Idiopathic Hypersomnia and Kleine-Levin Syndrome: Primary Disorders of Hypersomnolence Beyond Narcolepsy.

Daytime sleepiness is common amongst children and adolescents. Inadequate sleep duration, inappropriate school start times, and the delay in sleep phase of adolescence may all contribute. Nocturnal sleep disruption due to sleep disorders such as obstructive sleep apnea or restless legs syndrome/periodic limb movement disorder may also lead to daytime sleepiness. Profound sleepiness however, when occurring in the setting of adequate sleep duration, is rare amongst children and adolescents and may prompt consideration of a central disorder of hypersomnolence (CDH). Narcolepsy is the archetypal and most studied form of CDH and a detailed review of the presentation, evaluation, treatment of narcolepsy is included separately in this edition of Seminars in Pediatric Neurology. In addition to narcolepsy, 2 other forms of primary CDH exist, idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS). Onset of IH and KLS occurs most frequently during the pediatric age range and presentation may include signs of encephalopathy in addition to hypersomnolence. As such, they are of particular relevance to pediatric neurology and associated fields. Unfortunately, when compared to narcolepsy little is known about IH and KLS, at both the physiologic and clinical level. This review will focus on the presentation, evaluation, and management of idiopathic hypersomnia and Kleine-Levin syndrome in the pediatric population.

Idiopathic hypersomnia and Kleine-Levin syndrome.

Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS) are rare disorders of central hypersomnolence of unknown cause, affecting young people. However, increased sleep time and excessive daytime sleepiness (EDS) occur daily for years in IH, whereas they occur as relapsing/remitting episodes associated with cognitive and behavioural disturbances in KLS. Idiopathic hypersomnia is characterized by EDS, prolonged, unrefreshing sleep at night and during naps, and frequent morning sleep inertia, but rare sleep attacks, no cataplexy and sleep onset in REM periods as in narcolepsy. The diagnosis requires: (i) ruling out common causes of hypersomnolence, including mostly sleep apnea, insufficient sleep syndrome, psychiatric hypersomnia and narcolepsy; and (ii) obtaining objective EDS measures (mean latency at the multiple sleep latency test≤8min) or increased sleep time (sleep time>11h during a 18-24h bed rest). Treatment is similar to narcolepsy (except for preventive naps), including adapted work schedules, and off label use (after agreement from reference/competence centres) of modafinil, sodium oxybate, pitolisant, methylphenidate and solriamfetol. The diagnosis of KLS requires: (i) a reliable history of distinct episodes of one to several weeks; (ii) episodes contain severe hypersomnia (sleep>15h/d) associated with cognitive impairment (mental confusion and slowness, amnesia), derealisation, major apathy or disinhibited behaviour (hypersexuality, megaphagia, rudeness); and (iii) return to baseline sleep, cognition, behaviour and mood after episodes. EEG may contain slow rhythms during episodes, and rules out epilepsy. Functional brain imaging indicates hypoactivity of posterior associative cortex and hippocampus during symptomatic and asymptomatic periods. KLS attenuates with time when starting during teenage, including less frequent and less severe episodes. Adequate sleep habits, avoidance of alcohol and infections, as well as lithium and sometimes valproate (off label, after agreement from reference centres) help reducing the frequency and severity of episodes, and IV methylprednisolone helps reducing long (>30d) episode duration.

Kleine-Levin syndrome: A neuropsychiatric disorder.

