Transcript NEUROMUSCULAR COUNCIL CONSENSUS STATEMENT

NEUROMUSCULAR COUNCIL
CONSENSUS STATEMENT
THYMECTOMY FOR
NONTHYMOMATOUS AUTOIMMUNE
MYASTHENIA GRAVIS PATIENTS
Introduction
Through the years many neurologists have favored the
use of thymectomy in the management of patients with
nonthymomatous autoimmune myasthenia gravis (MG).
This wide acceptance is based largely upon case series and
retrospective studies which have suggested that
thymectomy may be beneficial. However, many of these
studies have shown variable results. Moreover, the absence
of controlled, prospective trials casts some doubt
regarding effectiveness of the procedure in this group of
patients. Thus, until the results of an ongoing
international, prospective, single blind randomized trial
controlling for medical therapy become available, the use
of thymectomy in this situation remains controversial.
In the local medical centers where thymectomy is
being performed, no standard guidelines in the selection of
patients and the pre- and post-operative management have
been created. This necessitates the formulation of such
guidelines.
Objectives
General Objective
The Neuromuscular Council of the Philippine
Neurological Association aims to improve outcomes
for MG patients by providing the initial framework for
decision-making for neurologists with regard to the
patient diagnosed with nonthymomatous autoimmune
MG who is a candidate for thymectomy.
Specific Objective
To develop a combined evidence- and consensusbased practice parameter to guide neurologists in
managing patients diagnosed with nonthymomatous
autoimmune myasthenia gravis who can be candidates
for thymectomy.
Methodology
Group Composition
The working group is composed of the members
of the Neuromuscular Council of the PNA.
Dr. Lina Renales
Dr. Rosalia Teleg
Dr. Valmarie Estrada
Dr. Darwin Dasig
Dr. Emmanuel Eduardo
Dr. Alejandro Diaz
Dr. Raymond Rosales
Dr. Jose Paciano Reyes
Dr. Ludwig Damian
Dr. Marita Dantes
Consensus Process
The initial draft of the consensus statement was a
synthesis of the survey, identification of the key clinical
issues, output of literature search using Medline and the
local registry and academic deliberation by the working
group over the identified key issues. Deliberation
included appraisal of the literature in terms of validity
and applicability, preparation of evidence-based
summaries and development of judgments by
consensus. This is to be followed by presentation of the
statements in a public forum composed of the PNA
fellows.
Disclaimer:
The assessment and recommendations provided
herein represent the best professional judgment of the
working group at this time, based on research data
gathered and on expertise currently available. The
conclusions and recommendations will be regularly
assessed as new information becomes available. The
consensus statement is intended to be an educational
guideline and is therefore neither rigidly prescriptive nor
restrictive.
Key Clinical Issues
Addressed
1.
2.
3.
Should thymectomy for nonthymomatous myasthenia
gravis be recommended?
What is the clinical profile of nonthymomatous
autoimmune MG patients likely to benefit from
thymectomy?
When is the ideal time to perform thymectomy?
4.
5.
6.
What is the preferred thymectomy technique to use?
What is the recommended pre-operative
management?
What is the recommended post-operative
management?
Consensus Proper
QUESTION 1:
Should thymectomy for nonthymomatous
autoimmune myasthenia gravis be
recommended?
A. Consensus Statement
Practice Recommendation
For patients with nonthymomatous autoimmune
MG, thymectomy is recommended as an option to
increase the probability of remission or improvement
(Level 2 evidence).
Research Recommendation
There is a need to conduct a well-designed,
prospective, controlled study to evaluate clinical
effectiveness of thymectomy in nonthymomatous,
autoimmune myasthenia gravis patients that utilize
comparison with standardized medical therapy and welldefined evaluation standards.
B. Summary of Evidence
To address the uncertainty of the usefulness of
thymectomy in nonthymomatous autoimmune MG
because of the lack of prospective and controlled
studies, the working group utilized the systematic review
done by the American Academy of Neurology.1 Their
review of 28 articles (Class II evidence 2) published
from 1953 to 1998 describing outcome in 21 MG
cohorts revealed the following observations:
1.
2.
Positive associations in most studies between
thymectomy and MG remission and improvement
with median rates of 2.1 for medication-free
remission, 1.6 for asymptomatic group and 1.7 for
improvement;
Confounding differences in baseline characteristics of
prognostic importance between thymectomy and
nonthymectomy groups in all studies;
3.
4.
