| | A patient with lithium intoxication developing at therapeutic serum lithium levels and persistent delirium after discontinuation of its administrationTo the Editor:
Lithium is often used in the treatment of mania but induces various toxic symptoms such as nausea, polyuria and tremor [1]. Therefore, during lithium administration, therapeutic serum lithium levels (0.4–1.0 mEq/L) should be maintained by frequent measurements for the prevention of toxipathy. However, toxipathy has been reported to develop even within the therapeutic lithium concentration range particularly in elderly patients [2].
Delirium as well as ataxia and convulsion represents lithium-induced severe neurotoxicity [2], [3]. We report an elderly manic patient who developed delirium after lithium administration within the therapeutic serum concentration range, and showed persistent delirium for more than 1 month after discontinuation of its administration.
1. Case Report  The patient was a 60-year-old man who had an independent daily life. In early April, 2001, he developed insomnia, logorrhea, and irritability. Subsequently, hyperactivity, decreased ability to concentrate, and excessive spending developed, and he was admitted to our department on June 10, 2001. On admission, marked logorrhea and flight of ideas, grandiosity, and irritability were observed. He had no history of depressive or manic episodes and was diagnosed according to the DSM-IV criteria [4] as having bipolar I disorder, single manic episode. Blood examination, electrocardiography, and chest X-ray examination on admission showed no abnormalities. Brain MRI revealed slight atrophy mainly in the temporal and frontal lobes and slight ventricular dilation. Electroencephalogram (EEG) showed a basic 10–12 Hz α rhythm predominantly in the occipital areas but no mixture of slow waves or paroxysmal discharges. Treatment was initiated with haloperidol (3 mg/day), and its daily dose was increased to 5 mg from 3 days after admission. From 8 days after admission, lithium carbonate (300 mg/day) was added. Since the manic state persisted, the daily dose of haloperidol was increased to 7.5 mg and that of lithium carbonate to 600 mg from 15 days after admission. The manic state gradually improved, but the logorrhea and hyperactivity persisted. Since extrapyramidal signs such as salivation and dysarthria were observed, the daily dose of haloperidol was reduced to 6 mg, and that of lithium carbonate was increased to 800 mg from 45 days after admission. Early in the morning on the 49th day after admission, disorganized speech, disorientation and visual hallucination suddenly developed. There were no symptoms such as fever or dehydration symptoms, and emergency blood examination showed neither an increase in serum CPK nor electrolyte abnormalities. Brain CT showed no abnormalities while EEG showed an 8–9 Hz slow α rhythm with frequent mixture of generalized 2–3 Hz high-amplitude slow waves, suggesting a decreased consciousness level. The serum lithium concentration on the same day was within the therapeutic range (0.97 mEq/L). However, based on the clinical findings and EEG abnormalities, a diagnosis of lithium-induced delirium was made. Immediately after the development of delirium, lithium carbonate administration was discontinued. The serum lithium level decreased to less than 0.1 mEq/L after several days, but the disorientation and irritability during night persisted. Therefore, 71 days after admission, the daily dose of haloperidol was increased to 10 mg, and citicoline (an intermediate in the biosynthesis of phosphatidylcholine used as a cognitive enhancer [5], 500 mg/day) administration was initiated. Eighty-five days after admission, the citicoline administration was discontinued, and nicergoline (an ergot alkaloid used as a cognitive enhancer [6], 15 mg/day) administration was initiated. The delirium nearly disappeared 90 days after admission (about 6 weeks after its development), and slow waves on EEG also disappeared. 2. Discussion As organic factors associated with mania developing at advanced age, cerebrovascular lesions, cerebral atrophy and so forth have been suggested [7]. In this patient, brain MRI showed no findings suggesting cerebrovascular lesions, but revealed slight atrophy mainly in the temporal and frontal lobes, and slight ventricular dilation. It is possible that these mild organic factors were involved in the development of mania at advanced age (60 years old) in this patient. Delirium in manic patients is often overlooked because some signs and symptoms of the two conditions overlap. In this patient, delirium abruptly developed after the manic state subsided to a certain degree. EEG at the development of delirium showed mixture of generalized high-amplitude slow waves, which was not observed on admission. In addition, there