SEMINARS I N NEUROLOGY-VOLUME
10. N O . 1 MARCH 1990
Hypermagnesemia and Neuromuscular Transmission
Although hypomagnesemia is frequently encountered in association with alcoholism, malnutrition, or both, hypermagnesemia occurs less commonly and only with the use of magnesium-containing pharmaceutical preparations. Normally, the serum magnesium concentration is 1.5 to 2.5 mEq/liter (2 to 3 mgldl) and is maintained by exchange with tissue stores (bone, liver, muscle, and brain) and by renal e x ~ r e t i o n .Patients ~.~ with renal insufficiency are predisposed to hypermagnesemia and should avoid magnesium-containing antacids and laxative~.'-~ Increase in magnesium levels caused by orally administered compounds is very rare in patients with normal renal f u n ~ t i o n . ' ~ ~can ~ Voccur t with enemas, but usually in association with a lesion of the gastrointestinal tract, such as perforation or m e g a ~ o l o n . ~Hypermagnesemia .~ is produced intentionally during treatment of preeclampsia with magnesium sulfate and sometimes causes toxic symptoms in preeclamptic women and newborns.*-lo
Levels between 3.5 and 7 mEq/liter are typically maintained in preeclamptic women without adverse effect^,^,^ but severe weakness often ensues at levels greater than 10 mEq/liter, and death due to respiratory muscle paralysis may occur. Extraocular muscles are relatively spared. At levels greater than 14 mEq/liter, there may be severe cardiac arrhythmias, including heart block and asystole. Magnesium was once thought to cause central nervous system (CNS) depression,'-"." but a study using human volunteers has shown clear sensorium, despite quadriplegia and levels as high as 15.3 mEq/liter.12 When CNS depression occurs, it may be due to associated hypoxia or h y p o t e n s i ~ n . ~ . ~ . ' ~ Symptoms referable to the autonomic nervous system, such as cutaneous flushing, dry mouth, pupillary dilation, urinary retention, and hypotension are common. These symptoms probably result from presynaptic blockade at autonomic ganglia.14
PATHOPHYSIOLOGY CLINICAL MANIFESTATIONS
Magnesium impairs neuromuscular transmission primarily by reducing acetylcholine release. Clinical manifestations of hypermagnesemia Calcium entry into the presynaptic terminal is necusually correlate well with serum magnesium lev- essary for acelylcholine release, and magnesium els.1."11,'2 Blockade of neuromuscular transmission competitively blocks calcium entry. Evidence impliis an important toxic r n a n i f e ~ t a t i o n l ~and ~ ~ .limits ~' cating this mechanism includes data from frog dosage in the treatment of preeclamp~ia.~.~ Above nerve and muscle preparations.lVhese demon5 mEq/liter, deep tendon reflexes are depressed. strated that endplate potentials evoked by nerve Reflexes are usually absent at levels of 9 to 10 mEq/ stimulation were reduced in amplitude in the presliter, and weakness is usually seen in that. range. In ence of high magnesium concentrations and that treating preeclampsia, deep tendon reflexes are this could be corrected by adding calcium. A less monitored, and it has been recommended that pronounced decrease in sensitivity of the motor magnesium be discontinued if they d i ~ a p p e a r . ~endplate to directly applied acetylcholine was also
Emory University School of Medicine, Department of Neurology, Atlanta, Georgia Reprint requests: Dr. Krendel, Department of Neurology, Emory University School o f Medicine, 1,365 Clifton Road, N.E., Atlanta, GA 30322 Copyright O 1990 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: University of Michigan. Copyrighted material.
David A. Krendel, M .D.
Figure 1. Diagram illustrating effects of magnesium on neuromuscular transmission. 1: The presynaptic membrane is depolarized. 2: Voltage-sensitive calcium channels open. 3: Calcium entry stimulates acetylcholine release. 4: Acetylcholine binds to receptor, resulting in endplate depolarization. Magnesium blocks calcium entry at step 2 (major effect) and diminishes the effect of acetylcholine at step 4 (minor effect).
