Narcolepsy in Singapore: Is it an elusive disease?

Article (PDF Available)inAnnals of the Academy of Medicine, Singapore 34(1):90-3 · February 2005with11 Reads
Source: PubMed
Abstract
The aims of the study were to determine the demographic, clinical, and polysomnographic characteristics of narcolepsy, and to address the difficulties in diagnosing narcolepsy and cataplexy, which is a cardinal symptom. We also ventured to investigate the differences between narcolepsy with and without cataplexy. Data were collected retrospectively from patients diagnosed with narcolepsy at the Sleep Disorder Unit of Singapore General Hospital over 5 years. Each patient had had a detailed clinical evaluation and overnight polysomnography (PSG) followed by a multiple sleep latency test (MSLT). A total of 28 cases were studied. Males made up 85.7% of the total and females, 14.3%. The mean age was 30.9 years. All had excessive daytime sleepiness. Other manifestations were cataplexy (48.1%), sleep paralysis (51.9%), hypnogogic hallucinations (84%), disturbed night sleep (29.2%), automatisms (17.4%) and catnaps (95.8%). The mean duration of symptoms was 7.24 years. In the MSLT, the mean values for mean sleep latency and number of sleep onset rapid eye movement (REM) periods (SOREMP) were 4.3 minutes and 2.7, respectively. Narcolepsy was associated with obstructive sleep apnoea and periodic limb movement disorder (35.7%). All the variables were compared between those who had narcolepsy with cataplexy and without cataplexy. The duration of presenting complaint, REM latency, respiratory disturbance index, number of SOREMPs and the presence of sleep paralysis were significantly different in the 2 groups. Narcolepsy predominantly affects young males. Concurrence of other sleep disorders is not uncommon. Some differences are evident between those who have narcolepsy with and without cataplexy.
90
Annals Academy of Medicine
Nacrolepsy in Singapore—U Seneviratne & K Puvanendran
Narcolepsy in Singapore: Is it an Elusive Disease?
U Seneviratne,
1
MBBS, MD, MRCP (UK), K Puvanendran,
1
MBBS, FAMS, FRCP (Lond)
1
National Neuroscience Institute
Singapore General Hospital Campus, Singapore
Address for Reprints: Dr Udaya Seneviratne, Department of Neurology, National Neuroscience Institute, Singapore General Hospital Campus, Outram Road,
Singapore 169608.
Email: udayasen@hotmail.com
Abstract
Introduction: The aims of the study were to determine the demographic, clinical, and
polysomnographic characteristics of narcolepsy, and to address the difficulties in diagnosing
narcolepsy and cataplexy, which is a cardinal symptom. We also ventured to investigate the
differences between narcolepsy with and without cataplexy.
Materials and Methods: Data were
collected retrospectively from patients diagnosed with narcolepsy at the Sleep Disorder Unit of
Singapore General Hospital over 5 years. Each patient had had a detailed clinical evaluation and
overnight polysomnography (PSG) followed by a multiple sleep latency test (MSLT).
Results: A
total of 28 cases were studied. Males made up 85.7% of the total and females, 14.3%. The mean
age was 30.9 years. All had excessive daytime sleepiness. Other manifestations were cataplexy
(48.1%), sleep paralysis (51.9%), hypnogogic hallucinations (84%), disturbed night sleep
(29.2%), automatisms (17.4%) and catnaps (95.8%). The mean duration of symptoms was 7.24
years. In the MSLT, the mean values for mean sleep latency and number of sleep onset rapid eye
movement (REM) periods (SOREMP) were 4.3 minutes and 2.7, respectively. Narcolepsy was
associated with obstructive sleep apnoea and periodic limb movement disorder (35.7%). All the
variables were compared between those who had narcolepsy with cataplexy and without
cataplexy. The duration of presenting complaint, REM latency, respiratory disturbance index,
number of SOREMPs and the presence of sleep paralysis were significantly different in the 2
groups.
