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Keywords:

  • orexin;
  • waist circumference;
  • body fat;
  • narcolepsy;
  • body weight

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Objective: To determine the prevalence of obesity among patients with narcolepsy, to estimate associated long-term health risks on the basis of waist circumference, and to distinguish the impact of hypocretin deficiency from that of increased daytime sleepiness (i.e., reduced physical activity) on these anthropometric measures.

Research Methods and Procedures: A cross-sectional, case-control study was conducted. Patients with narcolepsy (n = 138) or idiopathic hypersomnia (IH) (n = 33) were included. Age-matched, healthy members of the Dutch population (Monitoring Project on Risk Factors for Chronic Diseases and Doetinchem Project; n = 10, 526) were used as controls. BMI and waist circumference were determined.

Results: Obesity (BMI ≥ 30 kg/m2) and overweight (BMI 25 to 30 kg/m2) occurred more often among narcolepsy patients [prevalence: 33% (narcoleptics) vs. 12.5% (controls) and 43% (narcoleptics) vs. 36% (controls), respectively; both p < 0.05]. Narcoleptics had a larger waist circumference (mean difference 5 ± 1.4 cm, p < 0.001). The BMI of patients with IH was significantly lower than that of narcolepsy patients (25.6 ± 3.6 vs. 28.5 ± 5.4 kg/m2; p = 0.004).

Discussion: Overweight and obesity occur frequently in patients with narcolepsy. Moreover, these patients have an increased waist circumference, indicating excess fat storage in abdominal depots. The fact that patients with IH had a lower BMI than narcoleptics supports the notion that excessive daytime sleepiness (i.e., inactivity) cannot account for excess body fat in narcoleptic patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Narcolepsy is a disorder characterized by excessive daytime sleepiness (EDS),1 cataplexy, hypnagogic hallucinations, and sleep paralysis. Its prevalence amounts to 0.05% of the general population in the U.S. and Europe (1). The disease is caused by disruption of hypocretin (orexin) neurotransmission (2, 3, 4). The first report of narcoleptic patients being obese stems from as early as the 1930s (5, 6). Since then, increased body weight has been repeatedly observed in case studies of narcoleptic patients (7, 8, 9, 10, 11). Only recently, a few case control studies have quantified BMI in larger populations of narcoleptic humans (12, 13). However, these studies used self-reported (as opposed to measured) anthropometric data of the general population as control values. Moreover, measures of body fat distribution were not reported in these papers. The distribution of body fat over the various available depots is a critical determinant of the health risks associated with obesity (14). Abdominal fat accumulation in particular is the single most important risk factor for the development of type 2 diabetes, and it predisposes to cardiovascular disease, some forms of cancer (15), and psychosocial and work disability (16, 17).

The pathogenesis of increased body weight in narcolepsy is unclear, but it seems to be a consistent feature of both human patients and animal models of the disease (12, 18). Reduced physical activity as a result of increased (daytime) sleepiness may diminish energy expenditure, thereby causing obesity in narcoleptic humans and animals. Alternatively, it is conceivable that hypocretin deficiency per se promotes body fat accrual, as hypocretin peptides are involved in the regulation of energy balance (19, 20).

This study aimed to establish the prevalence of obesity among patients with narcolepsy. We measured BMI and waist circumference in a large population of narcoleptics and compared the results with anthropometric parameters measured in two large surveys of the general Dutch population. Also, to begin to understand the role of hypocretin deficiency in the pathophysiology of body fat accrual in narcolepsy, we measured anthropometric parameters in patients with idiopathic hypersomnia (IH), a disorder marked by EDS, but normal hypocretin neurotransmission (21, 22).

