Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1.

STUDY OBJECTIVES: The diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111-200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence. METHODS: Retrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type ("typical" or "atypical" cataplexy). RESULTS: Compared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings. CONCLUSION: Individuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.

Narcolepsy in Children: Sleep disorders in children, A rapidly evolving field seeking consensus.

Narcolepsy is a life-long sleep disorder with two distinct subtypes, narcolepsy type I and narcolepsy type II. It is now well recognized that the loss of hypocretin neurons underlies the pathogenesis of narcolepsy type I, however, the pathogenesis of narcolepsy type II is currently unknown. Both genetic and environmental factors play an important role in the pathogenesis of narcolepsy. There is increasing evidence that autoimmune processes may play a critical role in the loss of hypocretin neurons. Infections especially streptococcus and influenza have been proposed as a potential trigger for the autoimmune-mediated mechanism. Several recent studies have shown increased cases of pediatric narcolepsy following the 2009 H1N1 pandemic. The increased cases in Europe seem to be related to a specific type of H1N1 influenza vaccination (Pandemrix), while the increased cases in China are related to influenza infection. Children with narcolepsy can have an unusual presentation at disease onset including complex motor movements which may lead to delayed diagnosis. All classic narcolepsy tetrads are present in only a small proportion of children. The diagnosis of narcolepsy is confirmed by either obtaining cerebrospinal fluid hypocretin or overnight sleep study with the multiple sleep latency test (MSLT). There are limitations of using MSLT in young children such that a negative MSLT test cannot exclude narcolepsy. HLA markers have limited utility in narcolepsy, but it may be useful in young children with clinical suspicion of narcolepsy. For management, both pharmacologic and non-pharmacologic treatments are important in the management of narcolepsy. Pharmacotherapy is primarily aimed to address excessive daytime sleepiness and REM-related symptoms such as cataplexy. In addition to pharmacotherapy, routine screening of behavioral and psychosocial issues is warranted to identify patients who would benefit from bio-behavior intervention.

Temporal Changes in the Cerebrospinal Fluid Level of Hypocretin-1 and Histamine in Narcolepsy.

Study Objectives: To follow the temporal changes of cerebrospinal fluid (CSF) biomarker levels in narcoleptic patients with unexpected hypocretin level at referral. Methods: From 2007 to 2015, 170 human leukocyte antigen (HLA) DQB1*06:02-positive patients with primary narcolepsy and definite (n = 155, 95 males, 60 females, 36 children) or atypical cataplexy (n = 15, 4 males, 3 children) were referred to our center. Cerebrospinal hypocretin deficiency was found in 95.5% and 20% of patients with definitive and atypical cataplexy, respectively. CSF hypocretin-1 (n = 6) and histamine/tele-methylhistamine (n = 5) levels were assessed twice (median interval: 14.4 months) in four patients with definite and in two with atypical cataplexy and hypocretin level greater than 100 pg/mL at baseline. Results: CSF hypocretin levels decreased from normal/intermediate to undetectable levels in three of the four patients with definite cataplexy and remained stable in the other (>250 pg/mL). Hypocretin level decreased from 106 to 27 pg/mL in one patient with atypical cataplexy, and remained stable in the other (101 and 106 pg/mL). CSF histamine and tele-methylhistamine levels remained stable, but for one patient showing increased frequency of cataplexy and a strong decrease (-72.5%) of tele-methylhistamine levels several years after disease onset. No significant association was found between relative or absolute change in hypocretin level and demographic/clinical features. Conclusions: These findings show that in few patients with narcolepsy with cataplexy, symptoms and CSF marker levels can change over time. In these rare patients with cataplexy without baseline hypocretin deficiency, CSF markers should be monitored over time with potential for immune therapies in early stages to try limiting hypocretin neuron loss.

Cataplexy with Normal Sleep Studies and Normal CSF Hypocretin: An Explanation?

Patients with narcolepsy usually develop excessive daytime sleepiness (EDS) before or coincide with the occurrence of cataplexy, with the latter most commonly associated with low cerebrospinal fluid (CSF) hypocretin-1 levels. Cataplexy preceding the development of other features of narcolepsy is a rare phenomenon. We describe a case of isolated cataplexy in the context of two non-diagnostic multiple sleep latency tests and normal CSF-hypocretin-1 levels (217 pg/mL) who gradually developed EDS and low CSF-hypocretin-1 (< 110 pg/mL).

Narcolepsy with Cataplexy in an Elderly Woman.