were no underlying diseases or environmental factors as possible causes of delirium. Therefore, a definite diagnosis of delirium due to lithium intoxication was made. A few studies have shown the occurrence of delirium due to lithium intoxication even at serum lithium concentrations within the therapeutic range [2], [3]. These studies have suggested advanced age, combination with antipsychotics, and the presence of acute psychotic symptoms as risk factors. This patient showed no acute psychotic symptoms, but was relatively aged (60 years old) and treated with lithium in combination with haloperidol. Neurotoxicity by the interaction between lithium and haloperidol was first reported by Cohen and Cohen [1]. However, a subsequent retrospective review showed the absence of such an interaction in most patient treated with the combination of lithium and haloperidol, and similar incidences of side effects between this combination treatment and treatment with each drug alone [8]. Therefore, it is unlikely that the interaction between lithium and haloperidol in combination treatment was involved in the development of delirium in this patient. The treatment effects of lithium have been reported to be correlated with the brain lithium concentration rather than the serum lithium concentration [9]. Substantial variation in the brain lithium concentration has been observed even among patients with similar serum lithium concentrations [10]. In addition, in manic episodes, a marked increase in the brain lithium concentration without marked changes in the blood lithium concentration has been reported [9]. Therefore, in this patient, it is possible that the brain lithium concentration increased even though the serum lithium concentration was within the therapeutic range. Lithium-induced delirium generally improves rapidly (mostly within 1 week) after discontinuation of its administration [2]. However, in this patient, delirium persisted for more than 1 month after discontinuation of lithium administration, and its improvement required administration of high dose haloperidol, citicoline, and nicergoline. Concerning the cause of persistent delirium, it has been suggested that refractoriness that can not be controlled by drugs tends to occur when psychotic symptoms develop in the presence of advanced age and organic factors such as brain atrophy as in this patient [2]. It has also been reported that abrupt discontinuation of lithium administration induced the development and persistence of delirium in patients with serum lithium concentrations within or above the therapeutic range [3]. Therefore, it is also possible that abrupt discontinuation of lithium administration in this patient was involved in the persistence of delirium. In conclusion, in the presence of advanced age and organic factors (such as brain atrophy) in this patient, administration of lithium appeared to have induced delirium, and its abrupt discontinuation may have precipitated the persistence of delirium. References [1].
[1]
Cohen WJ, Cohen NH.
Lithium carbonate, haloperidol, and irreversible brain damage.
JAMA. 1974;230:1283–1287. MEDLINE [2].
[2]
Brown AS, Rosen J.
Lithium-induced delirium with therapeutic serum lithium levels (a case report).
J Geriatr Psychiatry Neurol. 1992;5:53–55. MEDLINE [3].
[3]
DePaulo JR, Folstein MF, Correa EI.
The course of delirium due to lithium intoxication.
J Clin Psychiatry. 1982;43:447–449. MEDLINE [4].
[4]
American Psychiatric Association.
Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994;. [5].
[5]
Schäbitz WR, Weber J, Takano K, Sandage BW, Locke KW, Fisher M.
The effects of prolonged treatment with citicoline in temporary experimental focal ischemia.
J Neurol Sci. 1996;138:21–25. |
CrossRef
[6].
[6]
Herrmann WM, Stephan K, Gaede K, Apeceche M.
A multicenter randomized double-blind study on the efficacy, and safety of nicergoline in patients with multi-infarct dementia.
Dement Geriatr Cogn Disord. 1997;8:9–17. MEDLINE [7].
[7]
Shulman KI, Herrmann N.
The nature and management of mania in old age.
Psychiatr Clin North Am. 1999;22:649–665. |
CrossRef
[8].
[8]
Goff DC, Baldessarini RJ.
Drug interactions with antipsychotic agents.
J Clin Psychopharmacol. 1993;13:57–67. MEDLINE [9].
[9]
Kato T, Inubushi T, Takahashi S.
Relationship of lithium concentrations in the brain measured by lithium-7 magnetic resonance spectroscopy to treatment response in mania.
J Clin Psychopharmacol. 1994;14:330–335. MEDLINE [10].
[10]
Gonzalez RG, Guimaraes AR, Sachs GS, et al.
Measurement of human brain lithium in vivo by MR spectroscopy.
AJNR Am J Neuroradiol. 1993;14:1027–1037. MEDLINE Department of Neuropsychiatry,Fukui Medical University, Fukui 910–1193, Japan PII: S0163-8343(02)00238-4 doi:10.1016/S0163-8343(02)00238-4 © 2003 Elsevier Science Inc. All rights reserved. | |
|
FULL TEXT