Narcolepsy–
cataplexy associated
with precocious
puberty

VIDEO

Abstract—In children, narcolepsy may be the symptom of a brain lesion or
genetic disease. The authors report two cases with severe narcolepsy– cataplexy emerging in childhood in close temporal association with obesity and
precocious puberty.
NEUROLOGY 2006;66:1577–1579

G. Plazzi, MD; A. Parmeggiani, MD; E. Mignot, MD; L. Lin, MD; M.C. Scano, MD; A. Posar, MD;
F. Bernardi, MD; R. Lodi, MD; C. Tonon, MD; B. Barbiroli, MD; P. Montagna, MD; and A. Cicognani, MD

The diagnosis of narcolepsy in children is challenging because it may be the symptom of a larger problem, e.g., a brain lesion or genetic disease, such as
Niemann–Pick Type C.1 Frequent misdiagnoses include epilepsy and psychiatric problems.1
Renewed interest in narcolepsy has led to earlier
diagnosis in children and direct observation of cases
closer to onset. These early-onset, rapidly diagnosed
cases represent a natural model to study the effect of
an acute dysfunction of the hypocretin system, a system that has widespread brain and spinal cord projections, regulating autonomic function, sleep, and
metabolism.2 These patients not only present sleep
abnormalities but also gain weight rapidly. This feature is intrinsic to childhood narcolepsy and may
correlate with a metabolic dysfunction linked to
hypocretin and leptin control.3
Experimental studies also suggest the hypocretin
system plays a major role in regulating the hypothalamopituitary gonadal (HPG) axis,4 but clinical
data are scarce.
This report describes two cases of severe narcolepsy– cataplexy emerging in childhood in close temporal association with obesity and primary
precocious puberty.
Case 1. A 7-year-old boy presented in July 2004 with severe
daytime somnolence impairing school performance, homework,
and sports activities. Nocturnal sleep became disturbed, with auditory and visual hallucinations while falling asleep, frequent prolonged arousals, and nightly terrifying dreams. Within 2 weeks,

Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 23 issue to find the title link for this article.

From the Department of Neurological Sciences, (G.P., A.P., M.C.S., A.P.,
P.M.), Department of Pediatrics (F.B., A.C.), and Department of Clinical
Medicine and Applied Biotechnology “D. Campanacci” (R.L., C.T., B.B.),
University of Bologna, Italy; and Howard Hughes Medical Institute (E.M.,
L.L.), Stanford University, CA.
The study was partially supported by NIH grant NS232724 to E. Mignot.
Disclosure: The authors report no conflicts of interest.
Received October 3, 2005. Accepted in final form February 7, 2006.
Address correspondence and reprint requests to Dr. Giuseppe Plazzi, Dipartimento di Scienze Neurologiche dell’Università di Bologna, Via Ugo Foscolo
7, 40123 Bologna, Italy; e-mail: giuseppe.plazzi@unibo.it

