J Neurol (1991) 238 : 262-264
Journal of
Neurology
© Springer-Verlag 1991
M a g n e s i u m deficiency as a cause o f acute intractable seizures D. Nuytten 1, J. Van Hees 1, A. Meulemans 2, and H. Carton 1 1Department of Neurology and 2Department of Emergency Medicine, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Received August 28, 1990 / Received in revised form December 6, 1990 / Accepted December 13, 1990
Summary. Clinical
and experimental investigations have shown that magnesium depletion causes a marked irritability of the nervous system, eventually resulting in epileptic seizures. Although magnesium deficiency as a cause of epilepsy is uncommon, its recognition and correction may prove life-saving. Two case reports are presented which emphasize the importance of recognizing hypomagnesaemia in patients with acute intractable seizures.
Key words: Epilepsy - H y p o m a g n e s a e m i a - Somatostatin
Introduction D i s t u r b a n c e s in m a g n e s i u m m e t a b o l i s m may exert a great i n f l u e n c e o n the c e n t r a l a n d p e r i p h e r a l n e r v o u s systems. I n several studies, the r e l a t i o n s h i p b e t w e e n m a g n e s i u m m e t a b o l i s m a n d n e u r a l f u n c t i o n has b e e n shown, a n d the i m p o r t a n c e of r e c o g n i z i n g h y p o m a g n e s a e m i a in several n e u r o l o g i c a l c o n d i t i o n s has b e e n e m p h a s i z e d [4-6, 11, 19]. I n 1934, H i r s h f e l d e r a n d H a u r y [8] n o t i c e d that the o c c u r r e n c e of seizures could be a m a n i f e s t a t i o n of magn e s i u m d e p l e t i o n . Several lines of e v i d e n c e suggest that h y p o m a g n e s a e m i a m a y play a n i m p o r t a n t role in epilepsy. It was early f o u n d that e x p e r i m e n t a l l y i n d u c e d m a g n e s i u m deficiency in rats causes a m a r k e d irritability of the n e r v o u s system, e v e n t u a l l y c u l m i n a t i n g in generalized seizures [1, 22]. F u r t h e r m o r e , in clinical practice, p a r e n t e r a l l y a d m i n i s t e r e d m a g n e s i u m sulphate has rem a i n e d the t h e r a p y of choice in eclamptic c o n v u l s i o n s [16]. D e s p i t e this e v i d e n c e , the exact role of m a g n e s i u m in the d e v e l o p m e n t of seizures still r e m a i n s poorly understood. I n this p a p e r we p r e s e n t two p a t i e n t s in w h o m differe n t k i n d s of c o n v u l s i o n s were associated with h y p o m a g n e s a e m i a . No o t h e r cause of epilepsy could be f o u n d a n d m a g n e s i u m r e p l a c e m e n t a b o l i s h e d the convulsions. Offprint requests to: D. N uytten
Case reports Case 1
A 20-year-old male had a history of recurrent abdominal pain and diarrhoea. The diagnosis of Crohn's disease had been made 5 years previously. Therapy with sulphasalazin and steroids was instituted with good effect. Very recently, however, he was admitted for the treatment of a colo-duodenal fistula. A limited bowel resection was performed. From an abscess around the ascending colon complications developed, with peritonitis and difficulty in wound healing. The fistula persisted for several weeks and therapy with somatostatin was instituted, as well as fluid balance correction because of a considerable loss of bowel fluid. Four weeks after the operation, the patient showed some periods of confusion together with extreme irritability, starting a few moments after the injection of somatostatin and lasting for several hours. Five days later, the patient gradually developed a confusional state with restlesness, perseverations in movements and myoclonic jerks of the extremities. This was followed by multifocal motor seizures. Each individual seizure had a clonic character and lasted 1-5 min, with brief seizure-free intervals. Meanwhile the patient had lost consciousness and intubation was necessary. Tachycardia, excessive sweating and a mild skew deviation of the eyes were present. Clinical examination revealed brisk tendon reflexes in the four limbs, a positive Chvostek's sign and bilateral clonus, without evidence of lateralization. Brain-stem reflexes were all present. A first attempt to stop the focal seizures with diazepam and phenytoin failed. The seizure activity persisted until phenobarbitone was administered intravenously. The cerebrospinal fluid was within normal limits. Electroencephalography revealed an epileptic focus in the right occipitotemporal region; CT did not reveal brain abnormality. Blood sugar, serum sodium, potassium and calcium levels were normal. The serum magnesium concentration, however, was depressed to 0.63 mEq/1 (normal value: 1.5-2mEq/1). Replacement therapy was started with 10 g magnesium sulphate for the first 24 h, and 6 g/day on the following days. After the 1st day, the epileptic activity on the EEG disappeared. The phenobarbitone treatment was discontinued and the patient regained consciousness. Two days later all signs of neuromuscular irritability, epileptic activity and confusion had disappeared. The serum magnesium level had returned to normal (1.57 mEq/1) and gradually the patient made a complete recovery. The EEG remained within normal limits and no anticonvulsant medication was needed. The excessive fluid loss through the duodenal fistula ceased an somatostatin administration was stopped. The magnesium therapy was continued via the oral route
263 for several months (1.2g Mg(OH)2/day), without recurrence of the seizure activity.
