Fast-track article

Daytime sleepiness with and without cataplexy

in Chinese–Taiwanese patients

Yu-shu Huang a, Mehdi Tafti b, Christian Guilleminault c,*

a Sleep Disorders Clinic, Chang-Gung University Hospital, Taipei, Taiwan, ROCb Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

c Stanford University Sleep Disorders Program, 401 Quarry Road, Suite 3301, Stanford, CA 94305, USA

Received 24 March 2006; received in revised form 8 May 2006; accepted 16 May 2006

Abstract

Background and purpose: Investigation of Chinese–Taiwanese patients with excessive sleepiness, but no association with other sleep

disorders, and with the presence or absence of cataplexy.

Patients and methods: Thirty-five patients, successively referred between 2002 and 2004, underwent polysomnography (PSG), repeat

multiple sleep latency test (MSLT), and human leukocyte antigen (HLA) typing. Three patients without cataplexy also had cerebrospinal

fluid (CSF) hypocretin measurements.

Results: DQB1*0602 was associated with cataplexy in over 90% of Chinese–Taiwanese cases. Absence of cataplexy and !2 sleep-onset

REM periods (SOREMPs) was seen in only two subjects, but presence of two SOREMPs did not dissociate DQB1*0602 positive and

negative or cataplexy positive and negative subjects. As a group, narcoleptics with cataplexy had a higher number of SOREMPs, and the

mean sleep latency was much shorter in narcoleptics with cataplexy than in the non-cataplectic patients, independent of the number of

SOREMPs.

Conclusions: Chinese–Taiwanese patients with cataplexy present with similar HLA findings as Black and Caucasian patients, but the

presence of two or more SOREMPs in Chinese–Taiwanese patients is not a sufficient diagnostic tool to identify narcolepsy. When cataplexy

is not present, description of PSG nd HLA findings may be a better approach than using a label with little scientific significance, allowing for

better collection of patients’ phenotype.

q 2006 Elsevier B.V. All rights reserved.

Keywords: Chinese; Cataplexy; HLA; Sleep onset REM period; Multiple sleep latency test

1. Introduction

An association between human leukocyte antigen (HLA)

DQB1*0602 and narcolepsy syndrome has been found in an

investigation of narcolepsy with cataplexy in different

ethnic groups [1]; however, there is still little data on

Chinese individuals, daytime sleepiness and narcolepsy.

Our short report presents the results of an investigation of

Chinese–Taiwanese (i.e. people born in Taiwan with

Chinese parents) patients, and the diagnostic dilemma of

sleep-onset REM periods (SOREMPs) when cataplexy is

1389-9457/$ - see front matter q 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.sleep.2006.05.009

* Corresponding author. Tel.: C1 650 723 6601; fax: C1 650 725 8910.

E-mail address: cguil@stanford.edu (C. Guilleminault).

absent in subjects presenting isolated excessive daytime

sleepiness (EDS).

2. Methods

All subjects were referred between the years 2002 and

2004 for investigation of EDS that had been present for

more than 6 months and was a clear handicap during the

daytime, impacting school performance or professional

activities.

All referred individuals had a complete physical,

neurological, psychiatric and otolaryngologic evaluation.

Subjects had been previously seen by internists, and blood

tests including hormonal testing particularly searching for

hypothyroidism had already been performed. No clear

explanation for daytime somnolence had been found, and

Sleep Medicine 7 (2006) 454–457

www.elsevier.com/locate/sleep

Y.-s. Huang et al. / Sleep Medicine 7 (2006) 454–457 455

subjects were referred to the largest specialized clinic in the

country, the only one dealing with young individuals with

EDS. All subjects had an in-depth sleep evaluation and filled

out a visual analog scale exploring subjective sleepiness

from 0:wide awake to 100:falling asleep and unable to stay

awake any longer [2].