cataplexy appeared: nonemotionally triggered episodes of tripping
during walking or running, or of sudden head and arms dropping
while eating. In mid July, he presented with continuous drowsiness, sleep attacks, and almost continuous hypotonia. Neurologic
examination disclosed bilateral ptosis, remarkable generalized hypotonia, dysmetria, and fluctuations of consciousness accompanied by head drops. Brain MRI (figure), routine CSF, search for
oligoclonal bands, protein and cellular counts, muscle biopsy, fibroblast skin biopsy (for Niemann–Pick Type C), and routine
screening for metabolic and autoimmune diseases were all negative. Epilepsy was suspected, and clonazepam, valproic acid, and
lamotrigine were given in various associations; IV corticosteroid
therapy (methylprednisolone) was also initiated, all without any
clinical changes.
In December 2004, the patient was referred to us when the
parents recognized his condition on a video spot on narcolepsy
sponsored by the Italian Narcolepsy Association (Associazione
Italiana Narcolettici [AIN]). We observed obesity (body mass index
[BMI] 21.9 kg/m2)—with a progressive weight gain of 16 kg since
disease onset, sleepiness, and a state of almost continuous cataplexy– hypotonia (see video—Case 1). He also displayed secondary
sexual characteristics. The diagnosis of narcolepsy– cataplexy was
readily confirmed by polysomnography (PSG) (table 1) and MSLT
(mean sleep latency of 2 minutes and 2/5 sleep-onset REM periods
[SOREMPs]). IQ (Wechsler Intelligence Scale for Children–
Revised) was normal (total score 87), as were the results of neuropsychological, memory, and attention assessments. HLA typing
was positive for HLA-DQB1*0602. CSF hypocretin-1 measurement was undetectable. Hypothalamic proton magnetic resonance
spectroscopy (1H-MRS) showed low N-acetyl-aspartate to creatine
ratio (NAA/Cr): 1.44 —normal values range 1.54 to 2.01. The diagnosis of idiopathic central precocious puberty was confirmed on
the basis of height (136 cm, 75th percentile), weight (40.5 kg,
⬎97th percentile), testicular enlargement (both 4 mL), pubic hair,
bone age (11 years), and hormonal evaluations (table 2). Narcolepsy was treated with modafinil and venlafaxine, with rapid
improvement.
Case 2. A 7-year-old girl presented in September 2003 with
overwhelming sleep attacks while playing, eating, or watching
television and nocturnal sleep disturbed by vivid and unpleasant
dreams. One month later, leg weakness, jaw shaking, and head
dropping started to occur whenever she laughed. No diagnosis was
given, and observation was suggested. A weight gain of 10 kg in 2
months, rapid height increase, and early signs of secondary sexual
development (breasts and pubic hair) were noted by the parents.
As in Case 1, the diagnosis was made 2 years later, after the
parents recognized the condition when viewing the AIN television
spot, directing their daughter to our department. Cataplexy,
sleepiness, hypnagogic hallucination, and automatic behavior
were all present. She presented with generalized mild hypotonia
and almost continuous cataplexy. Frank cataplexy was readily
elicited by laughing while watching cartoons (see video—Case 2).
Clinical examination disclosed obesity (BMI 21.5 kg/m2; height
142 cm, ⬎97th percentile; weight 43.3 kg, ⬎97th percentile). Head
circumference was more than the average for age (55.5 cm, ⬎98th
percentile). HLA typing indicated DQB1*0602. Brain MRI (see
figure) and routine CSF examination results were normal, and the
result of search for oligoclonal bands was negative, whereas CSF
hypocretin-1 was undetectable. 1H-MRS showed hypothalamic
NAA/Cr ratio below the normal range (1.36). PSG findings were
typical for narcolepsy (see table 1). MSLT mean sleep latency was
Copyright © 2006 by AAN Enterprises, Inc.

1577

Figure. Patients 1 and 2 sagittal fast
spin echo T1-weighted (TR ⫽ 600 milliseconds; TE ⫽ 12.1 milliseconds) (A),
axial fast spoiled gradient echo (TR ⫽
250 milliseconds; TE ⫽ 2.4 milliseconds) (B), and axial fluid-attenuated
inversion recovery (TR ⫽ 8,002 milliseconds; TE ⫽ 85 milliseconds, IT ⫽
2,000) MRIs. All images were acquired
with a slice thickness of 3 mm and
slice gap of 0 mm. Normal in both
cases.

1 minute, and 5/5 SOREMPs were observed. IQ (Wechsler Intelligence Scale for Children–Revised total score 114), neuropsychological, memory, and attention evaluation results were all normal.
The rapid height increase, early signs of secondary sexual development (breasts and pubic hair, bone age 11 years), and hormonal
examination (see table 2) indicated a central precocious puberty.
Narcolepsy was treated with modafinil and venlafaxine, with
improvement.

Discussion. In these two cases, narcolepsy– cataplexy, obesity, and precocious puberty were associated. A similar association was recognized in one
case 20 years ago.5 A peculiar feature of these children was the abrupt onset, the unusual severity of
cataplexy, and the significant weight gain. Because
narcolepsy is rare before age 6 years, the association
with precocious puberty may be more frequent than
anticipated. Indeed, in most prepuberal children, onset is closer to 10 to 12 years, and it may be impossible to document an early puberty at an age already
close to normal pubertal development. The temporal
Table 1 Nocturnal polysomnographic features
Polysomnographic features

Case 1

Case 2

TRT

576

718

TST

508

594

Sleep latency

3

9

Latency to REM sleep

15

1

Sleep efficiency

88.3

82.6

Stage 1 sleep, %

26.1

10.1

Stage 2 sleep, %

34.6

36

SWS, %

24.4

29.5

Stage REM sleep, %

14.9

24.5

Results are given as minutes.
TRT ⫽ total recording time; TST ⫽ total sleep time; REM ⫽
rapid eye movement; SWS ⫽ slow wave sleep.
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NEUROLOGY 66

May (2 of 2) 2006

association of narcolepsy onset with the recognition
of precocious puberty suggests causality, although
several mechanisms could be involved.
The association of hypersomnolence, cataplexy,
obesity, and precocious puberty in these cases may
reflect a broadly based hypothalamic abnormality
that included the hypocretin cell group and adjacent

