Magnesium has a profound effect on neural excitability; the most characteristic signs and symptoms of Mg deficiency are produced by neural and neuromuscular hyperexcitability. These create a constellation of clinical findings termed tetany syndrome (TS). TS symptoms include muscle spasms, cramps and hyperarousal, hyperventilation and asthenia. Physical signs (Chvostek's, Trousseau's or von Bonsdorff's) and abnormalities of the electromyogram or electroencephalogram can usually be elicited. Signs and symptoms of TS are frequently encountered in clinical practice, especially among patients with functional or stress-related disorders. The role of Mg deficit in TS is suggested by relatively low levels of serum or erythrocyte Mg and by the clinical response to oral Mg salts, which has been demonstrated in controlled studies. Among the more serious neurologic sequelae of TS are migraine attacks, transient ischemic attacks, sensorineural hearing loss and convulsions. Mg deficiency may predispose to hyperventilation and may sensitize the cerebral vasculature to the effects of hypocarbia. Mg deficiency increases susceptibility to the physiologic damage produced by stress, and magnesium administration has a protective effect; studies on noise stress and noise-induced hearing loss are taken as an example. In addition, the adrenergic effects of psychological stress induce a shift of Mg from the intracellular to the extracellular space, increasing urinary excretion and eventually depleting body stores. Drugs used in neurology and psychiatry may affect Mg levels in blood and may diminish signs of tetany, making assessment of Mg status more difficult. Pharmacologic use of Mg can decrease neurologic deficit in experimental head trauma, possibly by blockade of N-methyl-D-aspartate receptors. In conjunction with high doses of pyridoxine, Mg salts benefit 40% of patients with autism, possibly by an effect on doparnine metabolism.
Mg, Noise and Sensorineural Hearing Loss
Experimental support for a relationship between Mg status and sensorineural hearing loss comes from the work of Ising. They first studied auditory-evoked potentials in guinea pigs fed an Mg-deficient diet and then variably repleted with Mg-enriched drinking water. There was a significant negative correlation between the Mg content of perilymph and the degree of hearing loss induced by chronic noise stress (r = -0.86). Next, they studied auditory-evoked potentials in rats on Mg-enriched and Mg-poor diets exposed to noise stress for 16 h a day. The relatively mild Mg deficiency sustained over a period of 3 months produced a 20-35% decrease in Mg concentrations of plasma, erythrocytes and perilymph, yielded none of the pathological effects associated with severe Mg deficiency in rats and had no effect on auditory threshold. Noise stress produced low levels of hearing loss (7-14 dB) in rats fed Mg-enriched food and much greater hearing loss (24 dB) in Mg-deficient rats. The degree of hearing loss was negatively correlated with plasma and erythrocyte Mg levels. In a subsequent study they found that gentamycin-induced hearing loss was markedly increased by mild Mg deficiency. Administration of gentamycin for 5 days to normal rats caused an elevation of hearing threshold of 11 dB at 10 kHz and 13 dB at 20 kHz, which had decreased to 2 and 6 dB, respectively, a week later. In Mg deficiency, the hearing loss was 42 dB at 10 kHz and 43 dB at 20 kHz; I week later, despite a normal diet, hearing loss had not improved in the Mg-deficient group. Complete irreparable deafness occurred in 36% of Mg-deficient rats and in none of the normal rats given gentamycin. In a human study, fighter pilots occupationally exposed to noise stress underwent evaluation of hearing thresholds at 3, 4 and 6 kHz and serum Mg concentrations. The correlation between age-adjusted hearing loss and serum Mg was -0.61 (n = 24, p < 0.001). The authors speculate that alterations in K, Na and Ca transport induced by mild Mg deficiency are responsible for impaired function of cochlear hair bundles.
