1390

off magnesium and again after resuming magnesiumtherapy.

Departments of Pediatricsand Medicine,

University of Missouri, andVeterans Administration

Hospital,Columbia, Missouri 65201,

U.S.A.

CONSTANTINE S. ANAST

JAMES M. MOHSSHELDON L. KAPLANTHOMAS W. BURNS.

BIOLOGICAL EFFECT OF LITHIUM SALTS

SiR,—The so-called " diagonal relationship " in the

periodic table of the elements is a fundamental concept incomparative inorganic chemistry. By virtue of the well-established antagonism between Nal and Cai+ it seemsalso to have a significant bearing in biological systems.This topic has been dealt with in a recent symposium. 1A similar antagonism has been suggested for Li+ and

Mg2+, and this may be a step towards an explanation forthe therapeutic effect of lithium salts in the treatment ofmanic-depressive psychosis and also for its toxic effects.

Considering the close chemical relationship betweencalcium and magnesium, which to some extent can sub-stitute each other, we started with red cell as a system lowin calcium. Table I shows the results of giving lithiumcarbonate in a fortified wheat-flour diet for 14 days. The

magnesium concentration increased in plasma and decreasedin erythrocytes. The decrease was on a molar basis of thesame order of magnitude, since lithium erythrocyte con-centration apparently reaches a maximum of 50% of thatin plasma,2 indicating a displacement.

Checks were kept for acid/base disturbances and nonewere found-a finding in accordance with that of Andreoliet al. 3

Although the erythrocyte is considered to represent a

good model-system for electrolyte and membrane studies,the central nervous system has additional features, some ofwhich are reflected in the homoeostatic mechanisms of the

cerebrospinal fluid. The magnesium content in the

cisterna-magna fluid exceeds that of plasma by about15% in normal rats (table n). The effects of lithium-carbonate administration on the magnesium content of

cisterna-magna fluid are shown in table II, and a strikingreduction in magnesium content was observed. Thelithium concentration of the cerebrospinal fluid, like thatof erythrocytes, is somewhat less than 50% of the plasmaconcentration 4 and thus exceeds the displaced magnesium.The distribution ratio between cerebrospinal fluid and

plasma for magnesium did change from 1-16 to 0-82. Thelast value closely corresponds to the distribution ratio formagnesium between a plasma ultrafiltrate and plasma.The homoeostatic mechanism for magnesium has been

seriously affected by lithium.

1. Calcium and Cellular Function (edited by A. W. Cuthbert). London,1970.

2. Lyttkens, L., Søderberg, U., Wetterberg, L. Lancet, Jan. 6, 1973,p. 40.

3. Andreoli, V. M., Villani, F., Brambilla, G. Psychopharmacologia,1972, 25, 77.

4. Prockop, L. D., Marcus, D. J. Life Sci. 1972, ii, 859.

TABLE II-PLASMA AND CEREBROSPINAL-FLUID ANALYSIS AFTER

12 DAYS OF LITHIUM CARBONATE ADMINISTRATION (1-5 g. perkg. DIET)

---- -

_

i i i _--

*r<0001.

The cerebrospinal fluid and the extracellular fluid of thebrain are considered identical. Consistent behaviour ofneuronal and synaptic transmission must depend on a

constant ionic environment. When artificial cerebrospinalfluid is perfused, altered potassium concentrations provokebehavioural changes.’*’"

Similar experiments on the perfusion of unansesthetisedanimals with unphysiological concentrations of magnesiumor with the addition of lithium have not been performed.Probably less drastic effects would be produced, since

magnesium is more firmly bound to the cell membrane andcell organelles.The biological effect of lithium is not only due to the

reduced magnesium concentration, but also to a competitionfor binding sites and complex formation. Lithium is oneof the alkaline metals with the greatest ability to form

complexes. Its high ionic potential is the reason for the

stability of complexes with polyphosphates and amino-polycarbonic acids, like ethylenediamine tetracarbonic acid.

