Basal Metabolic Rate in Narcoleptic Patients

Abstract

Study Objectives:

We investigated basal metabolic rate (BMR) and energy expenditure (EE) in narcoleptic patients and in BMI- and age-matched controls in order to explore the hypothesis that a reduced BMR or EE plays a role in narcolepsy-associated obesity.

Design:

Control group design with comparison of EE and BMR. EE was determined by indirect calorimetry using the Deltatrac Metabolic Monitor system. BMR was calculated from the oxygen consumption (VO₂) and the carbon dioxide consumption (VCO₂) measurements after 12 hours of fasting in the morning.

Participants:

13 narcoleptic patients and 30 controls.

Results:

BMR and EE were not significantly reduced when all subjects were included into the analysis. Subgroup analysis revealed that only non-obese narcoleptics, but not obese narcoleptics had reduced BMRs in comparison to the BMI matched controls.

Conclusion:

Our study suggests that EE plays a role in narcolepsy associated obesity. We propose that narcolepsy may lead to a shift of individual BMI set points.

Citation:

Dahmen N; Tonn P; Messroghli L; Ghezel-Ahmadi D; Engel A. Basal metabolic rate in narcoleptic patients. SLEEP 2009;32(7):962-964.

PATIENTS SUFFERING FROM NARCOLEPSY TEND TO BE OBESE.^1,2 AMONG OTHER HYPOTHESES LOWER RESTING ENERGY EXPENDITURE HAS BEEN SUSPECTED to be the cause of the narcolepsy-associated obesity.^3,4 The use of indirect calorimetry is a well-established noninvasive method to measure the energy expenditure (EE) and the resting (basal) metabolic rate (BMR). Chabas et al. recently published an evaluation of eating behavior and energy balance of 7 typical and 6 atypical narcoleptic patients and 9 controls using indirect calorimetry. Narcoleptic patients were found to have a lower energy expenditure (EE) than controls (n = 13, P = 0.07). Thus, it was concluded that narcolepsy associated obesity could be the result of the difference in EE.³ However, cases and controls were not BMI matched and the results were only of trend significance. In an attempt to replicate this findings, Fronczek et al. determined the basal metabolic rate (BMR) of 15 male narcoleptic patients and 15 age- and BMI-matched controls and found no difference (P = 0.77).⁴

To clarify the controversy, we determined EE with the same method that Chabas had utilized and calculated the BMR using the formula employed in the Fronczek study in 13 narcoleptics and 30 healthy BMI- and age-matched controls.

METHODS

The 13 family history negative patients (n = 2 males; n = 11 females) were all unrelated and were either from the Department of Psychiatry, Mainz, or recruited with the help of the Deutsche Narkolepsie-Gesellschaft, a nationwide German patient organization. Total duration of narcolepsy symptoms, severity of daytime sleepiness, and frequency of the symptoms of cataplexy, automatic behavior, hallucinations, and sleep paralysis were assessed by unstructured and structured clinical interviews in including the Stanford Center for Narcolepsy Sleep Inventory (http://med.stanford.edu/school/Psychiatry/narcolepsy/sleepinventory.pdf). Patients were only enrolled into the study if unambiguous cataplexy in addition to severe daytime sleepiness was reported and when sleep laboratory confirmation of the diagnosis was present in the medical records. To exclude symptomatic narcolepsies, the medical history was assessed and a neurologic examination was performed.

To obtain increased statistical power, a control group of 30 unrelated (n = 8 males and n = 22 females) healthy volunteers was included. The study had a power of 85% to detect a 10% difference in energy expenditure under the assumption of a standard deviation of 10% and Gaussian distribution and a power of 32% in case of a 5% difference. In order to maximize similarities in lifestyle and habits between groups, the controls were either spouses or genetically unrelated acquaintances of the patients. Absence of narcolepsy, excessive daytime sleepiness, and other major sleep disorders was checked by clinical interview and by the administration of the Stanford Center for Narcolepsy Sleep Inventory. All probands were advised not to use any medications on the day of the study. All participants were of Caucasian origin. All participants gave written, informed consent. No participation fees were paid. The study design was approved by the local ethics committee.

Measurements of EE were by indirect calorimetry using the Deltatrac Metabolic Monitor (Datex Corporation, Helsinki, Finland) according to the instructions of the manufacturer. The Deltatrac was allowed to warm up and to stabilize before the beginning of measurements. Calibration was performed with Datex Ohmeda gases. Controls and cases had been advised not to eat after the regular dinner in the evening before the day of measurement. Measurements were performed during the morning before breakfast. The involved subjects were wearing a ventilated hood while supine on a day bed and relaxing quietly. In order to be able to relate the data directly to the results of the Fronczek study, the VO₂ and VCO₂ were additionally used to calculate the BMR according to the formula⁵:

BMR (kcal/24h) = (3.9 } VO2) + (1.1 } VCO₂) } 1.44

Descriptive results of continuous variables are expressed as means ± SD for Gaussian variables and as median and interquartile range for non-Gaussian variables. Group differences were tested by t-test after calculating of kurtosis and skewness ( < 0.8). To study possible effects of BMI, diagnosis, and gender on EE, linear regression was calculated. All analyses were 2-tailed and conducted with SPSS software (version 12.0 for Windows). P-values < 0.05 were considered to be statistically significant.