2.1. Polygraphic recordings

Patients were submitted to nocturnal polysomnography

(PSG) and multiple sleep latency test (MSLT) initially and

within 3 months of the first evaluation.

None of the subjects received medication at the time of

the initial evaluation, and when a replication of tests was

performed, any prescribed medication for sleepiness was

interrupted for over 1 month, and for longer if patients

received any anti-cataplectic medication.

Prior to any testing, subjects had been instructed to keep

a regular schedule for 15 days prior to the test and to

maintain 8.5 h of bedtime. They also had to fill out a daily

sleep log for these 15 days, indicating naps, sleep onset,

nocturnal events, last morning awakening, and presence of

attacks of muscle weakness, describing if partial or

complete and also describing duration and trigger.

PSG lasted for 8.5 h of nocturnal recording, with lights-

out time calculated from sleep logs. The following variables

were monitored: electroencephalogram (EEG) (C3/A2,

C4/A1, O1/A2) 2 electro-oculogram (EOG), chin and leg

electromyogram (EMG), an electrocardiogram (ECG)

(modified V2 lead), and a position sensor. Respiration was

monitored with nasal cannula, mouth thermistor, thoracic,

and abdominal piezzo-electric bands, and pulse-oximetry.

Video-monitoring was obtained during recording.

For each of the two tests, similar procedures were

followed: after the 8.5 h of bedtime, subjects had a urine

screen, ate breakfast and thereafter were prepared for five

standardized MSLT naps, performed following the rec-

ommendation of the American Academy of Sleep Medicine

(AASM). The first nap began 2 h after final awakening [3].

Subjects with a history of cataplexy were brought back to

the laboratory a third time and were video-monitored while

efforts were made to trigger cataplectic attacks and verify

the absence of deep tendon reflexes during cataplexy.

Family members participated in this effort, as they usually

knew well the type of jokes and situations that would trigger

attacks of muscle weakness. All subjects were also brought

back to the laboratory for blood to be drawn for HLA typing

after they signed a different informed consent form. Blood

was drawn at a different time from PSG and MSLT to avoid

any interference with polygraphic testing.

Three young adults (18–21 years) had spinal taps for

measurement of cerebrospinal fluid (CSF) hypocretin level

following the technique reported by Nishino et al. [4] These

three subjects had no cataplectic attacks.

2.2. Analysis

All tests analyses (PSG, MSLT, HLA typing, and CSF

analyses) were performed by individuals without knowl-

edge of the presence or absence of cataplectic attack and

without knowledge of findings at any of the specialized

tests.

The Mann–Whitney U-test (two-tailed) was used for

comparison between subgroups.

3. Results

The 35 subjects (13 women) successively seen with the

complaint of EDS during 3 years are included in the report.

None of the subjects were known snorers, were overweight

(O25 kg/m2), or had clinical symptoms or signs of a

syndrome associated with EDS, particularly obstructive

sleep apnea, upper airway resistance, or restless legs

syndrome. PSG confirmed that none of the subjects

presented sleep-disordered breathing or an abnormal

amount of periodic limb movement (as defined in ICSD-

2005 [5]). The mean age of the group was 18.85G8 years

(range 9–60). Only three subjects were older than 25 years

of age, and 77% of subjects were between 14 and 22 years.

3.1. Patients with cataplexy

Sixteen patients (six women) (mean age:17.3G10 years)

presented with cataplexy (45.7%). Cataplectic attacks were

both partial and complete in all subjects with duration

between 30 s and 4 min. They were triggered by laughter

(100% of subjects) and by surprise (81.25% of subjects).

EDS and cataplexy were reported to have started simul-

taneously in 75% of the cases, cataplexy had followed EDS

by about 6–9 months in 18.75% of subjects, and cataplexy

preceded EDS in one case (6.25%) by about 7–8 months.

3.2. Patients with isolated EDS

The 19 other patients (mean age: 20.1G11.4 years, not

significantly different (NS) from those with cataplexy) had

isolated EDS. This group included two of the three older

subjects, but the majority (75%) was aged between 14 and

25 years.