Conclusions: Narcolepsy predominantly affects young males. Concurrence of other sleep
disorders is not uncommon. Some differences are evident between those who have narcolepsy
with and without cataplexy.
Ann Acad Med Singapore 2005;34:90-3
Key words: Cataplexy, Hypnogogic hallucinations, Rapid eye movement, Sleep paralysis
Introduction
Narcolepsy is a sleep disorder characterised by excessive
sleepiness, disturbed nocturnal sleep and abnormal rapid
eye movement (REM) sleep-related events, such as
cataplexy, hypnogogic/hypnopompic hallucinations and
sleep paralysis.
1
The population prevalence rates vary with
the highest reported in Japan (0.59%)
2
and the lowest
among Israeli Jews (0.00023%),
3
probably reflecting ethnic
differences. There is a lack of data from Singapore.
Furthermore, it remains underdiagnosed and there may be
a long delay between onset and diagnosis. With this
backdrop, we undertook a study to retrospectively analyse
data from a group of patients with narcolepsy in order to
understand the demographic, clinical and polysomno-
graphic spectrum, as well as the problems encountered in
diagnosing this disorder in the local population.
Materials and Methods
Case Ascertainment and Acquisition of Data
Data were retrospectively collected from case records of
patients diagnosed with narcolepsy by a single physician
(PK) at the Sleep Disorder Unit of Singapore General
Hospital from January 1998 to December 2002. The sources
of referral were general practitioners, primary care doctors,
the emergency department and other specialists. All patients
had undergone detailed clinical evaluation and overnight
polysomnography (PSG) followed by multiple sleep latency
test (MSLT). Case records and PSG/MSLT reports were
scrutinised to obtain demographic, clinical and polysomno-
graphic data.
Overnight PSG consisted of continuous recordings from
4 electroencephalographic (EEG) leads (C4A1, C3A2,
O1A2, O2A1 of international 10 to 20 system: central
Original Article
January 2005, Vol. 34 No. 1
91
Nacrolepsy in Singapore—U Seneviratne & K Puvanendran
electrodes referred to ear), 2 electro-oculographic leads, 4
electromyographic (EMG) leads (2 sub-mental and bilateral
tibialis anterior), thermistors for nasal and oral air flow,
strain gauges for thoracic and abdominal excursion, finger
pulse oximetry and electrocardiography (ECG). The sleep
stages were scored according to the international criteria of
Rechtschaffen and Kales.
4
All patients maintained sleep
logs, which were scrutinised prior to PSG to ensure adequate
sleep hygiene. Those who were on concurrent medications
for underlying medical problems were advised to
discontinue sedative drugs at least a week before the test.
The PSG was performed in order to diagnose other
associated sleep disorders and to interpret the significance
of MSLT findings.
MSLT was conducted in the morning following PSG,
according to the American Sleep Disorders Association
guidelines.
5
It consisted of four 20-minute nap trials at
intervals of 2 hours. The recording montages were similar
to that of the PSG, except that chest and abdominal strain
gauges and thermistors were not included. Epochs were
scored according to the rules of Rechtschaffen and Kales.
4
Two parameters were taken into consideration from MSLT;
mean sleep latency and sleep onset rapid eye movement
periods (SOREMPs). Sleep latency was defined as the
duration in minutes from lights-out to the first epoch of
sleep in each nap trial. Mean sleep latency was calculated
from all 4 trials of each MSLT. SOREMPs were defined as
REM sleep occurring within 15 minutes of sleep onset.
Diagnostic Criteria
The diagnostic criteria published by the American Sleep
Disorders Association in the International Classification of
Sleep Disorders were used.