demonstrated. This finding suggests that magnesium also has some postsynaptic effect (Fig. 1). In humans, hypermagnesemia resembles the Lambert-Eaton syndrome, an autoimmune disorder in which antibodies directed against calcium channels have been found.l"n both conditions acetylcholine release from presynaptic terminals is impaired and weakness, usually sparing extraocular muscles, is characteristically associated with hyporeflexia and cholinergic dysautonomia.16 CLINICAL ELECTROPHYSIOLOGY
Normally, depolarization of the presynaptic terminal is the stimulus for the opening of calcium channels, but calcium entry is impaired in both the Lambert-Eaton syndrome and hypermagnesemia. Continuous rapid volleys of depolarization increase the amount of acetylcholine released by forcing calcium into the presynaptic terminal.17 This can be demonstrated electrophysiologically in the Lambert-Eaton syndrome. The initial compound muscle action potential (CMAP) after nerve stimulation is typically very small, but it more than doubles in size immediately after maximum exercise (postexercise facilitation) or during rapid repetitive stimulation at 20 to 50 Hz. Slow rates of repetitive stimulation (2 to 3 Hz) produce a progressive decrement over three to four stimuli,
which is also seen in myasthenia gravis.17 However, marked postexercise facilitation is not typically seen in myasthenia gravis. In two reported cases of weakness due to hypermagnesemia, electrophysiologic findings resembled those of the Lambert-Eaton syndrome. In one casels a patient who had severe constipation for 5 days received a large amount of magnesium citrate by enema. She became severely weak in both limb and facial muscles and required mechanical ventilation when the magnesium level was 3.1 mEqIliter. Nerve conduction studies showed low CMAP amplitudes with a 300% increase after exercise and a 254% increase during 1 second of 50 Hz stimulation. A progressive decline over three stimuli at 2 Hz was noted. Recovery after calcium administration was not prompt, but occurred gradually over several days. I n the other case4a patient who had been taking large quantities of magnesium-containing laxatives and antacids was hospitalized for malignant hypertension and acute renal failure. She became quadriplegic, with facial diplegia and ventilator dependence, when her magnesium level was 7 mEqAiter. An edrophonium test suggested the diagnosis of myasthenia gravis. Treatment with hemodialysis and one course of plasma exchange was accompanied by gradual decline in her magnesium level and recovery of strength. Repetitive nerve stimulation was done when her magnesium level was 4 mEq11iter. This showed very low initial CMAP amplitudes with an increase of 186%after exercise and a 50% decrement with 3 Hz stimulation, but no increment with 50 Hz stimulation. Later that day, CMAP amplitudes were higher but still below normal and there was no significant postexercise facilitation or decrement with 3 Hz stimulation. These are the only published reports of electrophysiologic studies in humans of neuromuscular blockade presumed to be due to magnesium alone. Both support experimental data implicating impairment of acetylcholine release from the presynaptic terminal as the major mechanism of neuromuscular blockade. However, both patients were unusual in that magnesium levels were below the range that is usually associated with weakness, yet both were paralyzed and ventilator-dependent. Also, in the first case, failure to recover promptly after calcium administration is atypical. It is possible that underlying subclinical disorders of neuromuscular transmission were unmasked by magnesium in these cases.
INCREASED SENSITIVITY TO MAGNESIUM
Magnesium can potentiate the action of neuromuscular blocking agents, as reported in women
Downloaded by: University of Michigan. Copyrighted material.
HYPERMAGNESEMIA AND NEUROMUSCULAR TRANSMISSION-KRENDEL
V O L U M E 10. NUMBEK 1 MARCH 1990
who underwent cesarean sections after treatment (1 gm over 3 minutes) will usually produce prompt with magnesium sulfate for p r e e c l a m p ~ i a . ' ~Pa* ~ ~ but transient improvement and is the treatment of tients with preexistirig disorders of neuromuscular choice for patients with moderate symptoms and transmission are particularly sensitive to magne- normal renal function, as may be encountered in sium. Severe weakness after magnesium adminis- the course of magnesium treatment for preeclamptration has been reported both in myasthenia sia. In patients with life-threatening hypermagnegra~is"-~ and ~ the Lambert-Eaton ~ y n d r o m e , ~ ~ semia, . ~ " particularly when associated with cardiac ardespite normal or mildly elevated levels. Magne- rhythmias, renal failure, or both, hemodialysis is sium was given parenterally to all except one nece~sary.~ Patients with preexisting disorders of patientz5 who had Lambert-Eaton syndrome and neuromuscular transmission exacerbated by magtook oral magnesium citrate. nesium usually do not respond promptly to calbut those with myasthenia gravis Increased sensitivity to magnesium may be the C;Um,~~,~x22-24 first or only clinical manifestation of myasthenia may improve with anticholinesterase medi~ation.'