Research Methods and Procedures

All patients with narcolepsy and IH registered in the outpatient database of the Department of Neurology of the Leiden University Medical Center were approached in January 2001 to participate in the study. All patients included had a history of EDS and a sleep latency of <8 minutes in the Multiple Sleep Latency Test. Sleep apnea, periodic limb movements during sleep, and restless legs syndrome were excluded as a cause of EDS. Narcolepsy was diagnosed on the basis of the presence of cataplexy and/or two or more sleep onset rapid eye movement periods (SOREMPs) in the Multiple Sleep Latency Test (23). IH was diagnosed in patients who had EDS without cataplexy or SOREMPs (24). Hypocretin-1 (Hrct-1) levels in cerebrospinal fluid (CSF), when available, were used as a definite biochemical marker of narcolepsy (4, 25). Consequently, patients who were clinically diagnosed with narcolepsy but had a normal Hrct-1 concentration in CSF were reassigned to the IH group (21, 22, 25).

All subjects gave written informed consent. Those who agreed to participate were visited at home. Patients were interviewed on their medication history and duration of disease. Anthropometric measurements employing methods identical to those used in the Monitoring Project on Risk Factors for Chronic Diseases (MORGEN Project) as described below were taken in all participants. Subjects were weighed using a calibrated electronic scale (Seca 771; Vogel & Halke GmbH&Co, Hamburg, Germany).

Reference data of BMI and waist circumference were derived from a cross-sectional population survey from the Dutch National Institute for Public Health and the Environment's MORGEN Project. The general purpose of the MORGEN Project was to determine the prevalence of risk factors for chronic diseases and the prevalence of some specific conditions in a sample of the general population. The project was carried out in municipal health centers of Amsterdam, Doetinchem, and Maastricht, three towns located in different regions in The Netherlands. Each year between 1993 and 1997, a new random sample of men and nonpregnant women, 20 to 59 years of age, was invited to participate. A total of 22, 415 men and women participated in the MORGEN Project. The participation rate varied from 40% to 51% between 1993 and 1997.

In Western societies, obesity is most prevalent among individuals with low education (26, 27). We did not check the educational level of the patient population participating in the present study. However, educational level is generally considered to be relatively low in narcoleptics (28, 29). The educational level of the control population was defined as the highest level reached and categorized in five groups: primary school, junior education, secondary education, vocational college, and university. To prevent bias by lower education in the narcoleptic patients, the case data were compared with low educational categories of the control population. All 10, 696 participants of the MORGEN Project with an educational level less than vocational colleges or university level were selected. Data on body weight and height were available in 4324 men and 6202 women and on waist circumference in 4299 men and 6184 women.

Normal values of individuals in the population who were ≥60 years were derived from a separate survey performed in Doetinchem. Participants of the Doetinchem Project were subjects who had taken part in the MORGEN Project or the Monitoring Project on Cardiovascular Diseases (1987 to 1991) (National Institute for Public Health and the Environment) and were re-invited for measurements again between 1998 and 2000. The maximum age of participants of the Doetinchem Project was 69 years. For the purpose of this study, a selection was made of all 519 subjects 60 to 69 years of age with the above-mentioned educational category. Data on body weight and height were available for 221 men and 297 women and data on waist circumference for 220 men and 297 women.

In the patient group of this study, as in the MORGEN Project and Doetinchem Project, body weight and height were measured by trained staff, with participants wearing light indoor clothing with emptied pockets and not wearing shoes. Body weight was measured to the nearest 0.1 kg on calibrated scales. To adjust for the weight of clothing, 1 kg was subtracted from body weight. Body height was measured to the nearest 0.5 cm. BMI was calculated as weight divided by height squared. Waist circumference was measured in centimeters at the level midway between the lower rib margin and the iliac crest, with participants in a standing position and breathing out gently. The mean of two measurements was used for the analyses. Waist action levels were defined according to Lean et al. (30): level 1, 94 to 101.9 cm in men and 80 to 87.9 cm in women; and level 2, ≥102 cm in men and ≥88 cm in women. Means and prevalence rates for the 20-to-59-year-old age group from the MORGEN Project were standardized to the 5-year age distribution in the Netherlands.

