Narcolepsy And Skin Temperature

4 posts in this topic

I found this article I had stored for quite a long time in my computer files. I download a lot of articles I find on the Internet in an attempt to help myself and my wife. Hopefully this one might be of some help to someone in terms of understanding how one's environment can trigger onsets and episodes. Smells, fumes, and now a study has been done upon skin temperature. Every little bit of new data helps. I hope....

I am including a URL that will take you to research that is being done in China on various conditions involving the nervous system. Stem cells are being used to help a lot of people who have traveled there seeking relief from their symptoms. Its interesting reading.


Keep an open mind.



To order reprints of this article go to:


To subscribe to Journal of Neurology, Neurosurgery, and Psychiatry go to:

Downloaded from jnnp.bmj.com on 27 April 2009

Manipulation of skin temperature improves nocturnal

sleep in narcolepsy

R Fronczek,1,2 R J E M Raymann,1 S Overeem,2,3 N Romeijn,1 J G van Dijk,2

G J Lammers,2 E J W Van Someren1,4

1 Netherlands Institute for

Neuroscience, Amsterdam, The

Netherlands; 2 Department of

Clinical Neurology and

Neurophysiology, Leiden

University Medical Center,

Leiden, The Netherlands;

3 Center for Sleep–Wake

Disorders ‘‘Kempenhaeghe,’’

Heeze, The Netherlands;

4 Department of Clinical

Neurophysiology, Neurology and

Medical Psychology, VU

University Medical Center,

Amsterdam, The Netherlands

Correspondence to:

Dr R Fronczek, Leiden University

Medical Centre, Department of

Neurology (K5Q), PO Box 9600,

2300 RC, Leiden, The



Received 4 January 2008

Revised 21 May 2008

Accepted 1 June 2008

Published Online First

30 July 2008


Objective: Besides excessive daytime sleepiness, disturbed

nocturnal sleep is a major complaint of patients

with narcolepsy. Previously, alterations in skin temperature

regulation in narcoleptic patients have been shown to

be related to increased sleepiness. This study tests the

hypothesis that direct control of nocturnal skin temperature

might be applied to improve the disturbed sleep of

narcoleptic patients.

Methods: Participants were eight patients (five males)

diagnosed as having narcolepsy with cataplexy according

to the ICSD-2 criteria, mean (SD) age 28.6 (6.4) years,

range 18–35 years. During two nights, sleep was

recorded polysomnographically while proximal and distal

skin temperature were manipulated using a comfortable

thermosuit that induced skin temperature to cycle slowly

with an amplitude of only 0.4uC within the comfortable

range normally observed during sleep. Logistic regression

was used to evaluate the effect of skin temperature

manipulation on the probability of occurrence of different

sleep stages and nocturnal wakefulness.

Results: Proximal skin warming significantly suppressed

wakefulness and enhanced slow wave sleep (SWS). In

contrast, distal skin warming enhanced wakefulness and

stage 1 sleep at the cost of SWS and REM sleep. The

optimal combination of proximal skin warming and distal

skin cooling led to a 160% increase in SWS, a 50%

increase in REM sleep and a 68% decrease in

wakefulness, compared with the least beneficial combination

of proximal skin cooling and distal skin warming.

Interpretation: Subtle skin temperature manipulations

under controlled conditions significantly improved the

typical nocturnal sleep problems in narcolepsy.

