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Research paper
Narcolepsy in Southern Chinese patients: clinical
characteristics, HLA typing and seasonality of birth
Y K Wing,1 L Chen,1 S Y Y Fong,1 M H L Ng,2 C K W Ho,1 S H Cheng,2 N L S Tang,3
A M Li4
1
Department of Psychiatry, The
Chinese University of Hong
Kong, Prince of Wales and
Shatin Hospitals, Shatin, Hong
Kong SAR; 2 Department of
Anatomical and Cellular
Pathology, The Chinese
University of Hong Kong, Prince
of Wales, Shatin, Hong Kong
SAR; 3 Department of Chemical
Pathology, The Chinese
University of Hong Kong, Prince
of Wales, Shatin, Hong Kong
SAR; 4 Department of Pediatrics,
The Chinese University of Hong
Kong, Prince of Wales, Shatin,
Hong Kong SAR
Correspondence to:
Dr Y K Wing, Professor,
FRCPsych, FHKAM (Psych),
Director of Sleep Assessment
Unit, Department of Psychiatry,
Shatin Hospital, The Chinese
University of Hong Kong, Shatin,
Hong Kong SAR; ykwing@cuhk.
edu.hk
Received 28 December 2007
Revised 5 March 2008
Accepted 8 March 2008
Published Online First 3 April 2008
ABSTRACT
Objective: To report clinical characteristics, human
leukocyte antigen (HLA) typing and seasonality of birth of
a series of 54 Southern Chinese patients suffering from
narcolepsy.
Methods: All subjects underwent detailed medical and
psychiatric interviews and a standardised nocturnal
polysomnogram followed by a daytime Multiple Sleep
Latency Test. Each subject also completed a set of sleep
questionnaires. HLA typing was performed in 91% of
subjects.
Results: A total of 78% and 22% of patients were
diagnosed with suffering from cataplectic and noncataplectic narcolepsy, respectively. The majority (n = 47,
87%) of patients were referred to our sleep clinic for
excessive daytime sleepiness (EDS). The cataplectic
narcolepsy differed from non-cataplectic narcolepsy by
having more rapid eye movement (REM)-related clinical
symptoms (more sleep paralysis and sleep-related
hallucination) and sleep disturbances (shorter REM
latency), as well as tighter association with HLA
DQB1*0602. A bi-modal peak pattern was observed at 11
and 39 years old. A similar bi-modal pattern also occurred
for EDS and cataplexy. Excess winter births were
observed for this series of patients. 81% of patients with
cataplectic narcolepsy were DQB1*0602-positive. There
were no differences between early- and late-onset cases
in the association with positive DQB1*0602 (71.4% vs
60%). Narcolepsy had prominent pernicious effects on
various social, academic, family and mental aspects in our
patients.
Conclusions: In our Southern Chinese narcolepsy series,
bi-modal peak pattern of age of onset, excess winter birth
and tight association of HLA DQB1*0602 with cataplectic
narcolepsy were found.
Narcolepsy is a life-long debilitating sleep disorder
that is characterised by excessive daytime sleepiness (EDS), cataplexy and other rapid eye movement (REM) sleep-related phenomena, such as
sleep-related hallucinations and sleep paralysis.1
Although hypocretin deficiency and a tight association with human leukocyte antigen (HLA)
DQB1*0602 were landmark discoveries in patients
with narcolepsy with cataplexy,2–4 differences
across ethnic groups have been widely suggested,
in respect to the disease prevalence, the predisposition or protection of various HLA class II alleles
and other clinical features.3 5 Few narcolepsy
studies have been carried out in Chinese patients.
Furthermore, these studies were further limited by
their small sample population.6–10 Our previous
studies in Hong Kong (southern) Chinese narcoleptics found out that all patients were HLA
1262
DR2- and DQ1-positive and the prevalence of
narcolepsy in Hong Kong Chinese was 0.034%
(95% CI 0.010% to 0.117%).7 11 The aim of this
study is to extend and update our report of the
Hong Kong Chinese narcolepsy series.
