Acute Lithium Intoxication and Neuroleptic Malignant Syndrome

Jasleen Gill, MD, Harmohan Singh, MD, Kenneth Nugent, MD


Pharmacotherapy. 2003;23(6) 

In This Article


Severe lithium toxicity usually correlates with elevated serum levels, and patients often have CNS signs and symptoms.[2] However, not all patients with high lithium levels have advanced symptoms, at least during the initial phase of intoxication.[4] This discrepancy between serum levels and clinical toxicity reflects delayed distribution of the drug into susceptible tissues. The initial volume of distribution after acute ingestion of lithium is 0.3-0.4 L/kg, which increases to 0.7-1.0 L/kg over the next 6-10 hours. Lithium accumulates in cerebral white matter and can be measured in the cerebrospinal fluid (CSF).[5] This accumulation in the CNS helps explain persistent symptoms in patients with falling serum lithium levels. However, CSF concentrations do not necessarily correlate with intracellular brain tissue levels or the coma level. For example, one report described a 50-year-old woman who was comatose from lithium overdose and did not regain consciousness until her lithium level fell to less than 0.4 mEq/L in her serum and 0.1 mEq/L in her CSF.[6]

Lithium does not bind to plasma proteins; it is excreted by the kidney, and this process is strongly influenced by factors that control sodium and water excretion. The half-life of lithium is approximately 29 hours. At toxic levels lithium may inhibit its own excretion. Some drugs and clinical conditions impair lithium excretion and increase neurotoxicity.[7] Renal dysfunction, sodium depletion, nonsteroidal antiinflammatory drugs, and some diuretics increase serum lithium concentration by reducing renal excretion. Some drugs, such as antidepressant and neuroleptic agents, increase lithium toxicity without changing renal clearance, presumably by increasing intracellular concentrations.

Lithium toxicity occurs in 75-90% of patients receiving long-term lithium therapy at some time during their management.[7] In most patients this toxicity represents mild side effects such as hand tremor. Most cases of lithium toxicity reported to poison control centers result from intentional overdoses. Of these cases, 15% are rated moderate to severe, but mortality is less than 1%.[7] Acute lithium neurotoxicity has various clinical manifestations[8] such as acute delirium with disorientation, fluctuating levels of consciousness, and hallucinations (visual, auditory, tactile); extrapyramidal syndromes with rigidity and other parkinsonian features; and corticospinal dysfunction with weakness, increased tone, hyperreflexia, and extensor plantar responses.

Lithium toxicity can cause seizures and EEG changes; these changes typically involve diffuse slowing and correlate poorly with serum concentrations. Patients with preexisting EEG abnormalities, seizures, and/or cerebral impairment may be at increased risk for acute neurotoxicity.[7] In some patients lithium toxicity causes persistent neurologic dysfunction, especially cerebellar dysfunction. One report described a patient with neurologic impairment (dementia, cerebellar signs, parkinsonism) and endocrine failure (hypothyroidism, testicular failure) after lithium self-poisoning.[9] This patient survived a prolonged hospital stay but had persistent CNS dysfunction. Other patients have developed permanent neurologic deficits secondary to lithium toxicity, such as cerebellar and basal ganglia dysfunction.[10,11] Our patient did not appear to have any of these symptoms during the last half of his hospital stay.

Our patient also had been receiving long-term fluoxetine. Patients with fluoxetine overdose usually experience tremulousness, agitation, irritability, insomnia, nausea, vomiting, diarrhea, and sweating. Our patient denied taking an overdose of fluoxetine and received activated charcoal and gastric lavage when first hospitalized. Consequently, fluoxetine toxicity was not considered a probable cause of his condition.

Serotonin Syndrome

Abrupt withdrawal of selective serotonin reuptake inhibitors (SSRIs) also can produce a clinical syndrome,[12] with influenza-like symptoms, vertigo, gait instability, and insomnia. When we first saw our patient, he was asymptomatic except for mild lethargy. Large doses of SSRIs can produce serotonin syndrome. Lithium increases 5-hydroxytryptamine (serotonin) metabolites in the CSF[8] and therefore can interact with SSRIs and cause serotonin syndrome. One report described acute neurotoxicity in a patient receiving fluoxetine 20 mg/day who received lithium 900 mg/day for 48 hours.[13] The patient experienced confusion, ataxia, and fever (101.8°F). Laboratory studies were normal except for leukocytosis.

