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SLEEP, Vol. 38, No. 8, 2015 1285 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
INTRODUCTION
Narcolepsy is characterized by excessive daytime sleepiness
(EDS) with or without cataplexy (sudden loss of muscle tone
typically triggered by strong emotion), hypnagogic hallucina-
tions and sleep paralysis, and disturbed nocturnal sleep.1 Until
recently, and at the time this study was conducted, the disorder
was categorized into narcolepsy with cataplexy (NwC) and
narcolepsy without cataplexy (NwoC) according to the revised
second edition of the International Classication of Sleep Disor-
ders (ICSD).2 ICSD-2-revised has now been replaced by ICSD-3,
which classies the disorder into narcolepsy type 1 (with hypo-
cretin deciency) characterized by EDS and one or both of
the following: cataplexy and a mean sleep latency of up to 8
min and two or more sleep onset rapid eye movement periods
Study Objectives: To evaluate the frequency, severity, and associations of symptoms of attention-decit/hyperactivity disorder (ADHD) in
children with narcolepsy with and without cataplexy.
Design: Cross-sectional survey.
Setting: Four French national reference centers for narcolepsy.
Patients: One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy
(NwoC, n = 22), and 67 healthy controls.
Interventions: The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime
sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,
Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic
measures were collected.
Measurements and Results: Clinically signicant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients
with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% condence interval [CI]: 4.5, 9.0) in controls
compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores
of inattention and hyperactivity/impulsivity were also signicantly higher in both narcolepsy groups compared with controls. No difference was
found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness,
fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modanil in 91%) showed a trend
toward lower narcolepsy symptoms but not lower ADHD symptoms.
Conclusions: Pediatric patients with narcolepsy have high levels of treatment-resistant attention-decit/hyperactivity disorder (ADHD) symptoms.
The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies.
Keywords: attention-decit disorder with hyperactivity, methylphenidate, modanil, narcolepsy, pediatrics
Citation: Lecendreux M, Lavault S, Lopez R, Inocente CO, Konofal E, Cortese S, Franco P, Arnulf I, Dauvilliers Y. Attention-decit/hyperactivity
disorder (adhd) symptoms in pediatric narcolepsy: a cross-sectional study. SLEEP 2015;38(8):1285–1295.
ADHD SYMPTOMS IN PEDIATRIC NARCOLEPSY
Attention-Decit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric
Narcolepsy: A Cross-Sectional Study
Michel Lecendreux, MD1,2; Sophie Lavault, Msc2,3; Régis Lopez, MD2,4; Clara Odilia Inocente, MD5; Eric Konofal, MD, PhD1,2, 3; Samuele Cor tese, MD, PhD6,7;
Patricia Franco, MD, PhD2,5,8; Isabelle Arnulf, MD, PhD2,3; Yves Dauvilliers, MD, PhD2,4
1AP-HP, Pediatric Sleep Center, CHU Robert-Debré, Paris, France; 2National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic
hypersomnia and Kleine-Levin Syndrome, France; 3AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service des Pathologies du Sommeil & Université
Pierre et Marie Curie - Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Paris, France; 4Sleep Disorders Center,
Depart ment of Neurology, Gui-de- Chauliac Hospital, CHU Montpellier, Inserm U1061, Montpellier, France; 5Integrative Physiolog y of Brain
Arousal System, CRNL, University Lyon 1, Lyon, France; 6Depart ment of Psychology, Developmental Brain-Behaviour Laboratory, University of
Southampton, Southampton, UK; 7New York University Child Study Center, New York, NY; 8Pediatric Sleep Unit, Hôpital Femme-Mère Enfant,
University Lyon 1, Lyon, France
Submitted for publication September, 2014
Submitted in nal revised form November, 2014
Accepted for publication January, 2015
Address correspondence to: Michel Lecendreux, MD, CHU Robert-De-
bré, 48, Boulevard Serurier, 75019 Paris, France; Tel: +33140031350;
Fax: +33140034770; Email: michel.lecendreux@rdb.aphp.fr
pii: sp-00552-14 http://dx.doi.org/10.5665/sleep.4910
(SOREMPs) during multiple sleep latency tests (MSLTs) per-
formed according to standard techniques (REM onset within 15
min of sleep onset during preceding nocturnal polysomnography
[PSG] may replace one of the SOREMPs during the MSLTs);
and a cerebrospinal uid (CSF) hypocretin-1 level ≤ 110 pg/mL.
Narcolepsy type 2 (without hypocretin deciency) is character-
ized by EDS and all four of the following: MSLT criteria as per
type 1, absence of cataplexy, CSF hypocretin-1 level > 110 pg/
mL (if a lumbar puncture was performed), and EDS not being
better explained by other causes.3
Childhood narcolepsy is usually characterized by higher
levels of EDS, more frequent spontaneous than emotion-trig-
gered cataplexy, and more frequent secondary forms of the
disease. In addition to nocturnal sleep difculties and EDS,
narcolepsy affects metabolic and neuropsychiatric dimensions
resulting in obesit y,4 depressive symptoms,5 and attention- def-
icit/hyperactivity disorder (ADHD) symptoms,6 all of which
contribute to reduced quality of life7 and lower academic per-
formance in young people.6,8 In th is repor t, we focus on ADH D
symptoms in pediatric narcolepsy.
ADHD is characterized by a persistent, age-inappropriate
pattern of behavior, which is present in multiple settings (e.g.,
SLEEP, Vol. 38, No. 8, 2015 1286 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
school and home) and may result in impaired social, educa-
tional, or work performance. Symptoms are divided into two
categories: inattention (e.g., difculty sustaining attention,
difculty organizing tasks, excessive distractibility) and/or
hyperactivity-impulsivity (e.g., excessive dgeting, difculty
remaining seated, difculty waiting turn) and several should
have been present before 12 years of age.9 Given that decits
of alertness and sleep disturbances have been hypothesized
to contribute to ADHD,10,11 comorbid ADHD symptoms are
likely to be found in young people with narcolepsy. ADHD
symptoms have been infrequently investigated in narcolepsy,
especially in children.12,13 Some retrospective reports in adults
with narcolepsy have identied frequent ADHD symptoms in
childhood.14,15 Given these ndings, there may be common un-
derlying pathophysiological mechanisms linking narcolepsy
and ADHD such that treatment for one condition may improve
and/or affect the other, especially since treatments for narco-
lepsy, such as modanil and methylphenidate,16 are also used
in children with ADHD.
We aimed to investigate ADHD symptoms in pediatric nar-
colepsy, using cross-sectional data from: (1) a large cohort
of children and adolescents with narcolepsy (with or without
cataplexy) referred to and followed up in four national narco-
lepsy reference centers in France, and (2) control children. Spe-
cically, we evaluated the frequency and severity of ADHD
symptoms, and their associations with EDS, insomnia, fatigue,
PSG characteristics, and psychostimulant treatment for nar-
colepsy. These associations were examined in both univariate
and multivariate analyses (e.g., including the effect of age, sex,
and body mass index z-score). In patients with clinically sig-
nicant levels of ADHD symptoms, the burden of depressive
symptoms, educational difculty, and lower quality of life
were also assessed. Given the exploratory nature of the study,
no a priori hypotheses were formulated.