Persistent positive associations between thymectomy
and improved outcomes after controlling for single
confounding variables such as age, gender and
severity of MG;
Conflicting associations between thymectomy and
improved MG outcomes in studies controlling for
multiple confounding variables simultaneously.
They concluded that it cannot be determined from
available studies whether the observed association
between thymectomy and improved MG outcome was
a result of thymectomy benefit or was merely a result
of multiple differences in baseline characteristics.
Thus, the benefit of thymectomy in nonthymomatous
autoimmune MG has not been established
conclusively.
QUESTION 2:
What is the clinical profile of nonthymomatous
autoimmune MG patients most likely to benefit
from thymectomy?
A. Consensus Statement
Practice Recommendation
The candidate most likely to benefit is the patient
with all of the following attributes (Level 2 evidence):
 generalized MG
 age between puberty and 60 years and
 positive titers for anti-Acetylcholine Receptor
Antibody (anti-AChR Ab) when applicable
 female gender
Research Recommendation
There is a need to conduct a well-designed
prospective, controlled study to evaluate clinical
outcome after thymectomy with respect to the disease
variables (e.g. grade or severity of the illness, age of the
patient, gender, duration of the disease, etc.), treating
these variables singly or in combination.
B. Summary of Evidence
1.
Gender
Women have been reported to have a better outcome than
men after thymectomy
2.
Age

There is general consensus that patients with generalized MG
between puberty and 60 years will benefit from thymectomy.
Most MG experts advocate cutoff ages ranging between 50 to
70 years with median at 60 years.
Thymectomy has been performed with favorable results in
childhood. Procedure, however, remains controversial in
younger children with ages ranging from 1 year to puberty.


3.
Clinical Severity

Patient subgroup analysis in one study indicated that only
those patients with MG with moderate weakness or greater
(Osserman 2B3 / MGFNA4 ) showed significant
improvement after thymectomy compared with control
subjects. Results, however, were confounded by baseline
patient differences across groups.
The studies reviewed did not include patients with pure ocular
MG.
Severe patients who underwent thymectomy had better
prognosis compared with severe patients who did not.


4.
Duration of Disease
No data have been gathered as yet regarding measurement of
outcome after controlling for single confounding variable like
duration of disease (whether within 1-2 years from onset or
beyond 2 years from onset).
No conclusive data likewise are available associating improved
MG outcome with thymectomy after controlling for multiple
confounding variables.
QUESTION 3:
When is the ideal time to perform
thymectomy?
A. Consensus Statement
Practice Recommendation
Thymectomy is best performed within 1 to 2
years from the time of diagnosis provided that the
patient has achieved:
 optimal muscle strength and
 optimal medical condition
 adequate cardio-pulmonary functions (Level 2
evidence)
Research Recommendation
There is a need to conduct a well-designed
prospective, controlled study to evaluate clinical
outcome after thymectomy with respect to the timing
of surgery.
B. Summary of Evidence
Some authors suggested that benefits from
thymectomy were achieved more readily the earlier the
surgery was done, with larger remission rates per unit
time (Class III evidence). However, it has been
postulated that this may be solely due to non-linear rate
at which MG patients achieve remission after diagnosis.
This means that for a given duration of time, MG
patients are more likely to remit earlier than later.
QUESTION 4:
What is the preferred thymectomy
technique to use?
A. Consensus Statement
Practice Recommendation
Properly performed total thymectomy using the
Extended Transsternal Approach may provide the
greatest resection with low morbidity and less risk for
recurrent laryngeal nerve injury (Level 2 evidence).
Research Recommendation
There is a need to conduct a well-designed
prospective, controlled study to evaluate clinical outcome
after thymectomy with respect to the different
thymectomy technique.
B. Summary of Evidence
The report of the Quality Standards Committee of the
American Academy of Neurology1 concluded that the
outcome comparisons between uncontrolled studies do not
provide conclusive evidence of the superiority of one
technique over another. This was due to the numerous
confounding differences in patients’ baseline characteristics
and new confounders (institutional, geographic and
historical differences).
Likewise, controlled trials reviewed failed to provide
convincing evidences that one technique was superior,
again due to the confounding differences and
inconsistent results. Moreover, operative techniques
employed were either not identified or limited to
standard transsternal and basic transcervical thymectomy.