~ gravis. Jn one instance2' a patient with no prior his- Those patients should not be at risk for arrhythtory of weakness became quadriplegic shortly after mias because magnesium levels are relatively low, receiving parenteral magnesium sulfate for pre- so that discontinuing magnesium and providing eclampsia. Her serum magnesium concentration supportive care may be sufficient. was only 3 mEqIliter. Repetitive nerve stimulation showed a normal initial CMAP amplitude, with a decrement at slow rates, but without significant faOTHER ELECTROLYTE DERANGEMENTS cilitation after exercise or with repetitive stimulation. These findings are typical of postsynaptic Other electrolyte derangements have not been neuromuscular blockade as seen in myasthenia established as causes of clinically significant neugravis, rather than the expected presynaptic block- romuscular blockade. This is surprising in the case ade due to magnesium. The patient gradually re- of hypocalcemia, considering the importance of covered over several days after magnesium was calcium influx for release of acetylcholine at the discontinued, and repetitive stimulation and ex- neuromuscular junction. The neuromuscular manamination became normal. She was found to have ifestation of hypocalcemia is tetany, caused by a markedly elevated acetylcholine receptor anti- spontaneous peripheral nerve depolarization.'.'' body titer, and 2 months later had markedly inHypokalemia causes weakness because of recreased jitter on single-fiber EMG, despite normal duced excitability of muscle cell membranes.l strength and a normal response to repetitive Depletion of intracellular potassium has been nerve stimulation. That the electrophysiologic find- postulated as a mechanism for exacerbations of ings suggested postsynaptic rather than presyn- myasthenia gravis that sometimes occur during iniaptic blockade may indicate increased sensitivity to tiation of steroid therapy, but low serum potassium magnesium's postsynaptic effect in a patient with levels do not correlate with weakness in that situasubclinical myasthenia gravis. t i ~ n . ~ ~
TREATMENT Because magnesium-induced weakness is almost always iatrogenic, prevention depends on the physician's awareness of situations in which it can occur. Avoidance of magnesium-containing compounds in patients with renal failure is the most important preventive measure. Parenteral magnesium should be avoided in patients known to have myasthenia gravis or the Lambert-Eaton syndrome, and the possibility that even orally administered magnesium preparations may cause weakness in these patients should be kept in mind. Treatment of hypermagnesemia depends on the severity of the clinical manifestation~.~.~."n mild cases, discontinuation of magnesium may be all that is required. Intravenous calcium gluconate 44
REFERENCES 1. Layzer RB. Mineral and electrolyte disorders. Neuromuscular manifestations of systemic disease. Philadelphia: FA Davis, 1985:47-78 2. Mordes JP, Wacker WEC. Excess magnesium. Pharmacol Rev 1978;29:273-300 3. Alfrey AC, Terman DS, Brettschneider L, et al. Hypermagnesemia after renal homotransplantation. Ann Intern Med 1970;73:367-71 4. Castlebaum AR, Donofrio PD, Walker FO, Troost BT. Laxative abuse causing hypermagnesemia, quadriparesis, and neurornuscular junction defect. Neurology (Cleve) 1989;39:746-7 5. Randall RE, Cohen MD, Spray CC, Rossmeise EC. Hypermagnesemia in renal failure. Ann Intern Med 1964;61:73-88 6. Lembcke B, Fuchs C. Magnesium load induced by ingestion of magnesium containing antacids. Contrib Nephrol l984;38: 185-94 7. Collins EN, Russell PW. Fatal magnesium poisoning. Cleve Clin Q 1949;16: 162-6
Downloaded by: University of Michigan. Copyrighted material.
SEMINARS I N NEUROLOGY
HYPERMAGNESEMIA AND NEUROMUSCULAR TRANSMISSION-KRENDEL 18. Swift TR. Weakness from magnesium containing cathartics. Muscle Nerve 1979;2:295-8 19. DeSilva AJC. Magnesium intoxication: an uncommon cause of prolonged curarization. Br J Anaesth 1973; 45: 1228-9 20. Ghoneim MM, Long JP. T h e interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970;32:23-7 21. Bashuk RG, Krendel DA. Myasthenia gravis presenting as weakness after magnesium administration. Muscle Nerve 1987;lO:666 22. Cohen BA, London RS, Goldstein PI. Myasthenia gravis and preeclampsia. Obstet ~ ~ n e r o1976;48 l ('SU~~I 1):35s-7 23. cedrge WK, Haan CL. Calcium and magnesium administration in myasthenia gravis. Lancet 1962;2:561 24. Gutmann L, Takamori M. Effect of Mg+ o n neuromuscular transmission in the Eaton-Lambert syndrome. Neurology (Minneap) 1973;23:977-80 25. Streib EW. Adverse effects of magnesium salt cathartics in a patient with the myasthenic syndrome (LambertEaton syndrome). Ann Neurol 1977;2:175-6 26. Critchley M, Herman KJ, Harrison M, Shields RA. Value of exchangeable electrolyte measurement in the treatment of myasthenia gravis. J Neurol Neurosurg Psychiatry 1977;40:250-2
+
Downloaded by: University of Michigan. Copyrighted material.