METHODS
Participants
All children (younger than 12 y) and adolescents (12–18 y)
with NwC or NwoC who were consecutively seen in the four
French national reference centers for narcolepsy (Hospital
Robert-Debré, Paris; Hospital Femme-Mère Enfant, Hospital
Pitié-Salpétrière, Paris; Hospital Gui de Chauliac, Montpellier)
between August 2008 and March 2011 were invited to take part
in a national research program on narcolepsy (NARCOBANK).
Patients underwent clinical assessment by the lead physician
at each center (ML, PF, IA, YD). Both parents and children
signed a written consent form. The study was approved by the
local ethics committee (Comité de Protection des Personnes
- Ile de France 06). According to a predened study protocol,
clinical and questionnaire data were collected in a computer-
ized database specically programmed for this study.
To achieve a positive diagnosis of narcolepsy, all patients had
a medical interview by the sleep specialist at each center, and
underwent PSG followed by MSLTs and class II HLA typing;
a subsample underwent measurement of CSF hypocretin-1
levels. Patients were classied as having narcolepsy according
to the criteria of ICSD-2-revised,2 including: (1) complaints of
EDS for at least 3 mo; (2) symptoms not better explained by
other medical or psychiatric disorders; (3) the absence of sec-
ondar y narc olepsy; (4) the prese nce of clea r-cut cat aplexy; and/
or (5) multiple sleep latency during MSLTs lower than 8 min
with two or more SOREMPs. NwC and NwoC patients were
included, who all met the ICSD-2-revised narcolepsy criteria.
PSG was performed from 20:00–22:00 (children) or from
23:00 to 07:00 (adolescents) and was followed the next day by
ve (or four at the Lyon study center) standard MSLTs at 09:00,
11:00, 13:00, 15:00, and 17:00, which were terminated after 20
min if no sleep had occurred, and after 15 min asleep if sleep
did occur. PSG included at least three (or eight)-lead EEG, two
electrooculograms, a chin electromyography, nasal pressure
trough cannula, thoracic and abdominal belts, electrocardi-
ography, and transcutaneous oximetry. Sleep stages, arousals,
and respiratory events were scored visually in accordance with
international criteria.17
HLA class II genotyping was planned to be undertaken in all
subjects. A lumbar puncture was performed when clinically nec-
essary or for research purposes with the specic agreement of
parent and child. The CSF samples were collected, immediately
frozen, and transferred to Gui de Chauliac Hospital (Montpel-
lier) for measurement of hypocretin-1 levels using a standard-
ized radioimmunoassay. Samples were thawed once and CSF
hypocretin-1 was determined in all available samples in dupli-
cate using radioimmunoassay kits (Phoenix Peptide, Phoenix
Pharmaceuticals, Inc., 330 Beach Road, Burlingame, CA 94010,
USA) according to the manufacturer’s instructions. The detec-
tion limit was 10 pg/mL and intra-assay variability was < 10%.
CSF hypocretin-1 levels ≤ 110 pg/mL were considered as low,
110–200 as intermediate, and > 200 as normal.18 All values were
cross-referenced to Stanford reference samples (HHMI Stan-
ford University Center for Narcolepsy, Palo Alto, CA).
Healthy young children and adolescents, who were siblings
of patients attending Hospital Robert-Debré, Hospital Femme-
Mère Enfant, and Hospital Pitié-Salpétrière, were recruited by
invitation from study investigators or through advertisements
displayed in these and other public hospitals between 2008
and 2011. They were included if they had no current daytime
sleepiness validated by a score lower than 9 in a modied
(adapted for children and adolescents) sleepiness scale.19 All
participants (plus the parents of minors) signed a written con-
sent for the study.
Clinical Examination
A complete physical examination was conducted and found
to be normal for both patients with narcolepsy (thus, no patients
with secondary narcolepsy were included in this analysis) and
for controls. Height and weight measurements were conducted
at time of entry in the study. Body mass index (BMI) was cal-
culated (weight/height2) and a z-score computed representing
a standardized measure of weight adjusted for height, sex, and
age relative to a smoothed reference distribution.20 Using stan-
dardized growth curves, overweight, which included obesity,
was dened, as per the International Obesity Task Force cri-
teria, as being on or above the centile trajectory corresponding
to a BMI of 25 kg/m2 at the age of 18 y. Obesity was dened
as being on or above the centile trajectory corresponding to a
BMI of 30 kg/m2 at the age of 18 y.21 No clinical assessment or
formal diagnosis of ADHD was undertaken.
SLEEP, Vol. 38, No. 8, 2015 1287 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
Interventions
Most patients were offered treatment for narcolepsy fol-
lowing the diagnosis of narcolepsy, which could include psy-
chostimulants, but no specic treatment for elevated ADHD
symptoms was initiated. Thus, it is important to note that psy-
chostimulant therapy in this study was optimized solely for the
treatment of narcolepsy.
Questionnaire Measures
Daytime sleepiness was evaluated with the Pediatric Day-
time Sleepiness Scale (PDSS),22 which has a score range of
0–44. Insomnia symptoms were evaluated using the Insomnia
Severity Index (ISI), which has a score range of score 0–28.23
Fatigue was scored with the Chalder fatigue scale24 using the
11-item version (score range of 0–11), which has been validated
in children and adolescents.25 Sy mptoms of ADHD were sco red
by parents using the ADHD rating scale (ADHD-RS), based
on the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV-TR)26 symptoms with a maximum score of 54.27 In
addition to continuous symptom scores, clinically signicant
levels of total ADHD (i.e., inattention + hyperactive-impulsive
symptoms), inattention only, and hyperactive-impulsive only
symptoms were calculated using 90th, 93rd, and 90th percen-
tile thresholds, respectively, based on published norms by age
and sex.28 Parents were asked if their children needed to repeat
a school grade, which was scored as binary yes/no response.
The Children’s Depression Inventory (CDI), which has a score
range of 0–54, was used to assess symptoms of Major Depres-
sive Disorder.29 Heal th-r elated quali t y of life was assess ed usi ng
a questionnaire developed for adolescents, the VSP-A (“Vécu et
Santé Perçue de l’Adolescent” [perceived health-related quality
of life in adolescents]),30 which has also been adapted for use in
children31 ; both versions have a score range of 0–100.
