Lithium in Kleine-Levin syndrome: a systematic review of case-based and observational evidence

Introduction Kleine-Levin syndrome (KLS) is a rare neuropsychiatric disorder characterized by recurrent episodes of hypersomnia associated with cognitive, behavioral, and psychiatric disturbances. There is no established treatment, although lithium has been proposed as a potential therapeutic option. Purpose This review aimed to systematically evaluate the available evidence regarding clinical outcomes and safety following lithium exposure in patients with KLS. Methods A systematic review of the literature was conducted, including case reports, case series, and observational evidence retrieved from MEDLINE, CENTRAL, Scopus, SciELO, LILACS, and other prespecified databases. Study selection, data extraction, and quality assessment were performed using Joanna Briggs Institute tools, and the certainty of evidence was evaluated using the GRADE approach. Due to the nature of the included studies, a meta-analysis was not feasible; therefore, a structured narrative synthesis with descriptive analysis was conducted. Results Twenty-two studies were included. Twenty-one case-based studies contributed individual-level data for 39 patients, who had lithium exposure without inseparable concomitant pharmacotherapy; one prospective, open-label, controlled study was synthesized separately. Most published individually analyzable cases described some degree of clinical improvement after lithium exposure; however, the magnitude or probability of benefit cannot be estimated from selected case-based evidence. Episodes during lithium exposure were reported in 26 patients, while 11 had no episodes and data were unavailable for two. Conclusions Clinical improvement was reported following lithium exposure in selected published cases of KLS, including reported reductions in episode frequency, duration, and severity. However, complete control of episodic activity was not consistently observed, and the available evidence is predominantly case-based and of very low certainty. Evidence regarding lithium safety in KLS was insufficient because adverse-event monitoring and reporting were sparse and non-systematic.