1
The minimum criteria are
excessive daytime sleepiness or recurrent daytime naps
occurring almost daily for at least 3 months with a history
of cataplexy. Both clinical and laboratory parameters are
taken into consideration in the other set of diagnostic
criteria. This combination consists of complaints of
excessive sleepiness or sudden muscle weakness, associated
features (sleep paralysis, hypnogogic hallucinations,
automatic behaviour, disrupted major sleep episode), at
least one of the polysomnographic parameters (sleep latency
<10 minutes, REM latency <20 minutes, MSLT mean
sleep latency <5 minutes, 2 or more SOREMPs) and the
absence of any other disorder that could account for
symptoms.
The main problem encountered in applying the above
was confirming the diagnosis based on SOREMPs in those
who had narcolepsy without cataplexy in association with
other sleep disorders such as obstructive sleep apnoea
(OSA) syndrome. These conditions can cause excessive
daytime sleepiness as well as SOREMPs in MSLT. To
overcome this difficulty, the following method was adopted.
Those who had associated OSA syndrome and SOREMPs
in MSLT were treated with nasal continuous positive
airway pressure (CPAP) therapy first, followed by repeat
PSG and MSLT while on CPAP. Those who continued to
have SOREMPs despite CPAP therapy were taken into
consideration for diagnosis of narcolepsy.
Statistical Analysis
Data analysis was performed using SPSS (version 10)
statistical software. All demographic, clinical and
polysomnographic data were analysed in the entire group
of narcolepsy using descriptive statistics. Demographic
variables included age, sex and ethnic distribution. The
clinical characteristics analysed were presenting symptoms,
duration of symptoms at presentation, clinical features and
other associated sleep disorders. Polysomnographic data
consisted of sleep latency, REM latency, total sleep time,
sleep efficiency, percentage of delta sleep, percentage of
REM sleep, arousal index, respiratory disturbance index
(RDI) and periodic leg movement index (PLMI). Mean
sleep latency and number of SOREMPs were analysed
from MSLT.
Subsequently all patients were categorised into 2
subgroups – narcolepsy with cataplexy and narcolepsy
without cataplexy. All variables between the 2 groups were
subjected to univariate analysis using the Chi-square test or
the Mann-Whitney U test in order to delineate the
significantly different factors between the 2 groups.
P
<0.05 was considered as statistically significant.
Results
A total of 28 patients were studied. Males made up 85.7%
of the total and females, 14.3%. The age range was 16 to 63
years, with a mean age of 30.9 years. The ethnic composition
consisted of Chinese (71.4%), Indian (14.3%), Malay
(10.7%) and others (3.6%) in comparison to that of the
general population (Chinese, 76.8%; Indian, 7.9%; Malay,
13.9%; and others, 1.4%).
6
The commonest presenting symptom was excessive
daytime sleepiness (EDS) (Table 1). The mean duration of
symptoms was 7.24 ± 4.95 years (range, 1 to 20). Analysis
of clinical data revealed that all patients suffered from EDS
while a few had disturbed night sleep as well (Table 2).
Concurrence of other sleep disorders was found in 35.7%.
In this group, 21.5% had periodic limb movement disorder
(PLMD) only, 7.1% had OSA only, and 7.1% had both
OSA and PLMD. The PSG and MSLT characteristics are
summarised in Table 3.
In the subgroup analysis between narcolepsy with and
without cataplexy, 5 variables emerged as significantly
different between the 2 groups. The narcolepsy with
92
Annals Academy of Medicine
Nacrolepsy in Singapore—U Seneviratne & K Puvanendran
cataplexy group demonstrated longer duration of
presenting symptoms (P = 0.046), longer REM latency in
PSG (P = 0.024), higher number of SOREMPs (P = 0.044),
higher prevalence of sleep paralysis (P = 0.021) and lower
RDI (P = 0.043).
Discussion
Narcolepsy is a chronic and disabling illness with
considerable physical and psychosocial impact, leading to
poor quality of life.
7,8
The onset usually occurs in
adolescence, though cases have been reported in children
and older patients.
Though this condition was first described over 100 years
ago, the diagnostic criteria still remain a focus of debate. In
1957, the classic tetrad of diagnostic criteria consisting of
excessive sleepiness, cataplexy, sleep paralysis and
hypnogogic hallucinations was proposed.