The four classical symptoms of narcolepsy are

excessive daytime sleepiness, cataplexy, hypnagogic

hallucinations and sleep paralysis.1 In recent

years, disturbed nocturnal sleep has gained increasing

attention as a fifth core symptom that severely

affects quality of life.1 Nocturnal polysomnography

in patients with narcolepsy shows a fragmentation

of the normal sleep pattern with frequent arousals

and a decrease in slow wave sleep.2–4 Several

hypnotics, including sodium oxybate (gammahydroxybutyrate),

are currently used to improve

nocturnal sleep in narcolepsy.5 Narcolepsy is

caused by a loss of the neuropeptide hypocretin

(orexin), a neurotransmitter that is produced by

neurons in the lateral hypothalamus.6 7

There is a relation between sleep and both core

body and skin temperature.8 9 In everyday life and

under laboratory conditions with a comfortable to

warm environmental temperature, core body temperature

is lower and the average skin temperature is

higher during the night than during the day.9 10

Sleep-onset latency is negatively correlated to the

temperature of distal skin areas (hands and feet).11

There seems to be a causal relation, since mild

warming of the skin compromises sustained vigilance

12 and facilitates sleep initiation.13 Moreover,

mild active manipulation of the skin temperature

within the comfortable and circadian range affects

night-time sleep in healthy controls.14

In a previous study, we reported disturbances in

skin-temperature regulation in narcolepsy.15 Narcoleptic

subjects showed a combination of a higher

distal skin temperature and a lower proximal skin

temperature, which in healthy subjects is associated

with the process of falling asleep.11 In a follow-up

study, we were able to improve both daytime

vigilance and maintenance of wakefulness by mild

manipulation of skin temperature and core body

temperature.16 To test the hypothesis that manipulation

of skin temperature might be applied to

ameliorate the disturbed nocturnal sleep in narcolepsy

as well, we performed subtle manipulations of

proximal and distal skin temperature during two

nocturnal sleep episodes in eight narcoleptic patients.



Eight narcoleptic patients (five males, 18–35 years

of age; mean (SD): 28.6 (6.4) years) participated

with informed consent. All suffered from excessive

daytime sleepiness and typical cataplexy according

to the ICSD-2 criteria for narcolepsy with cataplexy.

17 All subjects were free of medication, except

for one female subject using oral contraceptives. All

females participated between day 4 and day 12 of

the menstrual cycle (mid-follicular phase or

pseudo-follicular phase). All subjects participated

in the summer season (July/August). The protocol

was approved by the Medical Ethics Committees

of the Academic Medical Center in Amsterdam and

the Leiden University Medical Center. The same

eight subjects were used in the aforementioned

study, where both skin temperature and core body

temperature were manipulated during daytime.16


A previously described design was used to differentially

manipulate proximal and distal skin

temperature, and to determine the effects of these

manipulations on sleep depth.14 Subjects refrained

from caffeine, alcohol and tobacco for 8 h before

reporting at the sleep laboratory at 22:00. There

they were prepared for polysomnography and

fitted with a thermosuit. At midnight, lights were

turned off, and subjects were allowed to sleep until

Research paper

1354 J Neurol Neurosurg Psychiatry 2008;79:1354–1358. doi:10.1136/jnnp.2008.143610

Downloaded from jnnp.bmj.com on 27 April 2009

06:00. From 00:30 until 06:00, their proximal and distal skin

temperatures were manipulated. After this, subjects slept one

night at home, after which they returned for a second night in

the sleep laboratory, during which the temperature manipulation

sequence (see below) was inverted to that of the first night.

Temperature manipulations and measurement

Starting at 0:30, the temperature of the proximal skin (Tskinprox)

and the temperature of the distal skin (Tskin-dist) were

differentially manipulated by slowly altering the temperature of

the water that perfused the thermosuit (fig 1). The suit

temperature (Tsuit) stayed at constant plateaus of either 15 or

30 min with slow (15 min) transitions in between. The order of

the sequences of skin temperature manipulations was different

for each subject within its group and chosen in such a way that

it resulted in an optimal uniform distribution of combinations

of high and low Tsuit-prox and Tsuit-dist levels throughout the

night over all subjects, that is at any time of night there was an

equal proportion of ‘‘warm’’ and ‘‘cool’’ periods. Tsuit cycled

between 31.9 (0.1)uC (mean (SE)) in the ‘‘cool’’ and 34.8 (0.1)uC

in the ‘‘warm’’ condition, as measured once per minute on the

isolated inflow tubes at their connections with the thermosuit

using PT100 thermistors (RTD-3-3105, Omega, Stanford). This

range was specifically chosen to match the previously reported

range of temperatures normally present in the bed microclimate.

18 The environmental temperature was kept at 21uC. Skin

and core body temperature was recorded as described previously.