Sleepiness was reported as a social and professional

handicap by all and was of similar severity in subjects with

and without cataplexy: the visual analog scale—from 0

(continuously alert) to 100 (continuous, severe sleepiness)

(2)—showed a mean score of 74 for isolated EDS versus 72

for the narcolepsy–cataplexy group (NS). All subjects in

both groups reported taking daily naps and falling asleep at

school or work.

Y.-s. Huang et al. / Sleep Medicine 7 (2006) 454–457456

3.3. MSLT results

As mentioned, PSG and MSLT were repeated on all

subjects once during the following 3 months. The mean

MSLT was 3.21 min at the first study and 3.28 min at the

second study (NS). There were only three subjects where the

number of SOREMPs varied by 1 between the first and

second MSLT. This variation did not affect the number of

subjects with two or more SOREMPs as it modified only the

number of SOREMPs from 3 to 4, or 4 to 5 or vice versa.

Thus, for this report we considered the number of

SOREMPs noted in the first MSLT as nobody had ever

received any medication. The 16 patients with narcolepsy–

cataplexy had a mean of 3.69G1.3 SOREMPs, and 2

patients (12.5%) in this subgroup had only one SOREMP

even at repeat testing.

The 19 patients with isolated sleepiness had a mean of

2.63G0.9 SOREMPs (PZ0.006), but two patients only

(5.2%) had less than two SOREMPs at repeat MSLTs.

The subdivision into two groups revealed a significant

difference in mean sleep latency (SL). The mean SL for the

narcolepsy–cataplexy group was 1.64G1.76 compared to

5.21G1.60 min (PZ0.0001) for the isolated EDS subjects.

If we withdraw the two subjects without cataplexy and with

only one SOREMP, the mean sleep latency of the last 17

patients is 5.31G1.55 min (NS).

3.4. HLA results

HLA typing showed that 15/16 narcolepsy–cataplexy

subjects were HLA DQB1*0602. The subject with

cataplexy negative for 0602 haplotype was a 15-year-old

individual with typical cataplexy: three SOREMPs but a

mean SL of 5.9 min at MSLT.

HLA typing performed on the parents showed that in

non-adopted children (nZ14) at least one parent was

DQB1*0602, and one index case was homozygote. None of

the 19 isolated EDS subjects had -0602 haplotype, despite

the presence of many SOREMPs at MSLT. The three young

adults (18–21 years) that had CSF analysis for hypocretin

Table 1

Excessive daytime sleepiness (EDS) in 35 Chinese–Taiwaneses

NC group M (SD) C

EDS: nZ 19 1

Age (year) 20.16 (11.39) 1

MLST M (SD) sleep latency (min) 5.21 (1.60) 1

M (SD) SOREMP 2.63 (0.90) 3

!2 SOREMP nZ 2 2

R2 SOREMP nZ 17 1

HLA DQB1*0602, nZ 1 1

CSF Hypocretin (nZ3) Normal measurement: nZ3,

unknown nZ16

U

NC, non-cataplectic; C, cataplectic; MSLT, multiple sleep latency test; M, mean

period. As can be seen independently of presence/absence of cataplexy, presence

level, had respectively, 2, 3, and 3 SOREMPs at MSLT,

absence of cataplexy, and were HLA DQB1*0602 negative.

Hypocretin levels were all O220 mg/ml, i.e. within

normal range with the technique used [6].

