Kleine-Levin syndrome (ORPHA:33543)
Kleine-Levin syndrome (KLS) is a rare neurological disorder of unknown origin characterised by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioural disturbances.
Epidemiology
It affects around 1/500 000 individuals. Patients are mostly male (68-78% of cases) and adolescents (81% of patients), with a mean age of onset of 15 years (range 4-82 years).
Clinical description
The first episode is triggered by an infection in 72% of patients. Patients experience 7-19 neurological episodes with a duration of 10-13 days/episode and relapses every 3.5 months. One third of patients have episodes lasting longer than one month. Episodes recur more quickly in patients with childhood onset. During episodes, all patients have hypersomnia (with sleep periods lasting 15-21 hours per day), cognitive impairment (apathy, confusion, slowness and amnesia) and a specific feeling of derealization (a dream-like state with altered perception). Less frequently, patients experience hyperphagia (66% of patients), hypersexuality (53% of patients, principally men), anxiety, compulsive or mood disorders and depression (53% of patients, predominantly women). Sleep, vigilance, mood, and eating habits are similar to those of controls between episodes. The median disease course is 8-14 years, but tends to be longer in men, in patients with hypersexuality, and when onset occurs after 20 years of age.
Etiology
Susceptibility factors include perinatal and developmental problems. Familial clustering occurs in 5% of cases with multiplex families and similar symptoms. An association of KLS with HLA-DQ2 positivity was found in a small series but not replicated in larger independent sample groups. There is no family history of neuropsychiatric disorders. In 10% of cases, KLS arises secondary to various genetic, inflammatory, vascular or paraneoplastic conditions. In these cases the patients are older and have more frequent and longer episodes, but clinical symptoms, disease course and treatment response are similar to those of primary cases.
Diagnostic methods
Structural brain imaging, cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is noted in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypoarousal with low sleep efficiency. Functional brain imaging (brain scintigraphy or TEP scan) frequently show hypoperfusion/hypometabolism, mainly focused in the thalamic, hypothalamic and frontotemporal associative areas, especially when compared to images obtained between episodes. Reduced metabolism at the parietotemporal junction is marked during episodes, correlates with the intensity of derealization and persists during asymptomatic periods.
Differential diagnosis
The disorder should mainly be differentiated from epilepsy, migraine with aura, and bipolar disorder.
Management and treatment
The prevention of episodes is mainly based on lithium therapy, combined with regular sleep-wake habits, as well as avoidance of alcohol intake and infections. Lithium therapy stops episodes in 37% patients (vs. 3.4% if no treatment is given) and reduces the frequency/duration of episodes in 46% of other patients. The treatment is usually given to patients with frequent, prolonged or very severe episodes. Patients with rare (e.g., 1/y) episodes may not need any treatment. Antiepileptics (valproate, carbamazepine, lamotrigine) have marginal benefits. During episodes, patients feel better resting at home under parental supervision, unless psychotic or depressive symptoms require hospitalization. Stimulants are not effective. Trials of IV steroids may help terminate long episodes in around 40% of patients.
Prognosis
The prognosis is generally good, with most patients presenting less frequent and less severe episodes with advancing age and disappearance of the syndrome around 30-35 y old. During asymptomatic periods, around 20-30% of patients have mild difficulties focusing or remembering. Persistent psychiatric disorders occur in a minority of patients.

                            Last update: 
                            September 2018


                            - Expert reviewer(s): 
                            Pr Isabelle ARNULF