Narcolepsy with long sleep time: a specific entity?
Cyrille Vernet, MSc and Isabelle
Arnulf, MD, PhD
Sleep disorder unit, National reference center for narcolepsy and
hypersomnia, Pitié-Salpêtrière hospital, Paris 6 University and INSERM UMRS
975, France.
Submitted to: Sleep
Version: 3 (2nd revision)
Corresponding author: Isabelle Arnulf
Unité des Pathologies du Sommeil
Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital,
75651 Paris Cedex 13, France
isabelle.arnulf@psl.aphp.fr
Phone : +33 1 42 16 77 02
Fax : +33 1 42 16 77 00
Acknowledgment:
Cyrille Vernet received three unrestricted grants from ANTADIR AO2006,
UCB-Pharma Ltd AO2007 and CARDIF AO2007. Part of this work is financed by the
grant of PHRC
2007-P070138.
The authors have no conflict of
interest regarding the topic of the article. There is no ‘off label’ drug
mentioned in the article. Within the last two years, Isabelle Arnulf was in the
speaker’s bureau of UCB-Pharma Ltd, and
coordinated studies by Artelion Ltd and Bioprojet Ltd. Cyrille Vernet has no
conflict of interest.
Abstract
Background: The
classical narcolepsy patient reports intense feelings of sleepiness (with/out
cataplexy), normal or disrupted night-time sleep, and takes short and
restorative naps. However, with long-term monitoring, we identified some
narcoleptics resembling patients with idiopathic hypersomnia.
Objective: To isolate and describe a new subtype of narcolepsy with long sleep
time).
Setting: University Hospital
Design: Controlled, prospective
cohort
Participants: Out of
160 narcoleptics newly diagnosed within the past 3 years, 29 (18%) had a long
sleep time (more than 11 hr/24 hr). We compared narcoleptics with (n=23) and
without (n=29) long sleep time to 25 hypersomniacs with long sleep time as well
as to 20 healthy subjects.
Intervention:
Patients and controls underwent face-to face interviews, questionnaires, human
leukocyte antigen genotype (HLA), an overnight polysomnography, multiple sleep
latency tests, and 24-hour ad libitum
sleep monitoring.
Results: Narcoleptics with long
sleep time had a similar disease course, and evidenced similar frequencies of
cataplexy, sleep paralysis, hallucinations, multiple sleep onset in REM
periods, short mean sleep latencies and HLA DQB1*0602 positivity as narcoleptics
with normal sleep time did. However, they had longer sleep time during 24
hours, and higher sleep efficiency, lower Epworth sleepiness score and more
often unrefreshing naps. Only 3/23 had a ‘core’ narcolepsy (HLA and cataplexy
positive).
Conclusions: The subgroup of narcoleptics with a long sleep time comprises 18% of
narcoleptics. Their symptoms combine the disabilities of both narcolepsy
(severe sleepiness) and idiopathic hypersomnia (long sleep time and
unrefreshing naps). Thus, they may constitute a group with multiple arousal
system dysfunctions.
Keywords: Narcolepsy,
hypersomnia, sleep drunkenness, long sleep time, cataplexy
Introduction
The clinical symptoms of narcolepsy include chronic, severe, objective
daytime sleepiness with multiple daytime sleep onset REM periods. These markers
are associated, to various extents, with REM sleep-associated phenomena (i.e.,
cataplexy, hypnagogic hallucinations, sleep paralysis, REM sleep behavior
disorders), disturbed nocturnal sleep, periodic leg movements, depressive mood
and increased weight.1 During the night, the most specific feature
of nocturnal sleep is a REM sleep period at sleep onset, which is observed in
only 25% of patients during the first monitored night. In addition, sleep
efficiency in narcoleptics tends be lower than in controls.3 Up to 71% narcoleptics are unable to sleep
without awakening, and 83% complain of early awakenings (see a review in 2).
Recently, much emphasis has been placed on the frequent night-time awakenings,
which may follow an ultradian rhythm in narcoleptics. The existence of
narcoleptic dyssomnia has, in part, led to the recent treatment of sodium
oxybate given before and during sleep in narcoleptics, as a means to obtaining
a more continuous and deep sleep. It also helps alleviate cataplexy and daytime
sleepiness.
