Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

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.

The clinical characteristics of Kleine-Levin syndrome according to ethnicity and geographic location.

PURPOSE: Kleine-Levin syndrome (KLS) is a rare, relapsing-remitting, debilitating sleep disorder. Examining KLS characteristics in different ethnic populations may help elucidate the genetic basis of the disorder. No studies have examined KLS in Arabs. Therefore, we compared the clinical characteristics of Saudi Arabian KLS patients to those in other published cohorts to determine whether Arab patients have a distinct phenotype. METHODS: This study included all patients who were diagnosed with KLS at our center between June 2003 and July 2016 (P = 12; Six familial cases). All participants completed the Stanford KLS questionnaire. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale; eating attitudes were assessed with the Eating Attitudes Test-26. We compared the clinical characteristics of our patients to those in other published cohorts. RESULTS: Saudi Arabian patients with KLS had similar features to those in patients from different countries and ethnic backgrounds, with only minor differences in sleep duration during disease episodes (2-3 h shorter). However, between episodes, Saudi Arabian KLS patients reported worse sleep, greater daytime sleepiness and higher levels of baseline depression, which may be related to KLS or to local cultural practices. Ankylosing spondylitis was present in five of the six familial patients. CONCLUSION: Saudi Arabian patients with KLS exhibited similar clinical characteristics during episodes compared to patients with KLS of different ethnicities. However, a new and interesting finding is that KLS patients may have inter-episode behavioral and pathophysiological changes, which may suggest that KLS is not necessarily a static disorder.

Prevalence and Mimics of Kleine-Levin Syndrome: A Survey in French-Speaking Switzerland.

STUDY OBJECTIVE: Kleine-Levin syndrome (KLS) is a rare disease of unknown etiology, the diagnosis of which can be challenging. We aimed to estimate KLS prevalence in French-speaking Switzerland, and assess differences with mimicking conditions. METHODS: In this cross-sectional study, KLS patients were identified through a population-based approach, including at our hospital and contacting all sleep-certified facilities and neurologists in French-speaking Switzerland. Furthermore, we identified patients referred to our center for suspected KLS that received other diagnoses. Relevant clinical data of these two groups was compared. RESULTS: We identified 7 patients with diagnosed KLS (6 since 2009), leading to a prevalence estimation of 3.19 per million (95% confidence interval: 1.55-6.59). Median age at diagnosis was 17 years (range: 12-19), 71.4% of them were men, and mean diagnosis delay after the first episode was 20.1 ± 10.9 months. We identified 9 mimic patients referred to our center; they differed from KLS patients by their higher age at disease onset (median: 15 [range: 12-16] vs. 19 [range: 16-64] years; p < 0.001), suspected KLS as referral reason (more frequent in mimics, p = 0.003), and the presence of precipitating factors (more frequent in KLS, p = 0.011). Among the mimic patients, 77% (versus 28% in KLS) had a psychiatric diagnosis. CONCLUSIONS: This study suggests a relatively higher KLS prevalence than previously reported. As compared to KLS, mimic patients have higher age at symptom onset, are more often initially referred for KLS suspicion, and have a higher prevalence of psychiatric disorders.

Kleine-Levin Syndrome.

Kleine-Levin syndrome is a rare recurrent hypersomnia associated with symptoms of behavioral and cognitive impairment. This article reviews common presenting symptoms, differential diagnosis, diagnostic workup, and potential treatment options. Current updates on functional imaging studies and long-term neuropsychological studies are reviewed.

Kleine-Levin syndrome in 120 patients: differential diagnosis and long episodes.

OBJECTIVE: Kleine-Levin syndrome is a rare disease characterized by recurrent episodes of hypersomnia with behavioral and cognitive disturbances. We aimed at describing the diagnosis procedure, risk factors, and severe forms. METHODS: In consecutive patients referred for suspected Kleine-Levin syndrome, we detailed differential diagnoses, and atypical and secondary cases, compared typical patients with healthy subjects, and examined the characteristics of patients with prolonged (>30 days) episodes. RESULTS: Among 166 referred patients, 120 had typical primary Kleine-Levin syndrome (syndrome secondary to brain diseases; n = 4, atypical syndrome, n = 7; differential diagnoses that were mostly psychiatric, n = 29; incomplete information, n = 6). The prevalence in France was 1.8 per million. The patients were often male (64%) and had more frequent birth and developmental abnormalities (45%) than controls (despite normal karyotypes), and most (80%) had teenage onset, with no difference between patients with prolonged (n = 34) and short (n = 85) episodes. In patients with prolonged episodes, the durations of the first episode (32 ± 33 vs 11 ± 6 days) and subsequent episodes were longer (mean episode duration = 23 ± 19 vs 10 ± 3 days) and the disease course tended to be longer (9 ± 6 vs 6 ± 4 years). During episodes, patients with prolonged episodes had shorter sleep time, higher levels of anxiety, increased agitation, and more feelings of disembodiment and amnesia. Between episodes, they were more tired, needed more naps, fell asleep more rapidly, and had higher anxiety/depression scores. INTERPRETATION: Mental disorders are frequent differential diagnoses of Kleine-Levin syndrome. One-third of patients have prolonged (>1 month) episodes with more frequent immediate and long-term consequences of the disease, prompting therapeutic trials.