METHODS
Fifty-four (Men: Women = 26:28) patients with
narcolepsy were diagnosed in our sleep clinic since
the early 1990s. All patients were natives born in
Guangdong Province or Hong Kong SAR, except
one subject who emigrated to Hong Kong from
Shanghai, in the middle of China. Thus, all were
considered to be Southern Han Chinese in ethnic
origin. Each patient had detailed medical and
psychiatric interviews by experienced clinicians
and underwent a standardised overnight nocturnal
polysomnogram (N-PSG) followed by a Multiple
Sleep Latency Test (MSLT) on the following day.
In addition, each subject completed a set of sleep
questionnaires, including the Chinese version of
the Ullanlinna Narcolepsy Scale (UNS),12 Epworth
Sleepiness Scale (ESS) and questionnaires about
self-reported sleep habits and problems. The sleep
schedule and sleep diary for the week prior to NPSG were also obtained. Forty-two patients (78%)
(M:F = 20:22) were diagnosed as having narcolepsy
with cataplexy by the following criteria according
to ICSD-II:13 (1) EDS for more than 3 months; and
(2) a definite history of cataplexy; and/or (3) a
mean sleep latency (MSL) of (8 min with >2
sleep-onset REM periods (SOREMP) in the five
naps during MSLT; and (4) hypersomnia is not
better explained by other sleep disorders, medical,
mental, medication or substance use disorders.
Twelve patients (22%) (M: F = 6:6) who fulfilled
the above criteria, except the presence of definite
cataplexy, were diagnosed as having narcolepsy
without cataplexy.
Sleep assessments
The N-PSG included the measurement of central
(C3-A2, C4-A1) and occipital (O2-A1) electroencephalogram, bilateral electrooculogram, electromyogram of mentalis and bilateral anterior tibialis
muscles, electrocardiogram and respiratory airflow.
The MSLT containing five nap tests was performed according to the standard recommendation
to determine the sleep latency and SOREMPs.14
Sleep stages of both PSG and MSLT were scored in
30-s epochs following the Rechtschaffen and Kales
criteria.15 Sleep latency was defined as the elapsed
time from ‘‘lights-out’’ to the first epoch scored as
sleep. REM sleep latency was defined as the time
J Neurol Neurosurg Psychiatry 2008;79:1262–1267. doi:10.1136/jnnp.2007.143420
Research paper
Table 1 Demographic characteristics and sleep variables of narcolepsy patients
Age
Sex (percentage of male)
Duration of disease
REM sleep latency (minimum)
MSL (minimum)
SOREMP
UNS Score
Percentage of UNS >14
Cataplexy Subscore of UNS
Narcolepsy with cataplexy (n = 42)
(mean ¡ SD)
Narcolepsy without cataplexy (n = 12)
(mean ¡ SD)
p Value
27.8¡15.6
47.6
17.9¡11.4
40.9¡45.6
3.7¡3.2
3.3¡2.4
18.5¡7.2
75
4.5¡3.7
21.4¡12.7
50.0
11.3¡5.7
76.5¡49.1
5.0¡3.6
4.4¡3.7
12.8¡4.7
30
0.7¡1.3
NS
NS
0.006
0.038
NS
NS
0.007
0.02
,0.001
MSL, mean sleep latency; NS, not significant; REM, rapid eye movement; SOREMP, sleep-onset REM period; UNS, Chinese version of Ullanlinna Narcolepsy Scale.
from the beginning of sleep onset to the first epoch of REM
sleep. All computerised sleep data were further reviewed by
experienced polysomnographic technicians and clinicians.
Seasonality-of-birth pattern
The general birth rates in Hong Kong (nearly 2 millions births)
were obtained from the department of immigration of the Hong
Kong government. The birth rates throughout a year and
weighted distributions were all calculation based. The percentage of births for each month in patients with narcolepsy was
calculated and compared with that in the general population by
creating a control group with birth months corresponding to the
proportions calculated from the general population data.16
HLA genotyping
Forty-nine patients (91%) consented to HLA genotyping. Blood
samples were drawn from these patients. Sequencing-based
typing (SBT) of HLA-DRB and DQB were performed according
to the protocols established by the International
Histocompatibility Working Group (IHWG).17 Sequencing data
was analysed using the SBTengine software (Genome
Diagnostics, The Netherlands). Two patients were serological
typed and were excluded from the analysis.
