Magnesium Deficiency: a Possible Cause of Thiamine Refractoriness in Wernicke-Korsakoff Encephalopathy

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.959 on 1 August 1974. Downloaded from

Journal of Neurology, Neurosurgery, and Psychiatry, 1974, 37, 959-962

Magnesium deficiency: a possible cause of thiamine refractoriness in Wernicke-Korsakoff encephalopathy

D. C. TRAVIESA From the Department ofNeurology, University ofMiami School of Medicine, Miami, Florida, U.S.A.

SYNOPSIS The determination of blood transketolase before and serially after thiamine administration, and the response of clinical symptomatology after thiamine are reported in two normomagnesaemic patients and one hypomagnesaemic patient with acute Wernicke-Korsakoff encephalopathy. The response of the depressed blood transketolase and the clinical symptoms was retarded in the hypomagnesaemic patient. Correction of hypomagnesaemia was accompanied by the recovery of blood transketolase activity and total clearing of the ophthalmoplegia in this patient, guest. Protected by copyright. suggesting that hypomagnesaemia may be a cause of the occasional thiamine refractoriness of these patients.

Previous studies have shown that the clinical vestibular nuclei (Prickett, 1934; Dreyfus and entity of Wernicke-Korsakoff encephalopathy is Victor, 1961; Dreyfus, 1965). related to an exclusive deficiency of thiamine (Phillips et al., 1952). Furthermore, improvement Blood transketolase activity is markedly re- in clinical symptoms, once the syndrome has de- duced in patients with Wernicke-Korsakoff veloped, occurs only with the repletion of thi- encephalopathy and serial assays in these patients amine. It is this obvious and seemingly pure usually reveal a rapid and essentially complete causal relationship of thiamine deficiency and recovery of the reduced blood transketolase Wernicke-Korsakoff encephalopathy that neces- activity after the parental administration of sitates the total understanding of thiamine thiamine (Brin, 1962; Dreyfus, 1962). Because metabolism in the human if this disease is to be of the seemingly simultaneous recovery of fully understood. enzyme activity and clinical improvement in the

Both pyruvate decarboxylase and transketolase ophthalmoplegia, it has been hypothesized that http://jnnp.bmj.com/ enzymes are thiamine pyrophosphate dependent the dysfunction of the transketolase enzyme (Horecker and Smyroniotis, 1953). It has been system plays a role in the pathogenesis of shown, however, that in the central nervous Wernicke-Korsakoff encephalopathy. system of rats deprived of thiamine, pyruvate decarboxylase activity is apparently refractory to Transketolase is an enzyme in the hexose thiamine depletion, whereas a rapid diminution monophosphate shunt which requires not only thiamine pyrophosphate but also magnesium as of transketolase activity is earliest and most pro- on September 30, 2021 by nounced in the lateral vestibular nuclei of a co-factor. Wernicke-Korsakoff encephalo- thiamine deficient rats (Dreyfus and Hauser, pathy is a disease of the central nervous system 1965). If thiamine deprivation is prolonged, the in which there is considerable evidence that dys- initial decrease in transketolase activity is fol- function of the transketolase enzyme system lowed by stereotyped lesions in the lateral plays an aetiological role; however, the effect of hypomagnesaemia on the response to thiamine Address for reprints: Dr D. C. Traviesa, Department of Neurology, of transketolase enzyme activity and clinical Suite 448, Woodard Bldg, Jackson Memorial Hospital, 1700 N.W 10th Avenue, Miami, Florida 33136, U.S.A. symptomatology in patients with Wernicke- 959 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.959 on 1 August 1974. Downloaded from