A 72-year-old woman was referred for a 15-year history of brief attacks of generalized weakness that occurred when she was tense or startled. During these episodes, she squatted, closed her eyes, and had difficulty speaking, but there was no disturbance of consciousness. The cerebrospinal fluid level of orexin/hypocretin was low (92 ng/L), leading to a diagnosis of narcolepsy with cataplexy according to the International Classification of Sleep Disorders (ICSD)-2 criteria. Cataplexy should be considered for sudden attacks of weakness lasting less than 2 minutes and with no alteration of consciousness. Measurement of cerebrospinal fluid levels of orexin/hypocretin is recommended when the diagnosis is uncertain.

Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy.

OBJECTIVE: Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC), including reduced or increased sympathetic activity; to settle this important point, we aimed to measure the resting sympathetic and cardiovascular activities in patients with NC by direct microneurographic monitoring of muscle sympathetic nerve activity (MSNA) during wakefulness. METHODS: We studied 19 untreated patients with established criteria for NC and hypocretin deficiency and 19 sex- and age-matched healthy subjects. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR), whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. RESULTS: Patients with NC displayed lower resting MSNA, HR, and BP values than controls. Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA or HR, whereas no correlation was found with BP; however, patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. CONCLUSIONS: (1) Patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP.

Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case-control study.

Recent advances in the identification of susceptibility genes and environmental exposures provide strong support that narcolepsy-cataplexy is an immune-mediated disease. Only few serum cytokine studies with controversial results were performed in narcolepsy and none in the cerebrospinal fluid. We measured a panel of 12 cytokines by a proteomic approach in the serum of 35 patients with narcolepsy-cataplexy compared to 156 healthy controls, and in the cerebrospinal fluid of 34 patients with narcolepsy-cataplexy compared to 17 non-narcoleptic patients; and analyzed the effect of age, duration and severity of disease on the cytokine levels. After multiple adjustments we reported lower serum IL-2, IL-8, TNF-α, MCP-1 and EGF levels, and a tendency for higher IL-4 level in narcolepsy compared to controls. Significant differences were only found for IL-4 in cerebrospinal fluid, being higher in narcolepsy. Positive correlations were found in serum between IL-4, daytime sleepiness, and cataplexy frequency. The expression of some pro-inflammatory cytokines (MCP-1, VEGF, EGF, IL2, IL-1ß, IFN-γ) in either serum or CSF was negatively correlated with disease severity and duration. No correlation was found for any specific cytokine in 18 of the patients with narcolepsy with peripheral and central samples collected the same day. Significant decreased pro/anti-inflammatory cytokine profiles were found at peripheral and central levels in narcolepsy, together with a T helper 2/Th1 serum cytokine secretion imbalance. To conclude, we showed some evidence for alterations in the cytokine profile in patients with narcolepsy-cataplexy compared to controls at peripheral and central levels, with the potential role of IL-4 and significant Th1/2 imbalance in the pathophysiology of narcolepsy.

Elevated glial fibrillary acidic protein levels in the cerebrospinal fluid of patients with narcolepsy.

Glial fibrillary acidic protein (GFAP) is an established indicator of astrogliosis. Therefore, variable cerebrospinal fluid (CSF) concentrations of this protein might reflect disease-specific pathologic profiles. In patients with narcolepsy, a loss of hypocretin-1 (hcrt-1) neurons in the brain and low concentrations of hcrt-1 in CSF have been reported. We performed a commercially available enzyme-linked immunosorbent assay to investigate if GFAP also is altered in the CSF of these patients. Here we detected significantly higher CSF levels of GFAP in patients with low hcrt-1 levels, of which the majority had a diagnosis of narcolepsy and cataplexy (NC); however, this finding was not observed in patients with hcrt-1 levels that were within reference range. In conclusion, GFAP may be useful as an additional disease biomarker in patients with narcolepsy, and this hypothesis should be investigated in larger studies.

Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A.