Data are means ± SD, unless stated otherwise. Patient data were compared with the standardized data of BMI and waist circumference of the MORGEN Project, with two-sided unpaired t tests and the χ2 test when appropriate. The impact of drug use on anthropometric parameters was analyzed within groups of narcoleptic and IH patients by independent samples Student's t tests. Differences were considered significant at p < 0.05. Statistical analysis was performed using SPSS for Windows (release 9.0; SPSS Inc, Chicago, IL).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Case Characteristics

One hundred forty-five (92%) of the 158 narcoleptic patients and 26 (76%) of the 34 IH subjects who were approached agreed to participate in the study. Hrct-1 concentrations in CSF were available for 51 narcoleptic subjects and 12 IH patients. Hrct-1 was normal in the CSF of all 12 IH patients, whereas 7 patients initially classified as having narcolepsy also had normal levels. These patients were, therefore, reallocated to the IH group (21, 22). Consequently, our analyses were performed on data from 138 narcoleptics and 33 IH patients. Characteristics of the included patients are shown in Table 1. Sex distribution did not differ significantly between narcoleptics and IH patients. BMI, age, and the number of years that patients were affected were similar in men and women in both groups.

Table 1.  Characteristics of narcoleptic and IH patients
 NarcolepsyIH
 MenWomenMenWomen
  1. Data are in mean (range).

  2. Stimulants, methylphenidate or modafinil; Tricyclic AD, tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitor.

n (%)67 (49)71 (51)22 (67)11 (33)
Age (years)46.9 (20 to 82)49.9 (20 to 78)42.0 (26 to 55)35.5 (20 to 59)
BMI (kg/m2)28.7 (20.5 to 44.8)28.3 (19.9 to 47.8)25.1 (21.5 to 30.0)26.4 (18.5 to 35.4)
Waist (cm)101 (78 to 148)91 (65 to 130)93 (77 to 108)86 (63 to 112)
Years affected25 (2 to 64)27 (1 to 64)16 (1 to 34)18 (5 to 39)
Medication use, n (%)    
 Any of drugs below46 (69)59 (83)14 (64)8 (73)
  Stimulants41 (61)54 (76)13 (59)5 (45)
  Tricyclic AD15 (22)19 (27)0 (0)1 (9)
  SSRIs8 (12)7 (10)1 (5)3 (27)

Anthropometric Measures

Narcoleptic Patients

Table 2 shows the prevalence of overweight, obesity, and waist circumference action levels in narcoleptic patients compared with the general Dutch population. Obesity occurred more than twice, and waist action level 2 nearly twice, as often among narcoleptic patients than among controls. In Figure 1, the BMI and waist circumference of narcoleptic patients are plotted against their age. The 10th, 50th, and 90th percentile reference curves of the general population derived from the MORGEN Project are also shown. It seems that BMI and waist circumference of the majority of the narcoleptic patients, for a given age, were above the 50th percentile reference value. This notion is further substantiated in Table 3, which shows the proportion of patients who had a BMI or waist circumference above various percentile reference values per the age category. Half of all narcoleptic men and more than one-third of the women had a BMI above the 75th percentile reference value. The values for waist circumference showed a similar pattern. Finally, Figure 2 shows the mean difference (with 95% confidence limits) of BMI and waist circumference between narcoleptic patients and controls for various age categories. Obviously, both narcoleptic men and women were heavier and have increased waist circumference compared with controls at almost all ages. In women, the differences seem less obvious at middle age. For all patients analyzed conjointly, BMI was 3.4 kg/m2 (95% confidence interval: 2.4 to 4.3 kg/m2) higher and waist circumference was 5.1 cm (95% confidence interval: 2.5 to 7.8 cm) larger in narcoleptics (both p < 0.001).