8. Flowers CJ. Magnesium in obstetrics. Am J Obstet Gynecol 1965;91:763-76 9. Pritchard JA. T h e use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med 1979;23: 107-14 10. Lipsitz PJ. T h e clinical and biochemical effects of excess magnesium in the newborn. Pediatrics 1971;47:501-9 I 1. Fishman RA. Neurological aspects of magnesium metabolism. Arch Neurol 1965;12:562-96 12. Somjen G, Hilmy M, Stephen CR. Failure to anesthetize human subjects by intravenous administration of magnesium sulfate. J Pharmacol Exp Ther 1966;154:652-9 IS. DelCastillo J , Engback L. T h e nature of the neuromuscular block produced by magnesium. J Physiol (Lond) 1954; 124:370-84 14. Hutter OF, Kostial K. Effect of magnesium and calcium ions on the release of acetylcholine. J Physiol (Lond) 1954;124:234-41 15. Lang B, Vincent A, Murray NMF, Newsom-Davis J. Lambert-Eaton myasthenic syndrome: immunoglobin G inhibition of Ca2+flux in tumor cells correlates with disease severity. Ann Neurol 1989;25:265-72 16. Rubenstein AE, Horowitz SH, Bender AN. Cholinergic dysautonomia and Eaton-Lambert syndrome. Neurology (NY) 1979;29:720-3 17. Swift TR. Disorders of neuromuscular transmission other than myasthenia gravis. Muscle Nerve 1981;4:334-53
10. N O . 1 MARCH 1990
Hypermagnesemia and Neuromuscular Transmission
Although hypomagnesemia is frequently encountered in association with alcoholism, malnutrition, or both, hypermagnesemia occurs less commonly and only with the use of magnesium-containing pharmaceutical preparations. Normally, the serum magnesium concentration is 1.5 to 2.5 mEq/liter (2 to 3 mgldl) and is maintained by exchange with tissue stores (bone, liver, muscle, and brain) and by renal e x ~ r e t i o n .Patients ~.~ with renal insufficiency are predisposed to hypermagnesemia and should avoid magnesium-containing antacids and laxative~.'-~ Increase in magnesium levels caused by orally administered compounds is very rare in patients with normal renal f u n ~ t i o n . ' ~ ~can ~ Voccur t with enemas, but usually in association with a lesion of the gastrointestinal tract, such as perforation or m e g a ~ o l o n . ~Hypermagnesemia .~ is produced intentionally during treatment of preeclampsia with magnesium sulfate and sometimes causes toxic symptoms in preeclamptic women and newborns.*-lo
Levels between 3.5 and 7 mEq/liter are typically maintained in preeclamptic women without adverse effect^,^,^ but severe weakness often ensues at levels greater than 10 mEq/liter, and death due to respiratory muscle paralysis may occur. Extraocular muscles are relatively spared. At levels greater than 14 mEq/liter, there may be severe cardiac arrhythmias, including heart block and asystole. Magnesium was once thought to cause central nervous system (CNS) depression,'-"." but a study using human volunteers has shown clear sensorium, despite quadriplegia and levels as high as 15.3 mEq/liter.12 When CNS depression occurs, it may be due to associated hypoxia or h y p o t e n s i ~ n . ~ . ~ . ' ~ Symptoms referable to the autonomic nervous system, such as cutaneous flushing, dry mouth, pupillary dilation, urinary retention, and hypotension are common. These symptoms probably result from presynaptic blockade at autonomic ganglia.14
PATHOPHYSIOLOGY CLINICAL MANIFESTATIONS
Magnesium impairs neuromuscular transmission primarily by reducing acetylcholine release. Clinical manifestations of hypermagnesemia Calcium entry into the presynaptic terminal is necusually correlate well with serum magnesium lev- essary for acelylcholine release, and magnesium els.1."11,'2 Blockade of neuromuscular transmission competitively blocks calcium entry. Evidence impliis an important toxic r n a n i f e ~ t a t i o n l ~and ~ ~ .limits ~' cating this mechanism includes data from frog dosage in the treatment of preeclamp~ia.~.~ Above nerve and muscle preparations.lVhese demon5 mEq/liter, deep tendon reflexes are depressed. strated that endplate potentials evoked by nerve Reflexes are usually absent at levels of 9 to 10 mEq/ stimulation were reduced in amplitude in the presliter, and weakness is usually seen in that. range. In ence of high magnesium concentrations and that treating preeclampsia, deep tendon reflexes are this could be corrected by adding calcium. A less monitored, and it has been recommended that pronounced decrease in sensitivity of the motor magnesium be discontinued if they d i ~ a p p e a r . ~endplate to directly applied acetylcholine was also
