Lithium-related neurotoxicity despite serum concentrations in the therapeutic range: risk factors and diagnosis

We would like to comment on the interesting case report of lithium intoxication reported by Jing Peng. An 18-year old female with mania developed confusion, trembling extremities, slurred speech, increased muscle tension, and hyperactive tendon reflexes 20 days after initiating treatment with routine dosages of lithium bicarbonate. When admitted to the hospital due to her acute neurological condition, her serum lithium concentration was in the therapeutic range (0.57 mmol/L). Most of her symptoms spontaneously reversed one week after stopping the lithium. Since its approval by the Food and Drug Administration in 1970 as treatment for bipolar disorders, several studies have addressed lithium-related neurotoxicity and the related risk factors; these studies all emphasize the relatively narrow therapeutic index of lithium. With the exception of intentional ingestion of large doses of lithium as an act of self-harm (resulting in ‘acute intoxication’ in untreated individuals or ‘acute-onchronic intoxication’ in currently treated individuals), toxicity during prolonged treatment with lithium (‘chronic intoxication’) usually results from progressive lithium accumulation due to renal dysfunction, underlying diseases, low sodium intake, and drug– drug interactions such as loop diuretics, angiotensinconverting enzyme inhibitors, or non-steroidal antiinflammatory drugs. The recommended and routinely used tool to attribute any observed neurotoxicity to lithium is the measurement of serum lithium concentration: concentrations of 0.4-0.8 are considered therapeutic, concentrations of 0.8-1.2 mmol/L are considered safe, concentrations between 1.5-2.5 mmol/ L may be associated with mild toxicity, concentrations between 2.5 and 3.5 mmol/L result in severe toxicity, and concentrations greater than 3.5 mmol/L are lifethreatening. Like Dr. Peng’s patient, rare cases of lithium toxicity have been reported in patients with normal serum concentrations, sometimes labelled ‘lithium supersensitivity’ or ‘lithium-related idiosyncratic reaction’. Strayhorn and Nash first reported thirty-six such cases, 10 of whom had lithium concentrations <1.1 mmol/L. Lithium-related neuropsychiatric symptoms are polymorphous and may be difficult to differentiate from other disorders, so before concluding that lithium is responsible for the observed neurotoxicity, coexistent confounding pathologies including fever, infection, metabolic disturbances, and epilepsy have to be ruled out. Cases of lithium-related toxicity in the presence of serum lithium concentrations in the therapeutic range may unmask hitherto undetected and potentially treatable neurological pathologies, such as cerebral infarctions or tumors, so there may be value in conducting brain imaging to exclude this possibility in such cases.