Anesthetic Implications of Myasthenia Gravis
MARK ABEL, M.D.1, AND JAMES B. EISENKRAFT, M.D.2
Abstract
Myasthenia gravis is a disease of great significance to the anesthesiologist, because it affects the neuro- muscular junction. Many patients with this condition are treated by surgical thymectomy, using tech- niques developed by Mount Sinai physicians, including Dr. Paul Kirschner, Dr. Alan E. Kark, and the late Dr. Angelos E. Papatestas. The authors review the anesthetic considerations in the management of patients with myasthenia gravis who are undergoing thymectomy and other surgical procedures. Key Words: Myasthenia gravis, anesthesia, thymectomy.
Epidemiology and Pathophysiology velop respiratory failure. Thymoma is present in 10 –15% of patients with MG (5). In a now MYA S T H E N I A G R AV I S (MG) is an autoimmune classic paper, Osserman and Genkins, both disease characterized by weakness and fatiga- physicians at The Mount Sinai Hospital, pub- bility of skeletal muscles, with improvement lished a clinical classification of myasthenia following rest. It may be localized to specific gravis that is still in widespread use (6). muscle groups or it may be generalized. The in- The diagnosis of MG can be confirmed by cidence is 50–142 cases per million population several tests. The anticholinesterase test is pos- (1). MG is caused by a decrease in the numbers itive if strength improves with inhibition of of postsynaptic acetylcholine receptors at the cholinesterase. When cholinesterase is inhib- neuromuscular junction (2), which decreases ited, more acetylcholine is available to interact the capacity of the neuromuscular end-plate to with the decreased number of postsynaptic re- transmit the nerve signal. Initially, in response ceptors, increasing the likelihood of adequate to a stimulus resulting in depolarization, acetyl- end-plate depolarization. Edrophonium (Te n- choline is released presynaptically. In MG, the s i l o n®) is usually administered intravenously in number of activated postsynaptic receptors may small (2– 8 mg) doses for this test. This test be insufficient to trigger a muscle action poten- was introduced and popularized by Dr. Osser- tial (3). Further, with repeated stimulation, the man (7). Electromyography is also used in the decline in release of acetylcholine correlates diagnosis of myasthenia. Repetitive stimula- with the characteristic fatigability (4). tion of a peripheral motor nerve leads to de- creasing responses by the innervated muscle in P resentation and Diagnosis a patient with MG. The presence of anti-acetyl- choline antibodies in the serum, as detected by The characteristic presentation of MG is r a d i o i m m u n o a s s a y, is diagnostic of MG. Such fatigability of voluntary muscles. Most com- antibodies may not be detectable, however, in m o n l y, the eyelids and extraocular muscles are all patients with mild symptoms at presentation. involved. Bulbar involvement may be mani- fested as difficulty in chewing and swallowing. Tre a t m e n t Eighty-five percent of myasthenic patients go on to develop generalized weakness; some de- Treatment of MG may be medical or surg i- cal, utilizing one of three approaches: anti- cholinesterases (medical), immune suppression (medical), or thymectomy (surg i c a l ) . 1Assistant Professor of Anesthesiology and 2Professor of An e s t h e - Improving neuromuscular transmission by si o l o g y , Mount Sinai School of Medicine, New York, NY. means of anticholinesterase agents is the most Address correspondence to Mark Abel, M.D., Department of An e s t h e s i o l o g y , Box 1010, Mount Sinai School of Medicine, One common approach. Pyridostigmine (Mestinon) East 100th Street, New York, NY 10 0 2 9 - 6 5 7 4 . in a dose of up to 120 mg p.o. every 3 hours is 32 THE MOUNTSINAI JOURNALOF MEDICINE January/March 2002 used because it is tolerated well orally, with few If a thymoma presents an anterior mediasti- muscarinic side effects, and has a relatively nal mass, intrathoracic airway or vascular ob- long duration of action. Pyridostigmine 30 mg struction may occur upon the induction of anes- orally is equivalent to 1 mg intravenously or in- thesia. Flow-volume loops may be indicated t r a m u s c u l a r l y. p r e o p e r a t i v e l y. Maximal inspiratory and expi- Immune suppression is directed at prevent- ratory flow-volume loops obtained with the pa- ing or attenuating the destruction of acetyl- tient in the supine and upright positions will choline receptors at the motor end plate (8). measure the extent of the respiratory impair- Corticosteroids, which cause immune suppres- ment as well as whether the impairment is fixed sion, will improve the condition of most myas- or dynamic. thenics (9). Those who do not respond or who The preoperative management of the myas- cannot tolerate the side effects may respond to thenic patient will be influenced by the surg