Sleep-Wake Disorders in Childhood.

PURPOSE OF REVIEW: The presentation of sleep issues in childhood differs from the presentation in adulthood and may be more subtle. Sleep issues may affect children differently than adults, and distinct treatment approaches are often used in children. RECENT FINDINGS: Sodium oxybate was approved by the US Food and Drug Administration (FDA) in October 2018 for an expanded indication of treatment of sleepiness or cataplexy in patients with narcolepsy type 1 or narcolepsy type 2 aged 7 years or older, with side effect and safety profiles similar to those seen in adults. Restless sleep disorder is a recently proposed entity in which restless sleep, daytime sleepiness, and often iron deficiency are observed, but children do not meet the criteria for restless legs syndrome or periodic limb movement disorder. SUMMARY: Children's sleep is discussed in this article, including normal sleep patterns and effects of insufficient sleep. Sleep disorders of childhood are reviewed, including insomnia, obstructive sleep apnea, restless legs syndrome, parasomnias, narcolepsy, and Kleine-Levin syndrome. Children with neurologic issues or neurodevelopmental disorders frequently have sleep disorders arising from an interaction of heterogeneous factors. Further attention to sleep may often be warranted through a polysomnogram or referral to a pediatric sleep specialist. Sleep disorders may cause indelible effects on children's cognitive functioning, general health, and well-being, and awareness of sleep disorders is imperative for neurologists who treat children.

The neurophysiological basis of excessive daytime sleepiness: suggestions of an altered state of consciousness.

Excessive daytime sleepiness (EDS) is characterized by difficulty staying awake during daytime, though additional features may be present. EDS is a significant problem for clinical and non-clinical populations, being associated with a range of negative outcomes that also represent a burden for society. Extreme EDS is associated with sleep disorders, most notably the central hypersomnias such as narcolepsy, Kleine-Levin syndrome, and idiopathic hypersomnia (IH). Although investigation of these conditions indicates that EDS results from diminished sleep quality, the underlying cause for this impairment remains uncertain. One possibility could be that previous research has been too narrow in scope with insufficient attention paid to non-sleep-related aspects. Here, we offer a broader perspective in which findings concerning the impact of EDS on cortical functioning are interpreted in relation to current understanding about the neural basis of consciousness. Alterations in the spatial distribution of cortical activity, in particular reduced connectivity of frontal cortex, suggest that EDS is associated with an altered state of consciousness.

Neuroimaging in the Kleine-Levin Syndrome.

PURPOSE OF REVIEW: The purpose was to review the most recent literature on neuroimaging in the Kleine-Levin syndrome (KLS). We aimed to investigate if frontotemporal and thalamic dysfunction are key KLS signatures, and if recent research indicates other brain networks of interest that elucidate KLS symptomatology and aetiology. RECENT FINDINGS: In a comprehensive literature search, we found 12 original articles published 2013-2018. Most studies report deviations related to cerebral perfusion, glucose metabolism, or blood-oxygen-level-dependent responses in frontotemporal areas and/or the thalamus. Studies also report dysfunction in the temporoparietal junction and the oculomotor network that also were related to clinical parameters. We discuss these findings based on recent research on thalamocortical networks and brain stem white matter tracts. The hypothesis of frontotemporal and thalamic involvement in KLS was confirmed, and additional findings in the temporoparietal junction and the oculomotor system suggest a broader network involvement, which can be investigated by future high-resolution and multimodal imaging.

The sleep architecture of Saudi Arabian patients with Kleine-Levin syndrome.

OBJECTIVES: To establish baseline sleep architecture during an acute attack of Kleine-Levin syndrome (KLS) in a cohort of Saudi Arabian KLS patients and compare these characteristics with other published cohorts. Methods: This was a retrospective cohort study of the polysomnographic characteristics of 10 typical symptomatic Saudi Arabian KLS patients attending the University Sleep Disorders Center, King Saud University, Riyadh, Saudi Arabia between 2002 and 2015. Data were captured by nocturnal polysomnography during an acute attack of hypersomnia and compared with other published cohorts identified via a systematic literature search.  Results: Self-reported time asleep during episodes (11.1±6.7 hours) and recorded total sleep time (TST) (322.5±108.7 minutes) were generally shorter than other published cohorts. Sleep efficiency was poor at 75.0%±25.1%, with low relative amounts of rapid eye movement (REM) sleep (16.5±5.9% of TST) and deep non-REM sleep (stage N3; 10.5±6.0% of TST) and high relative amounts of non-REM sleep (stage N1; 7.0±4.3% of TST). The sleep architecture of Saudi Arabian KLS patients was similar to other published cohorts.  Conclusions: Sleep architecture of our cohort was relatively normal and broadly similar to other published studies, the main features being low sleep efficiency and low relative amounts of REM and stage N3 sleep. Time-course polysomnography studies with functional imaging may be useful to further establish the exact pathophysiology of this disease.

Klein-Levin syndrome versus bipolar disorder not otherwise specified- diagnostic challenges.