Disrupted night-time sleep in human narcolepsy parallels the fragmented
non-REM sleep observed in Dobermans with genetically abnormal hypocretin-2
receptor, though the total duration of sleep is not different from control
dogs.4 In murine narcolepsy, sleep episodes are similarly
fragmented, though the total time asleep in these transgenic animals (823 min)
is not significantly different from the 783 min observed in wild animals.5
In human narcolepsy, total sleep time was initially measured during a 24-hour
period, before the development of the multiple sleep latency test.6
Sleep duration was not found to be different between narcoleptics patients and
controls, as because daytime naps were balanced by ultradian intra-sleep
awakenings in narcoleptic patients.7 Combined, these results led to
the primary theory of sleep-state instability in narcolepsy, which refers to a
difficulty in consolidating either wakefulness (that is, an inability to
maintain wakefulness over long periods of the daytime) or sleep (referring to
an inability to maintain continuous sleep, with frequent awakening). As
narcolepsy is primarily caused by hypocretin deficiency, it has been
hypothesized that hypocretin could stabilize the wake-sleep switches.8
Although most narcoleptics fit this framework (that is, they generally
show disrupted sleep and short, restorative naps), we observed in our clinical
practice a subgroup of patients with narcolepsy who reported abnormally long
night-time sleep, with feelings of sleep drunkenness and unrefreshing long
naps. These clinical features were similar to those observed in idiopathic
hypersomnia with long sleep time. Idiopathic hypersomnia is now further divided
into hypersomnia with and without long sleep time.9 Hypersomnia with
long sleep time is characterized by a prolonged (>10 hr) night-time sleep,
with frequent sleep drunkenness and long, unrefreshing naps, reaching usually
more than 11-12 hrs asleep per day. Recently, we found that hypersomniacs (and
no healthy controls) slept longer than 11 hrs when monitored continuously
during night and day.10 Hypersomnia without long sleep time is
characterized by normal (<10 hr) sleep time, short (<8 min) mean daytime
latency during multiple sleep latency tests (MSLT) and fewer than two sleep
onset in REM periods (SOREMPs). This recent category, resembling narcolepsy
without REM sleep-associated abnormalities, has been isolated after studying a
group of patients with idiopathic hypersomnia.11 Here, we
systematically studied the narcoleptics with long sleep time (>11 hr /24 hr)
and contrasted them with patients suffering a classical narcolepsy and patients
suffering from idiopathic hypersomnia with long sleep time.
Methods
Subjects
Between 2005 and 2008, all (n=900) patients referred for excessive
daytime sleepiness without sleep-disordered breathing (pre-checked by
respiratory polygraphy) underwent the same, routine 48 hour protocol (see
below) in the sleep disorders unit, a tertiary care university hospital with a
biased over-recruitment of neurological cases. In this series, we identified
patients with hypersomnias of central origin who met the following inclusion
criteria: (1) complaints of excessive daytime sleepiness occurring daily for at
least three months; and (2) no improvement with an increase of the nighttime
length for 15 days; and (3) a mean sleep latency (MSL) during multiple sleep
latency tests (MSLT) lower than 8 minutes; or (4) a total sleep time > 10
hours (600 min) during night-time sleep monitoring. We excluded the patients
with: (1) sleep-disordered breathing, defined by a respiratory disturbance
index greater than 10 per hour (this index included apnea, hypopnea, and
respiratory effort related arousal events; flow limitation was measured on the
nasal canulae, and threshold was set at a minimum of five apnea/hour); and (2)
narcolepsy due to a medical condition (e.g. Parkinson’s disease, lupus, genetic
disease, depression); and (3) hypersomnia due to drug or substance use. No
patient received any psychotropic drug during the period of sleep monitoring.
