Postgrad Med J: first published as 10.1136/pgmj.55.648.701 on 1 October 1979. Downloaded from Postgraduate Medical Journal (October 1979) 55, 701-703

Lithium neurotoxicity P. K. NEWMAN M. SAUNDERS M.B., M.R.C.P. M.B., F.R.C.P. Department of Neurology, Middlesbrough General Hospital, Middlesbrough, Cleveland

Summary EEG showed diffuse delta activity, the spinal fluid The peripheral and central neurotoxic effects oflithium contained 5 x 109 white cells/I and a protein level of carbonate are illustrated by 4 case histories. Lithium 0.92 g/l. Myelography and air ventriculography were neurotoxicity is likely to be more common than the normal. The lithium level was then 0-7 mmol/l and literature suggests. Neurological sequelae may be ranged between 0.4 and 1 2 mmol/l until 1977 when irreversible and may be associated with therapeutic he was re-admitted in a stuporous state. Neurological serum levels. Prevention may be facilitated by more examination was otherwise unchanged. The lithium stringent case selection, EEG and clinical monitoring level was toxic at 2.3 mmol/l, the EEG showed and the development of improved methods of drug frontal delta activity and the spinal fluid remained level assessment. abnormal with 15 x 109 white cells/l and a protein of 1-16 g/l. Withdrawal oflithium resulted in a dramatic Introduction recovery from a bedridden and severely obtunded

Lithium carbonate has been used in therapeutics state, but he has remained moderately disabled by by copyright. for more than a century. The introduction of this his ataxia and paraplegia. A trial of steroid therapy drug to psychiatry (Cade, 1949) was overshadowed was unsuccessful following the emergence of further by the emergence of phenothiazine therapy, but it psychotic behaviour. now has an established place in the treatment of On clinical grounds the most probable cause of manic depressive affective psychosis (Task Force, this neurological illness is multiple sclerosis but the 1975). Despite regular drug monitoring, lithium highly active spinal fluid is distinctly unusual. Other therapy is frequently complicated by side effects and conditions were looked for but detailed investi- toxicity. Renal, endocrine, cardiovascular and gation was unhelpful. The onset of neurological gastro-intestinal side effects may occur but the most disability was closely associated with the initiation troublesome toxicity is seen with central nervous of lithium treatment and hence the authors suspect system involvement. Four cases of severe lithium that the clinical and biochemical agressiveness of http://pmj.bmj.com/ neurotoxicity seen recently in a single neurology this presumed demyelinative lesion is linked with unit are reported to illustrate the various levels of lithium. the nervous system that may be affected and to emphasize that neurological morbidity from this Case 2 drug is probably more widespread than has been A 42-year-old housewife had been treated with thought. It is stressed that these 4 cases presented lithium for several years because of a manic depres- from an area where lithium are sive illness. In 6 weeks before her patients taking 1976, admission, on October 1, 2021 by guest. Protected carefully monitored with frequent estimation of she complained of polyuria and polydipsia. She was serum levels. initially manic but gradually became more with- drawn and then comatose. Neurological examination Case reports revealed flaccid paralysis of all 4 limbs, absent Case I tendon reflexes and plantar responses. An EEG A 47-year-old industrial plant cleaner developed showed widespread high amplitude delta activity. a manic illness in 1970. Neurological examination The serum lithium level was 1.9 mmol/l several days was normal and he made a good recovery with after lithium had been discontinued. She was trans- electroconvulsive therapy and a short course of ferred to the Department of Neurology, Middles- lithium. In 1973 he relapsed and lithium was then brough General Hospital, where her spinal fluid was given continuously until 1977. Two months after found to be normal and where one month after her starting lithium he was found to have a spastic original admission she gradually regained conscious- paraplegia with ataxia and mental deterioration. An ness. It was then found that she had a profound 0032-5473/79/1000-0701 $02.00 © 1979 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.55.648.701 on 1 October 1979. Downloaded from 702 P. K. Newman and M. Saunders muscular weakness, most marked proximally. remained abnormal. All other investigations were Electromyography (EMG) showed widespread fibril- unhelpful and the patient steadily improved when lation in both proximal and distal muscle groups and lithium was stopped. the interference pattern was virtually absent. Motor This patient developed epileptic fits and an acute and sensory nerve conductions were moderately confusional state associated with toxic lithium levels. impaired, suggesting an axonal neuropathy. Repeat There was a vague history of several fits more than EMG and conduction studies showed progressive a decade previously. There was no suggestion of improvement which was matched by a clinical return alcoholic or other metabolic aetiology. Asterixis can to normality over 6 months. The EEG remains theoretically occur in any toxic metabolic state but abnormal with a slow dominant rhythm at 7-8 cycles does not appear to have been observed before in per second (c/s) and a general excess of theta activity. lithium toxicity. In this patient, a toxic lithium level was associated with coma, abnormal EEG and a widespread Discussion neuropathic process. Full recovery followed cessation These 4 cases of severe lithium neurotoxicity have of lithium treatment but a further episode of mania been seen within a relatively short period of time in has subsequently intervened. one unit. A recent survey of the reported cases of severe neurotoxicity mentioned only 38 cases Case 3 (Strayhorn and Nash, 1977). This experience suggests A 62-year-old housewife was admitted in May that the true frequency may be much higher than 1978, disorientated and profoundly retarded. She suspected and that many cases may pass undetected. had been on lithium for 7 months following the Lithium toxicity is usually classified as (i) mild - failure of tricyclics and phenothiazines to control fine tremor, weakness and lethargy, (ii) moderate - relapsing depression, mania and confusional epi- muscle fasciculation, ataxia, coarse tremor, dysarth- sodes, but this had been stopped several days before ria, inco-ordination, extrapyramidal syndromes, evaluation. Lithium levels had ranged from visual disturbances, confusional state, impaired

