EDUCATION / ENSEIGNEMENT
MYASTHENIA GRAVIS AND ANESTHESIA – A REVIEW OF THE LITERATURE
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Myasthenia gravis (MG) is an immunological disorder characterized by damaged acetylcholine receptors (AchR) due to antibody, which not only blocks the receptor site but also causes degenerations of the receptors.. It is closely associated with disorders of similar pathogenesis, such as pernicious anaemia, thyrotoxicosis, SLE, hypothyroidism, rheumatoid like arthritis, red cell aplasia and polymyositis. The disease is characterized by skeletal muscle weakness and fatigability upon sustained effort and commonly affects the ocular, bulbar and limb muscles.
Anticholinesterases, immunosuppressive drugs, plasmaphresis, and thymectomy are the four strategies in the treatment of myasthenia. The thymus plays a critical role in immuno surveillance and has been incriminated in its pathogenesis. There is therefore a general consensus that adults with myasthenia gravis should have thymectomy.
The anaesthetic management of the myaesthenic patient must be individualized to the severity of the disease and the type of surgery. Such patients may have an abnormal response to muscle relaxants, a restricted respiratory capacity with inability to cough and clear the increased secretions resulting from anticholinesterase therapy or have a co-existing cardiomyopathy.
It may be safe and advantageous to discontinue anticholinesterase therapy just before surgery in order to minimize their vagotonic side effects. It is also safe to decrease the dose of depolarizing and non-depolarising blockers required to maintain muscle relaxation during surgery. Furthermore, MG patients are at increased risk of developing post-operative respiratory failure and it is likely that they would require ventilatory support after surgery. Post-operative care should be done in the intensive care unit with tracheal suction and monitoring of respiratory function as well as chest physiotherapy.
Despite the anaesthetic, intra- and post-operative problems envisaged in patients with myasthenia gravis, cases with mild generalized MG could have uneventful operations if necessary precautions are taken. The course of MG is extremely variable, although, spontaneous remission is common, relapse is the rule.
La myasthénie gravis (MG) est liée à un dysfonctionnement du système immunitaire. (Il) Elle se caractérise par une anomalie des récepteurs de l’acétylcholine (AchR) causée par des anticorps avec pour conséquence non seulement un blocage du site des récepteurs mais également leur dégénerescence. Elle peut être associée à des affections de pathogénie identique telles que l’anémie pernicieuse, la thyréotoxicose, l’hypothyroïde ou encore la polyarthrite rhumatoïde, l’aplasie médullaire et la polymyosite.
La maladie se caractérise par une faiblesse des muscles squelettiques et une fatigabilité après un effort soutenu. Elle atteint généralement les muscles oculaires extrinsèques, les muscles pharyngo-laryngés et de la face ainsi que les muscles des membres.
Il existe quatre types de traitement contre la myasthénie : les anticholinesthérasiques, les immunodépresseurs, les échanges plasmatiques et la thymectomie. Le thymus qui joue un rôle décisif dans l’immuno-régulation et est impliquée dans la pathogénie . Ainsi, l’on s’accorde à penser que les adultes atteints de myasthénie gravis devraient avoir recours à une thymectomie.
La prise en charge anesthésique du malade myasthénique doit être individualisée selon la gravité de la maladie et le procédé chirurgical. En effet, ces patients peuvent avoir une réaction négative aux relaxants musculaires, souffrir d’une insuffisance respiratoire ou être dans l’impossibilité de tousser et d’expectorer les sécrétions importantes apparues après un traitement anticholinestérasique ou en rapport avec une myocardiopathie coexistante. Il est prudent d’interrompre le traitement anticholinesthérasique juste avant l’intervention afin de réduire les effets
En dépit des problèmes anesthésiques per-opératoires et post-opératoires pouvant survenir chez les patients atteints de myasthénie gravis, la forme légère généralisée peut être opérée sans complication à condition de prendre les précautions nécessaires.