BACKGROUND: From October 2009 to January 2010, approximately 470,000 children and adolescents in Norway ages 4-19 years were vaccinated with Pandemrix® against influenza A (H1N1 subtype). The vaccination coverage in this age cohort was approximately 50%. OBJECTIVES: Our study was performed to evaluate the possible association between Pandemrix® vaccination and narcolepsy in Norway. METHODS: Children and adolescents with sudden onset of excessive daytime sleepiness (EDS) and cataplexy occurring after the 2009-2010 vaccination period were registered by the National Institute of Public Health in cooperation with the Norwegian Resource Center for AD/HD, Tourette Syndrome, and Narcolepsy. RESULTS: Fifty-eight vaccinated children and adolescents (35 girls, 23 boys) ages 4-19 years (mean age, 10.5 years) were diagnosed as new cases of confirmed narcolepsy and were included in our study during 2010 and 2011. Forty-two children had onset of symptoms within 6 months after vaccination, with 12 of them having symptoms within the first 6 weeks. All had EDS, 46 had documented cataplexy, 47 had mean sleep latency less than 8 min, and 43 had two or more sleep-onset rapid eye movement sleep (SOREM) periods in multiple sleep latency tests (MSLT). Cerebrospinal fluid (CSF) hypocretin levels were measured in 41 patients, with low levels in all. Thirty seven patients that were analyzed had tissue type HLADQB1*0602. During the same period, 10 unvaccinated cases were reported (mean age, 12.5 years). CONCLUSION: The data collected during 3 years following vaccination showed a significantly increased risk for narcolepsy with cataplexy (P<.0001) and reduced CSF hypocretin levels in vaccinated children ages 4-19 years the first year after Pandemrix® vaccination, with a minimum incidence of 10 of 100,000 individuals per year. The second year after vaccination, the incidence was 1.1 of 100,000 individuals per year, which was not significantly different from the incidence of 0.5-1 of 100,000 per year in unvaccinated children during the same period.

Hypocretin deficiency develops during onset of human narcolepsy with cataplexy.

STUDY OBJECTIVES: Although hypothesized through animal studies, a temporal and causal association between hypocretin deficiency and the onset of narcolepsy with cataplexy (NC) has never been proven in humans. SETTING: Paediatric Department, Blekinge Hospital, Sweden, and Danish Center for Sleep Medicine, Glostrup Hospital, Denmark. PATIENT AND RESULTS: Two weeks after his second Pandemrix-vaccination, a 10 year old HLA-DQB1*0602-positive boy developed NC. The CSF hypocretin-1 level was 10 pg/ml. However, CSF saved from a pre-narcolepsy episode of Lyme disease revealed a normal hypocretin-1 level (318 pg/ml). CONCLUSIONS: We confirm that hypocretin deficiency develops in parallel to the onset of human narcolepsy with cataplexy.

Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness?

Sleep-wake disturbances are frequent in patients with Parkinson's disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep-wake disturbances in Parkinson's disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson's disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson's disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin-deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson's disease. Poorer sleep quality is linked to dopamine deficiency and other disease-related factors. Despite hypocretin cell loss in Parkinson's disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

Role of the hypocretin (orexin) receptor 2 (Hcrt-r2) in the regulation of hypocretin level and cataplexy.

Hypocretin receptor-2 (Hcrt-r2)-mutated dogs exhibit all the major symptoms of human narcolepsy and respond to drugs that increase or decrease cataplexy as do narcoleptic humans; yet, unlike narcoleptic humans, the narcoleptic dogs have normal hypocretin levels. We find that drugs that reduce or increase cataplexy in the narcoleptic dogs, greatly increase and decrease, respectively, hypocretin levels in normal dogs. The effects of these drugs on heart rate and blood pressure, which were considerable, were not correlated with their effects on cataplexy. Administration of these drugs to Hcrt-r2-mutated dogs produced indistinguishable changes in heart rate and blood pressure, indicating that neither central nor peripheral Hcrt-r2 is required for these cardiovascular effects. However, in contrast to the marked Hcrt level changes in the normal dogs, these drugs did not alter hypocretin levels in the Hcrt-r2 mutants. We conclude that Hcrt-r2 is a vital element in a feedback loop integrating Hcrt, acetylcholine, and norepinephrine function. In the absence of functional Hcrt-r2, Hcrt levels are not affected by monoaminergic and cholinergic drugs, despite the strong modulation of cataplexy by these drugs. Conversely, strong transient reductions of Hcrt level by these drugs do not produce episodes of cataplexy in normal dogs. The Hcrt-r2 mutation causes drug-induced cataplexy by virtue of its long-term effect on the functioning of other brain systems, rather than by increasing the magnitude of phasic changes in Hcrt level. A similar mechanism may be operative in spontaneous cataplexy in narcoleptic dogs as well as in narcoleptic humans.

Relationship between clinical characteristics of narcolepsy and CSF orexin-A levels.

