Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by episodic bouts of severe hypersomnia associated with cognitive and behavioral abnormalities and normal alertness and functioning in between episodes. The pathophysiology is unclear but may involve neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, viral/autoimmune etiology, or circadian abnormalities. No single treatment has been shown to be reliably efficacious; lithium has demonstrated the most consistent efficacy, although many do not respond and its use is limited by side effects. Due to the evidence of circadian involvement, we hypothesized that strengthening circadian signals may ameliorate symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, two patients with KLS are described with apparent resolution of hypersomnia episodes following ramelteon initiation. CITATION: Dominguez D, Rudock R, Tomko S, Pathak S, Mignot E, Licis A. Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon. J Clin Sleep Med. 2024;20(4):657-662.

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.

General Anesthetic Management of a Patient With Kleine-Levin Syndrome.

Kleine-Levin syndrome (KLS) is a rare sleep disorder characterized by periodic hypersomnia and behavioral or cognitive disturbances. Although prolonged emergence from general anesthesia and postoperative hypersomnia may occur in a patient with KLS, there is little information about the safe anesthetic management of these patients. We describe the case of a 22-year-old female previously diagnosed with KLS who was scheduled to have her third molars extracted under general anesthesia. Because the patient had symptoms of periodic hypersomnia and hyperphagia, the surgery was scheduled during a KLS crisis interval. General anesthesia was induced with propofol, remifentanil, and rocuronium, and maintained with desflurane and remifentanil. To prevent overuse of anesthetic agents, an electroencephalogram (EEG)-based depth of anesthesia monitor (SedLine; Masimo Corporation) was used intraoperatively. A neuromuscular monitor was also used to carefully titrate use of a neuromuscular blocking agent. After surgery, sugammadex was administered, and the patient quickly emerged within 10 minutes, as also confirmed by the EEG monitor. She had no KLS recurrence postoperatively. When anesthetizing patients with KLS, an EEG-based depth of anesthesia monitor and neuromuscular monitor may be warranted to ensure complete emergence from general anesthesia. In addition, elective surgery should be planned during crises intervals.

Increase in the Number and Duration of Sleep Episodes During Class After Reopening of Schools Following Closure due to COVID-19.

Sleep is important for the well-being of school-aged children. Almost all schools in Hyogo prefecture in Japan were closed from April 7 to May 31, 2020, owing to the coronavirus disease 2019 pandemic. The pandemic restrictions resulted in the disruption of the sleep routines of children. The number of children who experienced sleepiness in class after school closure increased. The number of children who visited our hospital 1 year before and after the closure was 208 (11.73 ± 3.24 years of age) and 155 (11.45 ± 3.30 years), respectively. The number of chief complaints of sleep-related symptoms at the first visits showed no significant difference between the two time periods. The percentage of patients who slept during class increased (but not significantly) after the school closure. However, the mean number and duration of sleep episodes during class significantly increased from 0.31 ± 0.76 to 1.04 ± 1.14 episodes/day and from 15.8 ± 38.6 to 45.7 ± 46.9 min/day (each P < 0.001) before and after school closure, respectively. The total number of patients in our hospital with the primary central disorders of hypersomnolence, i.e., narcolepsy, idiopathic hypersomnia, and Kleine-Levin syndrome, and the number of patients with insufficient sleep syndrome after the school closure significantly increased compared with those before closure (P = 0.034 and 0.048, respectively). School closure was associated with an increased incidence of sleeping during class; therefore, maintaining a stable daily routine for children with sleep disorders could have an alleviating effect.

Kleine-Levin syndrome related to pregnancy: a case report.

Kleine-Levin syndrome (KLS) is a rare disorder of recurrent hypersomnolence. The pathophysiology continues to be poorly understood. Autoimmunity, genetic polymorphisms, dysfunction of the hypothalamic axis, and abnormalities in functional imaging have been proposed. Several triggers have been described, including infection, toxins, head trauma, sleep deprivation, lactation, and menses. We present the first case report in the medical literature of KLS triggered by pregnancy and the first case of KLS from Armenia. Our patient has a pattern of mostly pregnancy-related episodes of several day sleepiness occurring monthly. This case adds to the published literature as we present a new association and explore the pathophysiology of KLS. CITATION: Khachatryan SG, Lastra AC, Vardanyan LV, Khachatryan LG, Attarian HP. Kleine-Levin syndrome related to pregnancy: a case report. J Clin Sleep Med. 2021;17(11):2325-2327.

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.

