Cerebellar lithium toxicity: a review of recent literature and tentative pathophysiology

Lithium is the archetype of mood stabilizing drugs. Its narrow therapeutic index mostly accounts for the occurrence of acute intoxications. There is, however, growing evidence that lithium can induce long lasting neurological sequelae. These appear to be multifactorial, resulting mainly from overdosage, concomitant neuroleptic treatment, and hyperthermia. The most frequent clinical feature is a permanent cerebellar syndrome. As regards the few pathological data available, there is a striking loss of cerebellar Purkinje cells, which is present in all published neuropathological reports on this condition. It is suggested that lithium, cytokines, and neuroleptics synergize to disrupt calcium homeostasis in Purkinje cells, and to elicit calcium-mediated neurotoxicity. This model might help predict high risk clinical situations and define useful working hypotheses as well.