RESULTS

Energy expenditure and BMR (Weir-formula) were lower in narcoleptic patients than in controls, although the differences were not statistically significant. Because we suspected that any potential association of BMR difference with narcolepsy might be dependent on the actual BMI, we performed a separate analysis on subjects with BMI < 30 (n = 8 narcoleptics, 18 controls; BMI P = 0.917). In this analysis EE and BMR of narcoleptics were significantly smaller than those of the controls. Results remained significant when only females were included (data not shown). A separate linear regression analysis with EE per kg as dependent variable and BMI, gender, and diagnosis as independent variables showed that both BMI (P < 0.001) and diagnosis (P = 0.033), but not gender (P = 0.079) significantly predicted EE. All data, including a synopsis of the results of Chabas et al. and Fronczek et al. are given in Table 1.

Table 1.

Results of BMR and EE Measurements, Including a Synopsis of the Results of Chabas et al.³ and Fronczek et al.⁴

Current study (Deltatrac)	Patients	Controls	P-values
N (male/female)	13 (2/11)	30 (8/22)
Age (years)	36.54 ± 13.5	36.37 ± 14.4	0.971
BMI (kg/m2)	27.6 ± 5.8	27.5 ± 5.9	0.953
BMR (kcal/24 h)	1573.5 ± 337.3	1689.2 ± 318.4	0.289
BMR (kcal//kg/24 h)	20.2 ± 2.6	21.4 ± 3.3	0.242
EE (kcal/24 h)	1438.31 ± 295.6	1572.50 ± 302.7	0.186
EE (kcal/kg/day)	18.38 ± 1.6	19.8 ± 2.8	0.090
EE (kcal/kg/24 h) Median (quartiles)	17.9 (17.2–19.6)	19.8 (17.6–21.4)	0.228
BMI < 30
N (male/female)	8 (1/7)	18 (3/15)
Age (years)	34.3 ± 10.8	30.2 ± 6.6	0.094
BMI	23.5 ± 2.0	23.8 ± 2.7	0.917
BMR (kcal/24 h)	1409.5 ± 260.8	1619.2 ± 308.3	0.139
BMR (kal/kg/24 h)	20.8 ± 3.0	23.6 ± 2.4	0.022
EE (kcal/24 h)	1282.5 ± 216.5	1488.4 ± 298.5	0.122
EE (kcal/kg/24 h)	18.9 ± 1.8	21.7 ± 2.1	0.007
Chabas et al. (Deltatrac)
N (male/female)	7 (2/5)	9 (3/6)
Age (years)	22 (20–33)	29 (25–35)	not matched
BMI (kg/m2)	28.6 (21.9–29.1)	22.9 (20.5–23.6)	not matched
EE (kcal/kg/24 h)	21.3 (19.7–23.1)	23.6 (20.9–25.5)	0.07
Fronzcek et al. (Oxycon B)
N (male/female)	15 (15/0)	15 (15/0)
Age (years)	29.2 ± 4.1	32.6 ± 16.2	0.55
BMI (kg/m2)	24.9 ± 2.6	26.2 ± 2.1	0.31
BMR (kcal/24 h)	1767.1 ± 226.5	1766.5 ± 226.5	0.99
BMR (kcal/kg/24 h)	19.9 ± 2.0	20.1 ± 2.2	0.77

The name of the calorimeter used is given in brackets.

DISCUSSION

In our analysis, the BMR (EE) of non-obese narcoleptics was lower than that of BMI-matched controls. The fact that only non-obese narcoleptics showed a BMR difference could indicate that narcolepsy induces a change in the individual BMI set point. Once the new (higher) set point is reached no more BMR abnormalities can be detected. The observed effect size (10% to 15%) is moderate and within the range reported in a variety of conditions. For example, 1 h of moderate passive smoking leads to a 5% increase in BMR⁶; for each degree rise in body temperature (Fahrenheit) there is a 7% increase in BMR⁷; an increase of 14% in EE has been observed in smoking patients with rheumatoid arthritis.⁸

Our study is limited by the small sample size and thus a type I error cannot be excluded. In addition the sample size did not allow to distinguish between orexin deficient and non-deficient patients. On the other hand, it is known that both orexin-deficient and orexin-non-deficient narcoleptic patients show increased BMIs.⁹ Given the sample sizes of the current studies, including our own, an independent larger replication study would certainly be worthwhile. Because replication samples systematically show smaller effect sizes than discovery samples one would expect the true effect size to be smaller than the 15% found in our sample. However, our data fit well with recent pathophysiological models on narcolepsy. The leading hypothesis is that narcolepsy is an autoimmune or otherwise neurodegenerative disease that leads to a specific degeneration in the hypothalamus and to the destruction of hypocretin-containing cells.¹⁰ It is well known that hypothalamic damage of other origins, particularly tumors or damage following treatment, may lead to so called hypothalamic obesity (HO). Recently, it has been shown that energy expenditure rather than energy intake has a role in HO associated obesity.¹¹ In addition narcoleptic patients as well as orexin deficient narcoleptic mice eat less than controls^12,13 and actigraphic studies have so far failed to show a general reduction of physical activity of narcoleptics.¹⁴

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.