Electroencephalographic patterns of lithium poisoning: a study of the effect/concentration relationships in the rat

Objectives Lithium overdose may result in encephalopathy and electroencephalographic abnormalities. Three poisoning patterns have been identified based on the ingested dose, previous treatment duration and renal function. Whether the severity of lithium‐induced encephalopathy depends on the poisoning pattern has not been established. We designed a rat study to investigate lithium‐induced encephalopathy and correlate its severity to plasma, erythrocyte, cerebrospinal fluid and brain lithium concentrations previously determined in rat models mimicking human poisoning patterns. Methods Lithium‐induced encephalopathy was assessed and scored using continuous electroencephalography. Results We demonstrated that lithium overdose was consistently responsible for encephalopathy, the severity of which depended on the poisoning pattern. Acutely poisoned rats developed rapid‐onset encephalopathy which reached a maximal grade of 2/5 at 6 h and disappeared at 24 h post‐injection. Acute‐on‐chronically poisoned rats developed persistent and slightly fluctuating encephalopathy which reached a maximal grade of 3/5. Chronically poisoned rats developed rapid‐onset but gradually increasing life‐threatening encephalopathy which reached a maximal grade of 4/5. None of the acutely, 20% of the acute‐on‐chronically and 57% of the chronically lithium‐poisoned rats developed seizures. The relationships between encephalopathy severity and lithium concentrations fitted a sigmoidal Emax model based on cerebrospinal fluid concentrations in acute poisoning and brain concentrations in acute‐on‐chronic poisoning. In chronic poisoning, worsening of encephalopathy paralleled the increase in plasma lithium concentrations. Conclusions The severity of lithium‐induced encephalopathy is dependent on the poisoning pattern, which was previously shown to determine lithium accumulation in the brain. Our data support the proposition that electroencephalography is a sensitive tool for scoring lithium‐related neurotoxicity.