Myasthenia Gravis/Multiple Sclerosis Case File

Myasthenia Gravis/Multiple Sclerosis Case File

Lydia Conlay, MD, PhD, MBA, Julia Pollock, MD, Mary Ann Vann, MD, Sheela Pai, MD, Eugene C. Toy, MD

Case 31

A 49-year-old woman presents to preadmission testing for the removal of her sigmoid colon secondary to diverticulitis. She has a 15-year history of myasthenia gravis, and is currently receiving pyridostigmine, 800 mg/day. She was on Prednisone 10 mg/day until about a month ago for her myasthenic symptoms. But as her symptoms improved, her steroids were discontinued. The patient’s past-surgical history include a bronchoscopy and mediastinoscopy 12 years ago followed by a thymectomy a few weeks later. She reports that she was on the ventilator in the ICU afterward on both occasions.

➤ What preoperative information is important in the patient with myasthenia gravis?

➤ What is the most important point to remember when anesthetizing a patient with myasthenia gravis?

➤ What are the major postoperative concerns in patients with myasthenia gravis?

ANSWERS TO CASE 31:

Myasthenia Gravis/Multiple Sclerosis

Summary: A 49-year-old woman presents for a sigmoid colectomy. She suffers from myasthenia gravis, and was intubated postoperatively following surgery for a thymectomy.

➤ Important preoperative information: The preoperative information important in a patient suffering from myasthenia gravis includes a history related to the severity of the disease, any related deficits, the patient’s baseline activity level, and any evidence of pharyngeal muscle dysfunction. It is important to understand her medication regimen, and the need for and/or frequency of plasmapheresis. A review of any previous anesthetic records is also important, and can provide useful information as to the dosage of drugs required. Pulmonary function tests are useful to estimate the likelihood of a need for postoperative ventilation, any extra-thoracic compression of the airway caused by the thymus, and the degree of restrictive lung disease.

➤ Anesthesia with myasthenia gravis: Patients with myasthenia gravis are exquisitely sensitive to nondepolarizing neuromuscular blockers. Markedly reduced doses, perhaps even as little as 1/10 of the usual dose of a nondepolarizing muscle relaxant is commonly sufficient. However, the response to neuromuscular blockers is variable, and can be affected by pyridostigmine. Therefore, the administration of small doses of muscle relaxant to determine a patient’s requirement is of paramount importance.

➤ Major postoperative concerns: The major postoperative concerns include assessing the need for prolonged ventilation, the ability to clear secretions, and optimizing the patient’s medication regimen.

ANALYSIS

Objectives

1. Acquaint the learner with the items in the preoperative evaluation that are particularly important in a patient with myasthenia gravis.

2. Understand how the pathophysiology of myasthenia gravis affects anesthetic drugs and the anesthetic plan.

3. Be able to anticipate the most common postoperative concerns in the myasthenic patient.

4. Become familiar with the perioperative issues encountered in a patient with multiple sclerosis.

Considerations

This patient is suffering from myasthenia gravis which has profound implications on the conduct of anesthesia for a sigmoid colectomy. It is important to carefully study her old anesthetic records, to asses her responses to the anesthetic technique, drugs, and doses which were used. This aides the anesthesiologist in optimizing the doses of anesthetic, in an attempt to minimize the likelihood or duration of postoperative ventilation. Following her previous surgeries, she required postoperative ventilation and admission to the ICU. However, the second surgery, a thymectomy, was performed with the intent of improving her myasthenia. So in this case, the history of requiring postoperative ventilation may or may not predict her requirements following this operation.

The physical examination should focus on the neurological system. Any neurological deficits should be documented. Special attention should be paid to her ability to cough and clear secretions, since pharyngeal muscles are often involved in this disease.

Pulmonary function tests (PFTs) help delineate the degree of restrictive pulmonary disease. Both myasthenia, and its treatment can cause respiratory muscle weakness, hindering the ability to extubate the patient at the end of the procedure. Studies have shown that a preoperative vital capacity of < 2.9 L, and a reduced FEV25-75 of <3.0 L/sec predict a need for postoperative ventilation. In myasthenics with an intact thymus, flow volume loops may also be required to assess any extrathoracic compression to the airway.

Some poorly-controlled patients with myasthenia gravis may need preoperative plasmapheresis to reduce the patient’s antibody load before surgery. Most anesthesiologists do not make any changes to the patient’s medication regimen on the day of surgery, although some choose to omit pyridostigmine on the morning of the surgery to reduce the need for neuromuscular blockers.