Diagnosis, disease course, and management of patients with Kleine-Levin syndrome.

Kleine-Levin syndrome is a rare sleep disorder that mainly affects adolescents and is characterised by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealisation, and psychiatric and behavioural disturbances. Boys are more frequently affected than girls. Just over half of patients have hyperphagia, are hypersexual (mainly boys), or have depressed mood (mainly girls), and 30% become anxious, delusional, and have hallucinations. Although some symptoms are similar to those in patients with encephalopathy, imaging and laboratory findings are unremarkable. The first episode of hypersomnia is often triggered by an infection, with relapses occurring every 1-12 months for a median of 14 years; disease duration can be much longer with childhood or adult onset than in patients with adolescent onset. Between episodes, patients generally have normal sleep patterns, cognition, mood, and eating habits. During episodes, electroencephalography might show diffuse or local slow activity. Functional imaging studies have revealed hypoactivity in thalamic and hypothalamic regions, and in the frontal and temporal lobes. Stimulants and mood stabilisers can be beneficial in the treatment of severe cases.

Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan.

STUDY OBJECTIVES: In Kleine-Levin Syndrome (KLS), new episodes of hypersomnia are often preceded by an acute flu-like syndrome or upper airway infection 3 to 5 days before onset. This study investigated the relationship between the occurrence of mild upper respiratory tract infections (URIs) in the general population and the occurrence and seasonality and hypersomnic episodes in KLS patients. DESIGN: This investigation was a longitudinal clinical study. Based on data obtained from the National Health Research Institutes between 2006 and 2007, the timing of hypersomnic episodes in 30 KLS patients were compared with calendar reports of URI events, and the results compared with age-matched general Taiwanese population. MEASUREMENTS: Clinical symptoms, physical examination, polysomnographic recording, SPECT study, and laboratory tests affirming KLS during both periods of hypersomnic attack and non-attack were collected. Every symptomatic episode was then followed up. The cross-correlation function (CCF) and bivariate correlations analysis were performed to see the relationship between KLS and URIs. RESULTS: A positive finding of CCF analysis and significant bivariate correlations were found between KLS episodes and URI in the general population (r = 0.456*). In onset of hypersomnia, significant correlations existed among "acute upper respiratory infections" (r = 0.446*), "acute bronchitis and bronchiolitis" (r = 0.462*), and "pharyngitis and nasopharyngitis" (r = 0.548*) subtypes of infections. A positive correlation between higher reports of symptomatic hypersomnia and URI also existed in a given season. A positive nonsignificant trend for "allergic rhinitis" (r = 0.400) was also found. CONCLUSION: The agent behind URI or its consequence (such as fever) is associated with increased incidence of KLS episodes and may explain periodic symptomatic recurrences.

Primary hypersomnias of central origin.

Hypersomnia is a frequently encountered symptom in clinical practice. The cardinal manifestation is inappropriate daytime sleepiness, common to all types of hypersomnias. Hypersomnias of central origin are a rare cause of excessive daytime sleepiness, much rarer than the hypersomnia related to other pathologies, such as sleep-disordered breathing. Narcolepsy, with or without cataplexy, remains the most well studied of the primary hypersomnias. Although recognized more than a century ago, it was not until the end of the 20th century that major breakthroughs led to a better understanding of the disease, with hope of more specific therapies. The authors review the major aspects of this disorder, including the newer treatment modalities. Idiopathic hypersomnia is also part of the primary hypersomnias. Although difficult to diagnose, certain peculiarities stand out to help us differentiate it from the more commonly seen narcolepsy. The recurrent hypersomnias, particularly the Kleine-Levin syndrome, will be discussed. This rare disorder has been studied more closely in the last few years with abundant epidemiologic data assembled through literature and worldwide case reviews. Understanding the primary central hypersomnias warrants a thorough look from the original description, as well as a peek at the future, while more efficacious diagnostic and therapeutic interventions are currently being developed.