960 D. C. Traviesa

Korsakoff encephalopathy has never been METHOD investigated. A sample of blood was drawn from each patient for The purpose of this paper is to report serial determination of serum magnesium, which was con- determinations of blood transketolase activity sidered an estimation of magnesium depletion. before and after thiamine and the response Seven millilitres of blood were drawn from each of clinical symptoms to thiamine in two patient and placed in heparinized tubes before and at normomagnesaemic and one hypomagnes- four and 12 hours after administration of 100 mg aemic patient with unequivocal Wernicke- thiamine intramuscularly. One 7 ml sample was also Korsakoff encephalopathy. The possible role of drawn at 36 hours from patient no. 3, who was hypomagnesaemia in the therapy of Wernicke- hypomagnesaemic. This patient received a total of Korsakoff encephalopathy will be discussed. 6 g of MgSO4 intramuscularly in three divided doses The three patients had the over a 12 hour period beginning 14 hours after intra- following historical muscular thiamine was administered. All samples of and physical findings in common. All three heparinized blood were centrifuged immediately. patients were severe chronic alcoholics with a The plasma was removed and a volume of distilled history obtained from relatives or friends of water equal to the packed erythrocyte volume was extreme malnutrition of at least four months' added to the erythrocytes to form a haemolysate. duration before admission. The common chief These were frozen and later used for determination complaint of the three patients was difficulty in of transketolase activity. Blood transketolase activity walking. Upon admission and before thiamine in six healthy normal subjects and in all experimental guest. Protected by copyright. administration, the patients showed all the samples collected was determined by the method salient clinical features of Wernicke-Korsakoff described by Brin (1966). The buffer solution in this study contained no magnesium. encephalopathy: nystagmus, ophthalmoplegia, Haemolysate, 0.5 ml from each sample, was placed ataxia, and mental disturbances (Table 1). in two tubes. Tube 1 served as the blank and con- All three patients showed diminution to pain, tained 0-65 ml of buffer. Tube 2 contained 0 45 ml of touch, and vibration in both lower extremities in buffer and was incubated at 38°C for 30 minutes fol- the typical stocking-type distribution. After lowed by the addition of 0-2 ml of a 7-0 mg/ml solu- thiamine administration, the symptoms and tion of sodium ribose-5-phosphate. This mixture was signs improved except for the Korsakoff's incubated for one hour at 38°C, followed by termina- psychosis in patients nos 2 and 3. The global tion of the reaction by the addition to both tubes of 6-0 ml 7.50/ trichloracetic acid. The tubes were confusional state in patient no. 1 improved and at rpm 10 1 he was left with a defective memory for recent centrifuged 3000 for minutes and 0 ml of the clear supernatant as well as 100 events. The in the three ug/ml and 50 ,ug/ ophthalmoplegia patients ml D-glucose standards were used to determine cleared completely in 10, six, and 48 hours re- spectrophotometrically the total hexose produced by spectively and nystagmus and ataxia improved the anthrone method described by Brin (1966). to a variable degree and over a longer period of Transketolase activity was expressed in ,tg hexose time after thiamine administration. per ml haemolysate per hour. http://jnnp.bmj.com/

TABLE 1

CLINICAL DETAILS OF THREE PATIENTS on September 30, 2021 by

Patient Ophthalmoplegia Nystagmus Ataxia Mental disturbance I (K.D.) 1. Bilateral horizontal gaze palsy Upbeating vertical jerk Trunk and lower limbs Acute confusional state 2. Upgaze palsy 2 (D.C.) Bilateral 6th nerve palsy Horizontal jerk Trunk and lower limbs Korsakoff's psychosis 3 (B.C.) 1. Right 6th nerve palsy Horizontal jerk Trunk and lower limbs Korsakoff's psychosis 2. Left horizontal gaze palsy Down beat vertical jerk J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.959 on 1 August 1974. Downloaded from

A possible cause of thiamine refractoriness in Wernicke-Korsakoff encephalopathy 961

TABLE 2 SERIAL BLOOD TRANSKETOLASE ACTIVITY BEFORE AND AFTER THIAMINE, SERUM MAGNESIUM LEVELS, AND DURATION OF OPHTHALMOPLEGIA AFTER THIAMINE IN THE THREE SUBJECTS

Patient Hour Blood transketolase activity Serum mg Duration ofophthalmoplegia post-thiamine t±g hexose /hr (NI. 2-3 mg/100 ml) after thiamine administration ml haemolysate (hr) Normal subjects (6) 1070 ± 80 SD

1 Before 605 ...... 2-3 4 714 10 12 1039

2 Before 490 ...... 2-4 4 617 6 12 938

3 Before 535 ...... 12 4 587 12 361001...... 3.0]682 6 g MgSO4 48

RESULTS (Table 2) support of a hypothesis that normal tissue guest. Protected by copyright. magnesium is necessary for the thiamine response The blood transketolase activity in the six in with Wernicke-Korsakoff normal subjects averaged 1070 Vg hexose/ml per patients encephalo- hour. The blood transketolase activity of the pathy. three patients with Wernicke-Korsakoff encephalopathy before the administration of DISCUSSION thiamine was markedly reduced. The response Experimental studies on the rat have shown that of the enzyme activity to parenteral thiamine there is an interdependence between magnesium was essentially complete in the normomagnes- and thiamine in the body (Zieve et al., 1968a). aemic patients 12 hours after intramuscular Transketolase activity in both the liver and blood thiamine. Furthermore, the ophthalmoplegia of thiamine depleted hypomagnesaemic rats is described earlier in these patients was com- markedly depressed and the recovery of the pletely gone in 10 and six hours respectively enzyme activity to thiamine is incomplete. Body after thiamine administration. In contrast, the growth is retarded in similar rats despite the response of blood transketolase activity and the administration of thiamine (Zieve et al., 1968a). ophthalmoplegia were retarded at 12 hours post- The mechanism by which magnesium deficiency

thiamine administration in the hypomagnesaemic interferes with the recovery of transketolase http://jnnp.bmj.com/ patient. The blood transketolase was 692 ,ug/ml activity is not clear. Several hypotheses have and the left gaze palsy and right sixth nerve palsy been given. The simple unavailability of mag- were not improved at 12 hours. Not until the nesium for the reaction has been considered un- hypomagnesaemia was corrected in this patient likely, since the in vitro addition of magnesium by the administration of MgSO4 did the blood at the time of transketolase assay does not in- transketolase activity become normal and the crease activity (Zieve et al., 1968b). Another

ophthalmoplegia clear completely. hypothesis is that there is a lack of pentose on September 30, 2021 by It is recognized that the small number of substrate for the reaction, because of the magne- patients-and, in particular the fact that only sium requirement for substrate formation (Zieve one patient with hypomagnesaemia was studied et al., 1968b). -makes it difficult to draw firm conclusions In the two normomagnesaemic patients re- from these observations. The different response ported here there was complete improvement in of the hypomagnesaemic patient to thiamine and ophthalmoplegia in 10 and six hours respectively the apparent influence of added magnesium is and a manifest improvement 45 minutes after sufficiently striking to warrant its presentation in thiamine administration. The nystagmus became J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.959 on 1 August 1974. Downloaded from