Statistical Analysis
Descriptive statistics for continuous variables were expressed
as median (min–max) and categorical variables as number (per-
cent). For continuous outcomes, between-group statistical com-
parisons were conducted within a Generalized Linear Models
(GLM) framework using appropriate family and link functions
depending upon whether responses and/or residual errors were
normally (BMI z-score, quality of life scores) or nonnormally
(ADHD-RS, CDI, PDSS, ISI, and fatigue scores) distributed.32
Given that data were obtained from four separate participating
study centers, a term for study center was added to all univar-
iate and multivariate models and estimated population marginal
means, otherwise known as least-squares (LS) means, and 95%
condence intervals (CIs) were calculated for between-group
comparisons to obtain adjusted estimates that took variations
attributable to study center into account. For nontransformed
variables, LS means were calculated, for log-transformed vari-
ables, LS geometric mean ratios (GMRs) were calculated, which
were also back-transformed where appropriate for graphical
representation. GLM analyses were conducted using the GLM
function within the R statistical soft ware platform version 3.0.2
(http://www.R-projec t.org).
For variables with distributions that could not be satisfacto-
rily transformed to normality (age at database registration, CSF
hypocretin-1), nonparametric comparisons were performed
using the npar.t.test function for comparisons of two groups
and the nparcomp function for comparisons of three or more
groups from the nparcomp package in R (http://cran.r-project.
org/web/packages/nparcomp/index.html). Differences in pro-
portions and associated 95% CIs were calculated using the
diffscoreci function from the PropCIs package in R (http://
cran.r-project.org/web/packages/PropCIs/index.html).
Appropriate transformations were performed for PSG vari-
ables that were not normally distributed prior to analysis. PSG
variables entered into the initial screening model were total
sleep time (minutes), sleep efciency (%), log percent time
in sleep stage 1, percent time in sleep stage 2, percent time
in sleep stage 3– 4, percent time in REM sleep, log latency to
sleep onset (minutes), log latency REM sleep onset (minutes),
log apnea-hypopnea (AHI) index (log AHI), log mean sleep
latency of the MSLT (minutes), and number of episodes of
SOREMPs. Missing data were too extensive to include peri-
odic limb movements during sleep.
Exploratory multivariate regression analyses were con-
ducted using GLMs as described previously; however, for ini-
tial PSG variable screening, stepwise selection was performed
using the stepAIC function from the MASS package in R
(http://cran.r-project.org/web/packages/MASS/index.html).
Statistical signicance was determined at a level of alpha
lower than 0.05, unadjusted for multiple comparisons in this
exploratory, cross-sectional study.
RE S ULTS
Demographic and Physical Characteristics at Database
Registration
Overall, 108 patients with narcolepsy and 67 control chil-
dren were recruited. Of these, 78/108 patients with narcolepsy
(72.2%) and 63/67 of controls (94.0%) had available ADHD-
RS scores. Age at database registration was signicantly lower
in the NwoC group compared with the NwC (P = 0.044) and
control gr oups (P = 0.012). The distribution of male and female
children/adolescents was comparable across groups. Com-
pared with the control group, BMI z-score (adjusted for age
and sex) was signicantly higher in the NwC (least squares
[LS]-mean difference 1.17; 95% CI: 0.48, 1.87; P < 0.001) and
NwoC group (LS-mean difference 1.22; 95% CI: 0.37, 2.07;
P = 0.005). Greater proportions of patients with narcolepsy
were overweight or obese compared with controls (Table 1).
As indicated in Table 2, there were signicantly more HLA
DQB1*06:02 positive patients in the NwC group than the
NwoC group (difference in proportion 20.5 percentage points;
95% CI: 3.6, 42.7; P = 0.040), and CSF hypocretin-1 was sig-
nicantly lower in the NwC group compared with the NwoC
group (P = 0.028). Approximately two-thirds of all patients
(73/108; 68.2%) were receiving treatment for narcolepsy. Of
those treated, nearly all patients were receiving modanil; ad-
ditional treatments included methylphenidate in approximately
50% of patients in both groups, and in the NwC group, so-
dium oxybate, venlafaxine, and other treatments were used.
In treated patients, 68/73 (93.2%) started treatment before
ADHD symptom measurement, 2/73 (2.7%) started treatment
at the time of ADHD symptom measurement, and 3/73 (4.1%)
started treatment shortly after ADHD symptom measurement.
SLEEP, Vol. 38, No. 8, 2015 1288 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
In untreated patients, 17/34 (50.0%) had ADHD symptoms
measured before the diagnosis of narcolepsy, 12/34 (35.3%) at
the time of diagnosis, and 5/34 (14.7%) shortly after diagnosis.
ADHD Symptoms and Categorization in Narcolepsy Versus
Controls
Total ADHD symptoms, inattention symptoms, and hyper-
active-impulsive symptoms were signicantly elevated in pa-
tients with narcolepsy compared with controls, irrespective of
treatment received and of the presence of cataplexy (Figure 1A);
total ADHD symptoms were twofold higher in NwoC than
in controls (least squares geometric mean ratio [LS-GMR]
2.049; 95% CI: 1.409, 2.980; P < 0.001) and 1.8-fold higher in
NwC than in controls (LS-GMR 1.788; 95% CI: 1.26, 2.536;
P = 0.001). Inattention symptoms were 2.2-fold higher in the
NwoC group versus controls (LS-GMR 2.170; 95% CI: 1.498,
3.144; P < 0.001) and 1.9-fold higher in the NwC group versus
controls (LS-GMR 1.873; 95% CI: 1.322, 2.654; P < 0.001).
Hyperactive-impulsive symptoms were 1.6-fold higher in the
NwoC group versus controls (LS-GMR 1.598; 95% CI: 1.048,
2.435; P = 0.029) and 1.5-fold higher in the NwC group versus
controls (LS-GMR 1.528; 95% CI: 1.055, 2.211; P = 0.025).
There were no signicant differences between the two narco-
lepsy groups for total ADHD, inattention, or hyperactive-im-
pulsive symptoms. In addition, in patients with available CSF
hypocretin-1 data (n = 35), no correlation was found between
CSF hypocretin-1 level and total ADHD symptom severity,
or inattention symptom severity or hyperactive-impulsive
symptom severity for either the
NwC or NwoC group.
Proportions with clinically sig-
nicant levels of ADHD symp-
toms were higher in patients with
NwoC and NwC compared with
controls (Figure 1B). For the
total ADHD category, compared
with controls, proportions were
signicantly higher in patients
with NwoC (difference 30.5 per-
centage points; 95% CI: 11.2,
52.6; P = 0.006) and in patients
with NwC (difference 14.9 per-
centage points; 95% CI: 3.7, 27.3;
P = 0.013). For the inattention
category, compared with controls,
proportions were signicantly
higher in patients with NwoC (dif-
ference 30.5 percentage points;
95% CI: 11.2, 52.6; P = 0.006)
and in patients with NwC (differ-
ence 11.4 percentage points; 95%
CI: 0.7, 23.2; P = 0.048). For the
hyperactive-impulsive category,
compared with controls, propor-
tions were signicantly higher
in patients with NwoC (differ-
ence 23.1 percentage points; 95%
CI: 4.9, 47.6; P = 0.034) and nu-
merically higher in patients with
NwC (difference 11.4 percentage points; 95% CI: −2.7, 20.4;
P = 0.053). There were no signicant differences in propor-
tions between the NwoC and NwC groups for the total ADHD,
inattention, or hyperactive-impulsive categories.