The review of the retrospective studies3 that was
published after the AAN Guidelines publication concluded
that the studies had conflicting results and had many
confounding variables such as patient population,
accompanying therapy, details of evaluation, extreme
variability and unpredictability of MG, variability of
selection of patients for thymectomy and
immunesuppressives drugs after surgery. The need for
properly designed prospective trials or a non-randomized
prospective study of two or more techniques remains.
In a separate article4 ,Jaretzski had written that the
more complete the thymic resection, the better the
outcome.
A retrospective trial comparing the late results of
basic transsternal and extended transsternal
thymectomies5 revealed that complete remission rates
were significantly higher in the extended group at 1, 2, 3
and 4 years follow-up (Level 2 evidence). Negative results
(no improvement, deterioration or death from MG) were
significantly lower in the extended thymectomy group.
The difference was postulated to be due to the removal
of ectopic foci of thymic tissue from the neck and
mediastinum.
Mantegazza et.al. performed a prospective,
uncontrolled trial comparing video-assisted thoracoscopic
extended thymectomy (VATET) and T3-B operative
techniques6 and concluded that VATET seems to be
effective in inducing complete stable remission similar to
T-3B TS approach (Level _ evidence). VATET had the
advantage of being easier to perform and having lower
morbidity and negligible esthetic sequelae.
QUESTION 5:
What is the recommended pre-operative
management?
A. Consensus Statement
The objective of a pre-operative management is to
ensure that there will be careful selection of patients for
thymectomy to optimize its long term benefits. The
patients must be in optimum medical condition prior to
surgery to avoid or minimize intraoperative and postoperative complications.
Management in the peri-operative period requires a
concerted effort among the neurologist, thoracic surgeon,
pulmonologist and other internists, the anesthesiologist
and the physiatrist.
Practice Recommendation
5.1
What are the steps to follow during preoperative management?
1. Perform a thorough neurologic evaluation and
clearance: Ensure that the patient has optimum
muscle power. When appropriate, correct
oropharyngeal, bulbar and respiratory muscle
weakness using the following regimen:
a) anti-cholinesterase inhibitors
(pyridostigmine, neostigmine) and/or any of
the following:
b) corticosteroids (prednisone, prednisolone)
c) other immunosuppressants when these become
necessary. Use of these, however, may require
several weeks to a several months before optimum
therapeutic benefit is obtained.
d) plasmapheresis or intravenous immune-globulin,
when applicable, in patients with moderate to
severe bulbar and respiratory muscle weakness or
in patients with a high titer of anti-Acetylcholine
Receptor antibodies.
5.1
2. Acquire adequate pulmonary evaluation and clearance to
assure presence of patent airways, optimum respiratory
muscle power, adequate clearing of secretions and
absence of respiratory infection.The following preoperative tests are recommended:
a) chest x-ray
b) arterial blood gases
c) pulmonary function test (including VC, FEV, MEF,
flow-volume loop) and exercise testing (with 6-8
hours off anticholinesterase inhibitor e.g.
Mestinon)
d) sputum G/S, C/S when necessary
e) chest CT scan when necessary
f) perfusion studies when necessary
5.1
3.
Perform cardiac evaluation as follows:
a) basic tests: ECG, chest x-ray;
b) complete cardiology evaluation and
clearance if
- the patient is 40 years old or
above
- if patient has history of ischemic
heart disease or other cardiac problems or
risks for developing cardiac problems.
c) 2D echocardiography when
necessary
d) stress test when necessary
e) nuclear medical tests when
necessary
5.1
4.
Search for and adequately treat concomitant medical
conditions:
a) Infection
b) Disorders associated with MG. Do the following
tests:
- ESR
- thyroid function tests
- blood sugar
- ANA
- rheumatoid factor
c) Disturbance in nutrition, fluids and
electrolytes
5.1
5. Check CBC and bleeding parameters (CT, BT, PT,
PTT).
6. Refer to Rehabilitation Medicine specialist to assure
good pulmonary capacity and adequate muscle tone.
7. Consider drug effects and drug interactions.
If the patient is on medications, ensure that there are
no side effects of these drugs or adverse drug reactions
that may interfere with or complicate the intra- and
post-operative course of the patient (Refer to Table on
Drug Effects and Interactions ).
Practice Recommendation
5.2 What is the recommended anesthetic
management?
1. Anesthesiologists must consider the patient’s disease
severity including:
- voluntary and respiratory muscle strength
- ability to protect and maintain patent airway
post-operatively
- the type of surgical procedure and the
surgeons’ preferences
- patient’s ongoing medication (e.g. Mestinon and
steroids).
