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.

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.

Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine-Levin syndrome.

OBJECTIVE: To measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine-Levin syndrome (KLS) during symptomatic and asymptomatic periods. PATIENTS/METHODS: Two patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode. RESULTS: CSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy-cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels. CONCLUSION: We reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus.

Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population.

STUDY OBJECTIVES: The International Classification of Sleep Disorders (ICSD-2) criteria for low CSF hypocretin-1 levels (CSF hcrt-1) still need validation as a diagnostic tool for narcolepsy in different populations because inter-assay variability and different definitions of hypocretin deficiency complicate direct comparisons of study results. DESIGN AND PARTICIPANTS: Interviews, polysomnography, multiple sleep latency test, HLA-typing, and CSF hcrt-1 measurements in Danish patients with narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwC), CSF hcrt-1 measurements in other hypersomnias, neurological and normal controls. Comparisons of hypocretin deficiency and frequency of HLA-DQB1*0602-positivity in the Danish and eligible NC and NwC populations (included via MEDLINE search), by (re)calculation of study results using the ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean). MEASUREMENTS AND RESULTS: In Danes, low CSF hcrt-1 was present in 40/46 NC, 3/14 NwC and 0/106 controls (P < 0.0001). Thirty-nine of 41 NC and 4/13 NwC patients were HLA-DQB1*0602-positive (P < 0.01). Hypocretin-deficient NC patients had higher frequency of cataplexy, shorter mean sleep latency, more sleep onset REM periods (P < 0.05) and more awakenings (NS) than did NC patients with normal CSF hcrt-1. Across populations, low CSF hcrt-1 and HLA-DQB1*0602-positivity characterized the majority of NC (80% to 100%, P = 0.53; 80% to 100%, P = 0.11) but a minority of NwC patients (11% to 29%, P = 0.75; 29% to 89%, P = 0.043). CONCLUSION: The study provides evidence that hypocretin deficiency causes a more severe NC phenotype. The ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean) is valid for diagnosing NC, but not NwC. HLA-typing should precede CSF hcrt-1 measurements because hypocretin deficiency is rare in HLA-DQB1*0602-negative patients.

Kleine-Levin syndrome in a 14-year-old girl: CSF hypocretin-1 measurements.

CSF hypocretin-1 measurements were performed during a period of hypersomnia and during an asymptomatic interval in a 14-year-old girl affected with severe Kleine-Levin syndrome. A twofold decrease in hypocretin-1 was evidenced during the period of hypersomnia in comparison with the asymptomatic interval. Together with previous data, this result is in favour of recurrent dysfunction at the hypothalamic level in Kleine-Levin syndrome.

Familial Kleine-Levin syndrome: two siblings with unusually long hypersomnic spells.

Kleine-Levin syndrome is a rare, sporadic disorder, with discrete spells of hypersomnolence occurring during adolescence, variously accompanied by megaphagia, behavioral changes, psychosis, and mild autonomic symptoms. Familial cases have not previously been reported. We describe 2 siblings who shared uncharacteristically prolonged episodes of hypersomnolence, and the HLA-DR2 haplotype. In one patient, levels of cerebrospinal fluid orexin (hypocretin) during an attack were normal. The presence of an increased sleep drive, despite the occurrence of large amounts of ostensibly restorative sleep, suggests the possible existence of a disorder of sleep satiety.