravis. Can J Anaesth,
1989;36:402-406.
64. Baraka A Suxamethonium block in the myasthenic patient. Correlation with plasma cholinesterase. Anaesthesia, 1992;47:217-219.
65. Mann R, Blobner M Neuromuscular monitoring in myasthenia gravis. Anaesthesist, 2000;49 Suppl 1:S26-28.
66. Unterbuchner C, Fink H, Blobner M The use of sugammadex in a
patient with myasthenia gravis. Anaesthesia, 2010;65:302-305.
67. de Boer HD, van Egmond J, Driessen JJ et al. Sugammadex in
patients with myasthenia gravis. Anaesthesia, 2010;65:653.
68. Tripathi M, Kaushik S, Dubey P The effect of use of pyridostigmine
and requirement of vecuronium in patients with myasthenia gravis. J
Postgrad Med, 2003;49:311-314.
Resumen: Kauling ALC, Almeida MCS, Locks GF, Brunharo GM

Miastenia Gravis: Relato de dos Casos y Revisin de la Literatura.
Justificativa y objetivos: La Miastenia Gravis (MG), es una enfermedad neurolgica autoinmune que afecta la porcin postsinptica
de la unin neuromuscular. Se trata de un reto para el anestesilogo

en funcin de la diversidad de las manifestaciones de la enfermedad

y por la posibilidad de complicaciones ventilatorias en el postoperatorio. El objetivo de este trabajo es demostrar la importancia de la
monitorizacin adecuada al bloqueo neuromuscular (BNM), en virtud
de las mltiples formas de presentacin de la MG.
Contenido: En este artculo, se describirn dos casos de pacientes
con MG: uno que present la forma clsica de sensibilidad al bloqueante neuromuscular (BNM), y el otro con una respuesta similar a la
de un paciente normal. La revisin de la literatura quedar restringida
a las caractersticas de la enfermedad, y la descripcin de su fisiopatologa estar dirigida a las reacciones a los BNM.
Conclusiones: Como conclusin, sugerimos que, en funcin de las
mltiples formas de presentacin y de tratamiento de la MG, es fundamental usar los monitores de la TNM cuando se usa BNM.
Descriptores: ANESTESIA, General; BLOQUEANTE MUSCULAR,
Atracurio; ENFERMIDADES, Muscular, Miastenia Gravis; MONITORACIN; TCNICAS DE MEDICIN, Eletromiografia.
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Documento descargado de http://dev.rba.elsevier.es el 17/09/2014.

Rev Bras Anestesiol

Myasthenia Gravis: Two Case Reports and Review of the

Myasthenia gravis (MG) is an autoimmune neurologic disease

Received from Universidade Federal de Santa Catarina (UFSC), Brazil.

of severe postoperative ventilatory complications 9,10. In the

MYASTHENIA GRAVIS: TWO CASE REPORTS AND REVIEW OF THE LITERATURE

carcinoma. On preoperative evaluation, she reported history

KAULING, ALMEIDA, LOCKS ET AL.

terized by weakness and fatigue of skeletal muscles due to

Table I Percentage of Muscle Involvement in MG 1,2,15

Ocular and bulbar

Ocular and limbs

Requiring ventilatory assistance

Death despite ventilatory assistance 8%

with muscle contraction have been identified. Among them

MYASTHENIA GRAVIS: TWO CASE REPORTS AND REVIEW OF THE LITERATURE

Table II Classification of MG According to the Ossermann Scale 34

Ocular myasthenia characterized by ptosis and diplopia

Slow onset, frequently ocular, with gradual evolution to skeletal musculature

Slow onset with dysarthria, dysphagia, and changes in mastication

Severe MG that manifests in two years

MG: Myasthenia Gravis.

Table III Classification of MG in Subgroups 3,13,15

Normal for age

AchR, ryanodine and titin receptors*

MG with anti-AchR antibody:

AchR, ryanodine and titin receptors*

Little affinity for AchR

AchR 50%; AchR with low affinity

Anti-AchR/MuKi antibody negative

except in subsynaptic nuclei. The direct consequence, when

is also involved on kinase receptors and neuregulin, which

KAULING, ALMEIDA, LOCKS ET AL.

axon through specific type P and Q calcium channels, called

The key elements of the postsynaptic region are, without

Revista Brasileira de Anestesiologia

MYASTHENIA GRAVIS: TWO CASE REPORTS AND REVIEW OF THE LITERATURE

a group of diseases causing changes in NMT 46. They were

es early. This type of MG is called fast channel syndrome.

KAULING, ALMEIDA, LOCKS ET AL.

When general anesthesia is the choice, additional care

Therefore, we suggest that due to the variety of response

Revista Brasileira de Anestesiologia

Rev Bras Anestesiol

Miastenia Gravis: Relato de Dois Casos e Reviso da

Recebido da Universidade Federal de Santa Catarina (UFSC), Brasil.

Revista Brasileira de Anestesiologia

RELATO DOS CASOS

KAULING, ALMEIDA, LOCKS E COL.

no invasiva aferida automaticamente, oximetria de pulso,

Figura 2 Traado eletromiogrfico do msculo adutor do polegar

MIASTENIA GRAVIS: RELATO DE DOIS CASOS E REVISO DA LITERATURA

Ao final do procedimento, a paciente recuperou a funo

Tabela I Percentual de Acometimento Muscular na MG

Com necessidade da AV.

Morte apesar da AV.

MG: Miastenia Gravis; AV: Assistncia Ventilatria.

nolgico da doena, comprovado pela melhora substancial

KAULING, ALMEIDA, LOCKS E COL.

um mecanismo de anticorpognese envolvido nessa forma

Tabela II Classificao da MG segundo a Escala de Ossermann 34

Miastenia ocular caracterizada com ptose e diplopia