9
Subsequently,
the importance of laboratory parameters in confirming the
diagnosis became apparent. The American Sleep Disorders
Association formulated diagnostic criteria based on clinical
features, PSG/MSLT parameters and HLA typing.
1
The
recent discovery of hypocretin-1 deficiency in narcolepsy
10
has added a new marker for diagnosis. Despite this
controversy, narcolepsy can still be considered a clinical
diagnosis supported by laboratory parameters.
Different prevalence rates reported in different countries
could be due to ethnic factors as well as methodological
and diagnostic criteria differences between those studies.
Among the ethnic Chinese in Hong Kong, the prevalence
was found to be 0.034%.
11
The Singapore population,
consisting of predominantly ethnic Chinese, is likely to
closely resemble that of Hong Kong. Extrapolating the
prevalence rate of narcolepsy in Hong Kong to the Singapore
population of 4.16 million,
6
we would expect around 1400
patients with narcolepsy in Singapore. However, our
impression is that only a fraction of this has sought medical
treatment. A survey conducted in Singapore revealed only
45 cases.
12
Therefore, it is very likely that narcolepsy
remains a hidden and elusive disease here.
There may be several reasons for underdiagnosis. One
possible explanation is difficulty in expressing sleepiness
and misinterpretation of it as a normal phenomenon. It has
been shown that those with excessive sleepiness may
complain of fatigue, tiredness and lack of energy rather
than sleepiness.
13
Socio-cultural influences may also play
a role; e.g., the disclosure of sleepiness may be considered
undesirable and unacceptable. Concurrence of other sleep
disorders, difficulty in recognising and delayed onset of
cataplexy could make diagnosis difficult for the clinician.
Above all, we believe the lack of awareness is a major
cause.
It is interesting to note the concurrence of other sleep
disorders. This has important diagnostic and therapeutic
implications. SOREMPs in MSLT is one of the diagnostic
features of narcolepsy. However, OSA can also cause
SOREMPs, making interpretation of the MSLT difficult.
In a previous study, we reported that 28.1% of patients with
OSA have SOREMPs in MSLT.
14
It would be useful to compare our data with studies from
different populations. It has been well reported that
narcolepsy is more prevalent among males.
15
However, in
our sample, males comprised 85.7%, which is much higher
than the figures reported in the West. This over-
representation of males could perhaps be an artificial figure
due to socio-cultural reasons. For example, females might
not readily seek medical attention, particularly when it is
difficult to express the symptoms of narcolepsy. In the
Table 1. Presenting Symptoms
Symptom %
EDS 46.3
EDS + headache 3.6
EDS + disturbed night sleep 3.6
EDS + disturbed night sleep + headache 3.6
EDS + dreams 7.2
EDS + dreams + disturbed night sleep 3.6
EDS + snoring 28.5
EDS + sleepwalking 3.6
EDS: excessive daytime sleepiness
Table 2. Clinical Features
Clinical feature %
EDS 100
Catnaps 95.8
Hypnogogic hallucinations 84.0
Sleep paralysis 51.9
Cataplexy 48.1
Disrupted night sleep 29.2
Automatisms 17.4
EDS: excessive daytime sleepiness
Table 3. Polysomnographic Features
Mean Standard
deviation
Sleep latency 17.8 min 35.2
REM latency 89.4 min 64.6
Total sleep time 423.8 min 72.1
Sleep efficiency 87.05% 12.3
Percentage of delta sleep 18.8% 12.1
Percentage of REM sleep 16.7% 7.6
Arousal index 12.9 9.4
Respiratory disturbance index 5.7 10.5
Periodic limb movement index 7 11.8
Mean sleep latency 4.3 min 2.7
Number of SOREMPs 2.7 0.7
REM: rapid eye movement; SOREMP: sleep onset REM period
January 2005, Vol. 34 No. 1
93
Nacrolepsy in Singapore—U Seneviratne & K Puvanendran
current study, patients most frequently presented in the
second decade, a trend similar to findings in a study in the
USA.