In previously treated patients, special care was paid to withdraw any
psychotropic drugs for at least 15 half-lives. In this group of 312 consecutive
patients with hypersomnia of central origin, we identified 160 patients with
narcolepsy, based on classical criteria (that is, with a mean sleep latency
during multiple sleep latency tests lower than 8 minutes and more than one
sleep-onset REM period or clear-cut cataplexy).9 Among these 160
narcoleptics, we isolated 29 (18.1%) patients with a diagnosis of narcolepsy
and long sleep time (that is, with a total sleep time greater than 11 hours
during 24-hour, long-term sleep monitoring). Among these 29 patients, only 23
had fully completed the various clinical measures. We contrasted their
clinical, demographical and polygraphical characteristics with a random sample
of 29 patients demonstrating a classical narcolepsy (short MSLT, multiple
SOREMPs or cataplexy), and with 25 randomly selected patients with idiopathic
hypersomnia with long sleep time (defined as with no more than one SOREMPs
during MSLT and a total sleep time > 11 hours on 24 hour sleep monitoring). Using
a threshold of 11 hours to define long sleep time was previously piloted while
monitoring 35 healthy volunteers during the 48-hour long procedure.11
In the International Classification of Sleep Disorders-revised, a cut-off of 10
hours night-time sleep and daytime sleepiness is used for defining hypersomnia
with long sleep time, while more than 11-12 hours of total sleep per 24 hours
is indicated as a typical finding when long term sleep monitoring are performed
in patients with hypersomnia with long sleep time.
Twenty healthy subjects volunteered to take part as controls after
recruitment by advertisement. They were matched by age and sex with the group
of narcoleptics with long sleep time. The subjects were selected after a
medical interview for having no complaints regarding their sleep, no excessive
daytime sleepiness (defined as the absence of spontaneous or elicited complaint
and also having a score at the Epworth sleepiness scale lower than 11), no
chronic sleep deprivation (determined using a questionnaire on sleep habit), no
shift or night work, no severe medical illness, and no use of medications known
to modify sleep and wakefulness. The control group took part to the 48-hour
sleep protocol. Control subjects were able to comply adequately with the study
requirements, signed an informed consent and were paid. The study was approved
by the local ethics committee.
Investigations
Participants were instructed to follow a regular sleep-wake rhythm, with
at least 8 hours in bed during the week preceding the 48 hour-long
investigations in the Sleep Disorders Unit. They underwent a face to face
interview about sleep symptoms (cataplexy, sleep drunkenness, sleep paralysis,
restorative naps) and completed a standardized comprehensive sleep
questionnaire including the Epworth sleepiness scale,12 the
Horne-Ostberg eveningness-morningness scale,13 the Pichot fatigue
scale,14 the Fatigue Severity Score,15 and the hospital
depression and anxiety (HAD) rating scale.16 The class-II human
leukocyte antigen (HLA) genotype was determined for all patients and
controls. The sleep and wake monitoring
procedure included (i) a habituation night with sleep and respiratory
monitoring from 11 pm to 6:30 am, followed the next day by (ii) five standard
sleep latency tests (MSLT) at 8 am, 10 am, noon, 2 pm, 4 pm, that were
terminated after 20 minutes if no sleep occurred, and after 15 min asleep if
sleep occurred 17; and (iii) followed the next evening by a long
term (24-hour) sleep monitoring. The aim of the long term sleep monitoring was
to elicit the maximum spontaneous amount of sleep in relaxed and quiet, but not
totally abnormal conditions, while any sleep episode, whether at night or
during daytime, was never be interrupted by the technicians. Controls and
patients were already in the sleep unit for 24 hours. They received dinner at 7
pm. TV, computer, and visit from friends were forbidden, but books, newspapers,
watches and daylight were allowed. After 9 pm, the participants were free to
determine when they wanted switch lights off for the evening, and were allowed
to sleep until they spontaneously awakened (and turned lights on) the next day.
In addition, all subjects were asked to lay down in the dark for two naps
during the morning and the afternoon. The nap attempts were discontinued by the
subjects after 30 min if they could not sleep, and were continued ad libitum when they fell asleep. Tests
were stopped at 5 pm the last day. In total, this procedure provided a 20-hour
long opportunity to sleep for all subjects. Subjects received a breakfast after
waking up, and a lunch if they woke up for. This procedure is highly
recommended in order to diagnose idiopathic hypersomnia,9, 18 but
does not yield standardized values for healthy subjects. As part of our current
study, we present normative values here.