i c a l azathioprine 2.5– 3.5 mg/kg. Cyclosporine has procedure and the preferences of the surg e o n been used in patients with MG (10) and com- and the anesthesiologist. Some choose to omit pares favorably with azathioprine (11 ) . anticholinesterase on the morning of surg e r y, to For patients with severe bulbar symptoms decrease the need for muscle relaxants (21), or respiratory compromise (myasthenic crisis), whereas others continue its use for psychologi- plasmapheresis is used (12). Significant im- cal support of the patient. If the patient is provement occurs over days, with decreased de- poorly controlled, a course of plasmapheresis pendence on ventilatory support (13). The pre- may be of benefit in the preoperative period sumed mechanism is the removal of antibodies, (22). The steroid-dependent patient will require allowing receptors to proliferate. Immune perioperative coverage. globulin given intravenously has been used to Anxiolytic, sedative, and opioid premedica- treat myasthenic crises when plasmapheresis tions are rarely given to patients who may have cannot be used. Its use has been associated little respiratory reserve. If the patient has pri- with good short-term improvement (14). marily ocular symptoms, a small dose of benzo- Thymectomy is used to treat MG, but the diazepine is acceptable. mechanism of its action remains speculative. Antibody titers decrease with clinical improve- Response to Anesthetic Drugs ment (15). Suggested mechanisms include re- moval of antigenic stimulus by the removal of Nondepolarizing Neuro m u s c u l a r B l o c k e rs myoid cells or alterations in immune regulation by removal of the thymus. For an up-to-date Neuromuscular blocking drugs act by inter- history of surgery of the thymus gland, as well rupting neuromuscular transmission at the level as speculation on the future, the recent review of the nicotinic acetylcholine receptors at the by Kirschner (16) is recommended reading. motor end plate. Their mode of action can be classified as antagonist (nondepolarizing) or Anesthesia Considerations — Pre o p e r a t i v e agonist (depolarizing), both producing block- Evaluation and Pre p a r a t i o n ade (23). The myasthenic patient is typically sensitive to nondepolarizing neuromuscular Preoperative evaluation of the MG patient blockers. The use of a small dose for priming includes review of the severity of the patient’s or defasciculation is not appropriate, because it disease and the treatment regimen. Specific at- may result in loss of airway protection or in res- tention should be paid to voluntary and respira- piratory distress. Sensitivity to nondepolariz- tory muscle strength. The patient’s ability to ing agents has been described in patients with protect and maintain a patent airway postopera- minimal disease (i.e., ocular symptoms only) tively may be compromised if any bulbar in- (24), in those in apparent remission (25), or volvement exists preoperatively. The ability to those with subclinical undiagnosed myasthenia cough and clear secretions may be compromised ( 2 6 ) . as well. Respiratory muscle strength can be Long-acting muscle relaxants such as d- quantified by pulmonary function tests (nega- tubocurarine, pancuronium, pipecuronium, and tive inspiratory pressure and forced vital capac- doxacurium, are best avoided in these patients. ity). These tests may be necessary as a refer- Intermediate and short-acting nondepolarizing ence to determine the optimal conditions for ex- agents can be used with careful monitoring of tubation postoperatively as well as the need for neuromuscular transmission, preferably with postoperative mechanical ventilation (17, 18). electromyogram (EMG) or mechanomyogram Vol. 69 Nos. 1 & 2 ANESTHESIAAND MYASTHENIAGRAVIS—ABEL 33
(MMG), which measure the evoked electrical or cular block by agonist action. The ED9 5 of suc- mechanical responses following electrical stim- cinylcholine in MG patients is 2.6 times that in ulation of a peripheral motor nerve. Stimuli can non-myasthenic patients (0.8 mg/kg vs. 0.3 be delivered singly (0.1 Hz or one every 10 sec- mg/kg) (34). The dose of succinylcholine used onds; 1 Hz or one per second), or in trains-of- for rapid airway control in normal patients, 1.5 four (TOF) stimuli (2 Hz) at 10-second inter- mg/kg, is approximately five times the ED9 5 i n vals. In the absence of a neuromuscular block, MG. A dose of 1.5 –2.0 mg/kg should be ade- a control response is obtained. This control quate for most myasthenics, for rapid sequence “twitch” is designated Tc. In the absence of a intubation (34). A case report of a myasthenic neuromuscular block, all responses should be of patient in complete remission showed a normal equal magnitude. Thus, with TOF stimulation, sensitivity to succinylcholine (37). Myasthenic the control, first, second, third and fourth re- patients are more likely than normal patients to sponses are equal (Tc=T1=T2=T3=T4). In the develop a phase II block, particularly with re- presence of a nondepolarizing block, Tc > T 1 peated doses of succinylcholine (38). and T4
