Manganese Metabolism in Epilepsy: Normal or Abnormal? - ACS

Chapter 10

Manganese Metabolism in Epilepsy: Normal or Abnormal? 1-4

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G. F. Carl , Carl L. Keen , B. B. Gallagher , and L. S. Hurley 1

Department of Neurology, Medical College of Georgia, Augusta, GA 30912 Department of Medicine, Medical College of Georgia, Augusta, GA 30912 Department of Psychiatry, Medical College of Georgia, Augusta, GA 30912 Medical Research Service, Veterans Administration Medical Center, Augusta, GA 30910 Department of Nutrition, University of California—Davis, Davis, CA 95616

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There is a relationship between manganese and epilespy that remains undefined. While animal experiments have shown that manganese deficiency increases seizure susceptibility, clinical work has established that mean whole blood manganese concentration is significantly lower in an epileptic population than it is in a control population. One suggestion has been that the lower blood manganese concentration in epileptics is due to seizure activity. Alternatively, others have suggested a possible genetic origin of the lower manganese levels in a subgroup of epileptics. It has also been reported that soft tissue manganese levels are responsive to adrenal steroids, and it is known that some epileptics with a temporal lobe focus exhibit abnormal pituitary/adrenal control suggesting a possible hormonal cause for the lower blood manganese levels. In 1961 Hurley and coworkers (1) observed that congenitally ataxic rats were more susceptible to seizures induced by electroshock than were controls. This report followed closely a publication of preliminary findings (2) i n d i c a t i n g that seizures induced i n rats by hydralazine i n j e c t i o n could be prevented by p r i o r i n j e c t i o n of manganese chloride. These preliminary findings were l a t e r confirmed (3) and indeed i t was shown that i t was the manganese deficiency that increased the seizure s u s c e p t i b i l i t y of the rats independent of the ataxia (3). The f i r s t report of abnormal manganese concentrations i n human e p i l e p t i c s was published i n 1967 and indicated high serum manganese concentrations i n e p i l e p t i c s compared to non-epileptic controls (4). The authors were apparently unaware of the previous animal work that demonstrated a l i n k between manganese deficiency and increased s u s c e p t i b i l i t y to seizure. It was not u n t i l 1978 that Tanaka (5) presented data i n d i c a t i n g that whole blood manganese concentrations were lower i n e p i l e p t i c children than i n control children of similar age. A year l a t e r Papavasiliou and coworkers (6) i n a study of 52 0097-6156/87/0354-0105S06.00/0 © 1987 American Chemical Society

Kies; Nutritional Bioavailability of Manganese ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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adult e p i l e p t i c patients found that the patients had a mean whole blood manganese concentration that was 76% that of 24 controls (p < 0.002). They examined t h e i r data for correlations between manganese levels and either serum anticonvulsant concentrations or seizure frequency. While they found no relationship between blood manganese and medication, seizure frequency did show a s i g n i f i c a n t (p < 0.001) relationship to blood manganese concentration by analysis of variance. These investigators also did a limited study into the p o s s i b i l i t y that there i s a genetic lesion underlying the lower blood manganese concentrations observed i n some e p i l e p t i c s . In t h e i r study the whole blood manganese concentrations i n six none p i l e p t i c r e l a t i v e s of e p i l e p t i c patients were normal r e l a t i v e to those i n the control population. Unfortunately, these r e l a t i v e s were not further i d e n t i f i e d , so that i t remains unknown to which patients they were related or whether or not they were related to the same or d i f f e r e n t patients. Interestingly, these investigators also measured manganese concentration i n the hair of patients and controls. Although the mean manganese concentration i n p a t i e n t s hair was lower than that of controls, the difference was not s t a t i s t i c a l l y s i g n i f i c a n t due to the v a r i a b i l i t y i n the h a i r manganese measurements. In addition, they found no s i g n i f i c a n t correlation between hair manganese and blood manganese concentrations. 1