Table 2.  BMI and waist action levels in narcoleptic patients and controls
 Narcolepsy (n = 138)MORGEN-project* (n = 10, 696)
  • Prevalence of overweight, obesity, and increased waist circumference in narcoleptic patients compared with the general Dutch population. All prevalences are significantly different (p < 0.05) between narcoleptic patients and controls.

  • Waist action levels are: level 1 in men 94 to 101.9 cm and in women 80 to 87.9 cm; level 2 in men > 102 cm and women > 88 cm (28).

  • *

    Standardized to the 5-year age and sex distribution in The Netherlands.

BMI ≥ 30 kg/m233%12.5%
BMI 25 to 29.9 kg/m243%36.4%
Waist level 239%22.7%
Waist level 136%23.7%
image

Figure 1. BMI (upper figures) and waist circumference (lower figures) of narcoleptic patients (dots) plotted in the 10th, 50th, and 90th percentiles of the accompanying normal Dutch population.

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Table 3.  Distribution of anthropometric parameters in narcoleptic patients over normal percentiles
 Men Women
 Proportion (% of n) Proportion (% of n)
Age>50th>75th>90th >50th>75th>90th
  1. The proportion of narcoleptic patients in each age category with a BMI and waist circumference above the 50th, 75th, and 90th percentile of the accompanying normal Dutch population. Number (n) reflects number of subjects in whom measurement was performed.

BMI       
 20 to 29 years (n = 13)857746(n = 11)822718
 30 to 39 years (n = 13)854631(n = 11)645527
 40 to 49 years (n = 6)835033(n = 13)622718
 50 to 59 years (n = 24)792913(n = 10)402020
 ≥60 years (n = 11)645536(n = 26)695023
 All ages (n = 67)795132(n = 71)633621
Waist circumference       
 20 to 29 years (n = 13)856931(n = 11)645536
 30 to 39 years (n = 13)544631(n = 9)785622
 40 to 49 years (n = 6)1005033(n = 12)582525
 50 to 59 years (n = 23)572213(n = 10)402020
 ≥60 years (n = 10)705030(n = 26)583112
 All ages (n = 65)734722(n = 68)523723
image

Figure 2. Differences in BMI (upper) and waist circumference (lower) in narcoleptic patients minus controls, for men (left) and women (right). Data are given per age category, in mean difference with the 95% confidence interval.

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IH Patients

As shown in Table 1, IH patients had a significantly lower BMI than narcoleptic subjects (25.6 ± 3.6 vs. 28.5 ± 5.4 kg/m2; p = 0.004), and their waist circumference tended to be smaller (90 ± 12 vs. 96 ± 14 cm; p = 0.052). These differences persisted when corrected for the slightly older age in the narcoleptic patient group (data not shown). Medication use was similar in IH and narcoleptic patients, except for tricyclic antidepressant use. Only one IH patient took a tricyclic antidepressant vs. 33 of the narcoleptic patients; exclusion of tricyclic antidepressant users did not change the difference between groups in BMI (IH 25.8 ± 3.5 kg/m2 vs. narcolepsy 28.2 ± 5.1 kg/m2; p = 0.013).

Impact of Drug Use

The influence of the use of medication on anthropometric data confidence intervals was analyzed conjointly for all drug categories and for each individual category [i.e., selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants, psychostimulants, and a small group comprising some other drugs]. Data were analyzed separately for narcoleptic and IH patients. In general, the use of medication was not related to BMI or waist circumference in narcoleptics or IH patients. As an exception, narcoleptic patients using SSRIs (n = 15) had a lower BMI than patients who did not use these drugs (25.8 ± 3.2 vs. 28.8 ± 5.5 kg/m2; p = 0.03).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

This study shows that obesity, defined as a BMI ≥30 kg/m2, occurs more than twice as often among patients with narcolepsy than among the general (Dutch) population. Moreover, in 39% of narcoleptics, the waist circumference attains a level at which medical intervention is required to prevent long-term complications of excess body fat. The fact that patients with IH, a condition characterized by EDS but normal hypocretin neurotransmission, are less obese may imply that hypocretin deficiency per se impacts body weight in narcoleptic humans. The anthropometric anomalies observed in narcoleptic patients do not seem to be the result of the use of drugs that potentially affect body weight (i.e., antidepressants, psychostimulants, SSRIs).