Associations with Clinically Significant ADHD Symptoms in
Narcolepsy
Because no signicant differences in levels of ADHD symp-
toms or categorization were observed between the NwoC and
NwC groups, we pooled both groups for subsequent analyses.
Patients with clinically signicant total ADHD symptoms had
greater proportions with school grade repetition compared with
patients without clinically signicant inattention symptoms,
but this difference was not statistically signicant (difference
5.0 percentage points; 95% CI: −15.3, 30.4; P = 0.670). Patients
with clinically signicant total ADHD symptoms had a statisti-
cally signicant 1.4-fold increase in depressive symptoms (LS-
GMR 1.395; 95% CI: 1.072, 1.817; P = 0.013) and a statistically
signicant 10% decrease in quality of life (LS mean difference
−10.165; 95% CI: −18.927, −1.403; P = 0.023) compared with pa-
tients without clinically signicant total ADHD symptoms.
ADHD Symptoms and Narcolepsy Symptoms
Subjectively rated EDS, insomnia, and fatigue were all as-
sociated with total ADHD symptoms, regardless of treatment.
A 10% increase in EDS was associated with a 5.0% increase
in total ADHD symptoms (95% CI: 2.0, 8.1; P = 0.001). A 10%
increase in insomnia was associated with a 6.2% increase in
Tab le 1 —Demographic, physical characteristics, and clinical features at database registration.
Controls
(n = 67)
Narcolepsy
without Cataplexy
(n = 22)
Narcolepsy with
Cataplexy
(n = 86)
Study center, n
Pitié-Salpétrière Hospital, Paris 34 3 2
Gui de Chauliac Hospital,
Montpellier
0110
Robert-Debré Hospital, Paris 19 12 59
Mother and Child Hospital, Lyon 14 6 15
Age, median (min–max), y 14.8 (7.0–17.9) 10.3 (5.9–17.4)* 14.0 (6.6–17.8)†
Age category, n (%)
Child < 12 y 22 (32.8) 12 (54.5) 25 (29.1)
Adolescent ≥ 12 y 45 (67.2) 10 (45.5) 61 (70.9)
Sex, n (%)
Male 27 (40.3) 10 (45.5) 48 (55.8)
Female 40 (59.7) 12 (54.5) 38 (44.2)
BMI
number with missing data, n 16 14
z-score, median (min, max) 0.61 (−1.84, 4.02) 1.94 (−0.64, 5.02)** 1.75 (−2.23, 5.75)***
Overweight (including obesity)
IOTF denition,‡ n (%) 5 (9.8) 11 (52.4)*** 43 (52.4)***
Obesity
IOTF denition,§ n (%) 2 (3.9) 5 (23.8) * 18 (22.0)**
Comparisons versus control: *P < 0.05, **P < 0.01, ***P < 0.001. Comparisons vs narcolepsy without
cataplexy: †P < 0.05. ‡BMI prediction ≥ 25 kg/m2 at 18 years of age. §BMI prediction ≥ 30 kg/m2 at 18 years
of age. BMI, body mass index; IOTF, International Obesity Task Force.
SLEEP, Vol. 38, No. 8, 2015 1289 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
total ADHD symptoms (95% CI: 3.8, 8.6; P < 0.001). A 10%
increase in fatigue was associated with a 4.7% increase in total
ADHD symptoms (95% CI: 2.8, 6.6; P < 0.001).
ADHD Symptoms, Narcolepsy Symptoms, and
Psychostimulants
Because a number of psychostimulants used in nar-
colepsy (e.g., modanil and methylphenidate) also have
activity against inattention and hyperactive-impulsive symp-
toms,33,3 4 we sought to examine levels of ADHD symptoms
in patients with narcolepsy who were either unexposed or
exposed to these treatments. The association between treat-
ment for narcolepsy and ADHD symptoms was analyzed by
comparing patients with narcolepsy not receiving treatment
(reference category) with patients with narcolepsy receiving
modanil or methylphenidate and with controls (dened as
in receipt of no treatment). The modanil and methylpheni-
date groups were split into two groups, those receiving lower
versus higher doses, based upon their median values of 5.56
mg/kg/day (range 2.53–15.20) and 0.52 mg/kg/day (range
0.17–3.20), respectively. Of the 22 patients with available
ADHD-RS scores receiving methylphenidate, 19 were also
receiving modanil. The numbers of patients in each treat-
ment group were too small to conduct meaningful analyses
for the other less commonly used treatments. With untreated
narcolepsy patients as the reference category, controls had
lower total ADHD symptoms (LS-GMR 0.618; 95% CI: 0.415,
0.922; P = 0.018), indicating that patients with narcolepsy had
higher ADHD symptoms regardless of treatment (Figure 2A).
In patients receiving modanil alone at any dose or methyl-
phenidate doses ≥ 0.52 mg/kg/day (+ modanil in 8/10), total
ADHD symptoms were not signicantly different from those
receiving no treatment. In patients receiving methylphenidate
doses < 0.52 mg/kg/day (+ modanil in 7/8), total ADHD
symptoms were higher than in those receiving no treatment
(LS-GMR 1.725; 95% CI: 1.217, 2.445; P = 0.002). In patients
treated with lower-dose methylphenidate < 0.52 mg/kg/day
versus no treatment similar higher levels were observed for
inattention (LS-GMR 1.597; 95% CI: 1.136, 2.246; P = 0.007)
and hyperactive-impulsive symptoms (LS-GMR 1.819; 95%
CI: 1.174, 2.818; P = 0.007).
Tab le 2 —Background clinical features of patients with narcolepsy.
Narcolepsy
without Cataplexy
(n = 22)
Narcolepsy with
Cataplexy
(n = 86)
Age at onset
Missing data, n 7 20
Median (min–max), y 7.8 (2.1–15.0) 9.8 (0.8–16.0)
HLA status
Missing data, n 112
HLA DQB1-06:02, n (%) 15 (71.4) 68 (91.9)†
H1N1 vaccination, n (%) 1 (4.3) 11 (12.8)
Onset post H1N1
Median (min–max), months NA 10.1 (3.6–17.7)
CSF Hypocretin-1, pg/mL
Missing data, n 16 57
Median (min–max) 65.5 (5–359) 10.0 (0–86)†
Value < 110 pg/mL, n (%) 4 (66.7) 29 (100)
Treated, n (%)* 16 (72.7) 57 (67.1)
Missing data, n 0 1
Modanil 15/16 (93.8) 52/57 (91.2)
Methylphenidate 9/16 (56.3) 27/57 (47.4)
Sodium oxybate 0 8/57 (14.0)
Venlafaxine 0 15/57 (26.3)
Other 2/16 (9.1) 12/57 (21.1)
*Patients could be in receipt of more than one treatment. †P < 0.05 vs
narcolepsy without cataplexy. CSF, cerebrospinal uid; HLA, human
leukocyte antigen genotyping; NA, not available. The “Other” category
includes: adranil, dexamphetamine, mazindol, melatonin, selective
serotonin reuptake inhibitors, intravenous immunoglobulins, and tricyclic
antidepressants.
