NEUROMUSCULAR COUNCIL CONSENSUS STATEMENT

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NEUROMUSCULAR COUNCIL CONSENSUS STATEMENT

• THYMECTOMY FOR NONTHYMOMATOUS AUTOIMMUNE
• MYASTHENIA GRAVIS PATIENTS

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Introduction
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• 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.

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• 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.

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Objectives
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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.

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Specific Objective

• To develop a combined evidence- and
  consensus-based practice parameter to guide
  neurologists in managing patients diagnosed with
  nonthymomatous autoimmune myasthenia gravis who
  can be candidates for thymectomy.

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Methodology
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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
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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.

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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.

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Key Clinical Issues Addressed
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• 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?

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• What is the preferred thymectomy technique to
  use?
• What is the recommended pre-operative management?
  
• What is the recommended post-operative management?

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Consensus Proper
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QUESTION 1

• Should thymectomy for nonthymomatous autoimmune
  myasthenia gravis be recommended?

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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 well-defined
  evaluation standards.

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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

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• 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

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• 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.

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• 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.

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QUESTION 2

• What is the clinical profile of nonthymomatous
  autoimmune MG patients most likely to benefit
  from thymectomy?

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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

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• 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.

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B. Summary of Evidence

• Gender
• Women have been reported to have a better
  outcome than men after thymectomy
• 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.

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• 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.

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• 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.

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QUESTION 3

• When is the ideal time to perform thymectomy?

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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)

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• 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.

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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.

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QUESTION 4

• What is the preferred thymectomy technique to
  use?

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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.

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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).

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• 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.

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• 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.

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• 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.

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• 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.

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QUESTION 5

• What is the recommended pre-operative management?

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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 post-operative
  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.

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Practice Recommendation

• 5.1 What are the steps to follow during
  pre-operative 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
• anti-cholinesterase inhibitors (pyridostigmine,
  neostigmine) and/or any of the following
• corticosteroids (prednisone, prednisolone)

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• 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.

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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 pre-operative tests are
  recommended
• a) chest x-ray
• b) arterial blood gases

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• 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

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5.1

• 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.

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• c) 2D echocardiography when
  necessary
• d) stress test when necessary
• e) nuclear medical tests when
  necessary

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5.1

• 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

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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 ).

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Practice Recommendation

• 5.2 What is the recommended anesthetic
  management?
• 1. Anesthesiologists must consider the patients
  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
• - patients ongoing medication (e.g. Mestinon
  and steroids).

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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.

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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

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• 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).

• 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.

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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.

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Practice Recommendation

• 5.3 Should pyridostigmine be continued or
  discontinued pre-operatively?

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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.

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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)

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Practice Recommendation

• 5.4 Should corticosteroids be continued or
  discontinued pre- and peri- operatively?

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A. Consensus Statement

• Practice Recommendation
• Steroids should be continued pre-operatively in
  steroid-dependent patients.

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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.

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QUESTION 6

• What is the recommended post-operative
  management?

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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

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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.

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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

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Practice Recommendation

• 6.4 Maintain adequate post-operative pain
  control.
• Avoid muscle relaxants and tranquilizing drugs.
• 6.5 Maintain adequate pulmonary toilet and
  physical therapy
• 6.6 Avoid or use very cautiously drugs
  interfering with neuro-muscular transmission
  (Refer to Table on Drugs Acting on NM Junction))

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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.

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Thank you very much!