Following the description of “the habitual and spurious palsies” by Thomas Willis in 1672, Erb, Goldflam, and Samuel Wilks in 1877 firmly established the clinical features of myasthenia gravis (MG) [1,2]. It is an uncommon disease with an incidence varying from 1 in 10,000 to 50,000 adults . The peak incidence occurs in the third to fifth decade with a second peak in the seventh decade. It affects females more than males at a younger age (20 to 40 years) in the ratio of 2:1, while there is reversal in sex predilection after 40 years with a male to female ratio of 4:1 [3,4]. It is doubtful that myasthenia gravis is increasing in frequency.
Myasthenia gravis is an immunological disorder characterized by damaged acetylcholine receptors (AchR) due to antibody, which not only blocks the receptor site but also causes degenerations of the receptors [5,6,7]. The disease is characterized by skeletal muscle weakness and fatigability upon sustained effort and commonly affects the ocular, bulbar and limb muscles [8,9]. It is closely associated with disorders of similar pathogenesis, such as pernicious anaemia, thyrotoxicosis, SLE, hypothyroidism, rheumatoid like arthritis, red cell aplasia and polymyositis [10,11].
Pathophysiology of myasthenia gravis and neuromuscular blockade
The serum concentrations of these antibodies as measured by binding assays correlate poorly with the clinical severity of weakness in patients with MG: 100% with moderately severe (IIB); 80% in mild generalized (IIA); 50% in ocular muscle; and 25% in remission . This suggests that factors other than the antibody titer may be important in determining the clinical severity of the weakness . One possible explanation is that the functional activity of the antibodies such as the ability to reduce the number of available AchR may be clinically relevant in its pathogenesis . The thymus plays a critical role in immuno surveillance and has been incriminated in the pathogenesis of MG [8,9]. It is abnormal in approximately 75% of myaesthenics. Sixty-five percent of the patients have thymic hyperplasia with active germinal centers, while 10% have thymic tumors (thymoma) .
Decreased release of acetylcholine by the presynaptic nerve terminals may also have a role in the fatigue of MG. Some studies [12,17] found decreased quantal content while many other studies found increased quantal quantity and increased acetylcholine release from nerve terminals in MG [6,14,18]. Thus, it is unclear whether quantal content is decreased or increased or unaffected in this condition. Furthermore, synaptic cleft is widened and post synaptic regions may be present where there is no overlying nerve terminals .
Phase 1 block: The depolarizing neuromuscular blocking agent suxamethonium (succinylcholine) acts as the name implies by depolarizing the neuromuscular end plate. Unlike acetylcholine, suxamethonium is not hydrolysed by acetylcholinestrase in the synaptic cleft. In the stead, it is hydrolysed by cholinesterase in plasma (pseudocholinesterase, acylcholine-acylhydrolase). As a result, the clearance of suxamethonium from the synaptic cleft, depends on diffusion from the cleft into the plasma and is much slower than the clearance of acetylcholine. Therefore, suxamethonium is able to react repeatedly with the receptor, causing a longer lasting depolarization of the end plate. In contrast, acetylcholine normally only reacts once with the receptor before it is hydrolysed. This continuous depolarization of the end plate inactivates the voltage dependent sodium channels of the muscle membrane adjacent to the end plate, thereby preventing depolarization of the muscle membrane and initiation of an action potential. This inactivation of the voltage dependent sodium channels (sometimes called accommodation block) last until suxamethonium has diffused away from the synaptic cleft and the end plate is repolarized. If suxamethonium remains at the neuromuscular junction for an extended period of time, either because of a prolonged infusion in a patient with normal plasma cholinesterase activity or because a relative overdose has been given to a patient with genotypically abnormal plasma cholinesterase, a phase II block ensues . The membrane potential gradually recovers to normal though the neuromuscular transmission is still blocked. The original depolarizing block changes to a non-depolarising-like block. This change in block characteristics has been described as a change from a phase I to a phase II block. Other less fortunate designations used are dual block, mixed block or desensitization block.