Three patients in a series of 41 patients with serotonin syndrome who were receiving lithium were identified.[14] In general, serotonin syndrome involves mild symptoms and resolves quickly with drug withdrawal and supportive care. However, some patients experience a severe syndrome that involves organ failure. The initial critical events are hyperthermia, muscle rigidity, volume contraction secondary to sweating and insensible fluid loss, and renal injury secondary to myoglobinuria and volume contraction. This severe syndrome is similar to NMS. It has also been suggested that both serotonin syndrome and NMS represent variants of drug-induced central hyperthermia.[15]

Serotonin syndrome often develops rapidly and involves prominent myoclonus and gastrointestinal symptoms. These characteristics and the patient's drug history usually allow differentiation from NMS. Our patient had been taking fluoxetine and lithium for months without difficulty before taking an intentional lithium overdose. His clinical course with late deterioration suggested that he developed NMS rather than serotonin syndrome or one of the other acute neurotoxicity syndromes discussed above.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome involves high fever, muscle rigidity, reduced levels of consciousness, tachycardia, autonomic dysfunction, rhabdomyolysis, acute renal failure, and respiratory failure. It typically occurs 3-5 days after the start of treatment with a neuroleptic drug and generally is unrelated to dosage or previous drug exposure. Drugs frequently implicated are haloperidol, fluphenazine, trifluoperazine, chlorpromazine, and thiothixene.[16] Severe neurologic sequelae usually do not occur in patients who survive the acute syndrome. The symptom complex in our patient on day 10 of his hospital stay is consistent with the diagnosis of NMS secondary to lithium toxicity. Most patients with NMS secondary to neuroleptic drugs continue to receive drug therapy before the onset of NMS.

The last lithium level in our patient before NMS onset was 0.5 mEq/L. Up to this point in his hospital course the patient had experienced intermittent confusion but was otherwise stable. This time course suggests that high, persistent lithium levels in brain tissue caused this syndrome to develop. The patient's baseline mental retardation may have been associated with alterations in CNS physiology that allowed for enhanced lithium effect on the dopaminergic system.[7] In addition, long-term therapy with fluoxetine may have influenced the serotonin-dopamine balance in his CNS. In one of two reports of fluoxetine-associated NMS, the patient took fluoxetine 9 days after an overdose of carbamazepine, methotrimeprazine, and tryptophan.[17] In the second report, the patient took both fluoxetine and remoxipride.[18]

Lithium has synergistic effects with neuroleptic drugs in the development of NMS. Four patients who experienced weakness, lethargy, fever, and confusion while receiving lithium and high doses of haloperidol were described.[19] These patients also had extrapyramidal signs (rigidity) and cerebellar dysfunction. Laboratory test results indicated leukocytosis, renal insufficiency, abnormal liver enzymes, and elevated creatine kinase levels. Two of these patients had persistent dyskinesia, and two had profound neurologic impairment (severe dementia) after the acute toxicity resolved.

These cases may represent either independent, persistent neurotoxicity from lithium in patients with concomitant NMS or additive neurotoxicity from these two classes of drugs. Lithium may enhance the dopamine-blocking effect of these drugs or inhibit dopamine synthesis. In a prospective series describing 24 patients with NMS, 14 (58%) were taking a neuroleptic drug and lithium.[20] Lithium toxicity increases the risk of NMS. In one report, NMS and lithium toxicity developed in a patient who took a lithium overdose and received one dose of haloperidol.[21]

Lithium and neuroleptic drugs may produce two distinct neurotoxic syndromes: NMS and acute lithium neurotoxicity (delirium, seizures, and abnormal EEG) secondary to increased intracellular levels of lithium.[22] Lithium has been implicated in some cases of NMS in patients with Parkinson's disease during levodopa withdrawal.[23] These cases suggest that the addition of lithium critically disturbs an already unstable dopaminergic system. Lithium also has been implicated in the recurrence of NMS in two patients.[24] One developed NMS while taking a neuroleptic agent alone, the other while taking both haloperidol and lithium. Both patients had bipolar disorder; lithium alone was restarted to control their psychiatric syndromes. Lithium 300 mg/day was started in one patient and lithium 1200 mg/day in the second patient approximately 1 week after the NMS resolved. Both patients experienced a relapse of the NMS, approximately 4 and 24 hours, respectively, after the initial lithium dose. In both patients, their temperatures, white blood cell counts, and creatine kinase levels increased. Possible pathogenic mechanisms could be lithium effects on tissue already sensitized by neuroleptic drugs and/or further decrease in an already compromised dopaminergic function. Neuroleptic malignant syndrome has been reported in patients receiving lithium and antidepressants such as amoxapine (one patient)[25] and amitriptyline (one patient).[26] Using MEDLINE searches, we found no reports of lithium as the sole cause of NMS.

Treatment of NMS involves supportive care, especially management of fever, electrolytes, and fluids, and possibly administration of drugs to reverse the underlying pathophysiologic processes. Dantrolene has been administered to inhibit peripheral heat generation. Bromocriptine, a central dopamine agonist, presumably restores dopaminergic function in patients with NMS that developed after treatment with neuroleptic drugs. However, in a prospective study of patients who received supportive care only (12 patients), dantrolene (2 patients), bromocriptine (2 patients), or both drugs (4 patients), the drug-treated patients had a more prolonged course and higher frequency of complications than those managed conservatively with supportive care only.[27] Consequently, the best treatment for NMS is uncertain. Our patient received supportive care only, in part because the diagnosis of NMS was made late in his course and in part because the pathogenesis of his multisystem organ failure differed from the initial CNS events.