The effect of Mg status on hearing loss is complicated by the effect of noise stress on Mg metabolism; this well-studied interaction has yielded considerable support for clinical theories concerning the relationship between stress and Mg in diverse situations. Consequently, it is reviewed here in detail. Two hours of noise stress in guinea pigs causes a mean reduction in erythrocyte Mg of 2 mmol/g dry weight and a simultaneous increase in serum Mg by 0.8 mmol/l, suggesting a shift of Mg from the intracellular to the extracellular compartment. In rats, chronic noise stress causes an increase in serum Mg and a decrease in erythrocyte and myocardial Mg. When Mg intake is normal, 20 days of noise stress raises the mean serum Mg from 0. 9 5 to 1. 15 mmol/l and lowers mean erythrocyte Mg from about 5.8 to 4.8 mmol/kg dry weight. After 24 h of silence, the serum Mg drops below the control level to 0.90 mmol/l, and the erythrocyte Mg increases but does not reach control levels, failing to rise above 5.4 mmol/kg dry weight, even with a fourfold increase in dietary Mg. Myocardial Mg decreases in parallel with erythrocyte Mg. The implication is that a net excretion of Mg occurs in response to noise stress, leaving the animal depleted. In fact, Mg excretion increases from a control value of 6 to 16 mmol/g creatinine under noise stress. Similar results occur in humans. Here are exposed 57 human volunteers to work under 7 h of traffic noise or 7 h of quiet. Under noise stress, the serum Mg increased by 2.4% (p 0.01), the urine Mg increased by 15 % (p 0.01) and the erythrocyte Mg decreased by 1.5% (p = 0.05). The degree of increase in serum Mg correlated with a decrease in work performance (r = 0.37, p = 0.05). Brewery workers laboring for I week in a noisy hall (95 dB) lost 5% of their blood cell Mg content compared to a similar group using ear protectors.
The metabolic effects of noise stress in humans and animals are accompanied by changes in catecholamine metabolism. Brewery workers working for 1 day with ear protection and 1 day without excrete significantly more norepinephrine (NE) and its metabolite vanilly1mandelic acid in urine under the noise stress condition. In a similar study of male volunteers exposed to traffic noise, urinary NE increased 8.5% (NS) and urinary epinephrine increased 27 % (p = 0.01) during the 7-hour period of noise stress. Pronounced increases in catecholamine excretion also occur in rats exposed to noise, although it appears that preexisting Mg deficiency is necessary for this effect to occur. The effect of Mg status on the behavioral and biochemical response to noise completes the cycle. Urinary catecholarnine excretion increases progressively with increasing dietary Mg deprivation in rats without noise stress. The addition of noise further increases NE but not epinephrine excretion; the more pronounced the noise and the greater the Mg deficit, the higher the catecholamine excretion, with epinephrine and NE excretion reaching 5 and 10 times control levels under extreme but nonlethal conditions. Noise stress in Mg-deficient rats causes a decrease in myocardial Mg and an increase in cardiac Ca concentration that is independently proportional to the degree of Mg deficiency and the duration of noise. The decrease in myocardial Mg displayed a negative linear correlation with the excretion of NE.
Erythrocyte Mg levels are inversely proportional to some effects of noise stress in humans and animals. Erythrocyte Mg is negatively correlated with self-reported noise sensitivity (r = -0.27, p = 0.05), with noiseinduced emotional lability (r = 0.37, p = 0.01) and with noise-induced feelings of tenseness (r = -0.29, p = 0.05) in human volunteers. The hypertensive effect of injected NE in noise-stressed rats was negatively correlated with erythrocyte Mg (r = -0.70, p < 0.01). Deposition of collagen in the rat heart, a sign of physiologic aging, is synergistically accelerated by noise stress and Mg deficiency. Mg supplementation prevents this effect; caffeine feeding increases it. In summary, noise exposure causes an increased excretion of catecholamines and a shift of Mg from the intracellular to extracellular space with a resulting increase in Mg excretion. This effect on Mg metabolism is initially protective; the relatively high serum Mg level of acute stress is thought to buffer the physiologic response to stress. Prolonged noise exposure causes a gradual Mg depletion associated with accelerated physiologic aging. Dietary Mg deficiency aggravates in a synergistic fashion all the effects of noise stress, including ototoxicity, adrenergic hyperactivity, Mg depletion, psychological and physiologic deterioration. Mg supplementation appears to protect against some of the effects of noise. Humans with relatively high intracellular Mg as measured by the erythrocyte level are less adversely affected by noise than are humans with relatively low erythrocyte Mg.