Sleep recordings

Polysomnographic sleep recordings were performed according to

standard procedures.19 An experienced sleep technician blind to

the temperature conditions scored sleep stages in 30-second

epochs according to the Rechtschaffen and Kales criteria using

Somnologica software.20

Table 1 Odds ratio (OR), CI and p value for the occurrence of each sleep state as modulated by the

temperature of the thermosuit warming the distal (Tsuit-dist) and proximal (Tsuit-prox) skin (per 1uC)

Tsuit-prox Tsuit-dist

OR (95% CI) p Value OR (95% CI) p Value

Wake 0.81 (0.77 to 0.84) ,0.001 1.11 (1.06 to 1.16) ,0.001

S1 0.98 (0.93 to 1.03) NS 1.22 (1.16 to 1.28) ,0.001

S2 1.02 (0.99 to 1.05) NS 1.01 (0.98 to 1.04) NS

SWS 1.23 (1.17 to 1.29) ,0.001 0.85 (0.81 to 0.89) ,0.001

REM 0.98 (0.93 to 1.03) NS 0.87 (0.83 to 0.92) ,0.001

REM, rapid-eye-movement sleep; S1, stage 1 sleep; S2, stage 2 sleep; SWS, slow-wave sleep.

Figure 1 (A) Example of a temperature profile induced in one patient during a single night. The lower traces show the temperature of the proximal

(solid line) and distal (dotted line) parts of the thermosuit. The upper traces show the actually induced proximal and distal skin temperatures. (B)

Graphical representation of the proportion of the sleep stages during the optimal (distal cooling and proximal warming) and least beneficial (distal

warming and proximal cooling) manipulation scheme. The proportions were derived in separate logistic regressions for each sleep stage. For graphical

purposes only, the figure was rescaled to 100%. REM, rapid-eye-movement sleep; S1, stage 1 sleep; S2, stage 2 sleep; SWS, slow-wave sleep.

Research paper

J Neurol Neurosurg Psychiatry 2008;79:1354–1358. doi:10.1136/jnnp.2008.143610 1355

Downloaded from jnnp.bmj.com on 27 April 2009

Statistical analysis

The main outcome measures of this study were the effects of

proximal and distal skin warming or cooling on the odds ratios for

the occurrence of each sleep stage (stage 1, stage 2, slow-wave

sleep, REM sleep and wakefulness). Mixed effect (or multilevel)

regression modelling was applied to account for the interdependency

of the data points inherent to the hierarchical structure of

the dataset: sleep epochs within nights within subjects (MLwiN

software, Centre for Multilevel Modelling, Institute of Education,

London).21 The analyses included all epochs during the skin

temperature cycles (from 00:30 until 6:00). To determine the

effects of skin temperature manipulation on the probability of

occurrence of each sleep stage or wakefulness, longitudinal

multilevel logistic regressions were applied for each sleep stage

classification, with the current presence or absence of that stage as

dummy coded dichotomous dependent variable and Tsuit-prox and

Tsuit-dist as predictor variables. Two-tailed significance levels were

set at 0.05. For a graphical representation, odds ratios (OR) were

translated into whole-night sleep stage probabilities for two

conditions, reflecting the most and least profitable combination of

upper (34.8 (0.1)uC) and lower (31.9 (0.1)uC) Tsuit levels (see

results). These probabilities can easily be calculated using the

transformation ex/(1+ex), where x represents the regressor part of

the best-fitting regression model.


Induced temperatures

With the thermosuit approach, we were able to differentially

manipulate proximal and distal skin temperature (see example of

one night in one patient in fig 1). The temperature manipulations

of the proximal part of the thermosuit accounted for 53.8% of the

variance in mean Tskin-prox. Tskin-prox averaged 35.1 (0.1)uC (mean

(SEM) at the warmest level versus 34.7 (0.1)uCat the coolest level.

Likewise, the independently manipulated temperature of the

distal part of the thermosuit accounted for 44.0% of the variance

in mean Tskin-dist. Tskin-dist averaged 35.5 (0.05)uC at the warmest

level versus 35.1 (0.05)uC at the coolest level. Thus, the

manipulations forced the skin temperature to cycle slowly within

a very subtle 0.4uC range (see temperature graph in fig 1). The

manipulations left core body temperature virtually unchanged

(skin temperature manipulations accounted for only 2.5% of the

variance in core body temperature).