Polysomnographic recordings included an electroencephalography (Fp1-A2,
C3-A2, O1-A2), left and right electro-oculograms, levator menti and bilateral
tibialis anterior surface electromyography, nasal pressure trough cannulae,
respiratory efforts using thoracic and abdominal belts, position, tracheal
sounds, pulse rate and transcutaneous oximetry (Medatec Ltd France) during the
first night. The respiratory sensors were removed during the MSLT and the
24-hour sleep monitoring. Sleep stages, arousals, periodic leg movements, and
respiratory events were scored visually according to standard criteria.19-22
The total sleep time, total sleep period, sleep and REM sleep latencies, the
durations and percentages of non REM sleep stage 1, 2, 3-4, and REM sleep were
determined during Night 1 and Night 2, and during the 24-hour monitoring
procedure. The indexes of sleep fragmentation (that is, the arousal index,
periodic leg movements, periodic leg movement-associated arousal index, and
apnea-hypopnea index), and minimal oxygen saturation during sleep were measured
during Night 1. In order to determine whether it was correlated with sleep
drunkenness, we noted the time of offset of the last slow wave sleep (SWS)
episode that lasted longer than 5 minutes during the second night sleep.
Statistical analysis
The patients with narcolepsy with long sleep time were compared as a
group to each of the other studied groups, in order to determine whether they
are more similar to those with classical narcolepsy or those with idiopathic
hypersomnia with long sleep time. We analyzed our between-group dichotomous
variables using chi-square tests, and analyzed our continuous variables using
analysis of variance (Statistica 7.1, Stat Soft Inc, Tulsa, OK). A p value less
than 0.05 was considered to be significant (with corrections for repeated measures).
Values are presented as mean ± SD (unless otherwise specified).
Results
Clinical differences between narcoleptics with long
sleep time and other groups
Among these 160 narcoleptics, we isolated 29 (18.1%) patients with a
diagnosis of narcolepsy with long sleep time (that is, with a total sleep time
greater than 11 hours on 24-hour, long-term sleep monitoring). None of these
participants had a personal or family history of long sleeper prior to the
sleepiness onset. Their demographic and clinical characteristics, compared to
other participant groups are summarized in Table 1. The age, body mass index
and sex ratio of narcoleptics with long sleep time did not differ from controls
(as expected by the matching procedure), nor did these differ from classical
narcoleptics. The age at symptom onset was similar in the narcoleptics with
(18.1±5.3 y) and without (19.9±6.2 y, P=0.46) long sleep time. At the time of
the polysomnography, the disease course was similar in narcoleptics with (9±8
y, range: 1-21 y) and without (8±8 y, range: 1-24 y, P=0.77) long sleep time.
Hypnagogic hallucinations, cataplexy, sleep paralysis, as well as sleep
drunkenness and HLA DQB1*0602 positivity were as frequent in narcoleptics with
and without long sleep time, but the naps were more frequently unrefreshing in
the narcoleptics with long sleep time, and the Epworth sleepiness score was
lower. All these symptoms (except
cataplexy), were observed in the group of patients with idiopathic hypersomnia
with long sleep time, but not in the controls. As for what can be defined as
‘core narcolepsy’ (i.e. the association in the same patient of clear cut
cataplexy, short MSL, multiple SOREMPs and HLA positivity), there were 3/23
(13%) patients with ‘core narcolepsy’ in the group of narcoleptics with long
sleep time, and 7/29 (24%) in the group of narcolepsy without long sleep time.
These percentages were not different. The demographical, clinical and sleep
characteristics of this subgroup is displayed in the Supplementary Table A.
Sleepiness and fatigue scores were similar for the three patient groups, and
all three patient groups scored higher than those in the control group did. The
same pattern was observed for anxiety and depression scores, which were
slightly higher in patients than in controls. As evidenced by their
Horne-Ostberg scores, narcoleptics with long sleep time had a more advanced
sleep phase than patients with idiopathic hypersomnia, but were not different
from controls and from other narcoleptics.
Polysomnographic differences between narcoleptics with
long sleep time and other groups
The polysomnographic measures for all groups are displayed in Table 2.