Research Laboratory,Lier Mental Hospital,

N-3400 Lierbyen, Norway.

RAGNAR HAAVALDSENPER INGVALDSEN.

LITHIUM AND LEVODOPA INPARKINSONISM

SIR,-Dr Dalen and Dr Steg (April 28, p. 936) reportedthat lithium was effective in the treatment of the hyper-kinetic involuntary movements which occur during thetreatment of Parkinson’s disease with levodopa. Our

experience with lithium carbonate and levodopa-inducedinvoluntary movements was different.’ We gave lithiumcarbonate (12-24 meq. per day; blood-lithium values,1-0-1-6 meq. per litre) to 4 parkinsonian patients withlevodopa-induced dyskinesias. The duration of lithiumtherapy was 12-85 days. We observed only slight reductionin dyskinesias in 2 of the 4 patients. None elected tocontinue lithium carbonate, because of either limited or noimprovement in their involuntary movements or thedisturbing side-effects (particularly anorexia, nausea, and

5. Pappenheimer, J. R., Heisey, S. R., Jordan, E. F., Downer, J. De C.Am. J. Physiol. 1962, 203, 763.

6. Katzman, R., Weitzman, E. D., Graziani, L., Escriva, A. Neurology,1964, 14, 267.

7. Van Woert, M. H., Ambani, L. M., Weintraub, M. I. New Engl. J.Med. 1971, 285, 1326.

TABLE I-BLOOD ANALYSIS AFTER 14 DAYS OF LITHIUM-CARBONATE ADMINISTRATION (1-5 g. per kg. TO A FORTIFIED WHEAT-FLOUR DIET)

sleepiness). Unlike the experience of Dr Dalen and DrSteg, we did not observe any aggravation of parkinsoniansymptoms by lithium carbonate.

Since lithium-carbonate therapy is technically difficultto regulate and potentially toxic, we caution against itsroutine use in levodopa-induced involuntary movementsuntil further controlled investigations determine itsoverall efficacy.

Departments of Internal Medicineand Pharmacology,

Yale University School of MedicineNew Haven, Connecticut, U.S.A.

MELVIN H. VAN WOERTLALIT M. AMBANI.

SUSTAINED-RELEASE LEVODOPA

SIR,-Our clinical observations with a sustained-release form of levodopa (’ Brocadopa Temtabs ’) agreewith those already reported,!.2 although we question theconclusion that such preparations have no practical value.It now appears that the " on/off " response to levodopaoccurs with increasing frequency and severity as theduration of treatment lengthens. If this brittle response is

mainly due to the fluctuations in circulating dopa levelswhich attend the oral administration of standard levodopapreparations, then sustained-release formulations mightprove helpful.We studied 3 parkinsonian patients who manifested

the " on/off " response to levodopa. Each was observedover 6-9 hours while kept fasting and supine in bed.Levodopa was given orally at optimum therapeutic doselevels every 2t hours in combination with a peripheraldecarboxylase inhibitor (MK 486, ’ Carbidopa’) 25 mg.every 5 hours. Plasma-dopa levels rose sharply after eachdose of levodopa (see figure). Peak circulating levels ofthe aminoacid were generally followed by periods ofmaximum suppression of parkinsonism and the appearanceof dyskinesias, while low plasma-dopa values presaged thereturn of severe parkinsonian signs and the disappearanceof dyskinesias. When these patients were studied underthe same conditions but received levodopa by means of a

1. Eckstein, B., Shaw, K., Sten, G. Lancet, Feb. 24, 1973, p. 431.2. Curzon, G., Friedel, J., Grier, L., Marsden, C. D., Parker, J. D.,

Shipley, M., Zilkhak, J. ibid. April 7, 1973, p. 781.