These data corroborate two previous reports showing increased BMI in narcoleptic subjects (12, 13). In contrast to these earlier investigations, we used measured (as opposed to self-reported) anthropometric data as control values. Because underreporting of BMI is particularly common among obese individuals (31, 32), the use of self-reported control data may bias the outcome of studies that aim to establish the prevalence of obesity. In addition to their BMI, we determined the waist circumference of our narcoleptic patients as a measure of abdominal fat accrual. Clearly, abdominal adiposity poses greater health risks than gluteofemoral obesity (33, 34, 35). Waist circumference can be categorized to predict long-term morbidity and mortality among obese patients (33, 36, 37, 38, 39). Waist action level 2, which occurred in 39% of narcoleptic subjects, is associated with a 4-fold increased risk for non-insulin-dependent diabetes and a 3-to-4 fold increased risk for at least one major cardiovascular event (36).

Thus, the present results imply that narcoleptic patients may be prone to developing cardiovascular disease, type 2 diabetes mellitus, and various other disabilities as a corollary of their tendency to become obese. To date, only one study has determined the prevalence of metabolic disease in narcoleptic subjects. Indeed, this study showed that type 2 diabetes occurs almost twice as often among narcoleptics than among the general Japanese population (40). We believe that our data warrant further evaluation of the cardiovascular and metabolic health risks of narcoleptic patients, particularly because increased long-term morbidity and mortality among narcoleptics may call for measures to prevent obesity at the time of the neurological diagnosis (41).

It is important to recognize some limitations of our study. First, the participation rate in the MORGEN Project was rather low (45% of invitees), which enhances the likelihood of selection bias. Second, we were not able to measure CSF hypocretin levels in all of our narcoleptic and IH subjects, potentially leading to misclassification of some patients. However, in this context it is important to note that CSF hypocretin levels are always normal in patients who are clinically diagnosed as IH (i.e., no cataplexy and/or SOREMPs) (21, 22, 25). This notion is corroborated by the present study, as all of our patients with the clinical diagnosis of IH who were tested had normal hypocretin levels. In contrast, some patients who are clinically classified as having narcolepsy harbor a normal CSF hypocretin concentration (25). Indeed, we had to reallocate seven patients from the narcolepsy to the IH group on the basis of their CSF hypocretin level. Thus, whereas it is unlikely that patients who were clinically classified as IH were misclassified, some of the narcoleptic patients may have had normal hypocretin concentrations and, therefore, should have been classified as IH instead. If so, this would by all odds merely conceal the difference in BMI between narcoleptics and controls and, therefore, not argue against our conclusions.