As expected, night-time sleep time was two-hours longer in narcoleptics with
long sleep time than those without, was one hour and 30 minute longer than for
control subjects, but was 50 min shorter than for patients with idiopathic
hypersomnia. Accordingly, this difference corresponded to one additional sleep
cycle in narcoleptics with long sleep time and hypersomniacs, as compared to
the other groups, while sleep cycle durations were similar across all groups.
Sleep efficiency was higher in narcoleptics with (92.4%) than without long
sleep time (87.1 %, P=0.04). In all groups, sleep onset latency was similar,
though REM sleep latency was shorter in narcoleptics than in controls. As
concerns sleep architecture, there were no differences between narcoleptics
with long sleep time and any other group for the percent of sleep stages 1, 2,
3-4 and REM sleep. All groups contained similar numbers of subjects with slow
wave sleep after 6 am, though the last slow wave sleep episode for the
narcolepsy with long sleep time group occurred later than in controls, and
earlier than in patients with idiopathic hypersomnia. As concerns sleep fragmentation
and movements, narcoleptics with long sleep time did not differ from other
patient groups, but had less arousals and more frequent periodic leg movements
than did controls. The respiratory disturbances indexes were generally low and
were not different between groups.
During the multiple sleep latency tests, the mean sleep latency was
shorter in narcoleptics (whether they had or not a long sleep time) than in
hypersomniacs or control subjects. There were as many SOREMPS in narcoleptics
with and without long sleep time.
During the 24 hour-long sleep monitoring, daytime sleep time was longer
in narcoleptics with long sleep time than in all other groups. On a 24-hour
basis, narcoleptics with long sleep time (as expected) produced longer sleep
amounts than the other narcoleptics or the controls, with a mean sleep amount
of 738 ± 58 min (12.3 hours,
range:11-14.5 hours), similar to the total sleep of patients with idiopathic
hypersomnia (that is, with no change in the breakdown of sleep stages). That
is, narcoleptics with long sleep time slept 3 hours more per 24 hr than the
other narcoleptics. An example of 24 hour-long sleep hypnogram in patients with
narcolepsy/cataplexy with and without long sleep time is displayed in Figure 1.
If one isolates the narcoleptics sleeping more than 10 hours per night,
they represent only 12/23 patients. Except they were younger (23.8 ± 6.7 y)
than the other narcoleptics (31.2 ± 10.1 y, P=0.03, a difference not seen when
the threshold for long sleep time is 11hr/24r), the differences with the three
other groups were similar to what we found before (supplementary Tables B and
C). Compared to other narcoleptics, they had a longer sleep at night and during
24 hr monitoring, with a higher sleep efficiency. Compared to controls, they
had more frequently HLA positivity and hypnagogic hallucinations, and higher
subjective scores of sleepiness, fatigue, anxiety and depression. Compared to
patients with idiopathic hypersomnia, they had higher Horne-Ostberg scores.
As a spinal tap is not considered a routine procedure for the diagnosis
of narcolepsy when it is possible by other means, we could gather only a single
measure of cerebrospinal hypocretin-1. This procedure was performed in Stanford
University in one of our narcoleptic patients with no typical cataplexy and
long sleep time. The hypocretin-1 level was undetectable (that is, it was lower
than 40 pg/mL).
Discussion
The subgroup of narcoleptics with long sleep time represents 18% of a
consecutive series of narcoleptics in a tertiary sleep disorders unit. This
subgroup shares many similarities with classical narcolepsy (namely, similar
rates of cataplexy, sleep paralysis, hypnagogic hallucinations, short daytime
mean sleep latency with multiple sleep onset in REM periods, and half were HLA
positive). This group, however, has per definition, longer sleep time during
the night and day, with higher sleep efficiencies. As for the increased sleep
amounts, this group most resembles the patients with idiopathic hypersomnia and
long sleep time, with both groups sleeping a mean 12 hours per day. The three
patient groups have similarly high scores of sleepiness and fatigue, and mild
scores of anxiety and depression, which clearly differentiate them from healthy
controls.