Given the surgical procedure, a general endotracheal anesthetic is appropriate. Long-acting neuromuscular blocking agents should be minimized. A low-dose lumbar epidural technique may provide sufficient relaxation and allow nondepolarizing muscle relaxants to be avoided all together, in addition to providing postoperative analgesia. Standard monitoring utilizing ECG, pulse oximetry, urine output, and blood pressure is adequate for this patient. If however, on the basis of history and PFTs postoperative ventilation is anticipated, then an arterial line may be inserted to enable blood gas sampling as she is weaned from the ventilator.

Since her medication regimen includes steroids, providing a stress dose of perioperative steroids may be appropriate under these circumstances.

APPROACH TO

Myasthenia Gravis/Multiple Sclerosis

DEFINITIONS

DEPOLARIZING MUSCLE RELAXANTS (DMR): Depolarizing muscle relaxants act by actually binding to the acetylcholine receptors and blocking access of the drug to the receptors. In the process of binding, the receptor is activated causing depolarization that is usually visible as fasciculations or brief muscle contractions. Succinylcholine is a depolarizing muscle relaxant. The action of succinylcholine is terminated by pseudocholinesterase, an enzyme found in the blood and hence its action lasts for only a few minutes.

NONDEPOLARIZING MUSCLE RELAXANTS (NDMR): Nondepolarizing muscle relaxants bind to acetylcholine receptors in a reversible manner and act by blocking the access of acetylcholine to the receptors on the motor end plate. NDMRs do not activate the receptor in the process, so neither depolarization nor fasciculations occur.

ACETYLCHOLINESTERASE INHIBITORS: Acetylcholinesterase is an enzyme that is responsible for breaking down acetylcholine. Drugs that block this enzyme, known as cholinesterase inhibitors, result in more acetylcholine being available. This reverses the effect of the nondepolarizing muscle relaxants in a competitive manner. The most commonly used acetylcholinesterase inhibitor in anesthesia is neostigmine. Other acetylcholinesterase inhibitors include edrophonium, prostigmine, and pyridostigmine. Pyridostigmine can be taken orally and is the drug of choice in the treatment of myasthenia gravis.

CLINICAL APPROACH

Myasthenia Gravis

Anesthesiologists should consider the impact of the patient’s muscular weakness on the anesthetic technique they choose. Volatile anesthetics cause some muscular weakness intraoperatively, an effect that is exaggerated in patients with myasthenia. A similar muscle-relaxing action is associated with neuraxial anesthetic technique such as epidural or spinal. Not always sufficient for surgical relaxation in normal patients, either volatile anesthetics or an epidural may provide sufficient relaxation in myasthenic patients. Allowing the nondepolarizing muscle relaxants to be used sparingly or avoided all together minimizes the possibility of prolonged paralysis associated with their use.

Regional anesthetics can also be performed without neuromuscular blocking agents, and some also provide excellent postoperative pain relief. However, it is important to take into consideration the patient’s preference for remaining awake (or not) and the surgeon’s comfort and speed. It is important to be cognizant that epidurals and spinals can impair respiratory effort if the motor and sensory levels rise high enough to impair the efficient working of the intercostal muscles.

Intubation is usually accomplished with succinylcholine, a depolarizing muscle relaxant. Using succinylcholine avoids the need for an intubating dose of a NDMR, and it’s possible that no NDMR will be needed for the operation. The onset of succinylcholine’s action may be delayed in myasthenic patients because of blockade of acetylcholine receptors by antibodies. In contrast, succinylcholine’s duration of action may be prolonged since it is metabolized by plasma pseudocholinesterase, which is also inhibited by anticholinesterase medications. Preoperative plasmapheresis may also deplete plasma pseudocholinesterase levels. The bottom line: the action of succinylcholine is unpredictable, and affected by a number of factors in patients with myasthenic gravis.

In the event that the myasthenic patient is bed or wheelchair bound, or where succinylcholine would be otherwise contraindicated, it may well be possible to intubate the patient with no muscle relaxant at all, or perhaps with the aid of a volatile agent.