The mechanism underlying the pathogenesis of obesity in narcolepsy is unknown. However, excess body fat accretion seems to be a consistent feature of both human patients and animal models of the disease (12, 13, 18). It has been suggested that diminished physical activity as a result of increased (daytime) sleepiness could reduce energy expenditure and thereby promote the storage of fat in narcoleptic patients. However, although Hara et al. reported that hypocretin deficient orx/atx mice have reduced motor activity during the dark phase of the light/dark cycle (18), studies in other narcoleptic rodents (2) and humans (42, 43) have demonstrated that a disrupted circadian distribution, rather than abnormal amounts of 24-hour sleep and mobility, characterizes this disorder. Moreover, our data show that IH patients, who also exhibit increased daytime sleepiness (23), have a BMI that is significantly lower than that of narcoleptic patients. Thus, increased sleep-time and associated reductions of physical activity and energy expenditure are not likely to explain the pathogenesis of excess body fat accrual in narcolepsy. Alternatively, various drugs that are used for the treatment of narcolepsy can modulate body weight. Tricyclic antidepressants are particularly known to cause significant weight gain (44), whereas SSRIs and psychostimulants can reduce body weight (45, 46). However, narcoleptic or IH patients using any drug for their condition were not heavier than those who did not (with the single exception of narcoleptic patients who used SSRIs being less obese than patients not using SSRIs, which implies that SSRI use among narcoleptic patients diminishes the observed difference in BMI between patients and controls). Also, exclusion of all drug users from the analyses did not change the significance of the findings (data not shown). May the disrupted hypocretin neural circuitry be directly involved? Hypocretin peptides were originally described as modulators of food intake (19). Intracerebroventricular injection of Hrct-1 (also called orexin-A) enhances food intake in rodents. Moreover, antihypocretin antibodies and Hrct-1 receptor antagonists cause hypophagia and weight loss in rats and mice (47, 48). Therefore, hypocretin deficiency per se would be predicted to reduce food intake (and reduce body weight). Indeed, studies in rodents (18) and humans (49) show that food intake in narcoleptic subjects is reduced rather than increased. Thus, although hypocretin deficiency may be involved in the pathogenesis of hypophagia in narcoleptic patients, it is unlikely to contribute to their weight gain. It is tempting to speculate that deficiencies of other neuropeptides, co-localized in hypocretin neurons, affect energy balance to increase body weight in narcolepsy. In keeping with this concept, hypocretin knockout mice have relatively normal body weight (2), whereas genetic ablation of hypocretin neurons leads to hypophagia and obesity (18). In this context, it is interesting that co-localization of cocaine and amphetamine regulated transcript (CART) and dynorphin (peptides involved in the regulation of energy balance) and hypocretin in hypothalamic neurons has recently been reported (50, 51).

In conclusion, this study shows that narcoleptic patients are prone to developing obesity. The fact that patients with IH grow less obese supports the contention that the destruction of hypocretin neurons is involved in the pathogenesis of obesity in narcolepsy. The waist circumference of narcoleptic patients often attains proportions that call for medical intervention to prevent long-term complications of excess fat accrual. It may be important to implement measures preventing body weight gain in narcoleptic patients at the time of their neurological diagnosis.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

No financial support or funding was involved in the performance of this study. The authors gratefully acknowledge the efforts of Dr. Marcel van der Meer, Youri Zuidwijk, Danielle L. Esmee, Leander van Gerven, E.J.M. Ladan-Eygenraam, and E.C. Sierat-van der Steen in collecting the data.