In 1980 Hoffman (7) reported that serum manganese concentrations were the same i n e p i l e p t i c s and non-epileptic controls i n populations of both adults and children. This observation suggests that the differences reported by Tanaka (5) and by Papavasiliou, et a l . (6) i n whole blood were due to differences i n manganese concentrations i n the blood c e l l s , probably erythrocytes. Whether t h i s apparent deficiency i n the erythrocytes of some e p i l e p t i c s translates into lower manganese concentrations i n other tissues of these e p i l e p t i c s i s unknown. To further examine the relationship between blood Mn concentration and seizure frequency, Papavasiliou and M i l l e r (8) injected mice with **Mn at various times before and after inducing a seizure by either maximal electroshock or pentylene tetrazole i n j e c t i o n . They followed the d i s t r i b u t i o n of the radioactive manganese i n the tissues of the mice and found that Mn injected immediately after the siezure was taken up more readily by the l i v e r (67% increase) and less readily by brain (53% decrease) and carcass (42% decrease) than Mn injected either into sham-seized mice or into mice before induction of a seizure. They also found that chronic electroshockinduced seizure a c t i v i t y i n mice (2/day, 6 day/wk, 3 wk) resulted i n a decrease i n brain manganese concentration (16%) and an increase i n l i v e r manganese concentration (67%) compared to sham-treated cont r o l s . These data were interpreted as indicating that the large energy demand of the seizure causes a s h i f t of manganese, which i s important i n energy metabolism, from other tissues (such as erythrocytes and brain) into the l i v e r . They argue that r e e q u i l i b r a t i o n of the manganese takes time, and intervening seizures further s h i f t the manganese toward the l i v e r . Consequently, whole blood manganese concentration (as well as manganese concentration i n other nonhepatic tissues) decreases as seizure frequency increases. 5

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in Epilepsy

A r e c e n t study from our l a b o r a t o r y u s i n g age, sex, r a c e and w e i g h t matched c o n t r o l s w i t h b l i n d e d a n a l y s e s c o n f i r m e d p r e v i o u s r e p o r t s o f l o w c o n c e n t r a t i o n s o f manganese i n whole b l o o d o f e p i l e p t i c s (11.8 ppb v s . 8.3 ppb,p < 0.001) ( 9 ) . We a l s o c o n f i r m e d t h e l a c k o f a c o r r e l a t i o n between a n t i c o n v u l s a n t m e d i c a t i o n and whole b l o o d manganese l e v e l s , e i t h e r as a f u n c t i o n o f t o t a l m e d i c a t i o n ( F i g u r e 1) o r i n d i v i d u a l a n t i c o n v u l s a n t s (Table I ) , but were u n a b l e t o c o n f i r m c o r r e l a t i o n between s e i z u r e frequency and b l o o d manganese c o n c e n t r a t i o n ( F i g u r e 2 ) . However, we d i d r e p o r t t h a t e p i l e p t i c s w i t h s e i z u r e s o f unknown e t i o l o g y had s i g n i f i c a n t l y lower b l o o d manganese c o n c e n t r a t i o n s than e p i l e p t i c s whose s e i z u r e s c o u l d r e a s o n a b l y be a t t r i b u t e d t o i n j u r y o r d i s e a s e . We suggested t h a t a subgroup o f e p i l e p t i c s may e x h i b i t low b l o o d manganese l e v e l s o f g e n e t i c o r i g i n . We a l s o examined plasma z i n c and copper concent r a t i o n s i n o u r p a t i e n t s and i n c o n t r o l s and found no d i f f e r e n c e s ( T a b l e I I ) i n d i c a t i n g t h a t t h e lower manganese l e v e l s a r e not a s i g n of a g e n e r a l i z e d t r a c e element d e f i c i e n c y . T h i s f i n d i n g c o n t r i b u t e s t o t h e c o n t r o v e r s y i n v o l v i n g copper and z i n c c o n c e n t r a t i o n s i n t h e b l o o d o f e p i l e p t i c s w h i c h h a s been r e v i e w e d i n one o f t h e most r e c e n t r e p o r t s on t h i s s u b j e c t ( 1 0 ) . Table I .