HOURS

Effect of oral or intravenous levodopa on plasma-dopa con-centrations (0----0), overall parkinsonian severity (8-8),and degree of dyskinesias (A-A).Oral levodopa given every 2! hours ( ). Parkinsonian

severity scored on a scale of 0 (absent) to 12 (very severe).Dyskinesias rated between 0 (absent) and 4 (very severe).

constant intravenous infusion, relatively steady plasmalevels of the aminoacid were associated with a notablystable clinical response (see figure).From these observations we conclude that the on/off

response to orally administered levodopa under the aboveconditions is largely due to fluctuations in circulating dopalevels rather than to some centrally mediated mechanism.As shown by Curzon et al.,2 the irregular response to theavailable sustained-release levodopa preparation reflectsthe failure of this compound to maintain clinically effectiveplasma-dopa concentrations for significantly longer periodsthan the standard form of levodopa. An effective sustained-release preparation which substantially reduced thesefluctuations in blood levels should benefit parkinsonianpatients. Therefore, additional efforts directed towards

development of such a preparation should be profitable.

Neurology Unit,National Institute of Mental Health,Bethesda, Maryland 20014, U.S.A.

ANNE C. WOODSGEORGE A. GLAUBIGERTHOMAS N. CHASE.

BRAIN DEATH AS DETERMINED BYCEREBRAL ARTERIOGRAPHY

SIR,-The accepted definition of brain death in patientswith cardiac function includes complete unreceptivity andunresponsivity to intense stimulation, lack of spontaneousrespirations or movement, areflexia, and two flat electro-

encephalograms (E.E.G.S) at least 24 hours apart in theabsence of hypothermia or depressant drugs.3 3 Thisdefinition of brain death was a major breakthrough, butmany potential donor organs are lost during the 24-hourwaiting-period, because cardiac function and/or renal

perfusion cannot be adequately maintained. I should liketo propose the substitution of complete absence of intra-cranial circulation for the two flat E.E.G.S in determiningbrain death.

Retrograde four-vessel cerebral arteriography by the

Seldinger method would be the quickest and perhaps theeasiest method to assess the absence of intracranial blood-flow. A left carotid arteriogram and a right brachial

arteriogram, however, would also suffice. A unilateralcarotid arteriogram would not be sufficient, because inunilateral intracranial lesions the pressure in the right andleft anterior and middle fossa and that in the posteriorfossa are not necessarily equal. 4,5 If the contrast material

puddled in the major neck vessels and none entered theintracranial circulation over a 5-minute period, then, withthe other criteria being met (excluding two E.E.G.S 24 hoursapart), brain death could be declared.

Riishede and Ethelberg 6 in 1953 reported non-filling ofthe intracranial portion of the internal carotid artery in 5patients with space-occupying intracranial lesions, and theyattributed it to tentorial herniation. Horowitz and Duns-more thought non-filling to be secondary to diencephalicreflexes, and Newton and Couch 11 suggested it might bedue to arterial spasm. Pribram 9 first proposed that non-filling of the internal carotid above the siphon is due toincreased intracranial pressure, and Mitchell et al. 10 experi-mentally confirmed that, when the intracranial pressureexceeds the systolic blood-pressure, intracranial blood-flowceases. Mitchell et al. presented 5 cases of non-filling and

3. J. Am. med. Ass. 1968, 205, 337.4. Cantu, R. C. Int. Surg. 1972, 57, 668.5. Langfitt, T. W., Weinstein, J. D., Cassell, N. F., Gagliardi, L. J.

J. Neurosurg. 1964, 21, 998.6. Riishede, J., Ethelberg, S. Archs Neurol. Psychiat. 1953, 70, 399.7. Horowitz, N. H., Dunsmore, R. H. J. Neurosurg. 1956, 13, 155.8. Newton, T. H., Couch, R. S. C. Radiology, 1960, 75, 766.9. Pribram, H. F. W. Neurology, Minneap. 1960, 11, 10.

10. Mitchell, O. C., Torre, E., Alexander, E., Davis, C. H. J. Neurosurg.1962, 19, 766.