Kleine-Levin syndrome (KLS) is a rare, relapsing-remitting disease that affects mostly adolescents. It is characterized by episodes lasting from 1 to several weeks, and comprises neurological (hypersomnia, confusion, slowness, amnesia) and neuropsychiatric symptoms (derealization and apathy). Some psychiatric symptoms (megaphagia, hypersexuality, anxiety, depressed mood, hallucinations, delusions) arise during episodes, albeit less frequently, while patients are normal between episodes. However, sudden severe (>18h/day of sleep) and recurrent hypersomnia helps to differentiate KLS from other psychiatric mimics. Derealization, the striking feeling of unreality or of being in a dream-like environment, is strongly associated with hypoperfusion of the associative temporoparietal junction cortex, whereas apathy is almost complete loss of autoactivation: teenagers stop using their cell phones and their only spontaneous initiative is to sleep. The cause of KLS is not known, but evidence suggests it could be a recurrent inflammatory encephalitis. Up to 5% of cases are familial, although no abnormal gene has yet been found. Hypersomnia episodes tend to become less frequent and to disappear with advancing age. However, 28% of patients have long-lasting episodes (>30 days), and around 15% have no signs of recovery after >20 years of living with the disorder. Patients' cognitive and psychiatric status should be regularly checked during asymptomatic periods, as 20-40% develop long-term mild cognitive impairment or mood disorders. Lithium therapy is beneficial for reducing episode frequency, and intravenous steroids can reduce the duration of long episodes.

Kleine-Levin syndrome: clues to aetiology.

Kleine-Levin syndrome (KLS) is the commonest recurrent sleep disorder, with a prevalence of 1-2 per million population. Clear diagnostic criteria are now defined, but effective treatment remains elusive. The significant body of published literature allows consideration of possible aetiological mechanisms, an understanding of which could guide the development of therapeutic strategies. Functional imaging studies have been inconclusive; although diencephalic abnormalities are a common finding, no consistent pattern has emerged, and these studies have not revealed the mechanism(s) underlying the development of the abnormalities detected. An autoimmune aetiology is consistent with the available data. In this review, we argue that, in order to further our understanding of KLS, there needs to be a co-ordinated international effort to standardise approaches to functional imaging studies, genetic analyses that specifically address the possibility of an autoimmune aetiology, and clinical trials of immunosuppressive therapies.

[Kleine Levin syndrome: Review of diagnosed cases of Buenos Aires, Argentina]. / Síndrome de Kleine Levin: reporte de casos de Buenos Aires, Argentina.

Kleine-Levin syndrome is an uncommon disorder with recurrent episodes of hypersomnia, and behavioral abnormalities such as binge-eating and hypersexuality. Our aims were to report cases of the Kleine-Levin syndrome diagnosed in Buenos Aires, Argentina and to characterize the clinical presentation of these patients. We evaluated patients with Kleine-Levin syndrome according to the International Classification of Sleep Disorders. Psychiatric, physical and neurological symptoms were present. Some patients were investigated with brain Magnetic Resonance Imaging, Single Photon Emission Computed Tomography, electroencephalogram and some with polysomnography. Seven patients (2 female, 5 male), ages from 8 to 47 years (median 20.7 years) were included in the study. The duration of symptoms was 1.5-20 days with a mean of 8. The range of interval between episodes: 2.5-24 months, median=13. All seven patients had a history of hypersomnia (one of them post head injury); 5 reported hyperphagia and 2 reduced appetite. Brain MRI was performed in 6 patients: 1 showed non-specific abnormalities and another presented diencephalic hematoma; the rest were normal. Our paper is the first one in Buenos Aires reporting Kleine-Levin syndrome of different ethiologies. The prevalence is difficult to estimate in our country.

Kleine-Levin Syndrome.

Kleine-Levin syndrome is a rare recurrent encephalopathy primarily affecting teenagers, characterized by relapsing-remitting episodes of hypersomnia along with cognitive, psychiatric and behavioral disturbances. During episodes, patients suddenly present hypersomnia (with sleep lasting 15-21 h/d), cognitive impairment (major apathy, confusion, slowness, amnesia), and a specific feeling of derealization (dreamy state, altered perception). Less frequently, they may also experience hyperphagia (66%), hypersexuality (53%, principally men), depressed mood (53%, principally women), anxiety, hallucinations, and acute brief psychosis (33%). Brain functional imaging is often abnormal. Stimulants are poorly beneficial during episodes, whereas lithium and valproate help reducing the episodes frequency and duration.

[Role and actions of the orphan rare diseases reference center for central hypersomnias in France]. / Quel apport des centres de référence maladies rares dans la prise en charge des hypersomnies rares?