Case 2 A 56-year-old man with liver cirrhosis and secondary varices of the oesophagus due to ethyl alcohol abuse was admitted to hospital after he was found "unconscious" in his car. Clinical examination showed an agitated patient with paresis of the right limbs. He was disorientated and confused and uttered a few incoherently phrases. Since he had recently stopped drinking, it was supposed that the patient had suffered an epileptic seizure due to alcohol withdrawal. Therapy with thiamine and sedatives was instituted. Since examination of the CT brain scan and cerebrospinal fluid did not show any abnormality, no anti-epileptic medication was administered. After 2 days the patient developed a motor seizure of the right limbs together with signs of confusion and agitation. The seizure lasted for 10 min but was followed by repeated lateralized seizures every 15 min. A further CT scan of the brain was normal. However, examination of the EEG revealed an epileptic focus in the left temporal region. Clinical examination showed brisk tendon reflexes in the right limbs with a Babinski sign. Phenytoin and diazepam did not stop the seizures. A lumbar puncture was again performed and revealed normal spinal fluid. There was no evidence of an intercurrent infection. Blood sugar, serum sodium, potassium and calcium levels were normal. There was a slightly elevated ammonium level for which lactulose therapy was instituted. The serum magnesium concentration was depressed to 0.42 mEq/1. Under cardiac monitoring, a bolus of 2 g magnesium sulphate was administered intravenously, followed by 5 g over the next 12 h. At the same time urine was collected for a 24-h estimation of magnesium. Six hours after the administration of magnesium, the encephalopathic picture had already cleared; the patient was fully awake and no longer disorientated. The seizures ceased and the epileptic activity on the EEG had disappeared. The following day, the serum magnesium level had returned to 1.86mEq/l and the magnesium in the collected urine was 4.1 g/24 h (in normal subjects more than 50% of the loading dose is excreted). In the following 4 days, the patient was treated with intravenous magnesium 6 g/day and later with Mg(OH)2 via the oral route at a dose of 1.2g/day, for several weeks. No recurrence of the epileptic phenomena was observed within a follow-up period of 6 months.
Discussion Magnesium is an essential constituent of the diet and the intake is mostly derived from green vegetables, m e a t and seafood [5, 21]. Magnesium depletion develops as a consequence of inadequate dietary intake, malabsorption or excessive gastrointestinal fluid loss. It has been reported to occur with alcoholic cirrhosis, sprue, prolonged diarrhoea, extensive bowel resection, bowel and biliary fistulas, prolonged nasogastric suction with administration of magnesium-free parenteral fluids and vigorous oral calcium supplementation, which m a y interfere with magnesium absorption [5, 14, 21]. The cause of the h y p o m a g n e s a e m i a in our two patients is probably a combination of several of these factors. Indeed, in case 1, there was a period of prolonged diarrhoea, together with an extensive bowel resection and the persistence of a bowel fistula. M o r e o v e r this patient had received magnesium-free parenteral fluids for m a n y days. In the second case, the magnesium depletion was caused by excessive alcohol consumption probably via dietary deprivation or via an increasing effect of al-
cohol on the urinary magnesium excretion [18]. Thirty percent of all alcoholics and 86% of patients with delirium tremens have h y p o m a g n e s a e m i a during the first 2 4 48 h after admission to hospital [7]. Patients with magnesium deficiency usually show signs of neuromuscular irritability such as muscular twitchings, abdominal cramps and a positive Chvostek's sign [5]. Central nervous system disturbances (agitation, confusion, ataxia, hallucinations) have also b e e n reported in cases of magnesium deficiency [4, 5]. They m a y begin insidiously or very abruptly, but sometimes there are no overt symptoms at all. In our patients it was especially the neuromuscular hyperexcitability (muscular twitchings, positive Chvostek's sign), together with the confusional state, that suggested a possible underlying h y p o m a g n e s a e m i c state. If these symptoms are found in a patient with a predisposition to magnesium deficiency (see above) the serum