One may object that
narcoleptics with long sleep time could be some former long sleepers that later
developed narcolepsy, and hence present with a mixture of a physiological trait
(long sleeper) and disease (narcolepsy). This is not the case here, as our
patients had no previous personal or family history of long sleep time. Acute
recent onset narcolepsy has been occasionally associated with increased sleep
amount, especially in children.23 However, in our series, there were
no children or patients with recent onset (lower than 1 year) narcolepsy, and
no different disease course between narcoleptics with and without long sleep
time was observed. This suggests that the long sleep time phenotype may last
beyond the first years of disease.
In the past, several
groups concluded that narcoleptics fail to demonstrate an excess need for sleep
when given a chance to sleep uninterrupted for 24 hours.7, 24 In
contrast, one patient with narcolepsy slept 17 hours during a 24-hour sleep
monitoring, while three other narcoleptics slept more than 11 hours in a series
of 8 narcoleptics monitored during bed rest.25 In a large study of
157 Italian patients with narcolepsy, narcoleptics declared to sleep one hour
more (per 24 hours) than the controls, with standard deviations suggesting that
some of them would sleep more than 11 hours.26 The occasional
presence of narcoleptics with sleep drunkenness and unrefreshing naps has not
been totally overlooked in the history of narcolepsy. Daniels early stated that
“Although patients with narcolepsy are
usually fresher early in the morning than during the remainder of the day, some
become very drowsy shortly after arising from a good night’s rest; an unusually
long night’s sleep may even increase the diurnal drowsiness.”27
In a group of 41 patients with narcolepsy/cataplexy, 59% did not feel
refreshed in the morning, 39% had an incomplete awakening suggestive of
sleep drunkenness, while 5% had non-refreshing naps.28 The
possibility of isolating a group of narcoleptics with long sleep time is of
both clinical and pathophysiological interest. Narcoleptics with long sleep
time may have more daytime problems than patients with classical narcolepsy do,
because they share the main features of narcolepsy, but have additional
difficulties waking up refreshed, being on time at work or at school in the
morning, and do not benefit from short, refreshing naps. In our experience,
they are the most difficult to treat, although this aspect was not formally
addressed in this paper.
The main limitation of
this series is the absence of measure of the CSF hypocretin-1 levels, except in
one narcoleptic. Though this narcoleptic was hypocretin-1 deficient and had a
long sleep time, we cannot yet determine how many narcoleptics with long sleep
time are also hypocretin-1 deficient; further research is required. As
hypocretin-1 is deficient in 88-93% of narcoleptics with clear-cut cataplexy,
HLA positivity, and no family history of narcolepsy,29,30 it has
been suggested that these clinical and biological characteristics define a homogenous
subgroup of ‘core narcolepsy’. This ‘core narcolepsy’ is however also found in
13 % of patients with long sleep time. The pathophysiology of the ‘narcolepsy
with long sleep time’ phenotype is unknown, as is the cause of idiopathic
hypersomnia, which challenges our concept of hypocretin as consolidating the
sleep-wake transitions. Hypocretin-deficient animals do not, however, display
increased amounts of sleep, suggesting that additional deficits in arousal
systems must be necessary for developing a true ‘hypersomnia’. Animals with
double invalidation of genes coding for neurotransmitters involved in
regulating arousal (e.g., hypocretin and histamine) could be useful for
investigating these hypotheses. Our patients may potentially have a double dysfunction
in their arousal systems. The observation of long sleep time during acute onset
narcolepsy, disappearing years after, suggests that some (but not all) patients
compensate for this deficit, with differences being potentially dependent on
their genetics. Furthermore, recent measures of CSF histamine levels in
narcoleptics, controls and patients with idiopathic hypersomnia suggest that
the histamine arousal systems can also be deficient in some of these subjects.30,31
Anyway, demographical and clinical data on sleep excess, as well as animal
models with excess sleep amounts, are yet lacking.32
After the recent sleep
disorders reclassification, the narcolepsy/hypersomnia landscape is becoming
richer with the addition of syndromes previously considered as atypical,
including narcolepsy without cataplexy and hypersomnia without long sleep time
(which resembles narcolepsy, but does not involve REM sleep abnormalities).
Mirroring this subgroup, narcolepsy with long sleep time resembles idiopathic
hypersomnia with long sleep time but contains numerous REM sleep abnormalities.