Figure 1—(A) Attention-decit hyperactivity disorder rating scale (ADHD-
RS) scores in controls versus patients with narcolepsy. †Data are back-
tr ansf orme d leas t squ ares (LS) mean s and 95 % con denc e int er val s (CI s)
adjusted for study center derived from a generalized linear model using
Gaussian family and log link. (B) Percent with clinically signicant ADHD
categorization in controls versus patients with narcolepsy. Comparisons
versus controls: * P < 0.05, ** P < 0.01, ***P < 0.001. NwC, narcolepsy
with cataplexy; NwoC, narcolepsy without cataplexy.
6.4
3.8
2.5
***
14.2
***
9.5
*
4.6
**
12.2
***
8.1
*
4.3
0
2
4
6
8
10
12
14
16
18
20
Total ADHD Inattention Hyperactive-
Impulsive
ADHD-RS Score ( 95% CI)†
4.8 4.8
6.3
**
35.3
**
35.3
*
29.4
*
19.7 *
16.1 14 .8
0
5
10
15
20
25
30
35
40
Total ADHD
(90th centile)
Inattention
(93rd centile)
Hyperactive-
Impulsive
(90th centile)
Percent with ADHD Categorization
A
B
Control (n = 63) NwoC (n = 17) NwC (n = 61)
SLEEP, Vol. 38, No. 8, 2015 1290 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
We also sought to establish whether a similar or different
pattern of treatment was observed for the other narcolepsy
symptoms of EDS, insomnia, and fatigue. With untreated
narcolepsy patients as the reference category, controls had sig-
nicantly lower EDS, insomnia, and fatigue, indicating that
patients with narcolepsy have higher levels of all three of these
symptoms regardless of treatment (Figure 2B). In contrast to
the ndings with ADHD symptoms, none of the treatment
groups were associated with any statistically signicant differ-
ences in EDS, insomnia, or fatigue compared with patients not
receiving treatment (Figure 2B).
Because treatments could have been introduced or added in
a stepwise fashion over time during the course of the clinical
management of patients with narcolepsy, we analyzed treat-
ments received by the length of time between narcolepsy diag-
nosis and ADHD symptom measurement. The ‘no treatment’
and low-dose modanil groups were associated with short
time intervals between diagnosis and symptom measurement,
whereas the high-dose modanil and both methylphenidate
groups (in conjunction with modanil in the majority) were
signicantly associated with longer time intervals between di-
agnosis and symptoms measurement compared with patients
not receiving treatment (Figure 2C).
Multivariate Analyses of the Association between ADHD
Symptoms and Other Variables
ADHD symptoms, narcolepsy symptoms, and psychostimulants
In multivariate analyses (including the effect of study
centre, EDS, insomnia, fatigue, age, sex, BMI z-score, in-
terval between diagnosis and symptom score measurement,
and treatment category), insomnia symptoms, fatigue, and
treatment with methylphenidate were associated with elevated
inattention symptoms (Table 3). For every 10% increase in in-
somnia, inattention symptoms increased by 4.5% (95% CI: 0.8,
8.4; P = 0.017); and for every 10% increase in fatigue, inatten-
tion symptoms increased by 2.7% (95% CI: 0.1, 5.4; P = 0.041).
In addition, both lower and higher dose of methylphenidate
were associated with 1.6- and 1.8-fold higher inattention symp-
toms, respectively (Table 3). For hyperactive-impulsive symp-
toms, a similar picture was evident. For every 10% increase
in insomnia, hyperactive-impulsive symptoms increased by
9.7% (95% CI: 5.3, 11.4; P < 0.001). In addition, higher-dose
modanil, and lower and higher methylphenidate doses were
associated with 2.5-, 2.5-, and 2.8-fold higher hyperactive-
impulsive symptoms, respectively (Table 3). Multivariate ad-
justed LS means and 95% CIs for ADHD-RS symptoms by
treatment category are shown in Figure 3.
ADHD symptoms, narcolepsy symptoms, polysomnographic
variables, and psychostimulants
Because PSG measures were not available for controls,
these analyses could only be performed in patients with nar-
colepsy. PSG was performed while not receiving treatment,
but took place on average 1.2 y before ADHD-RS question-
naires were administered (49 patients had PSG performed > 6
mo before ADHD symptom measurement, 34 up to 6 mo be-
fore, 13 at the time of ADHD symptom measurement, and 8
after ADHD symptom measurement). A stepwise regression
analysis was rst performed to identify PSG variables poten-
tially associated with total ADHD symptoms while control-
ling for study center variation. The only variable associated
with total ADHD symptoms was log latency to sleep onset;
a 10% increase in latency to sleep onset was associated with
a 2.1% increase in total ADHD symptoms (95% CI: 0.6, 3.8;
P = 0.011). In multivariate analyses (including study center,
Tab le 3 —Multivariate Generalized Linear Models analysis of the association of sleep symptoms (daytime sleepiness, insomnia, and fatigue) and
stimulants with attention-decit hyperactivity disorder symptoms in patients with narcolepsy and controls.
Variable
Inattention Hyperactive-Impulsive
GMR (95% CI) P GMR (95% CI) P
Log Pediatric Daytime Sleepiness Scale 1.114 (0.808, 1.536) 0.511 0.938 (0.703, 1.253) 0.666
Log Insomnia Severity Scale 1.590 (1.086, 2.329) 0.017 2.639 (1.714, 4.062) < 0.001
Log Fatigue Scale 1.324 (1.012, 1.731) 0.041 1.041 (0.801, 1.351) 0.766
Study Center 2 vs 1 1.053 (0.570, 1.948) 0.868 0.621 (0.233, 1.652) 0.340
Study Center 3 vs 1 0.983 (0.686, 1.410) 0.927 0.947 (0.66, 1.358) 0.766
Study Center 4 vs 1 0.491 (0.226, 1.065) 0.072 0.467 (0.195, 1.120) 0.088
Age 0.982 (0.946, 1.020) 0.355 0.971 (0.933, 1.011) 0.153
Male vs Female 1.057 (0.833, 1.342) 0.649 0.922 (0.718, 1.183) 0.523
BMI z-score 0.955 (0.877, 1.040) 0.293 0.940 (0.851, 1.038) 0.221
Years from diagnosis to symptom measurement 0.980 (0.902, 1.063) 0.620 0.930 (0.847, 1.021) 0.127
Controls vs untreated narcolepsy 0.835 (0.530, 1.317) 0.439 1.277 (0.796, 2.051) 0.311
Lower-dose MOD* vs untreated narcolepsy 1.311 (0.957, 1.796) 0.092 1.317 (0.862, 2.010) 0.203
Higher-dose MOD† vs untreated narcolepsy 1.471 (0.967, 2.237) 0.072 2.504 (1.611, 3.890) < 0.001
Lower-dose MPH‡ vs untreated narcolepsy 1.638 (1.095, 2.450) 0.016 2.511 (1.590, 3.966) < 0.001
Higher-dose MPH§ vs untreated narcolepsy 1.779 (1.139, 2.779) 0.011 2.811 (1.651, 4.787) < 0.001
Bold typeface indicates signicance at the level of α = 0.05. *Lower-dose modanil (< 5.56 mg/kg/day). †Higher-dose modanil (≥ 5.56 mg/kg/day). ‡Lower-
dose methylphenidate (< 0.52 mg/kg/day) + modanil in majority. §Higher-dose methylphenidate (≥ 0.52 mg/kg/day) + modanil in majority. BMI, body mass
index; CI, condence interval; GMR, geometric mean ratio; MOD, modanil; MPH, methylphenidate.