[Kleine-Levin syndrome].

KLeine-Levin Syndrome (KLS) is a rare disease characterized by recurrent episodes of hypersomnia associated with cognitive and behavioral disturbances, compulsive eating behavior and hypersexuality. Episodes are separated by weeks or months of normal sleep and behavior. The disease predominantly affects adolescent males. The median duration of the disease is eight years. Fifteen percent of the KLS population is of Jewish origin and the incidence reported in Israel is unproportionately high. The etiology and pathophysiology are unknown. The current concept is that the disease is caused by genetic predisposition combined with environmental factors. Autoimmune etiology has also been suggested. KLS poses diagnostic and therapeutic challenges. Diagnosis is usually based on clinical manifestations. Physical examination including neurological evaluation is usually normal. EEG, brain imaging and CSF examination are normal. Stimulants are partially effective on sleepiness. Lithium was reported to induce positive effects in preventing or delaying recurrences. Increased awareness to KLS among physicians in Israel is important due to the relatively higher incidence of KLS among Jewish and IsraeLi patients.

[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.

Kleine-Levin syndrome: a systematic study of 108 patients.

OBJECTIVE: Kleine-Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality. METHODS: We collected detailed clinical data and blood samples on 108 patients, 79 parent pairs, and 108 matched control subjects. We measured biological markers and typed human leukocyte antigen genes DR and DQ. RESULTS: Novel predisposing factors were identified including increased birth and developmental problems (odds ratio, 6.5). Jewish heritage was overrepresented, and five multiplex families were identified. Human leukocyte antigen typing was unremarkable. Patients were 78% male (mean age at onset, 15.7 +/- 6.0 years), averaged 19 episodes of 13 days, and were incapacitated 8 months over 14 years. The disease course was longer in men, in patients with hypersexuality, and when onset was after age 20. During episodes, all patients had hypersomnia, cognitive impairment, and derealization; 66% had megaphagia; 53% reported hypersexuality (principally men); and 53% reported a depressed mood (predominantly women). Patients were remarkably similar to control subjects between episodes regarding sleep, mood, and eating attitude, but had increased body mass index. We found marginal efficacy for amantadine and mood stabilizers, but found no increased family history for neuropsychiatric disorders. INTERPRETATION: The similarity of the clinical and demographic features across studies strongly suggests that Kleine-Levin syndrome is a genuine disease entity. Familial clustering and increased prevalence in the Jewish population support a role for a major genetic susceptibility factor. Considering the inefficacy of available treatments, we propose that disease management should primarily be supportive and educational.

Atypical Kleine--Levin syndrome: can insomnia and anorexia be features too?

BACKGROUND: Kleine-Levin syndrome is an uncommon disorder with recurrent episodes of hypersomnia, clearly associated with behavioral abnormalities like binge eating, hypersexuality and abnormal behavior. Many patients may not necessarily fulfill minimum criteria described for diagnosis. We aim to report such patients with atypical presentation resembling the Kleine-Levin syndrome. METHOD: We evaluated all patients at our clinic who had episodic disturbance in sleep and/or appetite lasting a few days to weeks, not necessarily fulfilling the International Classification of Sleep Disorders (ICSD) criteria for a diagnosis of Kleine-Levin syndrome, over 4 years. All clinical details, especially regarding sleep, appetite and behaviour during episodes, about prior and co-existing illnesses were noted. All patients were investigated with brain magnetic resonance imaging (MRI), electroencephalogram (EEG) and some with polysomnography. RESULTS: Eighteen patients (5 females, 13 males) ranging in age from 12 to 55 years (median 18 years) were included in the study. The median duration of symptoms was 1.5 years, and the median number of episodes in each patient was six. The range of episode length was 18-300 h with a mean of 91.2h. Fourteen patients had a history of hypersomnia, 3 had only insomnia and 3 had both during their episodes, while 5 patients reported hyperphagia, 11 reduced appetite and 2 no change in appetite. Ictal EEG revealed evidence of sleep, while polysomnography showed reduced rapid eye movement (REM) latency and normal sleep architecture during the episode. MRI was normal in all patients, except one who showed non-specific abnormalities. All patients showed improvement with carbamazepine. CONCLUSION: There are many patients with episodic alteration in sleep, appetite and behaviour with a course and treatment response similar to the classical Kleine-Levin syndrome, who otherwise do not fit the classical description for diagnosis of this condition.