magnesium level should always be determined. It remains a matter of debate whether magnesium deficiency plays a primary role in the d e v e l o p m e n t of seizure activity. H o w e v e r , clinical findings as well as experimental investigations have shown that magnesium deficiency may enhance neuronal excitability and provoke seizure activity [6, 11, 20]. In a study by M o d y et al. [12] in rat hippocampal slices, it was proposed that epileptiform activity arose because a decrease in brain magnesium altered the response of the N-methyl-D-aspartate ( N M D A ) - r e c e p t d r complex to amino acid transmitters. Since various N M D A - r e c e p t o r antagonists have potent anti-epileptic properties, activation of these receptors appears to be a crucial factor in the generation of epileptiform activity [13]. These findings were confirmed in slices of h u m a n epileptogenic neocortex. The epileptiform activity induced by lowering the magnesium level resembled the electroencephalographic pattern associated with tonic-clonic seizures [2]. The convulsions caused by magnesium deficiency mostly have a clonic and multifocal character but simple and complex partial seizures have also been described [4, 11]. The seizures are rather resistant to conventional anti-convulsive medication. Generalized epileptiform discharges as well as the presence of an epileptic focus m a y be seen on the E E G . The paresis of the right limbs found on clinical examination of the second case is probably to be considered as being a postictal p h e n o m e n o n (Todd's paralysis). It is r e m a r k a b l e that the periods of confusion and ext r e m e irritability and even the seizure activity in our first case seemed to be triggered by the administration of somatostatin. It is not yet clear if and in what way somatostatin can p r o v o k e epileptic discharges. Pittman and Siggins [15] have shown that somatostatin can have an excitatory or an inhibitory effect on neuronal firing, depending on the route of application, dose or target area of the brain. In amygdala kindling, an animal model of complex partial epilepsy, somatostatin levels were elevated in both the cortical and limbic areas of the brain [10]. The diagnosis of magnesium deficiency should be based on the serum magnesium m e a s u r e m e n t . Generally, a
264 c o n c e n t r a t i o n of l m E q / 1 is accepted as the critical level [9, 23]. H o w e v e r , serum m a g n e s i u m is not always a reliable indicator of total m a g n e s i u m deficiency. Since the ionized part of serum m a g n e s i u m is in equilibrium with m a g n e s i u m b o u n d in b o n e , the expected lowered magnesium serum level is usually c o u n t e r b a l a n c e d by the m a g n e s i u m released f r o m the bone. A l t h o u g h it is the quickest and simplest initial a p p r o a c h to the evaluation of m a g n e s i u m deficiency states, it is much better to check for a lowered 24-h urinary excretion of magnesium. A value b e l o w 2 m E q / 2 4 h m a y indicate m a g n e s i u m deficiency. A still m o r e sensitive index of m a g n e s i u m deficiency is the increased m a g n e s i u m retention after an intravenous loading dose of 10 m E q twice daily. In normal subjects, m o s t of this dose is excreted; in patients with m a g n e s i u m deficiency m o r e than 50% is retained [17]. In our two patients presented here, there was an extremely low serum m a g n e s i u m level; a low 24-h urinary excretion in the second case, after an intravenous dose of 12 g, c o n f i r m e d the diagnosis of a real h y p o m a g n e s a e m i c state. W h e n the diagnosis of h y p o m a g n e s a e m i a has b e e n p r o v e n , m a g n e s i u m administration is indicated. T h e rec o m m e n d e d doses for severe h y p o m a g n e s a e m i a (lower than 0 . 8 m E q / 1 ) are 1 . 5 m E q / k g b o d y weight intravenously over 24h. In less severe cases, 0 . 2 5 - 0 . 5 0 m E q / k g b o d y weight per day m a y be given until the plasma magnesium c o n c e n t r a t i o n b e c o m e s n o r m a l [3]. Prior to the administration of m a g n e s i u m salts, renal function should be assessed because a lowered glomerular filtration rate can result in a m a g n e s i u m intoxication. F o r acute emergencies such as convulsions, a bolus of 2 g MgSO4 (10 ml of 20% solution) should be given intravenously in l m i n , followed by c o n t i n u o u s administration [5].