Footnotes
  • 1

    Nonstandard abbreviations: EDS, excessive daytime sleepiness; IH, idiopathic hypersomnia; SOREMP, sleep onset rapid eye movement period; Hrct-1, hypocretin-1; CSF, cerebrospinal fluid; MORGEN Project, Monitoring Project on Risk Factors for Chronic Diseases; SSRI, serotonin re-uptake inhibitor.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References
  • 1
    Mignot, E. (1998) Genetic and familial aspects of narcolepsy. Neurology 50: S16S22.
  • 2
    Chemelli, R. M., Willie, J. T., Sinton, C. M., et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: 43751.
  • 3
    Lin, L., Faraco, J., Li, R., et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98: 36576.
  • 4
    Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., Mignot, E. (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355: 3940.
  • 5
    Cave, H. A. (1931) Narcolepsy. Arch Neurol Psychiatr 26: 50101.
  • 6
    Daniels, L. E. (1934) Narcolepsy. Medicine 13: 1122.
  • 7
    Roth, B. (1962) Narkolepsie und Hypersomnie VEB Verlag Volk und Gesundheit Berlin.
  • 8
    Bell, I. R. (1976) Diet histories in Narcolepsy. Guilleminault, C Dement, WC Passouant, P eds. Narcolepsy 2218. Spectrum New York.
  • 9
    Kotagal, S., Hartse, K. M., Walsh, J. K. (1990) Characteristics of narcolepsy in preteenaged children. Pediatrics 85: 2059.
  • 10
    Allsopp, M. R., Zaiwalla, Z. (1992) Narcolepsy. Arch Dis Child 67: 3026.
  • 11
    Dahl, R. E., Holttum, J., Trubnick, L. (1994) A clinical picture of child and adolescent narcolepsy. J Am Acad Child Adolesc Psychiatry 33: 83441.
  • 12
    Schuld, A., Hebebrand, J., Geller, F., Pollmacher, T. (2000) Increased body-mass index in patients with narcolepsy. Lancet 355: 12745.
  • 13
    Dahmen, N., Bierbrauer, J., Kasten, M. (2001) Increased prevalence of obesity in narcoleptic patients and relatives. Eur Arch Psychiatry Clin Neurosci 251: 859.
  • 14
    Björntorp, P. (1997) Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 13: 795803.
  • 15
    Calle, E. E., Thun, M. J., Petrelli, J. M., Rodriguez, C., Heath, C. W., Jr (1999) Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 341: 1097105.
  • 16
    Narbro, K., Jonsson, E., Larsson, B., Waaler, H., Wedel, H., Sjöström, L. (1996) Economic consequences of sick-leave and early retirement in obese Swedish women. Int J Obes Relat Metab Disord 20: 895903.
  • 17
    World Health Organization (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 894: 1253.
  • 18
    Hara, J., Beuckmann, C. T., Nambu, T., et al (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30: 34554.
  • 19
    Sakurai, T., Amemiya, A., Ishii, M., et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 57385.
  • 20
    Willie, J. T., Chemelli, R. M., Sinton, C. M., Yanagisawa, M. (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24: 42958.
  • 21
    Bassetti, C., Gugger, M., Mathis, J., et al (2001) Cerebrospinal fluid levels of hypocretin (orexin) in hypersomnolent patients without cataplexy. Actas de Fisiologia 7: 205
  • 22
    Kanbayashi, T., Yano, T., Ishiguro, H., et al (2002) Hypocretin-1 (orexin-A) levels in human lumbar CSF in different age groups: infants to elderly persons. Sleep 25: 3379.
  • 23
    International Classification of Sleep Disorders (1997) International Classification of Sleep Disorders: Diagnostic and Coding Manual, Revised American Sleep Disorders Association Rochester, MN.
  • 24
    Overeem, S., Mignot, E., van Dijk, J. G., Lammers, G. J. (2001) Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol 18: 78105.
  • 25
    Mignot, E., Lammers, G. J., Ripley, B., et al (2002) The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 59: 155362.
  • 26
    Molarius, A., Seidell, J. C., Sans, S., Tuomilehto, J., Kuulasmaa, K. (2000) Educational level, relative body weight, and changes in their association over 10 years: an international perspective from the WHO MONICA Project. Am J Public Health 90: 12608.
  • 27
    Seidell, J. C. (2000) Obesity, insulin resistance and diabetes—a worldwide epidemic. Br J Nutr 83(Suppl 1): S5S8.
  • 28