The extra-aural effects of noise can be produced by a wide variety of stressors, including overcrowding and prolonged handling of animals. Guinea pigs are so sensitive to the effects of handling that serum Mg changes induced by noise and diet can be obscured by experimental design that does not control for handling stress. Rats injected with direct- and indirect-acting sympathornimetic amines similarly develop intracellular Mg depletion, which is associated with an increase in intracellular Ca and Na; adrenergic activity appears to mediate the impact of stress on Mg metabolism. Dietary Mg depletion accelerates these electrolyte shifts; Mg supplementation reduces them. The type A or 'coronary prone 'behavior pattern in humans is characterized by time urgency, impatience, extreme competitiveness and hostility when compared to its opposite or type B pattern. When stressed psychologically, type A individuals show significantly greater increases in plasma and urinary catecholamines and cortisol than type B individuals, and correspondingly greater changes in heart rate, blood pressure and vascular resistance. In 1980, Altura first suggested that the type A behavior pattern may be associated with Mg deficiency. Henrotte studied the effect of a signal detection task on Mg metabolism of 20 type A and 19 type B French university students. Mental stress increased the urinary catecholamines and serum free fatty acids of both groups; the effects were significantly greater in type A than in type B individuals. Plasma Mg increased by 1.5% (p < 0.05), and erythrocyte Mg decreased by 0.5% (p < 0.01) in type A subjects; there was no change in these levels for the type B subjects. The high degree of statistical significance for these small changes was due to the homogeneity of response in type A subjects, producing a very low standard deviation. Henrotte attributes the flux of Mg from erythrocyte to plasma to the stimulation of 0-adrenergic receptors on the erythrocyte membrane.
The experimental observations of the effects of various types of stress on electrolyte and catecholamine levels are consistent with clinical observations of patients with TS. Excretion of catecholamines is 89% greater (p < 0.001), and excretion of vanillylmandelic acid is 53% greater (p < 0.01) in TS patients than in controls; this increase in adrenergic activity correlates with lower serum K and serum and erythrocyte Mg and higher venous blood pH. Ca and Na content of erythrocytes from TS patients is greater in patients with TS than in controls. Administration of Mg salts produces a small increase in serum K and serun and erythrocyte Mg in these patients but does not affect erythrocyte Ca or Na levels. There are no data to indicate that Mg therapy by itself lowers catecholamine excretion in these patients and most clinicians favor the use of P-blockers in addition to Mg. In reviewing his experience treating nervous children with TS, Ducroix concluded that the pathogenesis of the syndrome is still unclear, particularly with regard to the interaction of psychogenic and metabolic factors, and that the best test of Mg deficiency was a trial of oral Mg therapy. This is the ultimate position of Durlach and Fehlinger also. Both authors recommend the use of acidic salts of Mg, believing that they have superior absorption and do not aggravate the alkalosis manifested by some TS patients. Durlach recommends 5 mg/kg/day, and Fehlinger prefers 6-7 mg/kg/day. Ducroix prefers 10 mg/kg/day for children because of their low body weight and increased requirements for growth. Fehlinger has described a group of patients with a continuous requirement for oral Mg at doses of 400-1,400 mg/day. When hospitalized and given placebo instead of Mg, these patients drop their plasma Mg from a mean of 0.85 to 0.74 mmol/1 within 1 week and become acutely symptomatic.
Leo Galland, Great Smokies Diagnostic Laboratory, Asheville, N.C., USA