Conclusion Clinical and experimental evidence suggests that a lack of m a g n e s i u m m a y play an important role in the developm e n t of seizures. In epileptic states it is i m p o r t a n t to recognize h y p o m a g n e s a e m i a , since a d e q u a t e supplementation of m a g n e s i u m can p r o m p t l y reverse a life-threatening situation. T h e r e is no well-defined clinical picture of m a g n e s i u m deficiency. Nonetheless, seizure activity, n e u r o m u s c u l a r hyperexcitability and an e n c e p h a l o p a t h y m a y indicate a magnesium-deficient state. In o r d e r not to o v e r l o o k the diagnosis, it is r e c o m m e n d e d that the ser u m m a g n e s i u m level is m e a s u r e d in all patients with acute intractable seizures, while considering the factors which might lead to m a g n e s i u m deficiency.
References 1. Anderson WW, Lewis DV, Swartzwelder HS, Wilson WA (1986) Magnesium-free medium activates seizure-like events in the rat hippocampal slice. Brain Res 398:215-219 2. Avoli M, Louvel J, Pumain R, Olivier A (1987) Seizure-like discharges induced by lowering [Mg 2+]0 in the human epileptogenic neocortex maintained in vitro. Brain Res 417 : 199-203 3. Dyckner T, Wester PO (1982) Magnesium deficiency. Guidelines for diagnosis and substitution therapy. Acta Med Scand 661 [Suppl] :37-41 4. Fishman RA (1965) Neurological aspects of magnesium metabolism. Arch Neurol 12:562-568 5. Flink EB (1981) Magnesium deficiency. Etiology and clinical spectrum. Acta Med Scand 647 [Suppl] : 125-137 6. Hanna S, Harrison M, MacIntyre I, Fraser R (1960) The syndrome of magnesium deficiency in man. Lancet II : 172-176 7. Heaton FW, Pyrah LN, Beresford CC, Bryson RW, Martin DF (1962) Hypomagnesemia in chronic alcoholism. Lancet II : 802-805 8. Hirschfelder AD, Haury VG (1934) Clinical manifestations of high and low plasma magnesium. JAMA 102:1138-1141 9. Jackson CE, Meier DW (1968) Routine serum magnesium analysis. Correlation with clinical state in 5,100 patients. Ann Intern Med 69 : 743-748 10. Kato N, Higuchi T, Friesen HG, Wada JA (1983) Changes of immunoreactive somatostatin and J3-endorphin content in rat brain after amygdaloid kindling. Life Sci 32 : 2415-2422 11. Leaver DD, Parkinson GB, Schneider KM (1987) Neurological consequences of magnesium deficiency: correlations with epilepsy. Clin Exp Pharmacol Physiol 14 : 361-370 12. Mody I, Lambert JDC, Heinemann U (1987) Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysio157: 869-888 13. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307 : 462-465 14. Paymaster NJ (1976) Magnesium metabolism: a brief review. Ann R Coll Surg Engl 58 : 309-314 15. Pittman Q, Siggins G (1981) Somatostatin hyperpolarizes hippocampal pyramidal cells in vitro. Brain Res 221 : 402-408 16. Pritchard JA, Pritchard SA (t975) Standardized treatment of 154 consecutive cases of eclampsia. Am J Obstet Gynecol 123 : 543-552 17. Ryzen E, Elbaum N, Singer FR, Rude RK (1985) Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 4:137-147 18. Sargent WQ, Simpson JR, Beard JD (1974) The effects of acute and chronic ethanol administration on divalent cation excretion. J Pharmacol Exp Ther 190:507-514 19. Suter C, Klingman WO (1955) Neurologic manifestations of magnesium depletion states. Neurology 5 : 691-699 20. Vallee BL, Wacker WEC, Ulmer DD (1960) The magnesium deficiency tetany syndrome in man. N Engl J Med 262:155161 21. Wacker WEC, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278 : 658-663 22. Walther H, Lambert JDC, Jones RSG, Heinemann U, Hamon B (1986) Epileptiform activity in combined slices of the hippocampus, subiculum and enthorinal cortex during perfusion with low magnesium medium. Neurosci Lett 69 : 156-161 23. Woodbury J, Lyons K, Carretta R, Hahn A, Sullivan JF (1968) Cerebrospinal fluid and serum levels of magnesium, zinc and calcium in man. Neurology 18:700-705
Journal of
Neurology
© Springer-Verlag 1991
M a g n e s i u m deficiency as a cause o f acute intractable seizures D. Nuytten 1, J. Van Hees 1, A. Meulemans 2, and H. Carton 1 1Department of Neurology and 2Department of Emergency Medicine, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Received August 28, 1990 / Received in revised form December 6, 1990 / Accepted December 13, 1990
Summary. Clinical
and experimental investigations have shown that magnesium depletion causes a marked irritability of the nervous system, eventually resulting in epileptic seizures. Although magnesium deficiency as a cause of epilepsy is uncommon, its recognition and correction may prove life-saving. Two case reports are presented which emphasize the importance of recognizing hypomagnesaemia in patients with acute intractable seizures.