Emory University School of Medicine, Department of Neurology, Atlanta, Georgia Reprint requests: Dr. Krendel, Department of Neurology, Emory University School o f Medicine, 1,365 Clifton Road, N.E., Atlanta, GA 30322 Copyright O 1990 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: University of Michigan. Copyrighted material.
David A. Krendel, M .D.
Figure 1. Diagram illustrating effects of magnesium on neuromuscular transmission. 1: The presynaptic membrane is depolarized. 2: Voltage-sensitive calcium channels open. 3: Calcium entry stimulates acetylcholine release. 4: Acetylcholine binds to receptor, resulting in endplate depolarization. Magnesium blocks calcium entry at step 2 (major effect) and diminishes the effect of acetylcholine at step 4 (minor effect).
demonstrated. This finding suggests that magnesium also has some postsynaptic effect (Fig. 1). In humans, hypermagnesemia resembles the Lambert-Eaton syndrome, an autoimmune disorder in which antibodies directed against calcium channels have been found.l"n both conditions acetylcholine release from presynaptic terminals is impaired and weakness, usually sparing extraocular muscles, is characteristically associated with hyporeflexia and cholinergic dysautonomia.16 CLINICAL ELECTROPHYSIOLOGY
Normally, depolarization of the presynaptic terminal is the stimulus for the opening of calcium channels, but calcium entry is impaired in both the Lambert-Eaton syndrome and hypermagnesemia. Continuous rapid volleys of depolarization increase the amount of acetylcholine released by forcing calcium into the presynaptic terminal.17 This can be demonstrated electrophysiologically in the Lambert-Eaton syndrome. The initial compound muscle action potential (CMAP) after nerve stimulation is typically very small, but it more than doubles in size immediately after maximum exercise (postexercise facilitation) or during rapid repetitive stimulation at 20 to 50 Hz. Slow rates of repetitive stimulation (2 to 3 Hz) produce a progressive decrement over three to four stimuli,
which is also seen in myasthenia gravis.17 However, marked postexercise facilitation is not typically seen in myasthenia gravis. In two reported cases of weakness due to hypermagnesemia, electrophysiologic findings resembled those of the Lambert-Eaton syndrome. In one casels a patient who had severe constipation for 5 days received a large amount of magnesium citrate by enema. She became severely weak in both limb and facial muscles and required mechanical ventilation when the magnesium level was 3.1 mEqIliter. Nerve conduction studies showed low CMAP amplitudes with a 300% increase after exercise and a 254% increase during 1 second of 50 Hz stimulation. A progressive decline over three stimuli at 2 Hz was noted. Recovery after calcium administration was not prompt, but occurred gradually over several days. I n the other case4a patient who had been taking large quantities of magnesium-containing laxatives and antacids was hospitalized for malignant hypertension and acute renal failure. She became quadriplegic, with facial diplegia and ventilator dependence, when her magnesium level was 7 mEqAiter. An edrophonium test suggested the diagnosis of myasthenia gravis. Treatment with hemodialysis and one course of plasma exchange was accompanied by gradual decline in her magnesium level and recovery of strength. Repetitive nerve stimulation was done when her magnesium level was 4 mEq11iter. This showed very low initial CMAP amplitudes with an increase of 186%after exercise and a 50% decrement with 3 Hz stimulation, but no increment with 50 Hz stimulation. Later that day, CMAP amplitudes were higher but still below normal and there was no significant postexercise facilitation or decrement with 3 Hz stimulation. These are the only published reports of electrophysiologic studies in humans of neuromuscular blockade presumed to be due to magnesium alone. Both support experimental data implicating impairment of acetylcholine release from the presynaptic terminal as the major mechanism of neuromuscular blockade. However, both patients were unusual in that magnesium levels were below the range that is usually associated with weakness, yet both were paralyzed and ventilator-dependent. Also, in the first case, failure to recover promptly after calcium administration is atypical. It is possible that underlying subclinical disorders of neuromuscular transmission were unmasked by magnesium in these cases.