4. Discussion

Our study shows that Chinese–Taiwanese patients have

similar results as Caucasian patients when analyses of HLA

is performed on subjects with EDS and cataplexy: 15/16

(93.75%) were HLA DQB1*0602 [1,4], but the presence of

R2 SOREMPs did not dissociate DQB1*0602 positive and

negative or cataplexy positive and negative subjects. Only

two subjects had excessive sleepiness, no cataplexy and one

SOREMP. It left the diagnosis of 19 patients uncertain: two

subjects with cataplexy and the 0602 haplotype, with less

than two SOREMPs, at repeat MSLTs; and 17 patients

with an elevated number of SOREMPs, negative HLA

DQB1*0602, and, in three cases, normal CSF hypocretin

measurements. SOREMPs at MSLT were not diagnostically

beneficial (see Table 1).

Several different studies [7,8,9] with 100 or more

patients each showed that up to 25% of severe obstructive

sleep apnea syndrome (OSAS) patients may present two or

more SOREMPs. Chervin et al. [10] in a large OSA cohort

found a 4.5 percentage, Rye et al. [11] found also SOREMPs

in Parkinson’s patients, and Bishop et al. [12] noted them in

subjects without EDS complaint. In the early 1980s, the first

large investigation of patients with EDS, including

narcolepsy with cataplexy, had already indicated problems

with usage of SOREMPs as a diagnostic tool: there was the

need to repeat the MSLT up to five times to see R2

SOREMPs in patients with cataplexy [13]. It is difficult to

affirm the meaning of the finding of two or more SOREMPs

without many more important studies and the determination

of which groups of patients present a higher risk of this

abnormality than what is observed in the general population.

Currently, the only study performed on a large cohort [14]

was recently done on the Wisconsin Sleep Cohort, which

is mostly (O97%) composed of Caucasian individuals.

group M (SD) P-value (Mann–Whitney: two

tailed)

6

7.31 (10.08) 0.138

.64 (1.76) 0.000***

.69 (1.30) 0.006**

4

5 0.005*

nknownZnZ16

; (SD), one standard deviation; min, minute; SOREMP, sleep onset REM

/absence of DQB1*0602 haplotype, patients had R2 SOREMP.

Y.-s. Huang et al. / Sleep Medicine 7 (2006) 454–457 457

This investigation reports that multiple SOREMPs were

recorded in 13.1% of men and 5.6% of women [14] of

non-consulting subjects, i.e. an observation obtained from

a large percentage of subjects who were derived from a

cohort obtained from the general population of Madison,

Wisconsin.

In our study, there was a significant difference in the

mean number between the subjects with narcolepsy–

cataplexy and those without cataplexy, but this was a

group finding. Presence or absence of DQB1*0602 was not

a predictor of R2 SOREMPs, as at two different

opportunities, two subjects positive for the haplotype had

less, and in 16 cases negative for the haplotype had R2

SOREMPs. The tendency to qualify subjects as narcoleptics

based on the presence of at least two SOREMPs is not

supported by our findings. The ICSD-2005 took a strong

position and decided to call patients ‘narcoleptics without

cataplexy’ based only on the MSLT, which is considered a

‘specific finding’ [5], but this statement is not really

evidence-based.

It is possible that Chinese individuals have a different

propensity to present SOREMPs than Caucasians, but we

have no data on such a question. Our data are the first to

emphasize the problem of MSLT findings in Chinese

individuals and to suggest caution in applying a specific

diagnostic terminology based only on MSLT.

We believe that it would help epidemiologic studies and

better advance our knowledge on isolated EDS if a different

term is selected. It would be better, as already suggested

[15], to call subjects with EDS ‘hypersomniacs’ and add

results of PSG, MSLT, and HLA typing. SOREMPs may

indicate presence of an abnormal pressure for rapid eye

movement (REM) sleep, and this pressure may be related to

the state instability seen with disappearance of hypocretin. It

may also be related to non-REM (NREM) sleep instability,

demonstrated in major depressive disorders [16], and other

sleep disorders often never looked for in large cohort

studies, such as upper airway resistance syndrome,

particularly in teenagers [17]. There may also be a genetic

tendency that enhances the environmental pressure, and

systematic investigation of HLA may bring further

information despite the fact again that there was no

consistency between the presence or absence of

DQB1*0602 and number of SOREMPs. The mean SL,

significantly shorter than in isolated EDS, suggested more

accurately narcolepsy–cataplexy. This is similar to previous

findings that showed that 85% of narcoleptics with

cataplexy had SL of less than 5 min at MSLT [13].