Key words: Epilepsy - H y p o m a g n e s a e m i a - Somatostatin
Introduction D i s t u r b a n c e s in m a g n e s i u m m e t a b o l i s m may exert a great i n f l u e n c e o n the c e n t r a l a n d p e r i p h e r a l n e r v o u s systems. I n several studies, the r e l a t i o n s h i p b e t w e e n m a g n e s i u m m e t a b o l i s m a n d n e u r a l f u n c t i o n has b e e n shown, a n d the i m p o r t a n c e of r e c o g n i z i n g h y p o m a g n e s a e m i a in several n e u r o l o g i c a l c o n d i t i o n s has b e e n e m p h a s i z e d [4-6, 11, 19]. I n 1934, H i r s h f e l d e r a n d H a u r y [8] n o t i c e d that the o c c u r r e n c e of seizures could be a m a n i f e s t a t i o n of magn e s i u m d e p l e t i o n . Several lines of e v i d e n c e suggest that h y p o m a g n e s a e m i a m a y play a n i m p o r t a n t role in epilepsy. It was early f o u n d that e x p e r i m e n t a l l y i n d u c e d m a g n e s i u m deficiency in rats causes a m a r k e d irritability of the n e r v o u s system, e v e n t u a l l y c u l m i n a t i n g in generalized seizures [1, 22]. F u r t h e r m o r e , in clinical practice, p a r e n t e r a l l y a d m i n i s t e r e d m a g n e s i u m sulphate has rem a i n e d the t h e r a p y of choice in eclamptic c o n v u l s i o n s [16]. D e s p i t e this e v i d e n c e , the exact role of m a g n e s i u m in the d e v e l o p m e n t of seizures still r e m a i n s poorly understood. I n this p a p e r we p r e s e n t two p a t i e n t s in w h o m differe n t k i n d s of c o n v u l s i o n s were associated with h y p o m a g n e s a e m i a . No o t h e r cause of epilepsy could be f o u n d a n d m a g n e s i u m r e p l a c e m e n t a b o l i s h e d the convulsions. Offprint requests to: D. N uytten
Case reports Case 1
A 20-year-old male had a history of recurrent abdominal pain and diarrhoea. The diagnosis of Crohn's disease had been made 5 years previously. Therapy with sulphasalazin and steroids was instituted with good effect. Very recently, however, he was admitted for the treatment of a colo-duodenal fistula. A limited bowel resection was performed. From an abscess around the ascending colon complications developed, with peritonitis and difficulty in wound healing. The fistula persisted for several weeks and therapy with somatostatin was instituted, as well as fluid balance correction because of a considerable loss of bowel fluid. Four weeks after the operation, the patient showed some periods of confusion together with extreme irritability, starting a few moments after the injection of somatostatin and lasting for several hours. Five days later, the patient gradually developed a confusional state with restlesness, perseverations in movements and myoclonic jerks of the extremities. This was followed by multifocal motor seizures. Each individual seizure had a clonic character and lasted 1-5 min, with brief seizure-free intervals. Meanwhile the patient had lost consciousness and intubation was necessary. Tachycardia, excessive sweating and a mild skew deviation of the eyes were present. Clinical examination revealed brisk tendon reflexes in the four limbs, a positive Chvostek's sign and bilateral clonus, without evidence of lateralization. Brain-stem reflexes were all present. A first attempt to stop the focal seizures with diazepam and phenytoin failed. The seizure activity persisted until phenobarbitone was administered intravenously. The cerebrospinal fluid was within normal limits. Electroencephalography revealed an epileptic focus in the right occipitotemporal region; CT did not reveal brain abnormality. Blood sugar, serum sodium, potassium and calcium levels were normal. The serum magnesium concentration, however, was depressed to 0.63 mEq/1 (normal value: 1.5-2mEq/1). Replacement therapy was started with 10 g magnesium sulphate for the first 24 h, and 6 g/day on the following days. After the 1st day, the epileptic activity on the EEG disappeared. The phenobarbitone treatment was discontinued and the patient regained consciousness. Two days later all signs of neuromuscular irritability, epileptic activity and confusion had disappeared. The serum magnesium level had returned to normal (1.57 mEq/1) and gradually the patient made a complete recovery. The EEG remained within normal limits and no anticonvulsant medication was needed. The excessive fluid loss through the duodenal fistula ceased an somatostatin administration was stopped. The magnesium therapy was continued via the oral route
263 for several months (1.2g Mg(OH)2/day), without recurrence of the seizure activity.