Effect of temperature manipulation on sleep stage distribution

Thermosuitmanipulation of the temperature of the proximal and

distal skin significantly affected sleep depth and the occurrence of

wakefulness. Table 1 shows that proximal warming suppressed

wakefulness (OR 0.81, CI (0.77 to 0.84), p,0.001) and enhanced

slow-wave sleep (OR 1.23 (1.17 to 1.29), p,0.001; all OR

expressed per 1uC increase in Tsuit). In contrast, distal warming

enhanced wakefulness (OR 1.11 (1.06 to 1.16), p,0.001) and stage

1 sleep (OR 1.22 (1.16 to 1.28), p,0.001) sleep at the cost of slowwave

sleep (OR 0.85 (0.81 to 0.89), p,0.001) and REM sleep (OR

0.87 (0.83 to 0.92), p,0.001). There were no significant effects on

the occurrence of stage 2 sleep.

A graphical representation of the sleep-stage distribution is

given in fig 2. As compared with the least favourable skin

temperature combination, the optimal combination led to a

160% increase in slow-wave sleep, a 50% increase in REM sleep

and a 68% decrease in wakefulness.


This study shows that subtle manipulation of proximal and

distal skin temperatures has beneficial effects on nocturnal sleep

in narcolepsy. When the proximal skin was warmed, slow-wave

sleep increased, and wakefulness was suppressed. In contrast,

warming of the distal skin suppressed slow-wave and REM

sleep, while enhancing wakefulness and stage 1 sleep.

Fragmented nocturnal sleep is a major and difficult to treat

problem for many patients with narcolepsy. Currently, treatment

of this invalidating symptom is based on hypnotics, most

notably sodium oxybate,5 which increases slow-wave and REM

sleep, while suppressing wakefulness.3 22

The present study was designed in such a way that different

manipulation schemes were equally and randomly distributed over

the test subjects in a balanced way. As such, the effects cannot

have been caused by time of night or circadian effects, but can be

solely attributed to themanipulation of skin temperature. The fact

that subtle changes in skin temperature affect sleep in both

narcoleptic patients and healthy controls14 shows that the basic

hypothalamic circuitry involved in temperature and sleep regulation

is still responsive to manipulation in narcolepsy despite the

hypocretin deficiency. In this study, no subject experienced the

optimal or least beneficial combination of proximal and distal

manipulations continuously during a full night. Furthermore, sleep

time was restricted from midnight to 06:00. It would now be of

interest to confirm the positive effects found in this study using a

controlled trial in which the optimal or least beneficial temperature

conditions are applied continuously throughout a full night.

In conclusion, despite the hypocretin deficiency, the basic

hypothalamic circuitry involved in temperature and sleep

regulation is still responsive to manipulations in narcolepsy.

These results raise the intriguing possibility that selective

manipulation of skin temperature within the comfortable range

might in theory be applied to ameliorate one of the core

symptoms of narcolepsy; disturbed nocturnal sleep.

Acknowledgements: This work was supported by grants from The Netherlands

Organization for Scientific Research (projects SOW 014-90-001 and Innovation Grant

016.025.041) and the EU FP6 Sensation Integrated Project (FP6-507231). SO was

supported by a VENI grant from The Netherlands Organization for Scientific Research

(#916.56.103). We would like to thank J Stam (Academic Medical Center,

Amsterdam) for clinical surveillance during the protocol. Furthermore, we are very

grateful to S Wehrens, M Fisher, J Vis (NIN) and P van Someren (LUMC) for their

invaluable help during the collection and analysis of the EEG data.

Competing interests: None.

Ethics approval: Ethics approval was provided by the Medical Ethics Committees of

the Academic Medical Center in Amsterdam and the Leiden University Medical Center.

Patient consent: Obtained.


1. Overeem S, Mignot E, van Dijk JG, et al. Narcolepsy: clinical features, new

pathophysiologic insights, and future perspectives. J Clin Neurophysiol 2001;18:78–105.