Intravenous Anesthetic A g e n t s of the postjunctional membrane to acetyl- choline (71). This theoretically could cause Anesthetic management using barbiturates weakness in myasthenics if blood levels are and propofol for myasthenic patients without high enough. Ester anesthetics, which are me- untoward effects have been described (53, 54). tabolized by cholinesterase, may present partic- Propofol has the theoretic advantages of short ular problems in patients taking anti- duration of action without effect on neuromus- cholinesterases. Regional and local anesthesia cular transmission. should be performed using reduced doses of Opioid analgesics in therapeutic concentra- amide (rather than ester) local anesthetics to tions do not appear to depress neuromuscular avoid high blood levels. Tr a d i t i o n a l l y, block- transmission in myasthenic muscle (55, 56). ade of the innervation of intercostal muscles is H o w e v e r, central respiratory depression may be avoided to minimize the risk of respiratory a problem with opioids. The introduction of muscle weakness. Recently, however, the safe short-acting opioids makes these drugs more and successful use of thoracic epidural block- titratable in the myasthenic. Remifentanil’s ade with bupivacaine for intraoperative anes- short elimination half-life (9.5 minutes) (57) thesia and postoperative analgesia for transster- makes the drug appealing. To date, there are no nal thymectomy has been reported (72, 73). reports of its use in MG. There are reports of Spinal anesthesia has the advantage of reduced uneventful anesthesia using etomidate (58), al- drug dosage, whereas epidural techniques facil- thesin (58) and ketamine in myasthenic patients itate easier control of blockade level and may ( 5 9 ) . obviate the need for opioids in postoperative pain management. Interactions with Other D r u g s Anesthesia Management Many commonly used drugs affect neuro- muscular transmission to a small degree. In The safe use of general anesthesia requires normal patients, this is usually of no clinical attention to monitoring the patient and under- significance. In the myasthenic patient, upon standing the variable responses that the myas- e m e rgence from anesthesia and surg e r y, the in- thenic may have to many drugs. The EMG and teractions of these drugs with residual anes- the mechanomyograph are the preferred meth- thetic effect and the disease state of MG may be ods for monitoring neuromuscular transmis- more significant. sion. They record control values to compare The most commonly used drugs known to with those elicited throughout surgery and post- depress neuromuscular transmission are the o p e r a t i v e l y. Recently, submaximal train-of- aminoglycoside antibiotics and the polymyxins four stimulation in awake patients has been ad- ( 6 0 –62). Beta adrenergic blockers, regardless vocated (74). Similarly, the presence of fade of their mode of administration, have been (T4/T1 < 0.9) in the preanesthetic period pre- shown to exacerbate MG (63, 64). dicts decreased atracurium requirements in pa- Corticosteroids, although used in the treat- tients with MG (75). This technique, along ment of MG, may also exacerbate MG (62). with preoperative pulmonary function testing Corticosteroids have not been shown to aff e c t (17), may be useful in determining preoperative the dose-response to succinylcholine, but they baseline function. have been shown to decrease the dose require- Several general anesthetic techniques have ments for nondepolarizing relaxants in myas- been proposed, although none has been proven thenics (65). Procainamide was reported to to be superior to the others. Some prefer to cause weakness in a myasthenic patient (66). avoid muscle relaxants altogether and use po- Phenytoin has caused clinical weakness in a tent inhaled agents both for facilitating tracheal myasthenic patient (67); however, it has been intubation and providing relaxation for surg e r y. used without clinical side effects for seizure These agents allow neuromuscular transmission disorders in patients with MG (68). to recover, with rapid elimination of these agents at the end of surg e r y. In theory, desflu- Regional A n e s t h e s i a rane and sevoflurane may offer some advan- tages, due to their low blood solubility. Potentiation of neuromuscular blocking Sevoflurane is probably superior to desflurane, drugs by local anesthetics has been reported due to its lower incidence of excitatory airway (69, 70). These agents decrease the sensitivity reflexes during inhalational induction. Others Vol. 69 Nos. 1 & 2 ANESTHESIAAND MYASTHENIAGRAVIS—ABEL 35