Case 2 A 56-year-old man with liver cirrhosis and secondary varices of the oesophagus due to ethyl alcohol abuse was admitted to hospital after he was found "unconscious" in his car. Clinical examination showed an agitated patient with paresis of the right limbs. He was disorientated and confused and uttered a few incoherently phrases. Since he had recently stopped drinking, it was supposed that the patient had suffered an epileptic seizure due to alcohol withdrawal. Therapy with thiamine and sedatives was instituted. Since examination of the CT brain scan and cerebrospinal fluid did not show any abnormality, no anti-epileptic medication was administered. After 2 days the patient developed a motor seizure of the right limbs together with signs of confusion and agitation. The seizure lasted for 10 min but was followed by repeated lateralized seizures every 15 min. A further CT scan of the brain was normal. However, examination of the EEG revealed an epileptic focus in the left temporal region. Clinical examination showed brisk tendon reflexes in the right limbs with a Babinski sign. Phenytoin and diazepam did not stop the seizures. A lumbar puncture was again performed and revealed normal spinal fluid. There was no evidence of an intercurrent infection. Blood sugar, serum sodium, potassium and calcium levels were normal. There was a slightly elevated ammonium level for which lactulose therapy was instituted. The serum magnesium concentration was depressed to 0.42 mEq/1. Under cardiac monitoring, a bolus of 2 g magnesium sulphate was administered intravenously, followed by 5 g over the next 12 h. At the same time urine was collected for a 24-h estimation of magnesium. Six hours after the administration of magnesium, the encephalopathic picture had already cleared; the patient was fully awake and no longer disorientated. The seizures ceased and the epileptic activity on the EEG had disappeared. The following day, the serum magnesium level had returned to 1.86mEq/l and the magnesium in the collected urine was 4.1 g/24 h (in normal subjects more than 50% of the loading dose is excreted). In the following 4 days, the patient was treated with intravenous magnesium 6 g/day and later with Mg(OH)2 via the oral route at a dose of 1.2g/day, for several weeks. No recurrence of the epileptic phenomena was observed within a follow-up period of 6 months.
Discussion Magnesium is an essential constituent of the diet and the intake is mostly derived from green vegetables, m e a t and seafood [5, 21]. Magnesium depletion develops as a consequence of inadequate dietary intake, malabsorption or excessive gastrointestinal fluid loss. It has been reported to occur with alcoholic cirrhosis, sprue, prolonged diarrhoea, extensive bowel resection, bowel and biliary fistulas, prolonged nasogastric suction with administration of magnesium-free parenteral fluids and vigorous oral calcium supplementation, which m a y interfere with magnesium absorption [5, 14, 21]. The cause of the h y p o m a g n e s a e m i a in our two patients is probably a combination of several of these factors. Indeed, in case 1, there was a period of prolonged diarrhoea, together with an extensive bowel resection and the persistence of a bowel fistula. M o r e o v e r this patient had received magnesium-free parenteral fluids for m a n y days. In the second case, the magnesium depletion was caused by excessive alcohol consumption probably via dietary deprivation or via an increasing effect of al-
cohol on the urinary magnesium excretion [18]. Thirty percent of all alcoholics and 86% of patients with delirium tremens have h y p o m a g n e s a e m i a during the first 2 4 48 h after admission to hospital [7]. Patients with magnesium deficiency usually show signs of neuromuscular irritability such as muscular twitchings, abdominal cramps and a positive Chvostek's sign [5]. Central nervous system disturbances (agitation, confusion, ataxia, hallucinations) have also b e e n reported in cases of magnesium deficiency [4, 5]. They m a y begin insidiously or very abruptly, but sometimes there are no overt symptoms at all. In our patients it was especially the neuromuscular hyperexcitability (muscular twitchings, positive Chvostek's sign), together with the confusional state, that suggested a possible underlying h y p o m a g n e s a e m i c state. If these symptoms are found in a patient with a predisposition to magnesium deficiency (see above) the serum