SLEEP, Vol. 38, No. 8, 2015 1291 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
Figure 2—(A) Attention-decit hyperactivity disorder rating scale (ADHD-RS) scores.(B) Ot her subjective symptoms in contr ols and patients with narcole psy
by treatment received. (C) Interval in years between diagnosis and questionnaire symptom assessments in patients with narcolepsy by treatment received.
†Data are back-transformed least squares (LS) means and 95% condence intervals (CIs) adjusted for study center derived from a generalized linear
model using gaussian family and log link. Comparisons versus patients with narcolepsy not receiving treatment: * P < 0.05, ** P < 0.01, ***P < 0.001. HD-
MOD, higher-dose modanil (≥ 5.56 mg/kg/day); HD-MPH, higher-dose methylphenidate (≥ 0.52 mg/kg/day) + modanil in majority; LD-MOD, lower-dose
modanil (< 5.56 mg/kg/day); LD-MPH, lower-dose methylphenidate (< 0.52 mg/kg/day) + modanil in majority.
*
6.5 **
3.9
2.5
11.1
7.7
3.4
12.7
9.2
4.4
13.2
8.2
4.9
**
19.9
**
12.8
**
7.0
13.8
8.4
5.2
0
5
10
15
20
25
30
Tot al Inattention Hyperactive-Impulsive
ADHD-RS Score ( 95% CI)†
Control
(n = 63)
None [reference]
(n = 27)
LD-MOD
(n = 17)
HD-MOD
(n = 11)
LD-MPH
(n = 8)
HD-MPH
(n = 10)
Narcolepsy
A
***
23.0
37. 5 35.8 33.6
27.0
33.6
***
19.7
45.7 46 .1
36.5
49.3
38.4
***
15.5
57. 0
50.8
38.6
55.9
42.0
0
10
20
30
40
50
60
70
80
Pediatric Daytime Sleepiness Scale Insomnia Severity Index Fatigue Scale
Score as Percentage of Maximum (95% CI)†
B
0.5
0.6
***
2.1
***
2.8
**
1.8
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
No Tre atment
[reference category]
(n = 34)
Modafinil
< 5.56 mg/kg/day
(n = 22)
Modafinil
≥ 5.56 mg/kg/day
(n = 15)
Methylphenidate
< 0.52 mg/kg/day
(n = 16)
Methylphenidate
≥ 0.52 mg/kg/day
(n = 15)
Years from Diagnosis to Symptom
Measurement
(95% CI)†
C
SLEEP, Vol. 38, No. 8, 2015 1292 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
latency to sleep onset, EDS, insomnia, fatigue, age, sex, BMI
z-score, interval between diagnosis and symptom score mea-
surement, and treatment category), latency to sleep onset re-
mained signicant; for every 10% increase in latency to sleep
onset, inattention symptoms increased by 2.7% (95% CI: 0.2,
5.3; P = 0.032). In addition, higher methylphenidate dose was
associated with twofold higher inattention symptoms (Table 4).
For hyperactive-impulsive symptoms, a similar picture was
Tab le 4 —Multivariate Generalized Linear Models analysis of the association of polysomnographic latency to sleep onset, sleep symptoms (daytime
sleepiness, insomnia, and fatigue), and stimulants with ADHD symptoms in patients with narcolepsy.
Variable
Inattention Hyperactive-Impulsive
GMR (95% CI) P GMR (95% CI) P
Log Latency to Sleep Onset 1.326 (1.024, 1.718) 0.0322 1.437 (1.074, 1.923) 0.015
Log Pediatric Daytime Sleepiness Scale 1.178 (0.699, 1.984) 0.5393 0.966 (0.569, 1.640) 0.899
Log Insomnia Severity Scale 1.992 (0.995, 3.986) 0.0517 4.178 (1.859, 9.392) < 0.001
Log Fatigue Scale 1.116 (0.715, 1.742) 0.6288 0.903 (0.618, 1.321) 0.599
Study Center 2 vs 1 1.018 (0.407, 2.550) 0.9688 0.849 (0.223, 3.240) 0.811
Study Center 3 vs 1 0.927 (0.486, 1.767) 0.8181 1.223 (0.591, 2.530) 0.587
Study Center 4 vs 1 0.700 (0.204, 2.400) 0.5708 1.434 (0.355, 5.793) 0.613
Age 0.965 (0.915, 1.018) 0.1891 0.961 (0.914, 1.009) 0.112
Male vs Female 0.823 (0.568, 1.192) 0.3026 0.814 (0.572, 1.158) 0.252
BMI z-score 0.938 (0.814, 1.080) 0.3721 0.856 (0.725, 1.011) 0.066
Years from diagnosis to symptom measurement 0.991 (0.875, 1.123) 0.8856 0.938 (0.834, 1.054) 0.279
Lower-dose MOD* vs untreated narcolepsy 0.984 (0.598, 1.618) 0.9485 0.837 (0.475, 1.475) 0.538
Higher-dose MOD† vs untreated narcolepsy 1.187 (0.609, 2.314) 0.6146 2.354 (1.404, 3.946) 0.001
Lower-dose MPH‡ vs untreated narcolepsy 1.515 (0.856, 2.683) 0.1539 2.212 (1.278, 3.828) 0.005
Higher-dose MPH§ vs untreated narcolepsy 1.972 (1.060, 3.668) 0.0319 2.695 (1.438, 5.053) 0.002
Data exclude patients who received treatment on the day of the polysomnography examination (n = 3). Bold typeface indicates signicance at the level
of α = 0.05. *Lower-dose modanil (< 5.56 mg/kg/day). †Higher-dose modanil (≥ 5.56 mg/kg/day). ‡Lower-dose methylphenidate (< 0.52 mg/kg/day) +
modanil in majority. §Higher-dose methylphenidate (≥ 0.52 mg/kg/day) + modanil in majority. BMI, body mass index; CI, condence interval; GMR,
geometric mean ratio; MOD, modanil; MPH, methylphenidate.