Hypersomnia presents as excessive daytime sleepiness with a prevalence of 7.1% in general population. Hypersomnia has serious negative effects on persons functioning. The aetiology of hypersomnia can be due to neurological conditions, primary sleep disorders, Substance induced, Psychiatric disorders and idiopathic. Klein-Levin syndrome (KLS) is condition characterised by hypersomnia, hyperphagia and hypersexuality. Among the psychiatric disorders, hypersomnia is seen in bipolar depression. In bipolar disorder, hypersomnia can be present during the depressive episode and also inter-episodically. Here is a case report on hypersomnia and diagnostic challenges.

The "Known Unknowns" of Kleine-Levin Syndrome: A Review and Future Prospects.

Kleine-Levin syndrome (KLS) is a rare, homogeneous, debilitating sleep disorder characterized by episodic hypersomnia, cognitive impairment, and behavioral changes. The etiology, pathophysiology, and optimal management of KLS remain uncertain. We identify the 5 key areas requiring urgent attention: KLS immunopathogenesis studies, next-generation genetics, multimodal functional imaging, biomarker discovery, and clinical drug trials. A centralized registry of afflicted individuals must be established. Disease uniformity should make the identification of associated genetic or imaging biomarkers easier, but clinical efforts require laboratory-based research to model the disease and generate preclinical data for clinical translation.

Neuroimaging of Narcolepsy and Kleine-Levin Syndrome.

Narcolepsy is a chronic neurologic disorder with the abnormal regulation of the sleep-wake cycle, resulting in excessive daytime sleepiness, disturbed nocturnal sleep, and manifestations related to rapid eye movement sleep, such as cataplexy, sleep paralysis, and hypnagogic hallucination. Over the past decade, numerous neuroimaging studies have been performed to characterize the pathophysiology and various clinical features of narcolepsy. This article reviews structural and functional brain imaging findings in narcolepsy and Kleine-Levin syndrome. Based on the current state of research, brain imaging is a useful tool to investigate and understand the neuroanatomic correlates and brain abnormalities of narcolepsy and other hypersomnia.

Kleine-Levin syndrome; An update and mini-review.

Since 1962, when Critchley and Hoffman coined the term Kleine-Levin Syndrome (KLS) for the triad of hypersomnia, excessive eating and "often abnormal behavior" which they have observed in 11 adolescent boys, the number of patients recognized with this rare syndrome expanded, the spectrum of the clinical presentation, disease course, prognosis, gender specificity and the presence of familial cases were established. However, in spite of the progress made in neuroscience, the search for the cause, neuroanatomy, pathophysiology and drug treatment of KLS is still ongoing. In this mini-review we will describe in some detail the scientific efforts made to understand in depth the complex symptomatology of KLS and refer also to updated findings reached up till now.

A Polysomnography Study of Kleine-Levin Syndrome in a Single Center.

BACKGROUND: Kleine-Levin syndrome (KLS) is a rare sleep disorder characterized by recurrent episodes of hypersomnia. Polysomnographic (PSG) researches of KLS have been reported only in few publications in the past decades. This study aimed to investigate the characteristics of PSG of KLS. METHODS: This study, which was conducted from March 2010 to July 2014, included seven patients diagnosed with KLS in the Sleep and Wake Disorder Center of Huashan Hospital, Fudan University (Shanghai, China). PSG and multiple sleep latency tests (MSLT) were performed during their episodes and the results were evaluated. RESULTS: Five of the seven patients were males. The mean age at KLS onset was 15.6 ± 3.6 years. The number of episodes ranged from 2 to 7. The duration of episodes lasted from 4 to 11 days. The sleep architecture and proportion were normal in most of the patients. The average value of mean sleep latency was 6.9 ± 4.1 min. No sleep-onset rapid eye movement (SOREM) was detected in three of the patients, whereas one patient experienced one period of SOREM, and such episodes occurred twice in other two patients. CONCLUSIONS: We found that sleep architecture and proportion were normal in most KLS patients. However, the results of PSG and MSLT had no specificity for KLS patients.

Familial Kleine-Levin Syndrome: A Specific Entity?

STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is a rare, mostly sporadic disorder, characterized by intermittent episodes of hypersomnia plus cognitive and behavior disorders. Although its cause is unknown, multiplex families have been described. We contrasted the clinical and biological features of familial versus sporadic KLS. METHODS: Two samples of patients with KLS from the United States and France (n = 260) were studied using clinical interviews and human leukocyte antigen (HLA) genotyping. A multiplex family contained two or more first- or second-degree affected relatives (familial cases). RESULTS: Twenty-one patients from 10 multiplex families (siblings: n = 12, including two pairs of monozygotic twins; parent-child: n = 4; cousins: n = 2; uncle-nephews: n = 3) and 239 patients with sporadic KLS were identified, yielding to 4% multiplex families and 8% familial cases. The simplex and multiplex families did not differ for autoimmune, neurological, and psychiatric disorders. Age, sex ratio, ethnicity, HLA typing, karyotyping, disease course, frequency, and duration of KLS episodes did not differ between groups. Episodes were less frequent in familial versus sporadic KLS (2.3 ± 1.8/y versus 3.8 ± 3.7/y, P = 0.004). Menses triggered more frequently KLS onset in the nine girls with familial KLS (relative risk, RR = 4.12, P = 0.03), but not subsequent episodes. Familial cases had less disinhibited speech (RR = 3.44, P = 0.049), less combined hypophagia/hyperphagia (RR = 4.38, P = 0.006), more abrupt termination of episodes (RR = 1.45, P = 0.04) and less postepisode insomnia (RR = 2.16, P = 0.008). There was similar HLA DQB1 distribution in familial versus sporadic cases and no abnormal karyotypes. CONCLUSION: Familial KLS is mostly present in the same generation, and is clinically similar to but slightly less severe than sporadic KLS.