To illustrate this concept, we suggest a table classifying the four groups,
depending on sleep time, MSLT results and SOREMPs (Table 3). Patients suffering
this form of narcolepsy are more disabled than others, with shorter mean sleep
latencies and a trend for more frequent sleep drunkenness and unrefreshing
naps; hence, they may comprise a clinical spectrum that deserves specific
medical attention.
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Table 1-Clinical and biological
characteristics of narcoleptics with long sleep time (Total sleep time during
the 24-hours monitoring > 11 hours)
compared with patients with narcolepsy without long sleep time, idiopathic
hypersomnia with long sleep time and controls.
|
Patients |
Narcolepsy with long sleep time |
Narcolepsy without long sleep time |
Idiopathic hypersomnia with long sleep time |
Controls |
|
Number |
23 |
29 |
25 |
20 |
|
Age, y |
25.7 ± 10.6 |
30.8 ± 10.1 |
29.6 ± 12.5 |
29.4 ± 8.7 |
|
Body mass index, kg/m2 |
25.3 ± 6.0 |
24.5 ± 6.2 |
23.2 ± 3.6 |
23.9 ± 4.8 |
|
Women, % |
61 |
56 |
72 |
65 |
|
Hypnagogic
hallucinations, % |
44 |
68 |
32 |
10 * |
|
Sleep paralysis, % |
37 |
47 |
37 |
0 * |
|
Non refreshing naps, % |
80 |
33 * |
59 |
0 * |
|
Sleep drunkenness, % |
54 |
42 |
72 |
0 * |
|
Clear-cut cataplexy, % |
29 |
44 |
0 * |
0 * |
|
HLA DQB1*0602 positive, % |
53 |
54 |
30 |
10 * |
|
Core narcolepsy, % † |
13 |
24 |
NA |
NA |
|
Epworth Sleepiness score (0-24) |
14.8 ± 3.4 |
17.1 ± 3.4 * |
15.1 ± 4.5 |
5.8 ± 2.0 * |
|
Fatigue Severity Score (0-70) |
50.3 ± 10.6 |
55.1 ± 6.3 |
51.1 ± 10.7 |
31.6 ± 9.2 * |
|
Pichot Fatigue Score (0-32) |
27.9 ± 7.8 |
27.2 ± 7.2 |
24.9 ± 9.0 |
11.0 ± 3.5 * |
|
HAD anxiety (0-21) |
10.5 ± 5.7 |
11.9 ± 4.0 |
9.5 ± 4.5 |
5.6 ± 3.3 |
|
HAD depression (0-21) |
6.5 ± 3.1 |
5.3 ± 2.8 |
6.4 ± 5.0 |
3.9 ± 2.8 * |
|
Horne-Ostberg score |
50.6 ± 10.1 |
46.1 ± 14.7 |
39.3 ± 13.4 * |
54.8 ± 7.6 |
† Core narcolepsy: simultaneous presence of
clear-cut cataplexy and HLA DQB1*0602 positivity, which yields a 88-93%
sensitivity for hypocretin deficiency. * P<0.05 for a difference between
narcolepsy with long sleep time, HLA: human leukocyte antigen; HAD: score at
the hospital anxiety and depression scale
Table 2-Sleep measures during
night-time, MSLT and 24-hour long monitoring in narcoleptics with long sleep
time (Total sleep time during the 24-hours monitoring > 11 hours) compared with patients with
narcolepsy without long sleep time, idiopathic hypersomnia with long sleep time
and controls.