Some antibiotics such as aminoglycosides, polypeptides, tetracyclines, clindamycin and lincomycin may increase the sensitivity of myasthenia to muscle relaxants. Tricyclic antidepressant drugs, and quinidine may cause channel block while -blockers, calcium channel blockers and magnesium sulphate could aggravate or unmask myasthenia gravis [19,20]. Phenytoin, carbamazepine, azathioprine, corticosteroids, and methylxanthines also cause resistance to the effect of non-depolarising muscle relaxant .
In MG, there is a decrease in the number of functional AchRs available, with a subsequent decrease of the “safety margin” which is why they may demonstrate resistance to depolarizing blockers but extreme sensitivity to non-depolarising blockers. Intermediate acting relaxant such as atracurium vecurorium are rapidly eliminated and could be used [21,22].
Myasthenia Symptoms could be ocular, bulbar or generalized. Ocular symptoms are diplopia, ptosis and external opthalmoplegia while bulbar symptoms include nasal speech and regurgitation, atrophy of tongue and respiratory embarrassment. Skeletal muscle weakness is usually proximal but could be generalized and asymmetric in up to 85% of patients .
Extra ocular muscle involvement may be so severe occasionally to produce complete external opthalmoplegia usually unaccompanied with internal opthalmoplegia. Facial muscle involvement, at least to a minimal degree in the orbicularis oculi muscle region accompanies the extraocular muscle pareses in almost every instance . This is responsible for the characteristic facies in which there is a tendency towards obliteration of the normal folds, as well as a lack of compensatory furrowing of the forehead in the presence of ptosis producing a “snarling” expression.
More widespread bulbar muscle involvement affecting the muscles of mastication, palate, pharynx and larynx may be present initially, or more often constitute a further development during the course of illness . When the bulbar manifestations are conspicuous, it is reasonable to look upon such patients as having a “clinically malignant” form of myasthenia gravis . In some cases, weakness of the muscles of the extremities may represent an early and prominent feature, but only rarely is this unassociated with myaesthenic symptoms in the extraocular or bulbar musculature .
In congenital MG, prominent extra ocular involvement is usually noted in infancy, with relatively mild generalized weakness, which may not develop until later in life. There are pre-synaptic as well as post-synaptic defects. Anti-AchR antibodies are not found and the limited data suggest that it results from genetic defects rather than auto-immune dysfunction.
There is also no consistent response to plasma exchange or thymectomy . The association with consanguineous marriage and the involvement of siblings and other relatives also suggests a genetic basis.
Criteria for diagnosis of MG:
Osserman and Genkins clinical classification of MG .: Stages
Anticholinesterase preparations were introduced in 1934, and a therapeutic response to these agents is accepted as part of the definition of myaesthenia .
The Neostigmine test:
When the intravenous technique is to be employed, the patient should have an intravenous infusion of 5% dextrose started and should be in the supine recumbent position. Atropine 0.4 to 0.6 mg is first administered i.v. followed by 0.25 to 0.5 mg neostigmine given i.v. and there should be an improvement in muscle strength in 3 – 5 minutes. If there is insufficient improvement, further dose of neostigmine such as 0.25mg or less may be administered. Improvement of the degree of ptosis, range of ocular movement and force of hand grip are clinical measures of objective assessment.
The Edrophonium test:
The curare test:
The patient is placed in the recumbent position and with an intravenous infusion running. Subjective and objective assessments of muscle strength are made. 0.5 to 1 ml. of d-tubocurarine solution containing 1 mg/ml is injected over a 30 second period and muscle performance is retested 5 minutes later. If there is no marked change another 0.5 to 1 mg is given and muscle performance is tested 3 minutes later. Additional 0.5 to 1 mg. doses can be given at 3 minutes intervals up to a total of 4 mg. If a marked reduction of grip strength or vital capacity does not occur following the administration of 4 mg, it is unlikely that the patient has myasthenia gravis. If less than 4 mg of d -tubocurarine produces a significant decrease of the grip strength or vital capacity the diagnosis of myasthenia gravis is confirmed. The residual effect of d-tubocurarine should be reversed by intravenous neostigmine administered in 0.5 mg increments, the first dose being given with 0.4 to 0.6 mg atropine.