15
In our study, 51.9% of patients were found to be having
narcolepsy without cataplexy, as compared with 25% to
35% in larger series.
15,16
However, we observed that there
was considerable difficulty in obtaining the history of
cataplexy. Amongst those who had cataplexy, the history
was not forthcoming in the first consultation in about 50%
of patients. The history of cataplexy was elicited on repeated
direct questioning in subsequent consultations. It is also
possible that partial and subtle forms of cataplexy may have
been missed, which could not be verified due to the
retrospective nature of the study. Therefore, this high
figure could be an overestimate due to smaller sample size
and difficulties in eliciting the history of cataplexy. Aldrich
17
demonstrated that narcolepsy with cataplexy group had
lesser slow wave sleep, more stage 1 sleep, more
awakenings, lower sleep efficiency, higher incidence of
sleep paralysis and sleep-related hallucinations. This
contrasts with our findings where the narcolepsy with
cataplexy group had a longer duration of presenting
symptoms, longer REM latency (in PSG), higher number
of SOREMPs, higher prevalence of sleep paralysis and
lower RDI. The higher occurrence of sleep paralysis appears
to be the only common finding. This association could
perhaps be explained on the basis that both cataplexy and
sleep paralysis are REM events. Higher number of
SOREMPs in the cataplexy group is probably indicative of
severity of narcolepsy in those with cataplexy. Longer
duration of symptoms in the cataplexy group is
understandable as cataplexy may become obvious later in
the disease. We believe that our finding of longer REM
latency in the cataplexy group could be due to the first night
effect and has no clinical significance. However, head-to-
head comparison is difficult due to the smaller sample size
of our study.
Conclusion
We believe that narcolepsy is an underdiagnosed disorder
in Singapore. Though the sample size is small, our study
provides a useful insight into this largely underrecognised
condition. It predominantly affects young adults who are in
the most active stage of their lives. Symptoms may be
subtle and misinterpreted as normal. Symptoms of EDS
may not be obvious to the patient and it could be dismissed
REFERENCES
1. Diagnostic Classification Steering Committee. International classification
of sleep disorders: diagnostic and coding manual. Rochester, MN:
American Sleep Disorders Association, 1990.
2. Tashiro T, Kanbayashi T, Iijima S, Hishikawa Y. An epidemiological
study on prevalence of narcolepsy in Japanese. J Sleep Res 1992;1:228.
3. Lavie P, Peled R. Narcolepsy is a rare disease in Israel. Sleep 1987;10:
608-9.
4. Rechtschaffen A, Kales A. A Manual of Standardized Terminology,
Techniques and Scoring System for Sleep Stages of Human Subjects.
Washington, DC: US Government Printing Office, 1968.
5. Thorpy MJ. The clinical use of the Multiple Sleep Latency Test. The
Standards of Practice Committee of the American Sleep Disorders
Association. Sleep 1992;15:268-76. Erratum in: Sleep 1992;15:381.
6. Ministry of Health, Singapore. Health Facts Singapore 2002. Population
and vital statistics. Singapore: Ministry of Health, 2002.
7. Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy.
Sleep 1994;17:S45-S49.
8. Broughton R, Ghanem Q, Hishikawa Y, Sugita Y, Nevsimalova S, Roth
B. Life effects of narcolepsy: relationships to geographic origin (North
American, Asian or European) and to other patient and illness variables.
Can J Neurol Sci 1983;10:100-4.
9. Yoss RE, Daly DD. Criteria for the diagnosis of the narcoleptic syndrome.
Mayo Clin Proc 1957;32:320-8.
10. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S,
et al. The role of cerebrospinal fluid hypocretin measurement in the
diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;
59:1553-62.
11. Wing YK, Li RH, Lam CW, Ho CK, Fong SY, Leung T. The prevalence
of narcolepsy among Chinese in Hong Kong. Ann Neurol 2002;51:
578-84.