Drug Phenytoin Phenobarbital Primidone Carbamazepine Valproate

C o r r e l a t i o n Between Whole B l o o d Manganese C o n c e n t r a t i o n and Plasma A n t i c o n v u l s a n t Concentrations i n E p i l e p t i c P a t i e n t s

N 23 16 13 26 9

Slope +0.149 -0.012 +0.011 -0.024 +0.056

Manganese c o n c e n t r a t i o n s were photometry and a n t i c o n v u l s a n t A l t o . CA). Linear regression c o r r e l a t i o n between manganese concentration.

Intercept 6.25 7.40 6.25 8.72 7.78

Correlation Coefficient 0.291 -0.037 0.017 -0.020 0.182

measured by atomic a b s o r p t i o n s p e c t r o c o n c e n t r a t i o n s by EMIT (Syva, P a l o a n a l y s e s i n d i c a t e no s i g n i f i c a n t c o n c e n t r a t i o n and any a n t i c o n v u l s a n t

I t i s i n t e r e s t i n g t o n o t e t h a t g l u c o c o r t i c o i d s have been shown t o a f f e c t t h e d i s t r i b u t i o n o f manganese i n the body o f t h e mouse (11,12). S e i z u r e s have a l s o been shown t o a f f e c t manganese d i s t r i b u t i o n i n mice ( 8 ) , and, i n t e m p o r a l l o b e e p i l e p t i c s , t h e c o n t r o l o f t h e g l u c o c o r t i c o i d output from the a d r e n a l g l a n d i s a p p a r e n t l y abnormal ( 1 3 ) . J u s t how these independent o b s e r v a t i o n s might be r e l a t e d i s not c l e a r . When mice were t r e a t e d w i t h ACTH, C o r t i s o l o r p r e d n i s o l o n e , manganese showed a r e d i s t r i b u t i o n from t h e l i v e r t o t h e c a r c a s s (11,12). However, adrenalectomy d i d not have t h e o p p o s i t e e f f e c t , u n l e s s e x t r e m e l y h i g h doses o f manganese were g i v e n (12). But, a s d e s c r i b e d above, s e i z u r e s a p p a r e n t l y caused a r e d i s t r i b u t i o n o f manganese i n t h e o p p o s i t e d i r e c t i o n , from the c a r c a s s t o t h e l i v e r ( 8 ) . T h i s would i n d i c a t e t h a t t h e s e i z u r e s do n o t



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16.0-1

15.014.0 13.0 12.011.0 10.0-

9.0 8.07.06.0-

5.0 4.0 3.02.01.00

-I

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3

4

r-

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Medication Index F i g u r e 1. Whole b l o o d manganese l e v e l s i n e p i l e p t i c p a t i e n t s v s . m e d i c a t i o n i n d e x . Whole b l o o d manganese was measured by atomic a b s o r p t i o n spectrophotometry. The m e d i c a t i o n index i s a composite measure o f a n t i c o n v u l s a n t c o n c e n t r a t i o n s i n plasma as a r e l a t i o n s h i p o f each a n t i c o n v u l s a n t t o i t s t h e r a p e u t i c range. The m e d i c a t i o n i n d e x i n c r e a s e s as a f u n c t i o n o f t h e r e l a t i v e c o n c e n t r a t i o n o f each a n t i c o n v u l s a n t and as a sum o f a l l a n t i c o n v u l s a n t c o n c e n t r a t i o n s . There was no c o r r e l a t i o n between whole b l o o d manganese and m e d i c a t i o n i n d e x ( r = -0.236.)