Statistical analysis
Comparisons of narcolepsy with and without cataplexy
patients on age, BMI and other continuous sleep parameters
were made by independent t-tests. Binary variables were
analysed using Chi-square test and Fisher’s exact test for
pairwise comparisons. The month-of-birth data were analysed
by Chi-square test by comparing the observed frequencies to the
expected frequencies obtained from the general population.
Odds ratios (ORs) were calculated with 95% confidence
intervals. All statistical tests were computed using SPSS 13.0
for windows (SPSS Inc., Chicago, IL).
RESULTS
Subjects
Among our series, 47 (87%) patients were referred to our sleep
clinic for EDS, 3 (6%) for cataplexy and 4 (7%) for other sleep
problems, indicating that EDS was the most disabling symptom
among the narcolepsy tetrad. The mean age of the 54 patients
was 26¡15 (range: 8–63) years old and the mean age of onset
was 17¡11 (range: 7–52) years old. The mean duration between
the onset of the disease and the diagnosis for these patients was
16¡11 years. Forty-five patients were on medications and
followed-up regularly in our sleep clinic. Seven patients were
subjectively able to tolerate narcoleptic symptoms and refused
to take medications. Two late-onset patients died because of
other co-morbid diseases. Sixteen patients (30%) had co-morbid
obstructive sleep apnoea syndrome (OSAS). Ten of them
received continuous positive airway pressure (CPAP) treatments
and six of them were subjected to ENT surgeries or nasal steroid
spray.
Sleep characteristics
The detailed clinical characteristics of the patients are summarised in table 1. The cataplectic and non-cataplectic groups
were comparable in sex, age and age of onset of narcolepsy.
Cataplectic patients had a longer duration of disease, which was
in line with the previous study.18 The two groups did not show
significant differences in BMI, time in bed, total sleep time,
sleep efficiency, sleep latency, or apnoea and hypopnea index.
They also had the same distribution of different sleep stages.
Compared with the non-cataplectic group, the cataplectic group
had a shortened nocturnal REM sleep latency. In MSLT tests, 44
patients (81%) fulfilled the criteria of MSL (8 min with >2
SOREMPs. Forty patients (74%) had the ESS score >14,19
whereas 30 patients (56%) had the UNS score >14.7 11 12 UNS
was sensitive in discriminating between cataplectic and noncataplectic patients (table 1),7 11 whereas the two groups were
comparable in ESS scores. Three non-cataplectic patients
Table 2 Presence of the narcoleptic spectrum in narcolepsy patients
EDS
MSLT (8 min
MSLT (5 min
SOREMP >2
SRH
SP
Narcolepsy with
cataplexy (n = 42) (%)
Narcolepsy without
cataplexy (n = 12) (%)
Odds ratio (95% CI)
40/42
33/42
36/42
27/42
29/42
12/12
8/12
12/12
1/12
3/12
–
–
–
19.8 (2.3–168.6)
6.7 (1.6–28.9)
(95.2)
(78.6)
(85.7)
(64.3)
(69.0)
(100)
(66.7)
(100)
(8.3)
(25.0)
EDS, excessive daytime sleepiness; MSLT, Multiple Sleep Latency Test; SOREMP, sleep-onset REM period; SRH, sleep-related
hallucinations; SP, sleep paralysis.
J Neurol Neurosurg Psychiatry 2008;79:1262–1267. doi:10.1136/jnnp.2007.143420
1263
Research paper
without cataplexy, only one peak at about 9 years old was
observed (fig 2B). Female patients had the first peak at 9 years
old and the second one at 28 years old, which were earlier than
those of male patients (16 years old and 41 years old,
respectively) (fig 2C). The bi-modal peak pattern was also
observed for the onset of EDS and cataplexy (fig 2D). The
majority (91%) of patients reported that cataplexy occurred at
the same time or a few years later than EDS. One patient had an
early-onset of EDS at 15.5 years old while having a rather lateonset of cataplexy at 43 years old, which was delayed by 27.5
years.