magnesium level should always be determined. It remains a matter of debate whether magnesium deficiency plays a primary role in the d e v e l o p m e n t of seizure activity. H o w e v e r , clinical findings as well as experimental investigations have shown that magnesium deficiency may enhance neuronal excitability and provoke seizure activity [6, 11, 20]. In a study by M o d y et al. [12] in rat hippocampal slices, it was proposed that epileptiform activity arose because a decrease in brain magnesium altered the response of the N-methyl-D-aspartate ( N M D A ) - r e c e p t d r complex to amino acid transmitters. Since various N M D A - r e c e p t o r antagonists have potent anti-epileptic properties, activation of these receptors appears to be a crucial factor in the generation of epileptiform activity [13]. These findings were confirmed in slices of h u m a n epileptogenic neocortex. The epileptiform activity induced by lowering the magnesium level resembled the electroencephalographic pattern associated with tonic-clonic seizures [2]. The convulsions caused by magnesium deficiency mostly have a clonic and multifocal character but simple and complex partial seizures have also been described [4, 11]. The seizures are rather resistant to conventional anti-convulsive medication. Generalized epileptiform discharges as well as the presence of an epileptic focus m a y be seen on the E E G . The paresis of the right limbs found on clinical examination of the second case is probably to be considered as being a postictal p h e n o m e n o n (Todd's paralysis). It is r e m a r k a b l e that the periods of confusion and ext r e m e irritability and even the seizure activity in our first case seemed to be triggered by the administration of somatostatin. It is not yet clear if and in what way somatostatin can p r o v o k e epileptic discharges. Pittman and Siggins [15] have shown that somatostatin can have an excitatory or an inhibitory effect on neuronal firing, depending on the route of application, dose or target area of the brain. In amygdala kindling, an animal model of complex partial epilepsy, somatostatin levels were elevated in both the cortical and limbic areas of the brain [10]. The diagnosis of magnesium deficiency should be based on the serum magnesium m e a s u r e m e n t . Generally, a
264 c o n c e n t r a t i o n of l m E q / 1 is accepted as the critical level [9, 23]. H o w e v e r , serum m a g n e s i u m is not always a reliable indicator of total m a g n e s i u m deficiency. Since the ionized part of serum m a g n e s i u m is in equilibrium with m a g n e s i u m b o u n d in b o n e , the expected lowered magnesium serum level is usually c o u n t e r b a l a n c e d by the m a g n e s i u m released f r o m the bone. A l t h o u g h it is the quickest and simplest initial a p p r o a c h to the evaluation of m a g n e s i u m deficiency states, it is much better to check for a lowered 24-h urinary excretion of magnesium. A value b e l o w 2 m E q / 2 4 h m a y indicate m a g n e s i u m deficiency. A still m o r e sensitive index of m a g n e s i u m deficiency is the increased m a g n e s i u m retention after an intravenous loading dose of 10 m E q twice daily. In normal subjects, m o s t of this dose is excreted; in patients with m a g n e s i u m deficiency m o r e than 50% is retained [17]. In our two patients presented here, there was an extremely low serum m a g n e s i u m level; a low 24-h urinary excretion in the second case, after an intravenous dose of 12 g, c o n f i r m e d the diagnosis of a real h y p o m a g n e s a e m i c state. W h e n the diagnosis of h y p o m a g n e s a e m i a has b e e n p r o v e n , m a g n e s i u m administration is indicated. T h e rec o m m e n d e d doses for severe h y p o m a g n e s a e m i a (lower than 0 . 8 m E q / 1 ) are 1 . 5 m E q / k g b o d y weight intravenously over 24h. In less severe cases, 0 . 2 5 - 0 . 5 0 m E q / k g b o d y weight per day m a y be given until the plasma magnesium c o n c e n t r a t i o n b e c o m e s n o r m a l [3]. Prior to the administration of m a g n e s i u m salts, renal function should be assessed because a lowered glomerular filtration rate can result in a m a g n e s i u m intoxication. F o r acute emergencies such as convulsions, a bolus of 2 g MgSO4 (10 ml of 20% solution) should be given intravenously in l m i n , followed by c o n t i n u o u s administration [5].
