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: 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.

Can Quantitative Electroencephalography and Functional Near-Infrared Spectroscopy be a Good Guide in Kleine-Levin Syndrome?

There is scarce literature on functional neuroimaging data in Kleine-Levin syndrome. The current case report presents the electrical and metabolic status of cortical activity utilizing functional near-infrared spectroscopy (fNIRS) and quantitative electroencephalography (qEEG) before and after treatment of symptomatic phase of illness with modafinil.

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.

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

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.

IV steroids during long episodes of Kleine-Levin syndrome.

OBJECTIVE: To retrospectively compare the benefits (episode cessation) and risks of IV methylprednisolone (IV-MP) vs abstention during prolonged Kleine-Levin syndrome (KLS) episodes. METHODS: A total of 26 patients with KLS received 1 g/d IV-MP for 3 days during 1 to 6 episodes each (totaling 43 IV-MP sessions). The change of episode duration with IV-MP (vs previous episode duration) was compared with the change duration between 2 consecutive episodes in 48 untreated patients matched for age, sex, age at KLS onset, number of episodes, and disease duration (more treated than untreated patients had long episodes). RESULTS: Eleven patients (42.3%) had an episode that was at least 1 week shorter than the preceding one when they received IV-MP therapy, whereas shorter episodes were significantly less frequent (10.4%) in the untreated group. This benefit was more marked (65.5% responders, 12 fewer days in an episode vs 0 days in the untreated patients) when IV-MP was infused before the 10th day of the episode. Mild, transient adverse effects (insomnia, muscle pain, nervousness/restlessness, but no manic switching) were reported by 61.3% of patients. No specific responder profile was identified. CONCLUSION: In this open-labeled, naturalistic study, early IV-MP (following the protocol for multiple sclerosis relapses) had a good benefit/risk ratio during KLS episodes in patients with long episodes (with half of the patients having an early cessation of episodes). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with long episodes of KLS, IV steroids decrease the duration of KLS episodes.

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.

Disorders of Excessive Daytime Sleepiness Including Narcolepsy and Idiopathic Hypersomnia.

Central disorders of hypersomnolence are rare conditions with a poorly understood pathophysiology, making the identification and management challenging for sleep clinicians. Clinical history is essential for ruling out secondary causes of hypersomnolence and distinguishing among diagnoses. Current diagnostic criteria rely heavily on the polysomnogram and multiple sleep latency test. The current focus of treatment of hypersomnolence is on drugs that promote alertness. Additionally, in the case of narcolepsy type 1, medication management addresses control of cataplexy, the hallmark symptom of this disorder. Elucidation of pathophysiology of these disorders in the future will be essential to better categorization and management.

Pharmacological treatment for Kleine-Levin syndrome.

BACKGROUND: This is an updated version of the original Cochrane review, published in 2009, Issue 2.Kleine-Levin syndrome (KLS) is a rare disorder that mainly affects adolescent men. It is characterised by recurrent episodes of hypersomnia, usually accompanied by hyperphagia, cognitive and mood disturbances, abnormal behaviour, such as hypersexuality, and signs of dysautonomia.In 1990, the diagnostic criteria for Kleine-Levin syndrome were modified in the International Classification of Sleep Disorders, where KLS was defined as a syndrome comprised of recurring episodes of undue sleepiness lasting some days, which may or may not be associated with hyperphagia and abnormal behaviour. According to the International Classification of Sleepiness Disorders, 3rd version (ICSD-3), revised in 2014, the Kleine-Levin syndrome is a disorder characterized by recurrent episodes of hypersomnia that last from two days to four weeks, with at least annual recurrence, and hyperphagia (rapid consumption of a large amount of food), usually with onset in early adolescence in males but occasionally in later life and in women. A monosymptomatic form of the disorder with hypersomnia only can occur without binge eating or hypersexuality.The cause of Kleine-Levin syndrome remains unknown, and several treatment strategies have been used. Some medications have been reported to provide benefit in the treatment of patients with KLS, but because of the rarity of the condition, no long-term follow-up therapies have yet been described. OBJECTIVES: This review aimed to evaluate:1. whether pharmacological treatment for Kleine Levin syndrome was effective and safe.2. which drug or category of drugs was effective and safe. SEARCH METHODS: For the latest update, we searched the following sources: the Cochrane Epilepsy Group Specialized Register (7 April 2016); the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online CRSO (7 April 2016); MEDLINE (1946 to April 2016); LILACS (7 April 2016); ClinicalTrials.gov (7 April 2016); WHO International Clinical Trials Registry Platform ICTRP (7 April 2016); reference lists of sleep medicine textbooks; review articles and reference lists of articles identified by the search strategies. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-randomised controlled trials looking at pharmacological interventions for Kleine-Levin syndrome were eligible. We had planned to include both parallel-group and cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors (MMO and CC) had planned to extract the data reported in the original articles. MAIN RESULTS: No studies met the inclusion criteria for this systematic review. AUTHORS' CONCLUSIONS: Therapeutic trials of pharmacological treatment for Kleine-Levin syndrome with a double-blind, placebo-controlled design are needed.

Lithium therapy in Kleine-Levin syndrome: An open-label, controlled study in 130 patients.

OBJECTIVE: To compare the benefits and risks of lithium therapy vs abstention/other treatments in Kleine-Levin syndrome (KLS). METHODS: In a KLS cohort followed in a single center, 130 patients regularly took lithium carbonate (median dose 1,000 mg/day; n = 71; 40 children), valproate (n = 5), contraceptive pill (n = 5), or no treatment (n = 49). The disease characteristics (frequency, mean, and longest durations of episodes, time incapacitated per year) were compared before and after follow-up in the lithium vs abstention groups. RESULTS: The time between KLS onset and therapeutic onset was 69 ± 92 months. The patients were then followed up for a mean of 21.5 ± 17.8 months. Before treatment, the 71 patients treated with lithium tended to have a higher frequency of episodes per year (3.8 ± 2.9 vs 2.9 ± 2.6) and had a longer time spent incapacitated (57 ± 51 vs 37 ± 35 days) than the untreated patients. The mean (-8 ± 20 vs 2 ± 13 days) and longest (-18 ± 35 vs -5 ± 13) episode duration, the time spent incapacitated (-37 ± 65 days vs -10 ± 38), as well as the frequency of episodes per year (-2.6 ± 2.9 vs 1.3 ± 2.78) decreased significantly more in the treated than in the untreated patients. Side effects (reported by 50% of the patients) were mild and classical with lithium (tremor, increased drinking, diarrhea, and subclinical hypothyroidism). CONCLUSIONS: In this large, prospective, open-label, controlled study, the benefit/risk ratio of lithium therapy is superior to that of abstention, supporting the concept that lithium has anti-inflammatory/neuroprotective effects. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with KLS, lithium decreases the frequency and duration of KLS episodes.