0.65-1 1 mmol/l. Neurological examination demon- consciousness, (iii) severe - progression of any of the by copyright. strated a mild spastic tetraparesis, generalized brisk above to coma, seizures, muscular flaccidity, marked reflexes, extensor plantar responses, bilateral palmar- cerebellar syndromes, irreversible brain damage and mental reflexes and ataxia. The EEG was abnormal even death (Vacaflor, 1975; Jefferson and Greist, with widespread theta activity at 5-7 c/s and bi- 1977). Significant neurotoxicity has appeared with lateral runs of delta activity. All other investigations normal serum levels (Strayhorn and Nash, 1977) including spinal fluid examination were normal. She and the elderly and schizophrenics are particularly made a spontaneous recovery with resolution of her liable to side effects (Shopsin, Johnson and Gershon, ataxia, paresis and primitive reflexes but has sub- 1970). Neurological disability in mild and moderate sequently relapsed with further retardation and toxicity is usually readily reversible but severe confusion. neurotoxicity may be irreversible (Goldwater and This patient developed an organic brain syndrome Pollock, 1976). http://pmj.bmj.com/ during treatment with lithium. Considerable im- The first case above suggests that underlying provement of her physical state and partial resol- neurological disorders may be precipitated and ution of the abnormal mental state followed cess- exacerbated by lithium therapy for incidental ation of treatment. Interpretation of the role of psychotic disturbances and this has been previously lithium in this illness is difficult, as in so many cases observed in a case of myasthenia (Neil, Himmelhock of lithium neurotoxicity, but the conclusion is that and Licata, 1976). Although a patient with multiple lithium is implicated. sclerosis complicated by a manic illness was success- fully treated with a short course of lithium (Kemp, on October 1, 2021 by guest. Protected Case 4 Lion and Magram, 1977), the present authors feel A 44-year-old gardener was treated with lithium that lithium should be used with the utmost caution because of recurrent mania. Examination in April where psychotic illness is complicated by organic 1978 showed brisk reflexes and a bilateral intention neurological disturbance, and only if other control tremor. In May he had a succession of grand mal measures have been unsuccessful. Red cell lithium convulsions, was acutely confused, visually halluci- levels may prove a more reliable indicator of nated, confabulating and perseverating. In addition incipient toxicity than the currently available serum to the above findings he was dysarthric and exhibited levels (Hewick and Murray, 1976) and a series of marked asterixis, more left than right. The serum therapeutic serum levels should not invite com- lithium level was 1.65 mmol/l. The EEG was placency. Intercurrent illness, impairment of renal abnormal with bitemporal theta and delta activity. function or concomitant diuretic therapy may Repeat EEGs showed some improvement but precipitate toxicity in susceptible individuals. Postgrad Med J: first published as 10.1136/pgmj.55.648.701 on 1 October 1979. Downloaded from Lithium neurotoxicity 703

Early detection oftoxicity would be assisted by serial KEMP, K., LION, J.R. & MAG {AM, G. (1977) Lithium in the EEG monitoring of patients on lithium and perhaps treatment of a manic pat!ent with multiple sclerosis: a case report. Diseases of the Nervous Systern, 38, 210. by more frequent and more detailed clinical exam- NEIL, J.F., HIMMELHOCK, J.M. & LICATA, S.M. (1976) ination with urgent reassessment in the event of any Emergence of myasthenia gravis during treatment with abnormality being found. lithium carbonate. Archives of General Psychiatry, 33, 1090. SHOPSIN, G., JOHNSON, G. & GERSHON, S. (1970) Neuro- toxicity with lithium: Differential drug responsiveness. International Pharmacopsychiatry, 5, 170. References STRAYHORN, J.M. & NASH J.L. (1977) Severe neurotoxicity CADE, J.F.J. (1949) Lithium salts in the treatment of psychotic despite 'therapeutic' lithium levels. Diseases of the Nervous excitement. Medical Journal of Australia, 2, 349. System, 38, 107. GOLDWATER, L. & POLLOCK, M. (1976) Neurological TASK FORCE ON LITHIUM THERAPY (1975) The current status sequelae after lithium intoxication. New Zealand Medical of lithium therapy: Report of the A.P.A. Task Force. Journal, 84, 356. American Journal of Psychiatry, 132, 997. HEWICK, D.S. & MURRAY, N. (1976) Red blood cell levels VACAFLOR, L. (1975) Lithium side effects and toxicity: the and lithium toxicity. Lancet, 2, 437. clinical picture. In: Lithium Research and Therapy (Ed. by JEFFERSON, J.W. & GREIST, J.M. (1977) Primer of Lithium Johnson, F.N.), pp 212-216, Academic Press, London, Therapy, pp 139-150, Williams & Wilkins Co., Baltimore. New York. by copyright. http://pmj.bmj.com/ on October 1, 2021 by guest. Protected