titrate small doses (10– 25% of the ED9 5) of in- ceptors. It usually results from administration termediate-acting relaxants to the evoked MMG of excess anticholinesterase drugs. Nicotinic or EMG for both intubation and surgical relax- overstimulation results in involuntary twitch- ation, if required. The decision as to whether to ing, fasciculations, and weakness (sometimes reverse residual neuromuscular blockade at the leading to respiratory arrest). The weakness re- end of surgery is controversial. Some arg u e sults from an inability to coordinate muscle that the presence of anticholinesterases and an- contraction and relaxation. When the mus- timuscarinics will confuse efforts to diff e r e n t i- carinic effects are obvious, the diagnosis is eas- ate weakness due to inadequate neuromuscular ily made. Antimuscarinics and respiratory sup- transmission from cholinergic crisis in the re- port are indicated. When acetylcholinesterase covery room. They prefer spontaneous recov- inhibition in conjunction with antimuscarinics ery and extubation when the patient has demon- has been used to reverse residual neuromuscu- strated adequate parameters for extubation (i.e., lar blockade, weakness and fasciculations may head-lift, tongue protrusion). predominate in the absence of muscarinic Total intravenous anesthesia (TIVA) for the symptoms. To differentiate this from myas- management of myasthenics has been reported thenic crisis, an edrophonium (Te n s i l o n®) test (53). In the authors’ experience, hemodynamic may be administered. Also, in a myasthenic cri- instability in older patients makes this approach sis, the pupils will be dilated. In the absence of d i fficult, whereas younger patients usually tol- muscarinic symptoms, simply allowing the pa- erate it without diff i c u l t y. The use of remifen- tient to recover clinically, without elaborate tanil as part of T I VA may alleviate some of the testing, while maintaining mechanical respira- hemodynamic instability. tory support, constitutes a safe and practical ap- When possible, many clinicians prefer to proach. For these reasons, many clinicians pre- utilize regional or local anesthetic techniques. fer to avoid the use of muscle relaxants, or if Regional techniques may reduce or eliminate they do so, to allow the neuromuscular block to the need for muscle relaxants in abdominal recover spontaneously, avoiding the use of anti- s u rg e r y. Epidural techniques offer the advan- cholinesterase in the immediate postoperative tage of postoperative pain control with minimal p e r i o d . or no opioid use. C o n c l u s i o n s Postoperative Considerations Myasthenia gravis is a disease with many There have been several attempts to predict implications for the safe administration of anes- the need for postoperative ventilation (17, 76, thesia. The potential for respiratory compro- 77). Based on the preoperative condition of the mise in these patients requires the anesthesiolo- patient, the surgical procedure, and the residual gist to be familiar with the underlying disease anesthetic effects, a carefully planned extuba- state, as well as the interaction of anesthetic and tion may be carried out in most patients. A d e- nonanesthetic drugs with MG. Thymectomy is quate postoperative pain control, pulmonary a surgical procedure commonly undergone by toilet, and the avoidance of drugs that interfere patients with MG. with neuromuscular transmission will facilitate tracheal extubation. All patients with MG R e f e re n c e s should be closely monitored postoperatively in 1. Phillips LH. The epidemiology of myasthenia gravis. Neurol the postanesthesia care unit or the surgical in- Clin 1994; 12:263– 2 7 1 . tensive care unit, where respiratory support can 2. Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular be immediately reinstituted. Weakness after junction in myasthenia gravis: Decreased acetylcholine s u rgery presents a special problem in MG pa- receptors. Science 1973; 182:293– 2 9 5 . 3. Elmquist D, Hoffman W W, Kugelberg J, et al. An electrophysio- tients. The differential diagnosis includes logical investigation of neuromuscular transmission in myas- myasthenic crisis, residual effects of anesthetic thenia gravis. J Physiol (Lond) 1964; 174:417– 4 3 8 . drugs, nonanesthetic drugs interfering with neu- 4. Maselli RA. Pathophysiology of myasthenia gravis and Lam- romuscular transmission and cholinergic crisis. bert-Eaton syndrome. Neurol Clin 1994; 12:285– 3 0 3 . 5. Souadjian JV, Enriquez P, Silverstein MN, et al. The spectrum Cholinergic Crisis of disease associated with thymoma. Arch Int Med 1974; 1 3 4 : 3 7 4 – 3 7 9 . 6. Osserman KE, Genkins G. Studies in myasthenia gravis: C h o l i n e rgic crisis results from an excess of Review of a twenty-year experience in over 1200 patients. acetylcholine at the nicotinic and muscarinic re- Mt Sinai J Med 1971; 38:497– 5 3 7 . 36 THE MOUNTSINAI JOURNALOF MEDICINE January/March 2002
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