    Douglas, N. J. (1998) The psychosocial aspects of narcolepsy. Neurology 50(Suppl. 1): S27S30.
  • 29
    Goswami, M. (1998) The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 50(Suppl. 1): S31S36.
  • 30
    Lean, M. E., Han, T. S., Morrison, C. E. (1995) Waist circumference as a measure for indicating need for weight management. BMJ 311: 15861.
  • 31
    Nawaz, H., Chan, W., Abdulrahman, M., Larson, D., Katz, D. L. (2001) Self-reported weight and height: implications for obesity research. Am J Prev Med 20: 2948.
  • 32
    Palta, M., Prineas, R. J., Berman, R., Hannan, P. (1982) Comparison of self-reported and measured height and weight. Am J Epidemiol 115: 22330.
  • 33
    Seidell, J. C., Bouchard, C. (1999) Abdominal adiposity and risk of heart disease. JAMA 281: 22845.
  • 34
    Segal, K. R., Dunaif, A., Gutin, B., Albu, J., Nyman, A., Pi-Sunyer, F. X. (1987) Body composition, not body weight, is related to cardiovascular disease risk factors and sex hormone levels in men. J Clin Invest 80: 10505.
  • 35
    Rexrode, K. M., Buring, J. E., Manson, J. E. (2001) Abdominal and total adiposity and risk of coronary heart disease in men. Int J Obes Relat Metab Disord 25: 104756.
  • 36
    Lean, M. E., Han, T. S., Seidell, J. C. (1998) Impairment of health and quality of life in people with large waist circumference. Lancet 351: 8536.
  • 37
    Van Pelt, R. E., Evans, E. M., Schechtman, K. B., Ehsani, A. A., Kohrt, W. M. (2001) Waist circumference vs body mass index for prediction of disease risk in postmenopausal women. Int J Obes Relat Metab Disord 25: 11838.
  • 38
    Dobbelsteyn, C. J., Joffres, M. R., MacLean, D. R., Flowerdew, G. (2001) A comparative evaluation of waist circumference, waist-to-hip ratio and body mass index as indicators of cardiovascular risk factors. The Canadian Heart Health Surveys. Int J Obes Relat Metab Disord 25: 65261.
  • 39
    Seidell, J. C., Visscher, T. L. (2000) Body weight and weight change and their health implications for the elderly. Eur J Clin Nutr 54(Suppl 3): S33S39.
  • 40
    Honda, Y., Doi, Y., Ninomiya, R., Ninomiya, C. (1986) Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 9: 2549.
  • 41
    Seidell, J. C., Kahn, H. S., Williamson, D. F., Lissner, L., Valdez, R. (2001) Report from a Centers for Disease Control and Prevention Workshop on use of adult anthropometry for public health and primary health care. Am J Clin Nutr 73: 1236.
  • 42
    Broughton, R., Dunham, W., Newman, J., Lutley, K., Duschesne, P., Rivers, M. (1988) Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalogr Clin Neurophysiol 70: 47381.
  • 43
    Middelkoop, H. A., Lammers, G. J., Van Hilten, B. J., Ruwhof, C., Pijl, H., Kamphuisen, H. A. (1995) Circadian distribution of motor activity and immobility in narcolepsy: assessment with continuous motor activity monitoring. Psychophysiology 32: 28691.
  • 44
    Goldstein, B. J., Goodnick, P. J. (1998) Selective serotonin reuptake inhibitors in the treatment of affective disorders. III. Tolerability, safety and pharmacoeconomics. J Psychopharmacol 12(Suppl. B): S55S87.
  • 45
    Pijl, H., Meinders, A. E. (1996) Bodyweight change as an adverse effect of drug treatment. Mechanisms and management. Drug Saf 14: 32942.
  • 46
    Berken, G. H., Weinstein, D. O., Stern, W. C. (1984) Weight gain. A side-effect of tricyclic antidepressants. J Affect Disord 7: 1338.
  • 47
    Yamada, H., Okumura, T., Motomura, W., Kobayashi, Y., Kohgo, Y. (2000) Inhibition of food intake by central injection of anti-orexin antibody in fasted rats. Biochem Biophys Res Commun 267: 52731.
  • 48
    Haynes, A. C., Chapman, H., Taylor, C., et al (2002) Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice. Regul Pept 104: 1539.
  • 49
    Lammers, G. J., Pijl, H., Iestra, J., Langius, J. A., Buunk, G., Meinders, A. E. (1996) Spontaneous food choice in narcolepsy. Sleep 19: 756.
  • 50
    Peyron, C., Charnay, Y. (2002) Hypocretin (orexin) and narcolepsy. J Sleep Res 11: 260
  • 51
    Chou, T. C., Lee, C. E., Lu, J., et al (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21: RC 168: 16.