Seasonality-of-birth pattern
Figure 1 (A) Triggers of cataplexy in narcolepsy patients. (B)
Presentation of cataplectic attacks in narcolepsy patients.
Excess winter (November, December and January) births were
observed when compared to non-winter months (x21 = 9.12,
p = 0.003) (fig 3). A control group (n = 5400, 1:100) was
randomly generated from the general population data. Odds
ratios with 95% confidence intervals were calculated for each
month to compare the risk of that particular month versus all
other months. A peak of 20.4% for January births (OR: 2.8,
95%CI = 1.5 to 5.5) was found for the whole narcolepsy group
and a similar result was obtained for narcolepsy with cataplexy
patients (a peak of 21.4% for January births (OR: 3.0,
95%CI = 1.4 to 6.4)). Although there was an apparent trough
of October births, it was not statistically significant. If we
varied the number of subjects in the control group with 54
subjects or 54 000, similar results were obtained.16
HLA genotyping
reported cataplexy-like symptoms in UNS but the presence of
definite cataplexy in them was ruled out by further clinical
interviews.
All patients complained of EDS. Twenty-eight (52%) of them
reported sleep-related hallucinations and 32 (59%) reported
sleep paralysis. Twenty-four (44%) patients suffered from the
full tetrad symptoms of narcolepsy. Disturbance of nocturnal
sleep was also reported by 23 (43%) patients. A higher rate of
sleep-related hallucinations and sleep paralysis was observed in
cataplectic patients (table 2). There were no significant
differences in the prevalence of EDS and multiple SOREMPs
between the two groups (table 2).
Positive emotion such as laughter was the most common
trigger of cataplexy. Cataplectic attacks during movement and
sex have also been reported by a small number of patients
(fig 1A).20 Various presentations and localisations of cataplexy
are summarised in figure 1B.
Age of onset
Age of onset was investigated in this series of narcolepsy
patients. The bi-modal peak pattern was observed, with the first
major peak at around 11 years old and the second smaller peak
at around 39 years old (fig 2A). A trough was observed at
around 33 years old, which was considered to be the cut-off
point for early-onset (n = 48, 88.9%) and late-onset (n = 6,
11.1%) cases. Late-onset patients were older (late onset vs early
onset: 52¡6.8 vs 23.2¡12.6), had lower total sleep time
(371.5¡74.4 vs 432.1¡53.9 mins), a higher percentage of stage
1 sleep (24.2¡9.6 vs 13.7¡7%) and a lower percentage of slowwave sleep (1.6¡1 vs 15.7¡14.2%) in comparison with earlyonset patients. The disparity of sleep architecture was probably
related to the older age of late-onset cases. Narcolepsy with
cataplexy had the first peak at about 11 years old and the second
peak at about 39 years old. For patients with narcolepsy
1264
Eighty-one percent (30/37) of patients with cataplexy and
narcolepsy were DQB1*0602-positive and 60% (22/37) of them
were positive for both DRB1*1501 and DQB1*0602, which were
much higher than the rate in patients with narcolepsy without
cataplexy (table 3). There was no difference between earlyonset (30/42, 71.4%) and late-onset patients (3/5, 60%) in the
association of positive DQB1*0602.
Psychosocial impact of narcolepsy
Narcolepsy has pernicious effects on various social, academic
and family activities.21 22 Young adults that are in their most
critical stage of education and self-development are predominantly affected by this crippling disorder.23 One of our patients
even became a ‘‘hidden youth’’ due to narcolepsy, who was
isolated from the society and spent all his time on the internet
and computer games at home. Six patients had been given
stigmatic nicknames by their classmates or colleagues, such as
‘‘devil of sleep’’, ‘‘pig addictive to sleep’’, and so on. Various
physical, social and mental problems related to narcolepsy are
summarised in table 4.