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.

New hypothesis on pontine-frontal eye field connectivity in Kleine-Levin syndrome.

Previous studies have indicated involvement of the thalamus and the pons in Kleine-Levin syndrome. In the present study, functional connectivity of the thalamus and the pons was investigated in asymptomatic patients with Kleine-Levin syndrome and healthy controls. Twelve patients and 14 healthy controls were investigated by functional magnetic resonance imaging during rest. Resting state images were analysed using seed regions of interest in the thalamus and the pons. The results showed significantly lower functional connectivity between the pons and the frontal eye field in persons with Kleine-Levin syndrome compared with healthy controls. There were no connectivity differences involving the thalamus. Based on these findings, a relation is proposed between the sleep disorder Kleine-Levin syndrome and cerebral control of eye movements, which in turn is related to visual attention and working memory. This hypothesis has to be tested in future studies of oculomotor control in Kleine-Levin syndrome.

Cerebrospinal Fluid Orexin A Levels and Autonomic Function in Kleine-Levin Syndrome.

STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is a rare disorder of relapsing sleepiness. The hypothesis was that the syndrome is related to a change in the vigilance peptide orexin A. METHODS: From 2002 to 2013, 57 patients with relapsing hypersomnolence were clinically assessed in a referral academic center in Beijing, China, and 44 (28 males and 16 females; mean age 18.3 ± 8.9 y (mean ± standard deviation, range 9-57 y) were determined to have clinical and behavioral criteria consistent with KLS. Cerebrospinal fluid orexin A levels and diurnal blood pressure were measured in relapse versus remission in a subgroup of patients. RESULTS: Presenting symptoms included relapsing or remitting excessive sleepiness-associated parallel complaints of cognitive changes (82%), eating disorders (84%); depression (45%); irritability (36%); hypersexuality (18%); and compulsions (11%). Episodes were 8.2 ± 3.3 days in duration. In relapse, diurnal values for blood pressure and heart rate were lower (P < 0.001). In a subgroup (n = 34), cerebrospinal fluid orexin A levels were ∼31% lower in a relapse versus remission (215.7 ± 81.5 versus 319.2 ± 95.92 pg/ml, P < 0.001); in three patients a pattern of lower levels during subsequent relapses was documented. CONCLUSIONS: There are lower orexin A levels in the symptomatic phase than in remission and a fall and rise in blood pressure and heart rate, suggesting a role for orexin dysregulation in KLS pathophysiology.

Kleine-Levin syndrome. Familial cases and comparison with sporadic cases.

OBJECTIVES: To highlight the occurrence of familial cases and addresses, whether familial Kleine-Levine syndrome (KLS) presents the same spectrum of disease, as that seen in sporadic KLS.   METHODS: Between September and December 2014, reports of familial cases of KLS were identified by searching the Library of Congress, PubMed, and Web of Science databases restricted to the English language, with no restriction on date of publication. All cases were reviewed to identify familial cases consistent with current diagnostic criteria for sporadic KLS.   RESULTS: Six reviews and 11 case reports describing cases of familial KLS were identified. In 17 of the 29 familial cases identified, sufficient clinical details were described to be confident that these cases were familial and consistent with the description of KLS in the International Classification of Sleep Disorders 3rd edition (ICSD-3), and recent detailed reviews of sporadic KLS. CONCLUSION: A significant number of familial cases of KLS have been described that are consistent with the ICSD-3 description of KLS, and indistinguishable from sporadic KLS. This suggests that study of familial KLS using modern genetic techniques may be useful in elucidating the pathogenesis of this rare condition.

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.

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.

Kleine-Levin syndrome: a case report and review of literature.

BACKGROUND: Kleine-Levin syndrome presents with recurrent hypersomnia along with a number of other neuropsychiatric features, of which hyperorality has not been described frequently. METHOD: We report a male adolescent who presented with recurrent hypersomnia, hypersexuality, and hyperorality. Magnetic resonance imaging of the brain and overnight polysomnography followed by a multiple sleep latency tests were ordered. Excessive daytime sleepiness was assessed with the Epworth Sleepiness Scale. RESULTS: Magnetic resonance imaging of the brain did not reveal any abnormality. Overnight video-synchronized polysomnography and multiple sleep latency tests ruled out narcolepsy. Epworth Sleepiness Scale score at baseline was 22. He was prescribed lithium carbonate 300 mg twice a day. The symptoms improved within a week after starting lithium carbonate therapy. CONCLUSION: Kleine-Levin syndrome may present with hyperorality, and our patient responded well to lithium carbonate therapy.