LITHIUM II: IRREVERSIBLE NEUROTOXICITY

AFTER LITHIUM INTOXICATION

Author: Lily Nguyen, Philadelphia, PaSection Editor: Allison A. Muller, PharmD, D.ABAT

Lithium was first used for the treatment of mania in1949.1,2 After its introduction into psychiatry, therewere a number of case reports regarding the neuro-

toxicity of lithium. However, it was not until the 1980sthat the medical community began noticing that the neu-rotoxicity associated with lithium may not be just an acuteproblem.2 During this decade, several cases were reportedregarding persisting neurologic sequelae after lithium intox-ication. This syndrome gained much clinical attention andwas named syndrome of irreversible lithium-effectuated neu-rotoxicity (SILENT).2

Lithium is absorbed readily and almost completely fromthe gastrointestinal tract within 6 to 8 hours.1,3,4 The peakplasma concentration of lithium is achieved within 30 min-utes to 2 hours after oral ingestion; sustained-release formu-lations may take about 4 to 5 hours.3,4 Lithium is distributedin total body water and does not bind to plasma proteins.1,3,4

Excretion is almost entirely by the kidneys (95%).1,3 Theelimination half-life averages about 20 to 24 hours after asingle dose1,3; however, in the elderly or in patients takinglithium chronically, the half-life can be as long as 58 hours.4

Lithium has a narrow therapeutic index; the target plasmaconcentration ranges from 0.6 to 1.5 mEq/L.3,4 The lowerend of the therapeutic index may be safer for long-termuse in patients with bipolar disease, whereas the 0.9- to1.1-mEq/L range is favored in acute treatment of mania.1

The most common finding of lithium toxicity is al-tered mental status, which usually manifests as dysarthria,ataxia, tremor, and impaired cognitive function.5-9Other signsof lithium toxicity are detailed in “Lithium I: The Basics.”10

Most cases of lithium neurotoxicity are usually reversible11;however, there have been many cases reported in whichpatients had permanent neurologic deficits after an over-dose.5-9,11,12 Schou,12 in a literature study of 40 patient

cases, defined the neurotoxicity as “long-lasting” if symp-toms persisted for more than 2 months after the discon-tinuation of lithium. However, there are no case reportsor case studies of how long the syndrome could last.11

The most common signs and symptoms of persistentneurotoxicity were cerebellar abnormalities.11,12 These signsand symptoms were not specific to SILENT; however,they were seen in most cases of acute lithium toxicityand persisted in SILENT cases.2,4,5-9,11-13 Symptoms ofcerebellar dysfunction included truncal ataxia with clumsi-ness of motor activity.11,12 Sitting and gait ataxia werecommon.5-8,11 In 1 case report a patient still had a broad-based ataxic gait 4 years after lithium intoxication.5

Though less common than cerebellar dysfunction,there were other similar clinical presentations amongreported cases of persisting neurologic sequelae such asextrapyramidal syndromes, brainstem dysfunction, anddementia.2,11 Again, these signs and symptoms were seenin other cases of acute lithium toxicity and therefore werenot specific to SILENT.2,4,5,9,11,12

There were no distinguishing characteristics of thepatients who had irreversible neurotoxicity after lithiumoverdose. The signs, symptoms, and baseline characteris-tics upon initial presentation were not distinguishable fromother lithium intoxication cases.2,4,11

It is unlikely that high serum lithium levels were di-rectly responsible for permanent neurologic damage.8

The mean maximum recorded blood level in the 16 casesof permanent neurologic damage discussed by Donaldsonand Cuningham8 was 3.2 mEq/L, which was very similarto the 3.1 mEq/L reported by Hansen and Amdisen13 in19 cases of acute toxicity without permanent neurotoxicity.Kores and Lader,11 in their review, found that the gender,age, lithium daily dose, and lithium plasma level were notrelated to cerebellar signs of persistent sequelae or to chronicextrapyramidal signs, peripheral neuropathy, or cognitive im-pairment. Indeed, it is possible for SILENT to develop at lowor therapeutic lithium levels. In a review of 90 SILENT casesfrom the literature, Adityanjee et al2 reported that the patients’serum lithium levels ranged from 0.1 to 8 mEq/L.

The treatment of choice for lithium toxicity is hemo-dialysis.2,4,11,13 However, initially, the patient must receiveproper supportive care. A serum lithium level and bloodchemistry should be drawn early to assess the degree of

Lily Nguyen is PharmD Candidate, University of the Sciences in Philadel-phia, Philadelphia College of Pharmacy and Science, Philadelphia, Pa.

For correspondence, write: Lily Nguyen, University of the Sciences in Philadel-phia, 600 S 43rd St, Philadelphia, PA 19104; E-mail: lnguyen132@usip.edu.

J Emerg Nurs 2008;34:378-9.