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16.0-1

15.014.013.012.011.010.09.08.07.06.0-

5.0-

AJ03J0-

2.01.00-

4

5

Seizure Index F i g u r e 2. Whole b l o o d manganese l e v e l s i n e p i l e p t i c p a t i e n t s v s . s e i z u r e i n d e x . Whole b l o o d manganese was measured by a t o m i c a b s o r p t i o n spectrophotometry. S e i z u r e index i s a l i n e a r i z e d measure o f s e i z u r e frequency. There was no c o r r e l a t i o n between b l o o d manganese c o n c e n t r a t i o n and s e i z u r e i n d e x ( r = -0.067).



110 Table I I .

Copper (ug/ml) Zinc (ug/ml)

Comparison of Plasma Z i n c and Plasma Copper C o n c e n t r a t i o n s Between E p i l e p t i c s and Age, Sex, Race and Height/Weight R a t i o Matched C o n t r o l s

Epileptics N = 44 1.12±0.28

Controls N - 44 1.1310.37

0.5910.15

0.6210.36

Z i n c and copper v a l u e s a r e e x p r e s s e d as mean 1 S.D. Z i n c and copper were measured u s i n g flame atomic a b s o r p t i o n spectrophotometry. A two t a i l e d t - t e s t was used t o compare the means f o r copper (p = 0.8) and f o r z i n c (p = 0.6).

cause an i n c r e a s e i n g l u c o c o r t i c o i d s . However, i n p a t i e n t s whose s e i z u r e s o r i g i n a t e i n the t e m p o r a l l o b e , t h e r e i s an i n c r e a s e d s e c r e t i o n of b o t h ACTH and C o r t i s o l and the f o r m e r , a t l e a s t , does not seem to be d r u g i n d u c e d ( 1 3 ) . I n a d d i t i o n , s u r g i c a l r e m o v a l of

the s e i z u r e f o c u s from the t e m p o r a l l o b e a l l o w s ACTH and C o r t i s o l s e c r e t i o n t o r e t u r n t o normal whether o r not the s e i z u r e s a r e controlled. I t i s unknown a t t h i s time what e f f e c t the s u r g i c a l r e d u c t i o n of s e i z u r e s might have on the d i s t r i b u t i o n of manganese i n t h e s e p a t i e n t s o r whether t h e r e i s any r e l a t i o n s h i p between g l u c o c o r t i c o i d s and manganese d i s t r i b u t i o n i n humans. W h i l e a r e l a t i o n s h i p between e p i l e p s y and b l o o d manganese c o n c e n t r a t i o n has been e s t a b l i s h e d , the n a t u r e of the r e l a t i o n s h i p i s u n c l e a r . I t i s e v i d e n t t h a t c o n s i d e r a b l e work needs t o be done t o examine the mechanisms i n v o l v e d i n t h i s r e l a t i o n s h i p . I n our o p i n i o n , the e f f e c t s and e f f i c a c y of manganese s u p p l e m e n t a t i o n i n e p i l e p t i c p a t i e n t s w i t h low b l o o d manganese need t o be i n v e s t i g a t e d . Keen and coworkers (14,15) have shown t h a t i n r a t s whole b l o o d manganese c o n c e n t r a t i o n i s a r e f l e c t i o n of the r e l a t i v e l e v e l s of manganese i n s o f t t i s s u e s . I f t h i s i s t r u e i n e p i l e p t i c p a t i e n t s w i t h low b l o o d manganese, t h e n low c o n c e n t r a t i o n s of manganese can be e x p e c t e d i n the t i s s u e s of these p a t i e n t s . T h i s p o s s i b i l i t y needs t o be i n v e s t i g a t e d . I n t e r e s t i n g l y manganese t o x i c i t y i s m a n i f e s t e d i n i t i a l l y i n the c e n t r a l nervous system, g e n e r a l l y w i t h the i n d u c t i o n of b e h a v i o r a l changes o r P a r k i n s o n i a n - l i k e symptoms ( 1 6 ) . Whether t h e r e i s a r e l a t i o n s h i p between t h i s o b s e r v a t i o n and the d e f i c i e n c y of manganese i n some e p i l e p t i c s i s a m a t t e r f o r s p e c u l a t i o n , but the l i m b i c system seems t o be i n v o l v e d i n b o t h the b e h a v i o r a l e f f e c t s of manganese t o x i c i t y , and the m a n g a n e s e - d e f i c i e n c y - r e l a t e d epileptic s e i z u r e s , a t l e a s t those o f the t e m p o r a l l o b e t h a t r e s u l t i n i n c r e a s e d ACTH and C o r t i s o l l e v e l s (13). However, the s t r u c t u r e s of the t e m p o r a l l o b e a p p a r e n t l y have manganese c o n c e n t r a t i o n s not s i g n i f i c a n t l y d i f f e r e n t from o t h e r p a r t s of the b r a i n ( 1 7 ) .