Of all the diagnostic tests described above, the edrophonium or neostigmine tests are the easiest, quickest and safest.
Myaesthenic crisis: increasing myaesthenic symptoms resulting in paralysis of the respiratory, laryngeal, or pharyngeal muscles. It may be precipitated by physical exertion, surgery, pregnancy, psychosocial disturbance, anxiety, respiratory infections, emotional upset, infection, drugs (Streptomycin, Neomycin, curare, quinidine, steroids, sedatives, morphine ether, chloroform) and enema by depleting potassium stores. The tensilon test is useful. Treat the precipitating factor if identified and increase anticholinestrase medication and tracheostomy may be needed.
Cholinergic crisis: This is caused by the nicotinic action of excessive anticholinesterase medication on neuromuscular transmission.
Nicotinic effect – fasciculation, progressive muscle weakness from depolarisation block.
Tensilon test is harzardous: Tracheostomy and positive pressure respiration may be indicated. Atropine should be given at a dose of 2 mg hourly until signs of toxicity appear (dry mouth, pupil dilatation etc), or propantheline which is also vagolytic. Stop anticholinesterase therapy .
Differential diagnosis: Neurasthenia, psychogenic fatigue, physiologic fatigue drug induced myaesthenia, hyperthyroidism, botulism and Eaton – Lambert syndrome. Other differentials include amytrophic lateral sclerosis (ALS), gullain barre syndrome, poliomyelitis, nerve injury, transverse myelitis, and intracranial mass lesions.
Involvement of muscles innervated by multiple cranial nerves with absence of pupillary involvement suggests MG. Unlike psychogenic fatigue, MG is relieved by rest while unlike physiologic fatigue, there is no accompanying pain. Muscle wasting is very uncommon in MG as distinct from ALS and occurs in 10 to 20% of cases , although, some authors reported wasting in 41% of cases [16,28]. This was possibly due to chronic subclinical malnutrition in the study patients and disuse atrophy as a result of reduced muscle activity and mobility. In the Eaton-Lambert myaesthenic syndrome (ELS), fatigability may resemble that in myaesthenia, but other features differ (see table 1). The proximal limb weakness affects especially the pelvic and thigh muscles. Ocular and bulbar involvement is inconspicuous, and there are other symptoms such as aching, paraesthesia, dry mouth and impotence. The absent tendon reflexes, which are facilitated by vigorous muscle contractions, are a distinctive finding in ELS . The diagnosis is confirmed electro physiologically by demonstration of small compound muscle action potentials with a striking incremental response at higher rates of nerve stimulation. Furthermore, there is good response to amantadine or guanidine (20 to 50 mg in divided doses). These agents enhance release of acetylcholine as well as sensitize the chemoreceptors to acetylcholine .
Anticholinesterases, immunosuppressive drugs, plasmaphresis, and thymectomy are the four strategies in the treatment of myasthenia [12,13,14].
General measures: educate the patient of his condition and avoidance of precipitating factors should be emphasised.
1. Anticholinesterase drugs – Neostigmine (prostigmine) 15 mg 2-6 hourly
Extraocular muscle involvement could be relatively refractory to neostigmine or mestinon in terms of only partial subsidence with considerable residual involvement. This results in a variable degree of persistent disability both from cosmetic and occupational standpoints. A noteworthy observation has been that corticotropin (ACTH) therapy administered in a total dosage of 600mg, divided into single doses of 20mg every 6 hours is highly effective in reducing or eliminating the extraocular muscle pareses . The duration of the partial or complete remission has varied from three to as long as long as 12 months. Relapse is to be expected but in the ocular myaesthenic group, it often may be delayed and may be relatively mild. Corticotropin therapy may be repeated when necessary but the interval should not be less than 6 months. Although, corticotropin therapy understandably has been largely rejected for the treatment of generalized MG, it would seem reasonable to continue its use in the treatment of selected patients with ocular myasthenia in whom disability affecting the eyes cannot otherwise be adequately controlled.