Figure 3—Multivariate adjusted attention-decit hyperactivity disorder rating scale (ADHD-RS) scores by treatment received. †Data are back-transformed
least squares (LS) means and 95% condence intervals (CIs) adjusted for study center, daytime sleepiness, insomnia, fatigue, age, sex, BMI z-score,
interval between diagnosis and symptom score measurement, and treatment category derived from a generalized linear model using gaussian family and
log link. Comparisons versus patients with narcolepsy not receiving treatment: * P < 0.05, ** P < 0.01, ***P < 0.001. HD-MOD, higher-dose modanil (≥
5.56 mg/kg/day); HD-MPH, higher-dose methylphenidate (≥ 0.52 mg/kg/day) + modanil in majority; LD-MOD, lower-dose modanil (< 5.56 mg/kg/day);
LD-MPH, lower-dose methylphenidate (< 0.52 mg/kg/day) + modanil in majority.
7.4
4.5
2.6
7.7
5.6
1.8
9.9
7.6
2.7
**
15.1
8.7
***
6.1
***
16.8
*
9.8
***
6.1
***
18.0
*
10.7
***
7.0
0
5
10
15
20
25
30
Total Inattention Hyperactive-Impulsive
ADHD-RS Score
(95% CI)†
Control
(n = 63)
None [reference]
(n = 27)
LD-MOD
(n = 17)
HD-MOD
(n = 11)
LD-MPH
(n = 8)
HD-MPH
(n = 10)
Narcolepsy
SLEEP, Vol. 38, No. 8, 2015 1293 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
evident. For every 10% increase in latency to sleep onset,
hyperactive-impulsive symptoms increased by 3.5% (95% CI:
0.7, 6.4; P = 0.015); and for every 10% increase in insomnia,
hyperactive-impulsive symptoms increased by 14.6% (95%
CI: 6.1, 23.8; P < 0.001). In addition, higher-dose modanil,
lower-dose methylphenidate, and higher-dose methylphenidate
were associated with 2.4-, 2.2-, and 2.7-fold higher hyperac-
tive-impulsive symptoms, respectively (Table 4). No correla-
tion between methylphenidate dose and insomnia symptoms
(Spearman rho −0.036, P = 0.746) or log latency to sleep onset
(rho −0.147, P = 0.157) was demonstrated.
DISCUSSION
In children/adolescents with narcolepsy, ADHD symptoms
were approximately twofold higher compared with controls. In
terms of clinically signicant levels of ADHD symptoms, this
threshold was met in approximately 30% of NwoC patients
and 15% of NwC patients compared with approximately 5–6%
of controls. We showed that ADHD symptoms are associated
with a signicant burden in young patients with narcolepsy;
specically, patients with clinically signicant levels of ADHD
symptoms had higher levels of depressive symptoms and lower
health-related quality of life.
The overall prevalence of ADHD in controls was similar to
that identied both in a meta-analysis of studies examining
the prevalence DSM-IV ADHD diagnoses in unselected pop-
ulations (5.9–7.1%)35 and in a large epidemiological study of
ADHD prevalence conducted in France (3.5–5.6%).36 Thus, the
elevated rates observed in patients with narcolepsy compared
with controls are unlikely to be accounted for by selection
bias of controls, especially because these rates are consistent
with ndings of increased hyperactivity in an international
cross-sectional survey of 42 children and adolescents with
narcolepsy.6
Although the NwoC group appeared to show a numerically
higher level/severity of ADHD symptoms in our study, the dif-
ference versus the NwC group was not statistically signicant;
however, this numeric difference may have resulted from the
younger patient age in the NwoC group. In addition, no cor-
relation between CSF hypocretin-1 and ADHD symptoms was
demonstrated, suggesting that elevated ADHD symptoms in
narcolepsy might be secondary to EDS, fatigue, or nocturnal
sleep disturbance rather than a primary phenomenon directly
related to hypocretin deciency. However, very few patients
had available CSF measurements, so the lack of any association
might represent inadequate statistical power. Despite potential
differences between the NwoC and NwC groups, we pooled
these groups for subsequent analyses as HLA DQB1*06:02
was present in 71.4% of patients with NwoC, CSF hypocretin-1
was low in both groups, and patient age was lower in the NwoC
versus the NwC group, suggesting that patients with NwoC in
our cohort were likely to develop cataplexy later.37
Because treatments for narcolepsy, such as modanil and
methylphenidate,16 are also used in children with ADHD,33,34
we investigated ADHD symptoms in patients who were either
unexposed or exposed to treatment for narcolepsy. Results
from univariate and multivariate analyses differed, tending to
support different conclusions as to the effect of psychostimu-
lant therapy for narcolepsy on ADHD symptoms. In univariate
analyses, total ADHD, inattention, and hyperactive-impulsive
symptoms were signicantly higher in patients receiving
lower methylphenidate dose compared with patients receiving
no treatment. Neither the higher methylphenidate dose nor
the modanil groups were associated with signicant differ-
ences in ADHD symptoms versus those not receiving treat-
ment. Because of the cross-sectional nature of this study, it
was not possible to attribute any causal relationships to these
ndings; however, a number of possible explanations can be
considered. The observation that higher doses of modanil
and methylphenidate were associated with longer time in-
tervals between narcolepsy diagnosis and ADHD symptom
measurement compared with those not receiving treatment
or those receiving lower-dose modanil would suggest that
during the course of clinical management of patients with nar-
colepsy, the dose of treatments may be increased and/or new
treatments may be added to control narcolepsy symptoms.
Interestingly, the lower-dose methylphenidate group was as-
sociated with the longest interval and also with the highest
ADHD symptom level, which might suggest physician inertia/
reluctance to increase methylphenidate dose. In general, treat-
ments were associated with nonsignicant reductions in narco-
lepsy symptoms, especially in the higher-dose modanil and
methylphenidate groups, compared with patients receiving no
treatment (Figure 2B), but this appeared not to be the case for
ADHD symptoms, for which symptoms tended to be higher in
all treatment categories and signicantly higher in the lower-
dose methylphenidate group (Figure 2A). Despite the fact that
patients were being treated for narcolepsy and not specically
for ADHD, these ndings might suggest that, in contrast to
narcolepsy symptoms, ADHD symptoms in patients with nar-
colepsy might be somewhat resistant to treatment with psycho-
stimulants and might require a higher dose of methylphenidate.
In multivariate analyses, however, a different conclusion re-
garding the effect of psychostimulant therapy for narcolepsy
on ADHD symptoms was suggested. On including the effect
of study center, EDS, insomnia, fatigue, age, sex, BMI z-score,
interval between diagnosis and symptom score measurement,
and treatment category; longer latency to sleep onset, sub-
jective insomnia, subjective fatigue, and any use of methyl-
phenidate were modestly associated with higher inattention
symptoms. For hyperactive-impulsive symptoms, longer la-
tency to sleep onset, subjective insomnia and use of psycho-
stimulants, including higher-dose modanil and any dose of
methylphenidate, were strongly associated with higher hyper-
active-impulsive symptoms (Table 3, Table 4, and Figure 3).
The multivariate analysis ndings with respect to psycho-
stimulant use contrasted with the univariate analyses, in which
only the lower-dose methylphenidate group was associated
with higher ADHD symptoms. Given that low-dose methyl-
phenidate use was associated with the longest interval between
diagnosis and ADHD symptom measurement, it is likely that
patients receiving lower-dose methylphenidate had longer
duration of disease and a correspondingly greater burden of
ADHD symptoms. The multivariate analyses included time in-
terval between diagnosis and ADHD symptom measurement,
allowing for an assessment of the effect of psychostimulant
therapy on ADHD symptoms having adjusted for the potential
confounding effect of this and other variables.