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One point that i s abundantly clear about the relationship between manganese and epilepsy i s that much remains to be learned. Acknowledgement s The authors wish to express t h e i r gratitude for support from the Department of N u t r i t i o n of the University of C a l i f o r n i a at Davis and the Department of Neurology of the Medical College of Georgia and the Medical Research Service of the Veterans Administration.

Literature Cited 1.

Hurley, L. S.; Woolley, D. E.; Timiras, P. S. Proc. Soc. Exptl. Biol. Med. 1961, 106, 343-46. 2. Comens, P. In Metal-Binding in Medicine; Seven, M. J.; Johnson, L. A., Eds., Lippincott: Philadelphia, 1960; p 312. 3. Hurley, L. S.; Woolley, D. E.; Rosenthal, F.; Timiras, P. S. Am. J. Physiol. 1963, 204, 493-96. 4. Mindadse, A. A.; Tschikowani, T. I. Dtsch. Gesundheitsw. 1967, 22, 1746-48. 5. Tanaka, Y.; Presented at the American Chemical Society National Meeting, Chicago, 1978. 6. Papavasiliou, P. S.; Kutt, H.; Miller, S. T.; Rosal, V.; Wang, Y. Y.; Aronson, R. B. Neurology 1979, 29, 1466-73. 7. Hoffman, H. Klin. Wochenschr. 1980, 58, 157-58. 8. Papavasiliou, P. S.; Miller, S. T. Exptl. Neurol. 1983, 82, 223-36. 9. Carl, G. F.; Keen, C. L . ; Gallagher, B. B.; Clegg, M. S.; Littleton, W. H.; Flannery, D. B.; Hurley, L.S. Neurology 1986, 36, 1584-87. 10. Taylor, A.; Glose, K. Human Toxicol., 1986, 5, 195-200. 11. Hughes, E. R.; Cotzias, G. C. Am. J. Physiol. 1961, 201, 1061-64. 12. Hughes, E. R.; Miller, S. T.; Cotzias, G. C. Am. J. Physiol. 1966, 211, 207-10. 13. Gallagher, B. B.; Murvin, A.; Flanigin, H. F.; King, D. W.; Luney, D. Epilepsia 1984, 25, 683-89. 14. Keen, C L . ; Clegg, M. S.; Lonnerdal, B.; Hurley, L. S. N. Eng. J. Med. 1983, 308, 1230. 15. Clegg, M. S.; Lonnerdal, B.; Hurley, L. S.; Keen, C. L. Anal. Biochem. 1986, 157, 12-18. 16. Keen, C. L . ; Lonnerdal, B; Hurley, L. S. In Biochemistry of the Essential Ultratrace Elements; Frieden, E . , Ed.; Plenum: New York, 1984; pp 89-132. 17. Bonilla, E.; Salazar, E.; Villasmil, J. J.; Villalobos, R. Neurochem. Res. 1982, 7, 221-27. RECEIVED May 11, 1987


Manganese Metabolism in Epilepsy: Normal or Abnormal? - ACS

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