Azathioprine (imuran) has been used in the treatment of MG for over 30 years and takes about seven months to achieve remission . Cyclosporin A was shown to produce a significant improvement in muscle strength but was associated with sufficient toxicity to preclude its use as a first line immunosuppressive agent .
Cyclophosphamide has also been found promising. Plasmaphresis- with daily exchange of 2 liters of plasma has shown short-term clinical improvement . Intravenous Immunoglobulin usually given at a standard dose of 5 mls every 3 weeks or at a high dose of 0.4 g /Kg/day for 5 days have also been found useful [14,18,32]. Adjuvants include use of potassium salts, ephedrine at a dose of 15 – 30 mg tds. Ephedrine aids neuromuscular transmission by acting on the - and -noradrenergic receptors adjacent to the neuromuscular junction .
Emmergency measures are indicated if there is sudden dysphagia and/or respiratory crisis. Patients are advised to always carry 2 ampoules of 0.5 mg of prostigmine. This could be given subcutaneously or intramuscularly at a dose of 1 mg, two to three times in an hour till adequate respiration is achieved. Oxygen, suction apparatus, respirator, endotracheal intubation and/or tracheostomy may be required.
Radiotherapy before surgery has not been promising .
Conduct of anaesthesia in patients with myasthenia gravis:
Regional analgesia: whenever possible, local or regional technique should be employed. Because local anaesthetic agents may block neuromuscular transmission, it is better to use techniques, which involve the use of small quantities of these agents. Hence sub-arachnoid block (spinal) is preferable to the use of epidural or caudal analgesia .
General anaesthesia: When general anaesthesia is indicated, induction could be with light thiopentone, nitrous oxide and oxygen mixture [28,35]. It is however preferable to induce anaesthesia with inhalational agents such as halothane/oxygen, cyclopropane/oxygen or ether/oxygen; and maintain anaesthesia with the same agents. Endotracheal intubation should be performed after adequate topical analgesia of the pharynx and larynx. Cyclopropane may cause bronchospasm from its parasymptomimetic effect and may induce arrythmias because of the degenerative changes described in myasthenics. Ether should not be used for these patients because of its curare -like effect at the neuromuscular junction and also because of its irritant effect on the tracheobronchial tree; but it has been used safely in low analgesic concentration .
It is wise to avoid the use of neuromuscular blocking agents as much as possible. However, when their use is indicated as when intubation is difficult or respiration cannot be controlled with the inhalational agents alone, it is better to use small doses (1/10th of the usual dose) of non-depolarising rather than the depolarizing relaxant drugs . There has been a difference of opinion on the latter point. The depolarizing muscle relaxant such as decamethonium or suxamethonium act irregularly; clinically involved muscles of myaesthenic show increased sensitivity, while the non – involved muscles are resistant to the drugs. However, using the increased sensitivity of both the involved and non-involved myaesthenic muscles to non-depolarising muscle relaxants, good muscular relaxation can be produced by small doses of tubocurarine (0.5 – 2 mg) or gallamine tri-ethiodide (2.5 – 10mg). These small doses give constant and reliable action and are to be preferred to the variable effects of depolarizing agents [28,36].
In conclusion, the course of MG is extremely variable. Ocular symptoms may recur at intervals or remain static. Spontaneous remission is common but relapse is the rule. After 5 to 10 years, the disease enters a static phase with only moderate response to treatment and varying degree of residual disability.
TABLE 1. Characteristics of myaesthenia gravis and myaesthenic syndrome