Conclusion Clinical and experimental evidence suggests that a lack of m a g n e s i u m m a y play an important role in the developm e n t of seizures. In epileptic states it is i m p o r t a n t to recognize h y p o m a g n e s a e m i a , since a d e q u a t e supplementation of m a g n e s i u m can p r o m p t l y reverse a life-threatening situation. T h e r e is no well-defined clinical picture of m a g n e s i u m deficiency. Nonetheless, seizure activity, n e u r o m u s c u l a r hyperexcitability and an e n c e p h a l o p a t h y m a y indicate a magnesium-deficient state. In o r d e r not to o v e r l o o k the diagnosis, it is r e c o m m e n d e d that the ser u m m a g n e s i u m level is m e a s u r e d in all patients with acute intractable seizures, while considering the factors which might lead to m a g n e s i u m deficiency.
References 1. Anderson WW, Lewis DV, Swartzwelder HS, Wilson WA (1986) Magnesium-free medium activates seizure-like events in the rat hippocampal slice. Brain Res 398:215-219 2. Avoli M, Louvel J, Pumain R, Olivier A (1987) Seizure-like discharges induced by lowering [Mg 2+]0 in the human epileptogenic neocortex maintained in vitro. Brain Res 417 : 199-203 3. Dyckner T, Wester PO (1982) Magnesium deficiency. Guidelines for diagnosis and substitution therapy. Acta Med Scand 661 [Suppl] :37-41 4. Fishman RA (1965) Neurological aspects of magnesium metabolism. Arch Neurol 12:562-568 5. Flink EB (1981) Magnesium deficiency. Etiology and clinical spectrum. Acta Med Scand 647 [Suppl] : 125-137 6. Hanna S, Harrison M, MacIntyre I, Fraser R (1960) The syndrome of magnesium deficiency in man. Lancet II : 172-176 7. Heaton FW, Pyrah LN, Beresford CC, Bryson RW, Martin DF (1962) Hypomagnesemia in chronic alcoholism. Lancet II : 802-805 8. Hirschfelder AD, Haury VG (1934) Clinical manifestations of high and low plasma magnesium. JAMA 102:1138-1141 9. Jackson CE, Meier DW (1968) Routine serum magnesium analysis. Correlation with clinical state in 5,100 patients. Ann Intern Med 69 : 743-748 10. Kato N, Higuchi T, Friesen HG, Wada JA (1983) Changes of immunoreactive somatostatin and J3-endorphin content in rat brain after amygdaloid kindling. Life Sci 32 : 2415-2422 11. Leaver DD, Parkinson GB, Schneider KM (1987) Neurological consequences of magnesium deficiency: correlations with epilepsy. Clin Exp Pharmacol Physiol 14 : 361-370 12. Mody I, Lambert JDC, Heinemann U (1987) Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysio157: 869-888 13. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307 : 462-465 14. Paymaster NJ (1976) Magnesium metabolism: a brief review. Ann R Coll Surg Engl 58 : 309-314 15. Pittman Q, Siggins G (1981) Somatostatin hyperpolarizes hippocampal pyramidal cells in vitro. Brain Res 221 : 402-408 16. Pritchard JA, Pritchard SA (t975) Standardized treatment of 154 consecutive cases of eclampsia. Am J Obstet Gynecol 123 : 543-552 17. Ryzen E, Elbaum N, Singer FR, Rude RK (1985) Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 4:137-147 18. Sargent WQ, Simpson JR, Beard JD (1974) The effects of acute and chronic ethanol administration on divalent cation excretion. J Pharmacol Exp Ther 190:507-514 19. Suter C, Klingman WO (1955) Neurologic manifestations of magnesium depletion states. Neurology 5 : 691-699 20. Vallee BL, Wacker WEC, Ulmer DD (1960) The magnesium deficiency tetany syndrome in man. N Engl J Med 262:155161 21. Wacker WEC, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278 : 658-663 22. Walther H, Lambert JDC, Jones RSG, Heinemann U, Hamon B (1986) Epileptiform activity in combined slices of the hippocampus, subiculum and enthorinal cortex during perfusion with low magnesium medium. Neurosci Lett 69 : 156-161 23. Woodbury J, Lyons K, Carretta R, Hahn A, Sullivan JF (1968) Cerebrospinal fluid and serum levels of magnesium, zinc and calcium in man. Neurology 18:700-705
