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Indian Pediatr 2011;48: 319-321 |
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Tryptophan for the Treatment of Excessive
Daytime Sleepiness in Prader-Willi Syndrome |
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Yu Jin Lee, Shai Marcu,* Glenn Berall,†
and Colin M Shapiro*
From the Psychiatric Department of Gachon University Gil
Hospital, Incheon, Republic of Korea, *Youthdale Child and Adolescent
Centre, Toronto, Ontario, Canada, and †Pediatric Department of
North York General Hospital, Toronto, Ontario, Canada.
Correspondence to: Colin M. Shapiro, Youthdale Child and
Adolescent Sleep Centre 227 Victoria St Lower Level 2, Toronto, ON,
Canada, M5B1T8.
Email: [email protected]
Received: May 19, 2009;
Initial review: July 2, 2009;
Accepted: December 18, 2009.
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An 8-year old girl with Prader-Willi Syndrome presenting with excessive
daytime sleepiness improved following treatment with tryptophan;
possibly by consolidation of her fragmented sleep. Improvement was
recorded on a follow-up sleep study, one year after initiating treatment
with tryptophan. We conclude that tryptophan may be an useful medication
for excessive sleepiness in children with Prader-Willi Syndrome.
Key words: Excessive Daytime Sleepiness, Prader-Willi
Syndrome, Tryptophan.
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T
ryptophan
is an essential amino acid and the metabolic precursor of serotonin, which
has an important role in sleep. From the perspective of therapeutic use in
children, there has been only one study which demonstrated the efficacy of
low dose 5-hydroxytryptophan (5-HTP) i.e. another precursor of serotonin
in children with sleep terror [1].
Various sleep complaints have been reported in
Prader-Willi syndrome, including narcoleptic features like excessive
daytime sleepiness (EDS), sleep onset REM period (SOREMP), sleep apnea
syndrome (SAS), and fragmented nocturnal sleep [2]. Continuous positive
airway pressure has been known to be useful treatment for SAS and its
associated EDS in this syndrome. There is only one case report of
clomipramine trial which showed improvement of his sleepiness by 2 minutes
of sleep latency on multiple sleep latency test (MSLT) [3]. We tried
tryptophan to reduce excessive daytime sleepiness in Prader – Willi
syndrome.
Case Report
An eight year-old girl diagnosed with Prader-Willi
syndrome with deletion in the paternally derived chromosome 15 presented
with excessive daytime sleepiness. She would fall asleep when she was in a
car, or in the subway and had problems staying awake in class. She had no
symptoms of cataplexy, sleep related hallucinations, sleep paralysis, or
sleep apnea. There were no other symptoms suggestive of sleep apnea.
On physical examination, her height was 115cm (<5 th
centile), weight was 22.7 kg with a BMI of 17.2. She had a narrow face.
Her systematic examination was normal and there was no hypertrophy of her
tonsils or adenoids, and a structured interview of the child did not
reveal any history suggestive of depression. Two overnight
polysomnographic studies and two daytime tests (multiple sleep latency
test; MSLT and maintenance of wakefulness test; MWT) were conducted on day
1 and 2. Polysomnographic findings on second night were used for her
assessment. No significant sleep apnea episodes or snoring were recorded
during her sleep. Even though she did not complain of difficulty with her
nocturnal sleep, fragmented night time sleep (arousal index=9.8/h) was
observed. Day time sleepiness on the MSLT was prominent (sleep latency on
the MSLT was 4.4 minutes) and 3 SOREMPs were recorded in a four session
MSLT.
After obtaining informed consent, she was started on
oral tryptophan starting with a dose of 750 mg and titrating to 4500 mg,
by a 750 mg elevation at 2 weeks interval. Parents were instructed to
choose and maintain the dosage at which the child felt best. After 4-weeks
treatment her daytime sleepiness decreased. She was followed up every 3
months and her parents reported a significant improvement in the child’s
symptoms at a daily dose of 4500 mg of tryptophan taken in the evening for
1 year. Parents and teachers commented that she was able to learn more as
a result of her increased alertness. Routine laboratory investigations
including complete blood count, liver function tests and routine urine
examination were unremarkable at follow-up after 1-year.