DISCUSSION
Although extensive studies have been carried out on narcolepsy
across various ethnic groups, the study of narcolepsy in Chinese
patients has been relatively limited. In addition to our early
reported series,7–9 11 two small series in North China (northern
Chinese) were reported, but they only included patients with
narcolepsy with cataplexy.10 23 Another study reported a clinical
investigation of 35 Chinese patients with excessive sleepiness
from Taiwan.6 To our knowledge, there was no reported data
about the age of onset and seasonality of birth in Chinese
narcolepsy patients.
Sex differences were not found in our study, whereas the
Olmsted County study24 reported an excess of male patients in
J Neurol Neurosurg Psychiatry 2008;79:1262–1267. doi:10.1136/jnnp.2007.143420
Research paper
Figure 2 (A) Age of onset of patients
with narcolepsy. (B) Age of onset of
patients with narcolepsy with and without
cataplexy. (C) Age of onset of male and
female patients with narcolepsy. (D) Age
of onset of patients with EDS and
cataplexy.
Figure 3 Seasonality of birth of narcolepsy patients in comparison to
the general population. Bars depict seasonal birth rates (sum of
3 months) of narcolepsy patients.
J Neurol Neurosurg Psychiatry 2008;79:1262–1267. doi:10.1136/jnnp.2007.143420
their series. EDS was considered to be the most disabling
symptom among the narcolepsy tetrad, which affected all our
narcolepsy patients. More than half (54%) of the patients
experienced frequent irresistible sleep attacks, which was
consistent with previous reports.25 In comparison with noncataplectics, the cataplectic group had more REM-sleep related
disturbances as characterised by a shortened nocturnal REM
sleep latency and a higher prevalence of REM-related clinical
phenomena such as sleep-related hallucinations and sleep
paralysis. Although cataplexy is currently considered to be a
pathognomonic symptom of narcolepsy,13 25 our recent narcolepsy family study reported that there was only a slight increase
in the prevalence of cataplexy, in contrast to the high
heritability of shortened MSL and SOREMPs, in relatives of
narcolepsy probands.26 In addition, cataplexy was present
among the relatives of both probands with and without
cataplexy.26 The heritability issue and nosological status of
cataplexy should be further clarified as this might have a huge
impact on the diagnostic concept of narcolepsy. Although UNS
was sensitive in discriminating between cataplectic and noncataplectic patients, positive responses for cataplexy (based on
subset questions of UNS) were obtained from three noncataplectic patients. Cataplexy-like symptoms were reported in
7.8% of the general population of Hong Kong Chinese
1265
Research paper
Table 3 Positive HLA DR/DQ typing in narcolepsy patients
DRB1*1501+
DQB1*0602+
DRB1*1501– & DQB1*0602+
DRB1*1501– & DQB1*0602–
DRB1*1501+ & DQB1*0602+
Narcolepsy with cataplexy (%)
Narcolepsy without cataplexy (%)
p Value
Odds ratio (95% CI)
25/37
30/37
8/37
4/37
22/37
4/10
3/10
1/10
5/10
2/10
NS
0.004
NS
0.013
0.030
NS
10.0 (2.1–48.7)
NS
0.1(0–0.6)
5.9(1.1–31.6)
(68)
(81)
(22)
(11)
(60)
(40)
(30)
(10)
(50)
(20)
individuals.11 Additional attention should be paid and more
detailed questionnaires other than UNS, such as Cataplexy
Emotional Trigger Questionnaire (CETQ)27 and preferably
standardised clinical interviews, are needed to differentiate
between definite cataplexy and cataplexy-like symptoms.
In our series, the bi-modal peak pattern of age at onset was
observed for narcolepsy, EDS and cataplexy, which was
consistent with previous investigations in France and
Canada.28 A similar pattern was also observed even after
separating male and female, cataplectic and non-cataplectic
patients, except that non-cataplectic patients had only one peak
at an early age. The first peak in females was earlier than that of
males, which might be explained by the earlier pubertal
development of females. The second peak of females was also
earlier than that of males, which was similar with the findings
in Caucasian data.28 Although clear explanations for this bimodal peak pattern are still lacking, early-onset cases are
postulated to be more genetically determined, whereas lateonset …
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