Neuromuscular monitoring is indicated in patients with myasthenia gravis. Before the administration of any muscle relaxants, the presence of fade in the Train of Four predicts a reduced requirement for nondepolarizing muscle relaxants (NDMR) in myasthenic patients. NDMRs normally induce a fade response, where the height of the first twitch T1 is greater than the second twitch T2 >T3 >T4. During the case, it is imperative to dose NDMRs to provide adequate surgical relaxation without abolishing of all the twitches. This requires that NDMRs be used sparingly if at all, and long-acting NDMRs such as pancuronium and doxacurium should absolutely be avoided. Similarly, mivacurium, although one of the shortest acting NDMRs, is relatively contraindicated because it is dependent upon plasma pseudocholinesterase for its metabolism. If required, short- and intermediate-acting NDMRs like vecuronium or cisatracurium are appropriate. Myasthenics usually require 40% to 50% of the usual dose of vecuronium. But since the individual’s response can be so variable, the administration of very small doses, in succession if necessary, is appropriate.

The anesthesiologist must be aware of other drugs that may affect neuromuscular transmission. These include magnesium, corticosteroids, aminoglycoside antibiotics, lithium, and beta blockers. Similarly, some drugs inhibit pseudocholinesterase, including echothiophate eye drops and donepezil (Aricept). Many of these drugs can increase neuromuscular blockade and make matters worse for the myasthenic patient.

Extubation of myasthenic patients requires careful evaluation. First and foremost, the patient’s muscle strength must support spontaneous ventilation, and he or she must be able to handle and clear secretions. This usually means that there is no fade on the Train of Four (TOF), or at least a return to the patient’s baseline. The patient must be able to sustain a negative inspiratory pressure of at least 12 to 15 cm of water, able to lift his or her head off the pillow for at least 5 seconds, and obey commands prior to extubation.

On the other hand, the administration of neostigmine to reverse neuromuscular blockade, especially in patients already on large doses of pyridostigmine, can lead to a cholinergic crisis resulting from an exaggerated activation of nicotinic and muscarinic cholinergic receptors. Excessive salivation, miosis, bronchoconstriction, bradycardia, muscle weakness, jitteriness, muscle twitching, bowel cramps, nausea, urinary and bowel incontinence are some of the signs and symptoms of cholinergic crisis. The administration of anticholinergics like glycopyrrolate or atropine may mask the muscarinic actions during a cholinergic crisis, allowing nicotinic effects such as muscle weakness and twitching to predominate. Such nicotinic signs and symptoms are difficult to differentiate from an inadequate NDMR reversal, and from myasthenia itself. In order to avoid such confusion, many anesthesiologists avoid reversing residual NDMR paralysis. Instead they rely on careful dosing and the patient to remain intubated on the ventilator until all the NDMR’s effects have resolved.

Multiple Sclerosis

Another neuromuscular disorder commonly encountered by anesthesiologists is multiple sclerosis (MS). MS is a demyelinating disease which affects neurons in unpredictable patterns. Because of the nature of this disorder, any neurological deficits should be carefully noted and documented preoperatively, and the patient made aware of all preexisting deficits.

The most common perioperative concern in patients with MS is the possibility of an exacerbation of the disease after surgery. Any stressful condition, such as fever/hyperpyrexia, infection, pain, or fatigue may cause an exacerbation or relapse. It is very difficult to separate the effects of these factors from the effects of the stress of the surgery itself, or the anesthetic techniques or drugs that are used. It is important that the patient must be kept at normal body temperature in the operating room, since excessive heat seems to be harmful in this group of patients.

Avoiding the stress of postoperative pain is similarly a priority. Although the rationale is not understood, epidural analgesia is thought to be associated with fewer relapses of multiple sclerosis than a spinal. An epidural catheter can be placed in the preoperative period to provide postoperative analgesia and reduce catecholamine release and pain. Amide local anesthetics like bupivacaine 0.125% with the addition of a small amount of narcotic like hydromorphone 10 μg/cc can provide excellent postoperative pain relief. Ester-based local anesthetics  may also be used, bearing in mind that many of them are metabolized by pseudocholinesterase. Patients on pyridostigmine have reduced plasma pseudocholinesterase activity and hence normally short-acting ester-based local anesthetics like chloroprocaine may have an unpredictable duration of action.

Although epidural local anesthetics can cause some degree of motor weakness, bupivacaine 0.125% or 0.067% concentrations at rates of 4 to 10 cc/h should not cause appreciable motor block. It is important to titrate to analgesia and perform periodical neurological checks to ensure significant motor blocks

do not set in. Alternatively, patient controlled analgesia (PCA) can also be used in the postoperative period. Use of non-opioid oral and parenteral analgesics like ketorolac, ibuprofen, acetaminophen are desirable as they offer good analgesia without appreciable postoperative nausea, vomiting, sedation, or respiratory depression.