|
Patients |
Narcolepsy with long sleep time |
Narcolepsy without long sleep time |
Idiopathic hypersomnia with long sleep time |
Controls |
|
|
Number |
23 |
29 |
25 |
20 |
|
|
Night-time sleep |
|
|
|
|
|
|
Total sleep time, min |
607 ± 61 |
477 ± 61 * |
655 ± 57 * |
517 ± 60 * |
|
|
Sleep efficiency, % |
92.4 ± 6.7 |
87.1 ± 11.0 * |
93.9 ± 4.5 |
91.1 ± 4.6 |
|
|
Latency to, min |
|
|
|
|
|
|
Sleep onset |
25 ± 25 |
21 ± 30 |
28 ± 37 |
34 ± 21 |
|
|
REM sleep |
53 ± 34 |
55 ± 35 |
70 ± 30 * |
78 ± 32 * |
|
|
Sleep stages, % total |
|
|
|
|
|
|
Stages 1-2 |
53.3 ± 9.7 |
54.9 ± 8.1 |
55.1 ± 7.1 |
52.0 ± 7.4 |
|
|
Stages 3-4 |
22.1 ± 11.1 |
22.5 ± 5.3 |
20.7 ± 8.7 |
24.9 ± 6.1 |
|
|
REM sleep |
24.6 ± 6.4 |
22.2 ± 5.2 |
24.1 ± 6.9 |
22.8 ± 4.2 |
|
|
Sleep cycle numbers |
6.5 ± 1.1 |
5.2 ± 0.9 * |
6.5 ± 0.7 |
5.5 ± 0.8 * |
|
|
Sleep cycle duration, min |
95 ± 15 |
97 ± 13 |
103 ± 11 |
94 ± 11 |
|
End of the night |
|
|
|
|
|
|
SWS after 6 am, %
patients |
60.9 |
48.2 |
80.9 |
45.0 |
|
|
Time of last SWS episode, am |
8:03 ± 1.03 |
8:04 ± 1:08 |
9:47 ± 2:01 * |
6:21 ± 1:37 * |
|
|
Sleep fragmentation |
|
|
|
|
|
|
Arousals, n/h |
11.6 ± 5.0 |
14.0 ± 6.8 |
10.5 ± 6.0 |
21.8 ± 10.6 * |
|
|
Periodic legs movements, n/h |
6.8 ± 7.2 |
8.2 ± 14.4 |
9.4 ± 17.0 |
1.3 ± 1.5 * |
|
|
Periodic legs movement arousals, n/h |
1.3 ± 1.1 |
1.9 ± 3.4 |
1.2 ± 2.2 |
0.5 ± 0.7 * |
|
|
Apnea/hypopnea, n/h |
1.8 ± 2.9 |
1.9 ± 2.7 |
1.6 ± 3.6 |
2.3 ± 2.9 |
|
|
Daytime sleep time, min |
131 ± 52 * |
86 ± 57 * |
90 ± 62 * |
47 ± 33 * |
|
|
Sleep during 24 hour monitoring |
|
|
|
|
|
|
Total sleep time, min |
738 ± 58 |
562 ± 66 * |
745 ± 72 |
564 ± 61 * |
|
|
Sleep stages, % total |
|
|
|
|
|
|
Stages 1-2 |
54.1 ± 9.5 |
55.3 ± 7.6 |
57.6 ± 7.8 |
54.7 ± 7.1 |
|
|
Stages 3-4 |
21.9 ± 11.0 |
22.2 ± 5.6 |
20.0 ± 8.9 |
23.9 ± 5.6 |
|
|
REM sleep |
24.0 ± 6.1 |
22.0 ± 4.8 |
22.3 ± 6.3 |
21.3 ± 4.1 |
|
|
|
|
|
|
|
|
|
Multiple sleep latency test |
|
|
|
|
|
|
Mean sleep latency ± SE, min |
5.1 ± 0.5 |
6.5 ± 0.6 |
8.7 ± 0.9 * |
15.3 ± 0.8 * |
|
|
Number of SOREMPs |
3.3 ± 1.4 |
2.7 ± 1.5 |
0.2 ± 0.5 * |
0.2 ± 0.6 * |
|
* P<0.05 for a difference between narcolepsy with long sleep time;
SWS: slow wave sleep (non REM sleep stages 3-4); SOREMP: sleep onset in rapid
eye movements sleep period.
Table 3 - Suggested classification of the four groups
of patients without cataplexy, depending on sleep time, MSLT results and
SOREMPs
|
|
Total sleep time lower than 10 hr
and MSL lower than 8 min |
Total sleep time greater than 10
hr |
|
0 or 1 SOREMP |
Idiopathic hypersomnia without
long sleep time |
Idiopathic hypersomnia with long
sleep time |
|
2 or more SOREMPs |
Narcolepsy |
Narcolepsy with long sleep time |