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Keywords:

  • rapid eye movement sleep;
  • REM sleep propensity;
  • short-term REM sleep homeostasis;
  • sleep cycle;
  • sleep deprivation;
  • ultradian rhythms

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

We measured cerebrospinal fluid (CSF) hypocretin-1 levels in 11 patients with narcolepsy–cataplexy, five with narcolepsy without cataplexy and 12 with idiopathic hypersomnia (IHS). All patients were Japanese. As reported in Caucasian patients, undetectable or very low hypocretin-1 levels were observed in most (9 out of 11) Japanese narcolepsy–cataplexy patients. Our hypocretin-deficient narcoleptics included three prepubertal cases within few months after the disease onset. All nine hypocretin-deficient patients were human leuckocyte antigen (HLA) DR2 positive, while two who had normal CSF hypocretin-1 levels were HLA DR2 negative. In contrast, none of the narcolepsy without cataplexy and IHS subjects had undetectable low levels. Low CSF hypocretin-1 is therefore very specific for HLA DR2 positive narcolepsy–cataplexy, and the deficiency is likely to be established at the early stage of the disease.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

It has recently been reported that cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) concentration in the majority of patients with narcolepsy–cataplexy was so low that it could not be detected (Dalal et al., 2001; Nishino et al., 2001). However, it is not known whether CSF hypocretin-1 is also altered in patients with narcolepsy without cataplexy and idiopathic hypersomnia (IHS). It is also not known when the hypocretin deficiency is established in relation to the disease onset of narcolepsy–cataplexy. In this study, we therefore measured CSF hypocretin-1 in these primary excessive daytime sleepiness (EDS) disorders, including several prepubertal cases.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

Sixteen patients with narcolepsy and 12 IHS patients were included in the study (Table 1). Narcoleptic patients were diagnosed by International Classification of Sleep Disorders (ICSD) (Diagnostic Classification Steering Committee, 1990), and further divided into two groups: (i) cataplexy and EDS: this group was defined as narcolepsy–cataplexy, included 11 patients; (ii) no cataplexy, EDS, rapid eye movement (REM) sleep related symptoms (hyponagogic hallucinations, sleep paralysis) and two or more sleep onset REM periods (SOREMs) in multiple sleep latency test (MSLT): this group was defined as narcolepsy without cataplexy, included five patients. Idiopathic hypersomnia was defined as fulfilling the following criteria in this study: (a) EDS over 6 months, (b) no cataplexy, (c) no other evident cause of EDS, such as sleep apnea, periodic leg movements and insufficient sleep syndrome, (d) shortened MSLT with 0–1 SOREMs. Either patients or families gave informed consent for the lumbar puncture and CSF hypocretin measurements. CSF samples were kept at –80°C. Hypocretin-1 in CSF was measured using radioimmunoassay kits (Phoenix Pharmaceuticals, Belmont, CA, USA) as previously reported (Nishino et al., 2001). Intra-assay variability was 4.3% and the detection limit was 40 pg mL–1. All results are reported as the mean and standard deviation (SD). For the statistical analysis for the undetectable hypocretin cases, 40 pg mL–1 was arbitrarily used. The statistical significance was analysed using the Kruskal–Wallis, with post hoc Bonferroni–Dunn test.

Table 1.   Cerebrospinal fluid (CSF) hypocretin-1 levels and clinical features of narcolepsy and idiopathic hypersomnia (IHS) patients Thumbnail image of

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

Results of CSF hypocretin levels as well the clinical and demographic data for the EDS patients are shown in Table 1. The mean sleep latency was not significantly different among three groups. Among narcolepsy–cataplexy patients, seven of nine patients had undetectable hypocretin-1 levels and two patients had levels below 90 pg mL–1. These hypocretin-deficient patients were HLA DR2 positive and include three prepubertal narcolepsy–cataplexy cases; 6-, 7- and 10-year-old subjects, whose duration of disease was only 0.8, 0.2 and 0.3 years, respectively (Tsukamotoet al., in press). In contrast, hypocretin-1 levels of two HLA DR2 negative narcolepsy–cataplexy subjects (254, 267 pg mL–1) were in the control range [280 ± 33 pg mL–1 (mean ± SD), n=15] (Nishino et al., 2001).