5.2
2. For pre-operative medications:
Generally, anxiolytics, sedatives and
opioids are rarely given to patients with little
respiratory reserve.
Small dose benzodiazepines, when
necessary, may be given to patients with good
respiratory reserve.
5.2
3. Choice of anesthetic agents:
The anesthesiologist must confer with the
neurologist and the surgeon and other specialists
when needed.
There are several anesthetic agents that can be used
(see Table on Anesthetic Agents).
There is no anesthetic technique that is superior to
others. Choice depends on preference of the
doctors. These techniques have included:
a.
b.
c.
Avoidance of muscle
relaxants and use of
potent inhaled
anesthetics both for
facilitating tracheal
intubation and
providing relaxation for
surgery.
Titration of small doses
of intermediate acting
relaxants to the evoked
EMG.
Use of total
intravenous anesthesia
(TIVA).
d.
e.
Use of local or regional
anesthetic techniques.
The decision whether
to reverse residual NM
blockade at the end of
surgery or to wait for
spontaneous recovery
and extubate when
patient demonstrates
adequate parameters for
extubation remains
controversial.
5.2
There is need to monitor patients especially
noting interactions of the anesthetic
agents with other drugs and keeping in mind the
variable responses the myasthenic patients may
have to the anesthetic drugs.
Practice Recommendation
5.3 Should pyridostigmine be continued or
discontinued pre-operatively?
A. Consensus Statement
Practice Recommendation
Pyridostigmine or other anticholinesterase may be
continued pre-operatively if the patient derives
improved muscle strength with its use. The following
guidelines are recommended:
1. To allow a decrease in the blood level pre-operatively, give
pyridostigmine or anticholinesterase 4 to 6 hours pre-operatively.
In this way, it will not interfere with the anesthetic.
Pyridostigmine may be resumed post-operatively.
2. Pyridostigmine may cause increase in oral and tracheal
secretions especially in intubated patients. This can be titrated to
avoid or minimize problems in post-operative pulmonary toilet.
B. Summary of Evidence
Omitting pyridostigmine pre-operatively may
reduce the need for muscle relaxant as well as lessen the
effect of ester anesthetic agents. However, the omission
of the pyridostigmine on the day of surgery
predisposed myasthenic patients to the possibility of
respiratory discomfort and sensitivity to vecuronium.7
(Class I evidence)
Practice Recommendation
5.4
Should corticosteroids be continued
discontinued pre- and peri- operatively?
or
A. Consensus Statement
Practice Recommendation
Steroids should be continued pre-operatively in
steroid-dependent patients.
B. Summary of Evidence
Steroid-dependent patients have the possibility of
developing post-operative deterioration or crisis so that
they will require pre- and peri-operative coverage.8
(Level 2 evidence)
Steroids also decrease dose of non-depolarizing
relaxants to which myasthenic patients are highly
sensitive.
QUESTION 6:
What is the recommended post-operative
management?
A. Consensus Statement
Practice Recommendation
6.1 Closely monitor at Post-Anesthesia Care Unit or
Surgical Intensive Care Unit
Respiratory support can be immediately instituted
6.2 Predict as accurately as possible the best time to
extubate based on:
- Pre-operative condition of the patient
- Surgical technique used
6.2
- Residual anesthetic effect
- Parameters for weaning include: absence of crisis
triggers, objective findings showing adequate
muscle power, vital capacity > 10 ml/kg, negative
inspiratory force > 20 cm water, positive
expiratory force > 40 cm water.
Practice Recommendation
6.3 Predict as accurately as possible the need for
post-operative mechanical ventilation based on:
- Pre-operative condition of the patient
- Surgical technique used
- Residual anesthetic effect
- Parameters: Kaneda 1995/Eisenkraft
1986/or Leventhal 1980
Practice Recommendation
6.4
Maintain adequate post-operative pain control.
Avoid muscle relaxants and tranquilizing drugs.
6.5 Maintain adequate
physical therapy
pulmonary
toilet
and
6.6 Avoid or use very cautiously drugs interfering
with neuro-muscular transmission (Refer to Table on
Drugs Acting on NM Junction))
Practice Recommendation
6.7 Determine the best time to resume
pyridostigmine/anticholinesterase and
steroids/immunesuppressants and the appropriate
dose, considering that:
- Anticholinesterases can keep muscle power at
adequate levels.
- Anticholinesterases can increase oral and
tracheal secretions.
- Steroid-dependent patients will need
immediate post-operative coverage.
Thank you very much!