0099-1767/$34.00

Copyright © 2008 by the Emergency Nurses Association.

doi: 10.1016/j.jen.2008.04.026

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378 JOURNAL OF EMERGENCY NURSING 34:4 August 2008

intoxication and renal function.4 If the time of inges-tion was within 1 hour, gastric lavage should be consid-ered.14 Activated charcoal is not useful because it does notbind to lithium ions.4,14 Whole-bowel irrigation is only in-dicated for large ingestions and ingestions of sustained-release products.4,14 Normal saline solution should beadministered intravenously to reverse and prevent volumedepletion and tomaintain adequate urine output.4,14 Forceddiuresis has shown no increase in lithium clearance in clin-ical studies and therefore is not recommended.4 If con-servative therapy fails to decrease serum lithium levels,hemodialysis should be performed.4,13 Hemodialysis shouldbe performed in patients who present with coma, convul-sions, respiratory failure, deteriorating mental status, orrenal failure.4 Hemodialysis is also strongly recommendedfor patients with serum lithium levels above 4 mEq/L orfor those undergoing chronic lithium therapy whose levelsare between 2.5 and 4 mEq/L.4 In general, on the basis ofthe patient’s clinical condition and serum lithium level, he-modialysis should be started within the first 8 to 12 hours.11

The need for hemodialysis is not always clear cut, but be-cause of lithium’s potential to cause permanent neurologicdamage, it is prudent that this decision be made soonerthan later. Hansen and Amdisen13 recommend that hemo-dialysis be carried out for 10 to 12 hours and be repeatedif necessary to ensure removal of a sufficient amount oflithium from the blood. Serum lithium levels should bemonitored at short intervals after dialysis to ensure that theyremains low.13 Even though hemodialysis is recommendedearly during lithium intoxication,6,11,13 there is still no di-rect evidence that it can prevent permanent neurologicsequelae.11 It is also important to monitor the patient’s clin-ical signs and symptoms because neurotoxicity can occur attherapeutic serum lithium levels; in addition, because thelithium transfer between intracellular and extracellularcompartments is slow, the decrease in intracellular lithiumconcentration may be slower than the decrease in plasmalithium level.11

Once the acute toxicity is resolved, most patientsshow total recovery of neurologic function; however, asmall percentage of patients continue to exhibit signsand symptoms of permanent neurologic damage. Never-theless, because neurotoxicity can develop at therapeuticlevels, a patient’s clinical signs are most important, andserum lithium concentration should only be used to helpthe clinician in making treatment decisions.

Implications to Emergency Nursing Practice

There are 2 points regarding lithium intoxication thatcan make deciding on a treatment plan difficult: lithium’s

potential to cause permanent neurologic damage and thedifficulty in using lithium levels alone to assess this risk.Lithium intoxications are complex, and toxicology profes-sionals are available at your regional poison control centerto talk through these cases (800 222-1222 anywhere in theUnited States).

REFERENCES1. Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s

the pharmacological basis of therapeutics. 11th ed. New York:McGraw-Hill; 2006.

2. Adityanjee, Munshi KR, Thampy A. The syndrome of irre-versible lithium-effectuated neurotoxicity. Clin Neurophar-macol 2005;28:38-49.

3. Katzung BG, editor. Basic & clinical pharmacology. 10th ed.New York: McGraw-Hill; 2007.

4. Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol1999;10:666-74.

5. Apte SN, Langston JW. Permanent neurological deficits due tolithium toxicity. Ann Neurol 1983;13:453-5.

6. von Hartitzsch B, Hoenich NA, Leigh RJ, Wilkinson R, FrostTH, Weddel A, et al. Permanent neurological sequelae despitehaemodialysis for lithium intoxication. Br Med J 1972;4:757-9.

7. Lang EJ, Davis SM. Lithium neurotoxicity: the development ofirreversible neurological impairment despite standard monitor-ing of serum lithium levels. J Clin Neurosci 2002;9:306-9.

8. Donaldson IM, Cuningham J. Persisting neurologic sequelae oflithium carbonate therapy. Arch Neurol 1983;40:747-51.

9. Bartha L, Marksteiner J, Bauer G, Benke T. Persistent cognitivedeficits associated with lithium intoxication: a neuropsychologi-cal case description. Cortex 2002;38:743-52.

10. Nguyen L. Lithium I: the basics. J Emerg Nurs 2008;34:268-9.

11. Kores B, Lader MH. Irreversible lithium neurotoxicity: an over-view. Clin Neuropharmacol 1997;20:283-99.

12. Schou M. Long-lasting neurological sequelae after lithium in-toxication. Acta Psychiatr Scand 1984;70:594-602.

13. Hansen HE, Amdisen A. Lithium intoxication. (Report of23 cases and review of 100 cases from the literature). Q J Med1978;47:123-44.

14. Lithium carbonate. In: Klasko RK (Ed). POISINDEX sys-tem. Thomson Health Care, Greenwood Village (CO) (cited2007 May 24).

Submissions to this column are welcomed and encouraged. Submis-sions may be sent to:Allison A. Muller, PharmD, D.ABATThe Children’s Hospital of Philadelphia34th and Civic Center BlvdPhiladelphia, PA 19104215 590-2004 • mullera@email.chop.edu

PHARM/TOX CORNER/Nguyen

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