Although an abnormally low cerebrospinal fluid (CSF)-orexin level is well known to be a specific finding in narcoleptic patients, the relationships between the severity of the core symptoms of narcolepsy [i.e. daytime sleepiness and increased rapid eye movement (REM) propensity], as well as levels of obesity, and CSF-orexin levels have not been well elucidated. The aim of this study was to examine the relationship between these characteristic symptoms of narcolepsy and CSF-orexin level. Fifty-three patients with narcolepsy with cataplexy (NA/CA) and 17 without cataplexy (NA w/o CA) were enrolled. Sleep latency and sleep onset REM latency were measured using the multiple sleep latency test (MSLT). Multiple linear regression analysis was used to determine factors associated with both mean sleep latency and mean sleep onset REM latency on MSLT, with %body mass index (BMI), gender, onset age, length of excessive daytime sleepiness (EDS) morbidity, diagnostic subgroup and CSF-orexin levels being used as independent variables. The NA/CA group included a significantly higher number of patients with undetectable CSF-orexin levels and shorter sleep onset and rapid eye movement (SOREM) latency, as well as a higher %BMI, versus NA w/o CA. Multiple linear regression analysis revealed that sleep latency was associated significantly with CSF-orexin levels and gender. With regard to sleep onset REM latency and %BMI, only CSF-orexin levels appeared to be a significantly associated factor. In narcoleptic patients, the severity of both excessive daytime sleepiness and increased REM propensity, as well as the level of obesity, could be associated with CSF-orexin deficiency, rather than with subcategories of the disorder.

Traditional biomarkers in narcolepsy: experience of a Brazilian sleep centre.

UNLABELLED: This study was thought to characterized clinical and laboratory findings of a narcoleptic patients in an out patients unit at São Paulo, Brazil. METHOD: 28 patients underwent polysomnographic recordings (PSG) and Multiple Sleep Latency Test (MSLT) were analyzed according to standard criteria. The analysis of HLADQB1*0602 allele was performed by PCR. The Hypocretin-1 in cerebral spinal fluid (CSF) was measured using radioimmunoassay. Patients were divided in two groups according Hypocretin-1 level: Normal (N) - Hypocretin-1 higher than 110 pg/ml and Lower (L) Hypocretin-1 lower than 110 pg/ml. RESULTS: Only 4 patients of the N group had cataplexy when compared with 14 members of the L group (p = 0.0002). DISCUSSION: This results were comparable with other authors, confirming the utility of using specific biomarkers (HLA-DQB1*0602 allele and Hypocretin-1 CSF level) in narcolepsy with cataplexy. However, the HLADQB1*0602 allele and Hypocretin-1 level are insufficient to diagnose of narcolepsy without cataplexy.

Traditional biomarkers in narcolepsy: experience of a Brazilian sleep centre / Biomarcadores tradicionias em narcolepsia: experiência de um centro de sono brasileiro

This study was thought to characterized clinical and laboratory findings of a narcoleptic patients in an out patients unit at São Paulo, Brazil. METHOD: 28 patients underwent polysomnographic recordings (PSG) and Multiple Sleep Latency Test (MSLT) were analyzed according to standard criteria. The analysis of HLADQB1*0602 allele was performed by PCR. The Hypocretin-1 in cerebral spinal fluid (CSF) was measured using radioimmunoassay. Patients were divided in two groups according Hypocretin-1 level: Normal (N) - Hypocretin-1 higher than 110pg/ml and Lower (L) Hypocretin-1 lower than 110 pg/ml. RESULTS: Only 4 patients of the N group had cataplexy when compared with 14 members of the L group (p=0.0002). DISCUSSION: This results were comparable with other authors, confirming the utility of using specific biomarkers (HLA-DQB1*0602 allele and Hypocretin-1 CSF level) in narcolepsy with cataplexy. However, the HLADQB1*0602 allele and Hypocretin-1 level are insufficient to diagnose of narcolepsy without cataplexy.

Este estudo foi idealizado para avaliar as características clinicas e laboratoriais de uma população de narcolépticos atendidos num centro de referência na cidade de São Paulo (Brasil). MÉTODO: 28 pacientes realizaram polissonografia e teste de múltiplas latências do sono segundo critérios internacionais. O alelo HLADQB1*0602 foi identificado por PCR. A Hipocretina-1 no líquido cefalorradiano (LCR) foi mensurada por radioimunoensaio. Os pacientes foram divididos em 2 grupos conforme o nível de Hipocretina-1. Normal (N) - Hypocretin-1 >110pg/ml e baixa (B) - Hypocretina-1 <110pg/ml. RESULTADOS: Somente 4 pacientes do grupo N tinham cataplexia quando comparados com 14 pacientes do grupo B (p=0,0002). DISCUSSÃO: Estes resultados foram comparáveis com outros autores, confirmando a utilidade do uso de biomarcadores específicos (HLA-DQB1*0602 e nível da hipocretina-1 no LCR) em narcolepsia com cataplexia. Porém, o alelo HLADQB1*0602 e a dosagem da Hipocretina-1 são insuficientes para o diagnóstico da narcolepsia sem cataplexia.