Narcolepsy (with or without cataplexy), idiopathic hypersomnia (with or without long sleep duration) and Kleine - Levin syndrome are the main central rare hypersomnias. They may be considered models to help us to better understand the mechanisms controlling sleep and waking regulation in humans. When creating the national centers for rare hypersomnias, the aims were: 1) screening and earlier treatment of patients with hypersomnia; 2) improving patient care with guidelines, a specific patient's card, coordination of treatments between centers and professionals, and the development of new treatments; 3) encouraging research studies into the epidemiology, pathophysiology and genotype/phenotype through the creation of clinical, DNA, sera and cerebrospinal fluid banks; 4) increasing public awareness among patients and their relatives, the general public and in the mass media of rare hypersomnias; and 5) regular evaluation of our activities. These goals appear to have been achieved over the past 5 years. However, there are now financial difficulties to be faced, given the increasing demands of patients and professionals while having to stay within the same limited budgets.

Kleine-Levin syndrome: current status.

Kleine-Levin Syndrome is a periodic hypersomnia characterized by recurrent episodes of hypersomnia and other symptoms. This article reviews the research to date, outlines the clinical symptoms, and describes current testing and treatment. It concludes that the cause remains unknown and no treatment is effective in preventing recurrence, although modafinil may reduce duration of symptomatic episode.

Kleine-Levin syndrome: the first typical case in Thailand.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by periodic hypersomnia, cognitive and behavioral disturbances. Other unique symptoms in KLS are megaphagia, hypersexuality and some psychiatric disturbances such as compulsion and depression. Definite diagnosis requires the elimination of other potential etiologies. We reported a typical case of KLS in a young Thai man who suffered from seven episodes of periodic hypersomnia within 1.5 years and eventually he was diagnosed with Kleine-Levin syndrome after excluding known possible neurological conditions and sleep disorders.

Kleine-Levin syndrome.

Kleine-Levin syndrome, sometimes referred to as Rip van Winkle disease, is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioural and cognitive disturbances, hyperphagia and in some cases hypersexuality. Each episode lasts for one or two weeks, and affected people are entirely asymptomatic between episodes. No definite cause has been identified but hypothalamic dysfunction seems likely. Relapses may occur every few weeks or months, and the condition may last for a decade or more before spontaneous resolution. There is no effective treatment but stimulants such as methylphenidate and modafinil as well as the mood stabiliser lithium carbonate have been tried with varying success.

[Kleine-Levin syndrome: state of the art]. / Le syndrome de Kleine-Levin.

INTRODUCTION: Kleine-Levin syndrome is a rare neurological disorder (1-2 cases per million inhabitants) primarily affecting young subjects. It is characterized by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioral disturbances. Case-reports, small series, meta-analysis and a recent large, prospective trio study are consistent with a homogeneous, genuine disease entity. STATE OF THE ART: Patients are mostly male (68-78%) and adolescents (81%), with mean onset at 15 years (range 4-82 years). The first episode is triggered by an infection in 72% of patients. Patients experience an average of 7-19 episodes of 10-13 days each, relapsing every 3.5 months. Episodes recur more quickly in patients with childhood onset. The median disease course is 8-14 years, with longer course in men, in patients with hypersexuality, and when onset is after age 20. During episodes, all patients have hypersomnia (with sleep lasting 15-21 heures per day), cognitive impairment (apathy, confusion, slowness, amnesia) and a specific feeling of derealization (dreamy state, altered perception). Less frequently, patients experience hyperphagia (66%), hypersexuality (53%, principally men) and depressed mood (53%, predominantly women). Patients are remarkably similar to controls between episodes regarding sleep, vigilance, mood, and eating attitude, but have increased body mass index. Structural brain imaging, evaluation of the cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is notable in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypo-arousal with low sleep efficiency. The brain scintigraphy may show hypoperfusion, mostly focused on the thalamic, hypothalamic and fronto-temporal areas, especially when contrasted to images obtained between episodes. Newly identified factors include increased birth and developmental problems, Jewish heritage, genetics (5% multiplex families, suggesting autosomal recessive transmission). The association of KLS with HLA-DQ2, found in a small series, is not replicated in a larger independent sample. There is no increased family history for neuropsychiatric disorders. Some stimulants (amantadine, but more rarely modafinil or amphetamins) and mood stabilizers (lithium, valproate, but not carbamazepine) have marginal efficacy. In the 10% KLS cases secondary to various genetic, inflammatory, vascular or paraneoplasic conditions, patients are older, have more frequent and longer episodes, but their clinical symptoms, disease course and treatment response are similar to primary cases. PERSPECTIVE: The most promising findings are the familial clustering and a potential Jewish founder effect, supporting a role for genetic susceptibility factors. CONCLUSION: KLS is a puzzling and disabling disease. Until its cause will be identified, disease management should be primarily supportive and educational.