Table 2 Clinical and laboratory features
Case 1

Case 2

Age at puberty diagnosis, y

8*

7*

Testicular volume, mL

4*

—

Breasts
Pubic hair

—

3–4*

2*

2–3*

Bone age advanced, y

11*

11*

BMI, kg/m2

21.9

21.5

Testosterone, ng/mL

1.06*

—

Estradiol, pg/mL

—

38*

Prolactin, ng/mL

24.1

20.1

TSH, ␮U/mL

1.27

1.66

GH, ng/mL

3.1

4.9

ACTH, pg/mL

23

10

Basal FSH, mU/mL

1.7

5.6

Peak FSH, mU/mL

3.3*

13.4*

Basal LH, mU/mL

2.8

4.6

Peak LH, mU/mL

12.9*

29.2*

LH-RH test

* Indicators of precocious puberty.
BMI ⫽ body mass index; TSH ⫽ thyroid-stimulating hormone;
GH ⫽ growth hormone; ACTH ⫽ adrenocorticotropic hormone;
LH-RH ⫽ luteimizing hormone-releasing hormone; FSH ⫽
follicle-stimulating hormone; LH ⫽ luteinizing hormone.

structures. Indeed, sleepiness, obesity, and precocious puberty have been already described in an 11year-old boy presenting behavioral disturbances
(pica) and chronic lead intoxication.6 In this case,
however, cataplexy was absent, and narcolepsy was
ruled out by polysomnographic studies. Such a case
may have involved adjacent hypothalamic dysfunction while largely sparing the hypocretin cell group.
In our two cases, narcolepsy was fully documented
by PSG, MSLT, direct cataplexy observation, HLADQB1*0602 positivity, and low CSF hypocretin-1.
Hypothalamic involvement was also confirmed by
1
H-MRS findings mirroring those reported in adults
with narcolepsy– cataplexy.7 Whether or not the
broader hypothalamic abnormality was of temporary
(e.g., in the context of an inflammatory/autoimmune
process directed toward hypocretin cells) or more
permanent nature is unknown.
Alternatively, hypocretin could be involved in the
regulation of the HPG axis, with hypocretin deficiency precipitating puberty. However, this is unlikely because hypocretin is reported to increase
luteinizing hormone (LH) release, a factor known to
trigger puberty. Further, intracerebroventricular
(ICV) injections of hypocretin-1 in animals trigger
LH release in ovariectomized rats, whereas ICV injection of anti– hypocretin-1 antibodies abolished the
preovulatory LH surge in intact female rats.2
Additionally, hypocretin-1 promotes gonadotropinreleasing hormone (GnRH) release in hypothalamic
explants from male rats.8 Last, hypocretin deficient
adult male patients had decreased LH secretion but
normal response to GnRH.9

Finally, precocious puberty could be indirectly related to the rapid weight gain or metabolic dysregulation. Obesity and precocious puberty are known to
be associated in certain populations.10 Rapid weight
gain preceded the recognition of puberty in both of
our cases.
Acknowledgment
The authors thank Ms. Alessandra Laffi for secretarial assistance
and Ms. Anne Collins for English editing. They also thank Prof.
Piero Pirazzoli and Dr. Luca Vignatelli for help in revising the
manuscript.

References
1. American Academy of Sleep Medicine. International classification of
sleep disorders. 2nd ed. Diagnostic and coding manual. Westchester, IL:
American Academy of Sleep Medicine; 2005.
2. Ferguson AV, Samson WK. The orexin/hypocretin system: a critical
regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 2003;24:141–150.
3. Kotagal S, Krahn LE, Slocumb N. A putative link between childhood
narcolepsy and obesity. Sleep Med 2004;5:147–150.
4. Russell SH, Small CJ, Dakin CL, et al. Effects of orexins on the
hypothalamic-pituitary-adrenal system. J Neuroendocrinol 2000;12:
1174–1178.
5. Chisholm RC, Brook CJ, Harrison GF, Lyon L, Zukaitis D. Prepubescent narcolepsy in a six year old girl. Sleep Res 1985;15:113. Abstract.
6. Boris NW, Hagino OR, Steiner GP. Case study: hypersomnolence and
precocious puberty in a child with pica and chronic lead intoxication. J
Am Acad Child Adolesc Psychiatry 1996;35:1050–1054.
7. Lodi R, Tonon C, Vignatelli L, et al. In vivo evidence of neuronal loss in
the hypothalamus of narcoleptic patients. Neurology 2004;63:1513–
1515.
8. Kohsaka A, Watanobe H, Kakizaki Y, Suda T, Schioth HB. A significant
participation of orexin-A, a potent orexigenic peptide, in the preovulatory luteinizing hormone and prolactin surges in the rat. Brain Res
2001;898:166–170.
9. Kok SW, Roelfsema F, Overeem S, et al. Altered setting of the pituitarythyroid ensemble in hypocretin-deficient narcoleptic men. Am J Physiol
Endocrinol Metab 2005;288:E892–E899.
10. Laron Z. Is obesity associated with early sexual maturation? Pediatrics
2004;113:171–172.

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