One positive finding of our study was that presence of

HLA DQB1*0602 is a good marker for Chinese individuals

with cataplexy, as it was shown to be for African–

Americans and Caucasians [1]. Measurement of CSF

hypocretin can also be a useful test, but cultural belief

makes CSF measurements much more difficult to obtain

than in other cultures.

References

[1] Mignot E, Lin X, Arrigoni J, et al. DQB1-0602 and DQA1-0102

(Dqw1) are better markers than DR2 for narcolepsy in caucasian and

black. Am Sleep 1994;17:S60–S7.

[2] Mc Cormack HM, Horne DJ, Sheater S. Clinical applications of visual

analogue scales: a critical review. Psychol Med 1998;18:1007–19.

[3] Littner MR, Kushida C, Wise M, et al. Standards of Practice

Committee of the American Academy of Sleep Medicine. Practice

parameters for clinical use of the multiple sleep latency test and the

maintenance of wakefulness test. Sleep 2005;28:113–21.

[4] Nishino S, Ripley B, Overseem S, et al. Hypocretin (orexin)

deficiency in human narcolepsy. Lancet 2000;355:39–40.

[5] American Academy of Sleep Medicine. The international classi-

fication of sleep disorders. Diagnostic and coding manual. 2nd ed.

Westchester, Ill: American Academy of Sleep Medicine; 2005.

p. 81–90.

[6] Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid

hypocretin measurement in the diagnosis of narcolepsy and other

hypocretins. Arch Neurol 2002;59:1553–62.

[7] Guilleminault C, Partinen M, Quera-Salva MA, et al. Determinants of

daytime sleepiness in obstructive sleep apnea. Chest 1988;94:32–7.

[8] Biniaurishvilli RG, Fry JM, Di Philipo MA, Goldberg R. MSLT-

REM sleep episodes, excessive daytime sleepiness, and sleep

structure in OSA patients. Sleep Res (Abstr.) 1994;23:131.

[9] Goncalves MA, Paiva T, Ramos E, Guilleminault C. Obstructive sleep

apnea syndrome, sleepiness and quality of life. Chest 2004;125:

2091–6.

[10] Chervin RD, Aldrich M. Sleep onset REM periods during MSLT in

patients evaluated for sleep apnea. Am J Respir Crit Care Med 2000;

161:426–31.

[11] Rye DB, Bliwisw DL, Dihenia B, Gurecki P. Daytime sleepiness in

Parkinsons disease. J Sleep Res 2000;9:63–9.

[12] Bishop C, Rosenthal L, Roerhrs T, Roth T. The frequency of multiple

sleep onset REM periods among subjects with no excessive daytime

sleepiness. Sleep 1996;19:727–30.

[13] van den Hoed J, Kraemer H, Guilleminault C, et al. Disorders of

excessive daytime somnolence: polygraphic and clinical data for 100

patients. Sleep 1981;4:23–37.

[14] Mignot E, Lin L, Finn L, et al. Correlates of sleep onset REM periods

during the multiple sleep latency test in community adults. Brain;

in press.

[15] Moscovitch A, Partinen M, Guilleminault C. The positive diagnosis of

narcolepsy and narcolepsy’s borderland. Neurology 1993;43:55–60.

[16] Lopes MC, Quera-Salva MA, Guilleminault C. Cyclic alternating

pattern in patients with major depressive disorder treated by a novel

agent: agomelatine. Sleep Med (Abstr.) 2005;6:s86.

[17] Lopes MC, Guilleminault C. Chronic snoring in children: a

demonstration of sleep disruption. Pediatrics; in press.