2. Montplaisir J, Billiard M, Takahashi S, et al. Twenty-four-hour recording in REMnarcoleptics

with special reference to nocturnal sleep disruption. Biol Psychiatry


3. Mamelak M, Black J, Montplaisir J, et al. A pilot study on the effects of sodium

oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep


4. Hudson JI, Pope HG, Sullivan LE, et al. Good sleep, bad sleep: a meta-analysis of

polysomnographic measures in insomnia, depression, and narcolepsy. Biol Psychiatry


5. Billiard M, Bassetti C, Dauvilliers Y, et al. EFNS guidelines on management of

narcolepsy. Eur J Neurol 2006;13:1035–48.

6. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy

and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat

Med 2000;6:991–7.

7. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep

and wakefulness. Trends Neurosci 2001;24:726–31.

8. Van Someren EJW. Sleep propensity is modulated by circadian and behaviorinduced

changes in cutaneous temperature. J Therm Biol 2004;29:437–44.

9. Van Someren EJW. Mechanisms and functions of coupling between sleep and

temperature rhythms. Prog Brain Res 2006;153:309–24.

10. Marotte H, Timbal J. Circadian rhythm of temperature in man. Comparative study

with two experiment protocols. Chronobiologia 1981;8:87–100.

Research paper

1356 J Neurol Neurosurg Psychiatry 2008;79:1354–1358. doi:10.1136/jnnp.2008.143610

Downloaded from jnnp.bmj.com on 27 April 2009

11. Krauchi K, Cajochen C, Werth E, et al. Warm feet promote the rapid onset of sleep.

Nature 1999;401:36–7.

12. Raymann RJEM, Van Someren EJW. Time-on-task impairment of psychomotor

vigilance is affected by mild skin warming and changes with aging and insomnia.

Sleep 2007;30:96–103.

13. Raymann RJEM, Swaab DF, Van Someren EJW. Cutaneous warming promotes

sleep onset. Am J Physiol Regul Integr Comp Physiol 2005;288:R1589–97.

14. Raymann RJEM, Swaab DF, Van Someren EJW. Skin deep: cutaneous temperature

determines sleep depth. Brain 2008;131:500–13.

15. Fronczek R, Overeem S, Lammers GJ, et al. Altered skin-temperature regulation in

narcolepsy relates to sleep propensity. Sleep 2006;29:1444–9.

16. Fronczek R, Raymann RJEM, Romeijn N, et al. Manipulation of core body and skin

temperature improves vigilance and maintenance of wakefulness in narcolepsy. Sleep


17. American Academy of Sleep Medicine. International classification of sleep

disorders. 2nd edn. Rochester: American Academy of Sleep Medicine, 2005.

18. Goldsmith R, Hampton IF. Nocturnal microclimate of man. J Physiol 1968;194:


19. Van Sweden B, Kemp B, Kamphuisen HA, et al. Alternative electrode

placement in (automatic) sleep scoring (Fpz-Cz/Pz-Oz versus C4-A1). Sleep


20. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and

scoring systems for sleep stages of human subjects. Los Angeles: UCLA Brain

Information Service/Brain Research Institute, 2007.

21. Twisk JWR. Applied longitudinal data analysis for epidemiology. Cambridge:

Cambridge University Press, 2003.

22. Scrima L, Hartman PG, Johnson FH Jr, et al. The effects of gamma-hydroxybutyrate

on the sleep of narcolepsy patients: a double-blind study. Sleep 1990;13:479–90.

Share this post

Link to post
Share on other sites

i cannot read all that. i read a little.

i had problems with persistent fever for - i think - 9 months. i have a lot of research if u need it. i don't know why you have this research, but i'm happy to share.

Share this post

Link to post
Share on other sites

Not sure if the info helps, but all of the women in family (on the maternal side) all naturally run low temps (97.5ish) and 5 have been diagnosed with sleep disorders. Yet I had a persistent low grade fever for about two years; my first normal temp occurred about 3 months ago. Also, myself, mother, and sister all have Raynaud's.

Sorry, there are probably more skin temp connections I could make, but I'm running into my sleepy brick wall.

Share this post

Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now