Postoperative Management

If the patient cannot be safely extubated in the operating room, she must be transferred to an intensive care unit or PACU where close monitoring is possible and a plan to wean the patient off the ventilator in place. Prolonged postoperative ventilation is undesirable, since it is often associated with respiratory infections, resulting in more difficulties with extubation later on. Postoperatively a complete neurological examination must be performed to document any new deficits.

Comprehension Questions

31.1. A 40-year-old woman with myasthenia gravis presents for abdominal surgery. She has no other comorbidities or risk factors. Which the following tests is most likely to be useful at the pre-anesthetic visit?

A. Pulmonary function tests

B. Electrocardiogram

C. Chest x-ray

D. CBC

31.2. Which of the following is metabolized by pseudocholinesterase?

A. Cisatracurium

B. Succinylcholine

C. Pyridostigmine

D. Dexamethasone

31.3. Which of the following anesthetic management plans apply specifically to patients with multiple sclerosis?

A. Preanesthetic documentation of all neurological deficits

B. Provision of stress doses of steroids if the patient has recently abruptly stopped steroids

C. Avoidance of spinal anesthesia

D. Keeping the body temperature normal and avoiding hyperthermia

ANSWERS

31.1. A. Pulmonary function tests, old anesthetic records, and a complete neurological examination are useful because they give an idea of preexisting neurological deficits and also help plan the course of the anesthetic based on previous performance and pulmonary function. An electrocardiogram, chest x-ray, and CBC in an otherwise healthy 40-year-old female is unlikely to add additional information that is helpful in the management of this patient.

31.2. B. Succinylcholine, is metabolized by the plasma enzyme pseudocholinesterase. Thus in patients taking cholinesterase inhibitors, the action of succinylcholine may be prolonged. Answer A, cisatricurium, is metabolized by Hoffmann degradation. C, pyridostigmine, is a drug used predominantly for the treatment of myasthenia gravis. Pyridostigmine bromide is an analogue of neostigmine that inhibits acetylcholinesterase as well as plasma pseudocholinesterase, and thus the breakdown of acetylcholine. D, dexamethasone, is not metabolized by pseudocholinesterase.

31.3. D. Higher body temperatures have been associated with an increase in neuronal demyelination and relapses. Hence, keeping normal body temperature and avoiding hyperthermia in patients with multiple sclerosis is important. Pre-anesthetic documentation of neurological deficits is important because new deficits can sometimes appear postoperatively. Stresses such as pain and anxiety have been implicated in relapses. Although there is no definitive proof that spinal anesthesia is associated with relapses and onset of new neurological deficits, most anesthesiologists would avoid spinal anesthesia in a patient with sever multiple sclerosis. Stress doses of steroids are controversial but most anesthesiologists would consider a dose of steroid in any patient who has abruptly stopped steroid medications.

Clinical Pearls

➤ Myasthenics are usually exquisitely sensitive to nondepolarizing muscle relaxants and these drugs should be used sparingly if at all.

➤ Patients suffering from myasthenia gravis have a varied and unpredictable response to nondepolarizing muscle relaxants.

➤ Drugs that can increase muscle weakness in myasthenics include neuromuscular blocking agents, volatile anesthetics, anticholinesterases, aminoglycoside antibiotics, beta blockers, prolonged steroid administration, lithium, magnesium, and local anesthetics.

➤ In patients with multiple sclerosis, minimizing surgical stress, controlling pain, fever, hemodynamic fluxes to intubation as well as maintenance of normal body temperature are goals of the anesthetic plan.

References

Abel M, Eisenkraft JB. Anesthetic implications of myasthenia gravis. Mt Sinai J Med. 2002;69(1-2):31-37. 

Hirsch NP. Neuromuscular junction in health and disease. Br J Anaesthesiol. 2007;99(1):132-138. 

Miller RD. Anesthesia. 6th ed. vol 1. Pennsylvania: Elsevier, Churchill Livingstone; 2005. 

Naguib M, el Dawlatly AA, Ashour M, Bamgboye EA. Multivariate determinants of the need for postoperative ventilation in myasthenia gravis. Can J Anaesthesiol. 1996;43(10):1006-1013.

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