Melanie klein, una princesa que creó su propio reino / Melanie klein a princess who created her own kingdom

Las formulaciones kleinianas no pueden ser encuadradas como un mero desarrollo del psicoanálisis freudiano, dado que suponen cambios radicales en su metapsicología, núcleo intocable del sistema. En todo caso, Melanie Klein merece un lugar de privilegio entre las mujeres pioneras que aportaron ideas originales a la psicología del inconsciente y aunque siempre se autoconsidera una fiel seguidora de Freud, terminó desarrollando su propio reino (AU)

Melanie Klein's formulations should not be framed as a mere development of Freudian Psychoanalysis. In fact, they represent a radical change in his methapsychology, the otherwise known, as an untouchable core of the system. Nevertheless, Melanie Klein deserves to have a privileged position among those female psychoanalysts who, in one way or another, contributed with original ideas to the psychology of the unconsciousness. Although, she always considered herself simply as a Freud's follower, she ended up developing her own reign of knowledge (AU)

The Kleine-Levin syndrome as a neuropsychiatric disorder: a case report.

The Kleine-Levin syndrome (KLS) is characterized by periodic, sudden-onset episodes of hypersomnia, compulsive hyperphagia, and behavioral-emotional disorders (typically indiscriminate hypersexuality, irritability, impulsive behaviors), lasting from a few days to a few weeks, with almost complete remission in the intercritical periods. Depression, confusion, and thought disorders are frequently associated with the critical symptomatology, and they may suggest other psychiatric diagnoses (schizophrenia, mood disorder, conversion disorder) or a substance abuse. A diencephalic-hypothalamic dysfunction is suspected, even if this composite symptomatology cannot easily be linked to a simple mechanism. The aim of this article is to illustrate problems in differential diagnosis, using a case approach. History, course, and therapeutic intervention in a 21-year-old patient with KLS, associated with a clear psychiatric symptomatology and a critical affective pattern, is reported. Psychiatric correlates of KLS are discussed, including the relationship with affective disorders and the possible emotional impact of the attacks. Implications regarding a combined psychological and pharmacological treatment are also discussed.

[Kleine-Levin syndrome--diagnostic and therapeutic problems]. / Das Kleine-Levin-Syndrom--diagnostische und therapeutische Probleme.

An overview of the literature is given and an attempt is made to describe the diagnostic problems associated with this etiologically unclear disorder. The only successful therapy to date is treatment with lithium. A case study is presented of a 14-year-old boy with typical symptoms. Within a period of 12 months the boy had 6 episodes characterized by hypersomnia and hyperphagia, each lasting between 8 and 14 days. The symptom-free intervals lasted from 10 days to 8 months. Extensive medical and neurological evaluation including single-photon emission-computed tomography (SPECT) showed no abnormalities, and no criteria for another psychiatric disorder were met. After the sixth episode we considered treating the patient with lithium, but this option was rejected by his family. The patient has remained asymptomatic (36-month follow-up). A possible relationship to endogenous psychotic disorders and the role of neurotransmitter metabolism are discussed. Computer-assisted analysis of electroencephalographic activity revealed high signal complexity, which we believe suggests a primary cortical regulatory defect.