INCREASED SENSITIVITY TO MAGNESIUM
Magnesium can potentiate the action of neuromuscular blocking agents, as reported in women
Downloaded by: University of Michigan. Copyrighted material.
HYPERMAGNESEMIA AND NEUROMUSCULAR TRANSMISSION-KRENDEL
V O L U M E 10. NUMBEK 1 MARCH 1990
who underwent cesarean sections after treatment (1 gm over 3 minutes) will usually produce prompt with magnesium sulfate for p r e e c l a m p ~ i a . ' ~Pa* ~ ~ but transient improvement and is the treatment of tients with preexistirig disorders of neuromuscular choice for patients with moderate symptoms and transmission are particularly sensitive to magne- normal renal function, as may be encountered in sium. Severe weakness after magnesium adminis- the course of magnesium treatment for preeclamptration has been reported both in myasthenia sia. In patients with life-threatening hypermagnegra~is"-~ and ~ the Lambert-Eaton ~ y n d r o m e , ~ ~ semia, . ~ " particularly when associated with cardiac ardespite normal or mildly elevated levels. Magne- rhythmias, renal failure, or both, hemodialysis is sium was given parenterally to all except one nece~sary.~ Patients with preexisting disorders of patientz5 who had Lambert-Eaton syndrome and neuromuscular transmission exacerbated by magtook oral magnesium citrate. nesium usually do not respond promptly to calbut those with myasthenia gravis Increased sensitivity to magnesium may be the C;Um,~~,~x22-24 first or only clinical manifestation of myasthenia may improve with anticholinesterase medi~ation.'~ gravis. Jn one instance2' a patient with no prior his- Those patients should not be at risk for arrhythtory of weakness became quadriplegic shortly after mias because magnesium levels are relatively low, receiving parenteral magnesium sulfate for pre- so that discontinuing magnesium and providing eclampsia. Her serum magnesium concentration supportive care may be sufficient. was only 3 mEqIliter. Repetitive nerve stimulation showed a normal initial CMAP amplitude, with a decrement at slow rates, but without significant faOTHER ELECTROLYTE DERANGEMENTS cilitation after exercise or with repetitive stimulation. These findings are typical of postsynaptic Other electrolyte derangements have not been neuromuscular blockade as seen in myasthenia established as causes of clinically significant neugravis, rather than the expected presynaptic block- romuscular blockade. This is surprising in the case ade due to magnesium. The patient gradually re- of hypocalcemia, considering the importance of covered over several days after magnesium was calcium influx for release of acetylcholine at the discontinued, and repetitive stimulation and ex- neuromuscular junction. The neuromuscular manamination became normal. She was found to have ifestation of hypocalcemia is tetany, caused by a markedly elevated acetylcholine receptor anti- spontaneous peripheral nerve depolarization.'.'' body titer, and 2 months later had markedly inHypokalemia causes weakness because of recreased jitter on single-fiber EMG, despite normal duced excitability of muscle cell membranes.l strength and a normal response to repetitive Depletion of intracellular potassium has been nerve stimulation. That the electrophysiologic find- postulated as a mechanism for exacerbations of ings suggested postsynaptic rather than presyn- myasthenia gravis that sometimes occur during iniaptic blockade may indicate increased sensitivity to tiation of steroid therapy, but low serum potassium magnesium's postsynaptic effect in a patient with levels do not correlate with weakness in that situasubclinical myasthenia gravis. t i ~ n . ~ ~