The CSF hypocretin-1 levels in narcolepsy without cataplexy patients (277 ± 54 pg mL–1) and IHS patients (259 ± 57 pg mL–1) were not significantly different from those in controls. However, three of the 12 IHS patients had moderately low CSF hypocretin-1 concentrations (152, 189 and 198 pg mL–1), and these were below the 95% confidence range of the age-matched controls (Nishino et al., 2001).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

Our results in Japanese narcolepsy–cataplexy patients are in accordance with those of Caucasian subjects (Dalal et al., 2001; Nishino et al., 2001): all of the HLA DR2 positive narcolepsy–cataplexy patients have undetectable or very low levels of CSF hypocretin-1, and two patients who were DR2 negative had normal levels. Furthermore, hypocretin deficiency is likely to occur in the early stages of the disease, as undetectable levels were observed in three prepubertal subjects, only a few months after the disease onset. We also found that all five narcolepsy without cataplexy patients and 9 of the 12 IHS patients had normal CSF hypocretin-1 levels. As the ICSD criteria of diagnosis of narcolepsy had two standards, EDS without cataplexy accompanied by REM sleep-related symptoms and two or more SOREMs during an MSLT meets the narcolepsy criteria (Diagnostic Classification Steering Committee, 1990). However, Honda (1988) emphasized that a positive history of cataplexy associated with EDS was essential for the diagnosis of narcolepsy, because the clinical symptoms and HLA DR2 positive rate were different between the two groups. Our results of hypocretin measures support Honda's hypothesis and suggest that narcolepsy without cataplexy are not caused by the hypocretin ligand deficiency and are etiologically different from narcolepsy–cataplexy. Our results also suggest that hypocretin ligand deficiency is not involved in the majority of IHS cases. However, the roles of hypocretin neurotransmission in a subset of IHS should be further determined, as about 25% of our IHS patients had moderately low hypocretin-1 levels.

Interestingly, the severity of EDS as indicated by the average of MSLT among these primary EDS disorders does not depend on the hypocretin-1 levels, and the hypocretin-1 levels seems to reflect specifically the presence or absence of cataplexy and HLA DR2 positively. In conclusion, our results confirm the diagnostic and nosological importance of CSF hypocretin ligand deficiency in narcolepsy–cataplexy. Hypocretin ligand deficiency is not the major cause for EDS in patients with narcolepsy without cataplexy and IHS, and the pathophysiological mechanisms of EDS in these patients should be determined further.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

We are grateful to Drs K. Kawanishi, S. Takasaki, Y. Tamura, T. Shiomi, H. Kubota and J. Arii for collecting the samples. The present study was performed through Special Coordination Funds of the Ministry of Education, Culture, Sports and Technology, and a Grant-in-Aid for Cooperative Research from the Ministry of Health, Labour and Welfare of Japan.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References
  • 1
    Dalal, M. A., Schuld, A., Haack, M., Uhr, M., Geisler, P., Eisensehr, I., Noachtar, S. and Pollmacher, T. Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology, 2001, 56: 17491751.
  • 2
    Diagnostic Classification Steering Committee (Thorpy, M. J., Chairman). International Classification of Sleep Disorders: Diagnostic and Coding Manual. American Sleep Disorders Association, Rochester, MN, USA, 1990.
  • 3
    Honda, Y. Clinical features of narcolepsy: Japanese experience. In: Y. Honda and T. Juji (Eds) HLA in Narcolepsy. Springer-Verlag, Berlin, 1988, pp. 24–57.
  • 4
    Nishino, S., Ripley, B., Overeem, S., Nevsimalova, S., Lammers, G. J., Vankova, J., Okun, M., Rogers, W., Brooks, S. and Mignot, E. Low CSF hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann. Neurol., 2001, 50: 381388.
  • 5
    Tsukamoto, H., Ishikawa, T., Fujii, Y., Fukumizu, M., Sugai, K. and Kanbayashi, T. Undetectable Level of CSF hypocretin-1 (Orexin-A) in prepubertal boys with narcolepsy. Neuropediatrics (in press).