Hypocretin deficiency in narcolepsy with cataplexy is associated with a normal body core temperature modulation.

Narcolepsy with cataplexy (NC) is a sleep disorder caused by the loss of the hypothalamic neurons producing hypocretin. The clinical hallmarks of the disease are excessive daytime sleepiness, cataplexy, other rapid eye movement (REM) sleep phenomena, and a fragmented wake-sleep cycle. Experimental data suggest that the hypocretin system is involved primarily in the circadian timing of sleep and wakefulness but also in the control of other biological functions such as thermoregulation. The object of this study was to determine the effects of the hypocretin deficit and of the wake-sleep cycle fragmentation on body core temperature (BcT) modulation in a sample of drug-free NC patients under controlled conditions. Ten adult NC patients with low cerebrospinal fluid (CSF) hypocretin levels (9 men; age: 38 ± 12 yrs) were compared with 10 healthy control subjects (7 men; age: 44.9 ± 12 yrs). BcT and sleep-wake cycle were continuously monitored for 44 h from 12:00 h. During the study, subjects were allowed to sleep ad libitum, living in a temperature- and humidity-controlled room, lying in bed except when eating, in a light-dark schedule (dark [D] period: 23:00-07:00 h). Sleep structure was analyzed over the 24-h period, the light (L) and the D periods. The wake-sleep cycle fragmentation was determined by calculating the frame-shift index (number of 30-s sleep stage shifts occurring every 15 min) throughout the 44-h study. The analysis of BcT circadian rhythmicity was performed according to the single cosinor method. The time-course changes in BcT and in frame-shift index were compared between narcoleptics and controls by testing the time × group (controls versus NC subjects) interaction effect. The state-dependent analysis of BcT during D was performed by fitting a mixed model where the factors were wake-sleep phases (wake, NREM stages 1 and 2, slow-wave sleep, and REM sleep) and group. The results showed that NC patients slept significantly more than controls during the 24 h due to a higher representation of any sleep stage (p < .001) during L, whereas the total amount of night sleep and its architecture were comparable in the two groups. Wake-sleep fragmentation was higher (p < .001) in NC subjects especially during L. Despite these differences, mesor (24-h mean), amplitude, and acrophase (peak time) of BcT circadian rhythm were comparable in narcoleptics and controls, and no between-group differences were detected in the time-course changes and in the state-dependent modulation at night of BcT. These data indicate that the hypocretin deficit in drug-free NC patients and their altered wake-sleep cycle couple with an intact modulation of BcT.

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.

Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls.

STUDY OBJECTIVE: To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1. METHODS: Patients meeting the ICSD-2 criteria for narcolepsy with and without cataplexy and who had CSF hypocretin-1 results available were selected from the Stanford Narcolepsy Database on the basis of CSF availability and adequate age and sex matching across 3 groups: narcolepsy with low CSF hypocretin-1 (n=34, 100% with cataplexy), narcolepsy without low CSF hypocretin-1 (n=24, 75% with cataplexy), and normal controls (n=23). Low CSF hypocretin-1 was defined as CSF < or =110 pg/mL (1/3 of mean control values). Six of 34 patients with low CSF hypocretin-1, six of 24 subjects with normal CSF hypocretin-1, and all controls were unmedicated at the time of CSF collection. CSF histamine was measured in all samples using a fluorometric HPLC system. RESULTS: Mean CSF histamine levels were: 133.2 +/- 20.1 pg/mL in narcoleptic subjects with low CSF hypocretin-1, 233.3 +/- 46.5 pg/mL in patients with normal CSF hypocretin-1 (204.9 +/- 89.7 pg/mL if only patients without cataplexy are included), and 300.5 +/- 49.7 pg/mL in controls, reaching statistically significant differences between the 3 groups. CONCLUSION: CSF histamine levels are reduced in human narcolepsy. The reduction of CSF histamine levels was more evident in the cases with low CSF hypocretin-1, and levels were intermediate in other narcolepsy cases. As histamine is a wake-promoting amine known to decrease during sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.

CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome.

STUDY OBJECTIVE: To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. DESIGN: Cross sectional studies. SETTING AND PATIENTS: Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. RESULTS: We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean +/- SEM; 176.0 +/- 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 +/- 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 +/- 16.4 pg/mL), and idiopathic hypersomnia (161.0 +/- 29.3 pg/ mL); the levels in OSAS (259.3 +/- 46.6 pg/mL) did not statistically differ from those in the controls (333.8 +/- 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 +/- 16.3 pg/ mL) and idiopathic hypersomnia (143.3 +/- 28.8 pg/mL), while the levels in the medicated patients were in the normal range. CONCLUSION: The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.