Un caso de síndrome de Kleine-Levin / A case of Kleine-Levin syndrome

El síndrome de Kleine-Levin es una entidad rara de causa desconocida, generalmente observada en adolescentes varones, que se caracteriza por episodios autolimitados de hipersomnolencia, asociados a alteraciones cognitivas y del comportamiento. Su escasa frecuencia, la falta de totalidad de síntomas al momento del diagnóstico, junto con el solapamiento con sintomatología psiquiátrica, hace que sea una patología de detección tardía, siendo generalmente diagnosticada una vez que otras causas han sido descartadas. Presentamos el caso de un paciente varón de 13 años, que ingresó por cuadro febril, con disminución del nivel de conciencia, asociado a alteraciones del comportamiento y síntomas psicóticos. Fue ingresado en el servicio de Pediatría de nuestro hospital por sospecha de síndrome encefálico, tratado con corticoides y posteriormente inmunoglobulinas ante la sospecha de etiología autoinmune, pero tras sucesivos episodios similares y un adecuado diagnóstico diferencial se le diagnosticó síndrome de Kleine-Levin, iniciando tratamiento con modafinilo con buena respuesta

Kleine-Levin syndrome is a rare entity of unknown cause, usually observed in male adolescents. It is characterised by self-limited episodes of hypersomnolence associated with cognitive and behavioural alterations. Its low frequency, as well as lack of showing all the symptoms at the time of diagnosis, together with overlap with psychiatric symptoms, makes it a disease of delayed detection. It is generally diagnosed once other causes have been ruled out. The case is presented of a 13 year-old male patient, who was admitted due to a febrile illness, with a decreased level of consciousness, associated with behavioural alterations and psychotic symptoms. He was admitted to the Paediatric Department of our hospital, due to a suspicion of encephalic syndrome. He was treated with corticosteroids and later immunoglobulins. But, due to the suspicion of an autoimmune origin, and after successive similar episodes and an adequate differential diagnosis, he was diagnosed with Kleine-Levin syndrome. Treatment was started with modafinil, achieving a good response

[Sleep disorders in neurological department and Kleine-Levin syndrome]. / Rasstroistva sna v nevrologicheskom statsionare i sindrom Kliaine-Levina.

The authors present a case-report of a 22-year-old man with Kleine-Levin syndrome (KLS) and consider the historical description of the syndrome, its symptoms, diagnostic criteria, its place in modern classifications of sleep disorders and KLS pathogenesis. Own data on the frequency of different sleep disorders in inpatients of a neurological unit are presented.

Sleeping beauty syndrome presenting with insomnia.

A young man previously diagnosed with Kleine-Levin syndrome (KLS) presented with abnormal behaviour over the last 8 days. This included decreased sleeping hours and appetite, hypersexuality, aggressiveness and visual hallucinations. All blood tests and investigations in the emergency department yielded normal results. A preliminary diagnosis of a KLS episode with psychosis was made and the patient was started on a regimen of aripiprazole 10 mg once daily along with lorazepam 2 mg intravenously in two divided doses in the event of agitation or insomnia. On discharge 5 days later, the patient had returned to his premorbid level of functioning and was willing to follow up in the neurology clinic. He was discharged on aripiprazole 10 mg once daily and lorazepam 2 mg two times daily as needed for 2 weeks to help with his agitation and insomnia, as well as lithium carbonate 400 mg at night.

A Case of Kleine-Levin Syndrome: Diagnostic and Therapeutic Challenge.

Kleine-Levin syndrome (KLS) is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioral and cognitive disturbances, hyperphagia, and in some cases hyper sexuality. Etiology is unknown, and there is no specific clinical or imaging test for this syndrome even though the illness has well-defined clinical features. Also, there is no effective treatment for KLS. KLS is self-limited, so the prognosis for these patients is not so bad. This study presents our case report and comprehensive workout that led to diagnosis which is primarily clinical. Our patient is a 20-year-old man referred to our clinic because of sleeping problems. At the age of 14, he presented with complaints of the excessive duration of sleep, increased appetite, excessive daytime sleepiness, loss of interest in social activities during attendance of high school and hallucinations. The excessive diagnostic procedure does not find pathological. Kleine-Levin syndrome (KLS) is a rare sleep disorder of unknown etiology which diagnosis is clinical and diagnostic workup is mainly to exclude other similar conditions. There is no specific therapy, but the disease is self-limited and with good prognosis.

[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 (KLS) is a rare disorder characterized by discrete episodes of hypersomnia associated with cognitive and behavioural abnormalities, as well as normal alertness and function between episodes. The prevalence of KLS may be underestimated as it is often misdiagnosed and managed as another sleep disorder, neurological disorder or psychiatric condition. KLS is more typically seen in adolescence than at other ages, and is more common in males than in females. There are currently neither standard biomarkers nor specific imaging study findings, making the diagnosis of KLS a challenge. Furthermore, there are no consistently effective therapies. The prognosis, however, is felt to be overall favorable, as episodes become progressively milder and less frequent before resolving entirely in most patients.

[A young boy with periodic strange behavior and hypersomnia: Kleine-Levin syndrome]. / Een puber met periodiek vreemd gedrag en slaperigheid: syndroom van Kleine-Levin.

Kleine-Levin syndrome is a rare neuro-psychiatric disease. Most of the young patients are males who present with hypersomnia, cognitive dysfunction, altered perception, eating disorder (e.g. hyperphagia) or disinhibited behaviour (e.g. hypersexuality). Psychiatric symptoms such as apathy, delusions and hallucinations, depressed mood and compulsive behaviours also appear often and result frequently in a psychiatric referral. These symptoms, however, should be distinguished from those of psychiatric diseases as early as possible in order to ensure that patients do not receive the wrong treatment. We present the case of an 11-year-old boy in whom the psychiatric symptoms were initially the most prominent ones.