962 D. C. Traviesa more pronounced as the ophthalmoplegia im- ketolase and clinical refractoriness to thiamine proved and ataxia and mental disturbances were in the hypomagnesaemic patient, as well as im- much more refractory to therapy. In contrast, provement in symptoms and recovery of trans- the hypomagnesaemic patient with Wernicke- ketolase activity after the correction of hypo- Korsakoff encephalopathy showed no improve- magnesaemia in this patient, supports the ment of ophthalmoplegia 12 hours after thi- hypothesis that hypomagnesaemia is a cause of amine. MgSO4 therapy was begun 14 hours the thiamine refractoriness that is seen occasion- after thiamine administration and the ophthal- ally in patients with acute Wernicke-Korsakoff moplegia subsequently reversed over the next 34 encephalopathy. hours. Therefore, at least in these patients, clinical improvement seemed to have been corre- The author wishes to express thanks to Dr Barry lated with the level of blood transketolase Fistoff and Dr Peritz Scheinberg for their en- activity. couragement and help. The presence of cirrhosis has been shown to be associated with a delayed response of both blood REFERENCES transketolase activity and lateral rectus palsy in Brin, M. (1962). Erythrocyte transketolase in early thiamine patients with Wernicke-Korsakoff encephalo- deficiency. Annals of the New York Academy of Sciences, pathy, presumably because of the inability to 98, 528-541. in disease Brin, M. (1966). Transketolase: clinical aspects. In Methods phosphorylate thiamine hepatic (Cole in Enzymology, vol. 9, pp. 506-514. Edited by S. P.guest. Protected by copyright. et al., 1969). Although hepatic enzymes were Kolwick and N. 0. Kaplan. Academic Press: New York. initially elevated in the three Cole, M., Turner, A., Frank, O., Baker, H., and Leevy, C. M. patients reported (1969). Extraocular palsy and thiamine therapy in here, all enzymes became normal after three to Wernicke's encephalopathy. American Journal of Clinical six days of vitamins and diet. Only patient 1 had Nutrition, 22, 44-51. an elevated prothrombin time which reverted to Dreyfus, P. M. (1962). Clinical application of blood transketolase determinations. New England Journal ofMedicine, normal four days after hospitalization. The 267, 596-598. physical examination of the hypomagnesaemic Dreyfus, P. M. (1965). The regional distribution of trans- patient 3 revealed no evidence of hepatomegaly, ketolase in the normal and the thiamine deficient nervous system. Journal of Neuropathology and Experimental ascites, spinal angiomata or dilated veins on the Neurology, 24, 119-129. abdominal wall. Liver function tests done on the Dreyfus, P. M., and Hauser, G. (1965). The effect of thiamine first hospital day demonstrated mild elevation of deficiency on the pyruvate decarboxylase system of the central nervous system. Biochimica et Biophysica Acta, 104, serum glutamic oxalacetic transaminase (110 78-84. mU/ml)* and lactate dehydrogenase (220 mU/ml) Dreyfus, P. M., and Victor, M. (1961). Effects of thiamine but normal alkaline phosphatase (65 deficiency on the central nervous system. American Journal mU/ml), of Clinical Nutrition, 9, 414-425. total bilirubin (10 mg/100 ml), albumin (3*7 mg/ Horecker, B. L., and Smyrniotis, P. Z. (1953). The coenzyme 100 ml) and prothrombin time (11.7 s; control function of thiamine pyrophosphate in pentose metabol- tests were on ism. Journal of the American Chemical Society, 75, 1009- 11 6 s). Liver function normal the http://jnnp.bmj.com/ 1010. third hospital day and throughout the rest of the Phillips, G. B., Victor, M., Adams, R. D., and Davidsen, hospital course. Cirrhosis, therefore, was an C. S. (1952). A study of the nutritional defect in Wernicke's unlikely cause for the blood transketolase and syndrome. Journal of Clinical Investigation, 31, 859-871. Prickett, C. 0. (1934). The effect of a deficiency of vitamin B1 ophthalmoplegia refractoriness occurring in this upon the central and peripheral nervous systems of the rat. patient. American Journal of Physiology, 107, 459-470. There is evidence suggesting that depressed Zieve, L., Doizaki, W. M., and Stenroos, L. E. (1968a). activity of transketolase in the central nervous Effect of magnesium deficiency on growth response to

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