SLEEP, Vol. 38, No. 8, 2015 1294 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
The association of ADHD symptoms, and in particular
hyperactive-impulsive symptoms, with insomnia and psycho-
stimulant therapy in multivariate analyses might suggest that
psychostimulant therapy could delay the onset of nocturnal
sleep, which in turn could exacerbate ADHD symptoms. This
is especially relevant because it is known that ADHD in the
absence of narcolepsy is associated with signicantly in-
creased objective latency to sleep onset and subjective sleep
onset difculties, night awakenings, difculties with morning
awakenings, and EDS compared with controls.38 However, in
the current study, we found no correlation between methylphe-
nidate dose level and either subjectively rated insomnia symp-
toms or objective PSG latency to sleep onset. Therefore, this
hypothesis remains unconrmed and warrants further investi-
gation in suitably designed longitudinal studies. If conrmed,
th is wou ld have sig n icant implications with respect to psycho -
stimulant therapy in narcolepsy, which, while addressing EDS
and fatigue, might exacerbate insomnia. It is important to note
that, with the exception of modanil (and methylphenidate in
the United States) in adults, most treatments for narcolepsy are
used off-label with no randomized trial evidence to support
their use. Therefore, there is an unmet need for well-conducted
randomized controlled trials of novel agents in pediatric nar-
colepsy, such as sodium oxybate, which not only increase day-
time alertness, but also consolidate nocturnal sleep.39– 42
The strengths of this study are that it employed preplanned
data-collection methods and, to our knowledge, represents the
largest cohort of pediatric patients with narcolepsy evaluated
to date. A number of limitations must be acknowledged. This
was a cross-sectional, observational, nonrandomized study,
and ADHD symptoms were not measured before the onset of
narcolepsy or before and after the initiation of psychostimu-
lants; therefore, causality cannot be attributed to any of the
ndings, which should be viewed as exploratory and hypoth-
esis-generating in nature. Data on ADHD symptoms were
available for only 72.2% of patients with narcolepsy. However,
this rate is similar to that found in a large observational study
investigating the determinants of mental health outcomes in
children, which employed specic interventions to improve
response rates.43 Of note, a rate of responding of this magni-
tude was not found to result in signicant differences between
non-responders and responders in terms of the associations
between individual characteristics and ADHD symptoms.43
Data were obtained from four different study centers; thus,
although the effect of study center variation was statistically
controlled in both univariate and multivariate analyses, some
of the observed differences could have been attributable to this
or other unknown sources of variation. No clinical assessment
or formal diagnosis of ADHD was undertaken and the age of
onset of ADHD symptoms was not known. Regarding PSG
measures, it was not possible to assess the association of peri-
odic limb movements of sleep with ADHD symptoms because
of the extent of missing data. Although PSG measures excluded
patients in receipt of treatment, in a substantial proportion of
cases PSG took place a number of years before ADHD-RS
questionnaires were measured. The sample size of the NwoC
group was too small to reliably assess differences between the
NwC and NwoC groups. In addition, sample sizes in the treat-
ment subgroups were also small, limiting the certainty of the
ndings with respect to the inuences of treatment for narco-
lepsy on ADHD symptoms. CSF hypocretin-1 measurements
were available in only a small proportion of patients and serum
ferritin levels were not collected. Finally, a small proportion
of patients with narcolepsy (12%) had been exposed to H1N1
vaccination, raising the possibility that the inclusion of these
patients in the analysis might have altered the pattern of ob-
served associations compared with that in a population of pa-
tients with purely idiopathic narcolepsy. To test this possibility,
we re-ran the multivariate analysis presented in Table 4 but
excluding patients exposed to H1N1 vaccination. We found an
identical pattern of signicant associations (data not shown),
which strongly suggested that the inclusion of patients exposed
to H1N1 vaccination had not limited the generalizability of our
ndings.
In conclusion, pediatric patients with narcolepsy have a
high level of ADHD symptoms, approximately twofold higher
compared with controls, with a higher burden of depressive
symptoms and poorer quality of life. Moreover, in contrast
to narcolepsy symptoms, for which some benet of therapy
was observed, ADHD symptoms appeared to be largely un-
responsive to psychostimulant therapy. Although univariate
analysis suggested that suboptimal doses of methylphenidate
might be associated with poor control of ADHD symptoms,
multivariate analysis suggested that insomnia, use of higher-
dose modanil, and use of methylphenidate at any dose might
be associated with elevated ADHD symptoms, especially
hyperactive-impulsive symptoms. It remains unclear, there-
fore, whether psychostimulant therapy is effective for ADHD
symptoms in pediatric narcolepsy and whether hypersomnias
and ADHD may or may not share a common underlying patho-
physiology. Indeed, the lack of inuence of age on ADHD
symptoms in young patients with narcolepsy might suggest a
different pathophysiological mechanism for ADHD symptoms
to that in young patients with ADHD without narcolepsy. Thus,
the optimal treatment for ADHD symptoms in pediatric narco-
lepsy warrants further investigation in longitudinal interven-
tion studies.
DISCLOSURE STATEMENT
This was not an industry supported study. The study is
part of a larger study nanced by a grant (PHRC AOM07-
138, Principal Investigator: Isabelle Arnulf) from the French
Health Ministry and supported by Assistance Publique - Hôpi-
taux de Paris (AP-HP). Dr. Lecendreux has served as a con-
sultant for Bioprojet, Shire, UCB, and Jazz Pharma and has
received research support from Shire and UCB and honoraria
from UCB and Shire. Dr. F r anc o has participated in speaking
engagements for UCB Pharma. Dr. Arnulf has participated
in speaking engagements for and served on the board of UCB
Pharma and Jazz. Dr. Dauvilliers has participated in speaking
engagements for and served on the board UCB Pharma, Jazz,
and Bioprojet. Dr. K ono fal is on the speakers’ bureau of
Shire and Eunethydis Guidelines Europe ADHD. The other
authors have indicated no nancial conicts of interest. In-
stitutions where work was performed: Centre Pédiatrique
des Pathologies du Sommeil, CHU Robert-Debré, 48 boule-
vard Serurier, 75019 Paris, France; Service des Pathologies
du sommeil, Pavillon Marguerite Bottard, Groupe Hospitalier
SLEEP, Vol. 38, No. 8, 2015 1295 ADHD Symptoms in Pediatric Narcolepsy—Lecendreux et al.
Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75651 Paris
cedex 13, France; Unité de sommeil, Neurologie, Hôpital Gui
de Chauliac, 80 avenue Augustin Fliche, 34295 Montpellier
Cedex 5, France; and Unité de Sommeil Pédiatrique, Hôpital
Femme-Mère Enfant, 59, boulevard Pinel, 69500 Bron, France.
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