12. Puvanendran K. Sleep disorders. In: Ong YY, Woo KT, Ng HS, Tan P,
Tang OT, editors. A Clinical Approach to Medicine. Singapore: World
Scientific Publishing, 2001:985-96.
13. Chervin RD. Sleepiness, fatigue, tiredness, and lack of energy in
obstructive sleep apnea. Chest 2000;118:372-9.
14. Seneviratne U, Puvanendran K. Excessive daytime sleepiness in
obstructive sleep apnea: prevalence, severity, and predictors. Sleep Med
2004;5:339-43.
15. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of
narcolepsy in Olmsted County, Minnesota: a population-based study.
Sleep 2002;25:197-202.
16. Guilleminault C, Mignot E, Partinen M. Controversies in the diagnosis
of narcolepsy. Sleep 1994;17:S1-S6.
17. Aldrich MS. Diagnostic aspects of narcolepsy. Neurology
1998;50:S2-S7.
as tiredness, which is more culturally acceptable. Cataplexy,
which is one of the cardinal features, may be absent in
some. There is a need to raise awareness among the general
public and the medical profession.
  • [Show abstract] [Hide abstract] ABSTRACT: Much has been learned about the pathophysiology of narcolepsy over the last several decades. It is likely that hypocretin-producing cells in the lateral hypothalamus are selectively destroyed in genetically susceptible individuals carrying 1 or more alleles of HLA DQB1*0602. Despite advances, the causes of narcolepsy and how to prevent it remain elusive. Classic epidemiology aims not only to enumerate occurrence of disease in populations, but also to identify etiologic risk factors. This review details what the application of classic epidemiology has taught us so far about narcolepsy and suggests directions for future studies to clarify its etiology. The prevalence of narcolepsy with cataplexy has been examined in many studies and falls between 25 and 50 per 100,000 people. Information on incidence is limited, with 1 study finding the incidence of narcolepsy with cataplexy to be 0.74 per 100,000 person-years. The search for etiologic risk factors has yet to yield important associations. Factors most thoroughly examined include body mass index, immune responses, and stressful life events. Such associations may reflect a consequence rather than a cause of disease. As with other diseases characterized by selective cell loss, such as Parkinson disease or type 1 diabetes mellitus, narcolepsy is likely caused by environmental exposures before the age of onset in genetically susceptible individuals. Matching efforts in these other diseases and using large well-designed epidemiologic studies of narcolepsy, investigators must intensify the search for these exposures, focusing on the first 2 decades of life. Identification of modifiable risk factors will help to prevent this disease.
    Article · Feb 2007
  • [Show abstract] [Hide abstract] ABSTRACT: To report clinical characteristics, human leukocyte antigen (HLA) typing and seasonality of birth of a series of 54 Southern Chinese patients suffering from narcolepsy. 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. A total of 78% and 22% of patients were diagnosed with suffering from cataplectic and non-cataplectic 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. 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.
    Article · May 2008
    Y K WingY K WingL ChenL ChenS Y Y FongS Y Y Fong+1more author...[...]
  • [Show abstract] [Hide abstract] ABSTRACT: Narcolepsy is generally considered an illness of youth because of its incidence peaks around the second to third decade of life. However, there have been a handful of cases that reported the onset of narcolepsy after age 35 and well into the seventies. In addition to the late onset of primary narcolepsy, there is a certain amount of delay in diagnosing this condition; hence, there are reports of subjects who could not be diagnosed until later in life even though their symptoms started at a more typical age. There are certain neurological conditions that lead to symptomatic narcolepsy, most of which present at a later point in life than the primary narcolepsy. This chapter discusses each of these three subpopulations, together with challenges in the diagnosis and treatment of the older individual with the small armamentarium of medications that we have for this disabling and chronic illness.
    Article · Jan 2010 · Journal of neurology, neurosurgery, and psychiatry
Show more