TREATMENT Because magnesium-induced weakness is almost always iatrogenic, prevention depends on the physician's awareness of situations in which it can occur. Avoidance of magnesium-containing compounds in patients with renal failure is the most important preventive measure. Parenteral magnesium should be avoided in patients known to have myasthenia gravis or the Lambert-Eaton syndrome, and the possibility that even orally administered magnesium preparations may cause weakness in these patients should be kept in mind. Treatment of hypermagnesemia depends on the severity of the clinical manifestation~.~.~."n mild cases, discontinuation of magnesium may be all that is required. Intravenous calcium gluconate 44
REFERENCES 1. Layzer RB. Mineral and electrolyte disorders. Neuromuscular manifestations of systemic disease. Philadelphia: FA Davis, 1985:47-78 2. Mordes JP, Wacker WEC. Excess magnesium. Pharmacol Rev 1978;29:273-300 3. Alfrey AC, Terman DS, Brettschneider L, et al. Hypermagnesemia after renal homotransplantation. Ann Intern Med 1970;73:367-71 4. Castlebaum AR, Donofrio PD, Walker FO, Troost BT. Laxative abuse causing hypermagnesemia, quadriparesis, and neurornuscular junction defect. Neurology (Cleve) 1989;39:746-7 5. Randall RE, Cohen MD, Spray CC, Rossmeise EC. Hypermagnesemia in renal failure. Ann Intern Med 1964;61:73-88 6. Lembcke B, Fuchs C. Magnesium load induced by ingestion of magnesium containing antacids. Contrib Nephrol l984;38: 185-94 7. Collins EN, Russell PW. Fatal magnesium poisoning. Cleve Clin Q 1949;16: 162-6
Downloaded by: University of Michigan. Copyrighted material.
SEMINARS I N NEUROLOGY
HYPERMAGNESEMIA AND NEUROMUSCULAR TRANSMISSION-KRENDEL 18. Swift TR. Weakness from magnesium containing cathartics. Muscle Nerve 1979;2:295-8 19. DeSilva AJC. Magnesium intoxication: an uncommon cause of prolonged curarization. Br J Anaesth 1973; 45: 1228-9 20. Ghoneim MM, Long JP. T h e interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970;32:23-7 21. Bashuk RG, Krendel DA. Myasthenia gravis presenting as weakness after magnesium administration. Muscle Nerve 1987;lO:666 22. Cohen BA, London RS, Goldstein PI. Myasthenia gravis and preeclampsia. Obstet ~ ~ n e r o1976;48 l ('SU~~I 1):35s-7 23. cedrge WK, Haan CL. Calcium and magnesium administration in myasthenia gravis. Lancet 1962;2:561 24. Gutmann L, Takamori M. Effect of Mg+ o n neuromuscular transmission in the Eaton-Lambert syndrome. Neurology (Minneap) 1973;23:977-80 25. Streib EW. Adverse effects of magnesium salt cathartics in a patient with the myasthenic syndrome (LambertEaton syndrome). Ann Neurol 1977;2:175-6 26. Critchley M, Herman KJ, Harrison M, Shields RA. Value of exchangeable electrolyte measurement in the treatment of myasthenia gravis. J Neurol Neurosurg Psychiatry 1977;40:250-2
+
Downloaded by: University of Michigan. Copyrighted material.
8. Flowers CJ. Magnesium in obstetrics. Am J Obstet Gynecol 1965;91:763-76 9. Pritchard JA. T h e use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med 1979;23: 107-14 10. Lipsitz PJ. T h e clinical and biochemical effects of excess magnesium in the newborn. Pediatrics 1971;47:501-9 I 1. Fishman RA. Neurological aspects of magnesium metabolism. Arch Neurol 1965;12:562-96 12. Somjen G, Hilmy M, Stephen CR. Failure to anesthetize human subjects by intravenous administration of magnesium sulfate. J Pharmacol Exp Ther 1966;154:652-9 IS. DelCastillo J , Engback L. T h e nature of the neuromuscular block produced by magnesium. J Physiol (Lond) 1954; 124:370-84 14. Hutter OF, Kostial K. Effect of magnesium and calcium ions on the release of acetylcholine. J Physiol (Lond) 1954;124:234-41 15. Lang B, Vincent A, Murray NMF, Newsom-Davis J. Lambert-Eaton myasthenic syndrome: immunoglobin G inhibition of Ca2+flux in tumor cells correlates with disease severity. Ann Neurol 1989;25:265-72 16. Rubenstein AE, Horowitz SH, Bender AN. Cholinergic dysautonomia and Eaton-Lambert syndrome. Neurology (NY) 1979;29:720-3 17. Swift TR. Disorders of neuromuscular transmission other than myasthenia gravis. Muscle Nerve 1981;4:334-53