[Sleep disorders and child and adolescent psychiatric illnesses]. / Schlafstörungen bei kinder- und jugendpsychiatrischen Erkrankungen.

As a symptom of many psychiatric disorders of childhood and adolescence, sleep disturbances often complicate the course and treatment of the underlying disorder. A somatic aetiology, e.g., as in Kleine-Levin syndrome or narcolepsy, may lead to diagnostic misinterpretations. It is not clear whether specific alterations of sleep architecture already exist in this age group and are thus trait markers for psychiatric disorders. Although it is well-known that sleep problems in adults, especially insomnia, are important in the later development of depressive syndromes, it is not clear whether persistent sleep problems during childhood constitute markers of vulnerability for psychiatric disorders. This review demonstrates interactions between sleep disturbances and psychiatric disorders of childhood and adolescence and their importance for assessment and therapy.

Clinical and polysomnographic characteristics of 34 patients with Kleine-Levin syndrome.

There is only scant information on sleep characteristics and long-term follow-up in patients with Kleine-Levin syndrome (KLS). This study describes the clinical course, results of polysomnography and long-term follow-up in a relatively large group of patients with KLS. During the years 1982-97, we encountered 34 patients (26 males and eight females) with KLS. We were able to obtain the original polysomnographs from 28 males and four females. In 25 patients, data regarding their present state of health were obtained. Fourteen agreed to be present at a detailed interview and examination while 11 gave the information by phone. The mean age at onset was 15.8 +/- 2.8 years and the mean diagnostic delay, 3.8 +/- 4.2 years. The mean duration of a single hypersomnolent attack was 11.5 +/- 6.6 days. The main abnormal findings extracted out of 35 polysomnographs obtained from 32 patients during and/or in-between attacks included: decreased sleep efficiency, and frequent awakenings from sleep stage 2. All 25 patients reported present perfect health, with no evidence of behavioral or endocrine dysfunction. In adolescents with periodic hypersomnia, the diagnosis of KLS should be explored. Sleep recordings during a hypersomnolent period will often show frequent awakenings from sleep stage 2. The long-term prognosis is excellent.

Kleine Levin syndrome (KLS) in young females.

During the years 1982-1998, we encountered 7 adolescents and one young woman suffering from KLS. In 4 patients, hypersomnolence was accompanied by hyperphagia and hypersexuality, while in the remaining 4, recurrent hypersomnia was the only symptom. Mean age at onset of hypersomnolent attacks was 15.1+/-3.5 yrs. The mean duration of a hypersomnolent attack was 9.9+/-5.4 days, and the number of attacks per patient was 6.2+/-3.4. Polysomnographic recordings from 3 patients inbetween attacks, and from one patient during an attack, showed relatively normal sleep structure with decreased sleep efficiency due to numerous awakenings from sleep stage 2. Besides the recurrent hypersomnia, all patients enjoyed good health, with no evidence of behavioral or endocrine dysfunction. Similarly aged males with KLS from our clinic and previously reported females, had similar clinical features.

Kleine-Levin syndrome and psychosis: observation from an unusual case.

OBJECTIVE: This study evaluated the possible pathologic relation between Kleine-Levin syndrome (KLS) and mood disorders. BACKGROUND: A 28-year-old man with a remote history of KLS had the sudden onset of a manic episode with psychotic features after the end of hypersomnolence. METHOD: The patient received an extensive laboratory examination, including single photon emission computed tomography and magnetic resonance imaging. RESULTS: Single photon emission computed tomography showed decreased tracer perfusion in the basal ganglion, hypothalamus, and right frontotemporal region. Magnetic resonance imaging revealed a cystic lesion in the pineal region. CONCLUSIONS: Hypothalamic dysfunction has been described in KLS and mood disorders, but pineal gland dysfunction has been mentioned only rarely. The clinical and neuroimaging findings suggest the need for further study of KLS.

Síndrome de Kleine-Levin: Revisäo Bibliográfica / Kleine-Levin Syndrome: Bibliographic review

A Síndrome de Kleine-Levin é caracterizada pela tríade: hipersônica, megafagia e hipersexualidade. Jovens do sexo masculino säo mais comumente afetados. A patogênese da doença é desconhecida. Seu diagnóstico é baseado em dados clínicos. Näo há dados específicos aos exames laboratoriais. O tratamento é baseado em estimulantes centrais, antidepressivos, lítio e antagonistas da serotonina