Sleep studies performed after 1-year of treatment
showed a lower arousal index in her nocturnal polysomnography, and she
stayed awake during all the four sessions without any SOREMP episode in
MSLT compared to baseline findings. Table I shows results of
her sleep studies at baseline and follow-up after taking tryptophan.
Discussion
To our knowledge, this is the first report of
tryptophan trial for treatment of excessive daytime sleepiness by
consolidating fragmented sleep in a patient with Prader Willi syndrome.
The underlying mechanism of narcolepsy symptoms in Prader-Willi syndrome
still remains unclear. Hypothalamic dysfunction involved in hypocretin/orexin
system was considered as one of possible causes [4]. Hypothalamic
dysfunction in PWS can manifest as abnormal response to hypercarbia in
conjunction with the dysregulation of REM sleep [5].
In this girl, tryptophan was effective for her
sleepiness. One explanation of the improvement might be the hypnotic
nature of tryptophan. In this case, the consolidation of fragmented
nocturnal sleep with tryptophan could be verified by marked reduction of
arousal index in the follow-up study. An increase in sleep efficiency and
a decrease in wakefulness time after sleep onset also indicated
improvement in her sleep. The improvement of her nocturnal sleep is the
likely source for the positive impact on her excessive daytime sleepiness.
TABLE I
Comparison of Sleep Study Findings at Baseline and Following Tryptophan Therapy in Prader-Willi Syndrome
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Overnight study |
Baseline |
Follow-up |
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Total time in bed (min) |
536.5 |
558 |
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Total sleep time (min) |
495.5 |
546 |
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Sleep period time (min) |
534 |
555.5 |
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Sleep latency (min) |
1.5 |
1.5 |
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Sleep efficiency (%) |
92.4 |
98 |
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REM latency (min) |
72 |
76 |
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WASO (%) |
7.4 |
1.8 |
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Stage 1 (%) |
1.6 |
2.8 |
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Stage 2 (%) |
46.8 |
50 |
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SWS (%) |
25.6 |
21.3 |
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REM (%) |
17.9 |
22.9 |
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Apnea hypopnea index (No./hour) |
0.4 |
0 |
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Arousal index (No./hour) |
9.8 |
4.7 |
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Daytime sleep study |
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Mean sleep latency in MSLT (min) |
4.4 |
Awake |
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No. of SOREMP in MSLT |
3/4 |
0/4 |
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Mean sleep latency in MWT (min) |
19 |
18 |
WASO: Wake After Sleep Onset, SWS: Slow Wave Sleep, MSLT: Multiple Sleep Latency Test,
SOREMP: Sleep Onset REM Period, MWT: Maintenance Wakefulness Test.
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Serotonin as a wakefulness promoter might be another
feasible explanation of tryptophan’s effect on her sleep. Previous studies
noted that serotonin facilitates wakefulness by its action on 5-HT 2
receptors and subsequently provokes sleep by sleep promoting mechanism in
the regulation of arousal state by serotonin [6]. In animal models, the
mechanism of serotonergic activation seems to be up to the timing of the
administration of 5-hydroxytryptophan (5-HTP), when it is at dark onset or
light onset. 5-HTP injected at dark onset increases NREM sleep, while
administration at light onset initially provokes wakefulness with increase
NREM sleep during the subsequent dark period [7]. This patient has taken
the tryptophan in the evening, which was usually 2 hours before her
bedtime, which was after dark onset. Therefore, the improvement of her
sleepiness by the consolidation of her nocturnal sleep rather than by
promoting wakefulness effect itself from the serotonergic activation might
be more plausible explanation.
In this patient, the baseline MSLT had shown three
SOREMPs of four sessions. There was no SOREMP on the follow-up MSLT with
tryptophan. This result may be accounted for by the fact that tryptophan
as the metabolic precursor of serotonin acted as a REM sleep suppressant
[7]. Another explanation for the effect on REM sleep might be that
hypothalamic prolactin, which exists in the same neurons as hypocretin/orexin,
is considered to play important role in REM sleep regulation [8] and might
have a hypnotic effect via another neuro-transmitter i.e. VIP [9].
Some studies have reported the role of growth hormone
treatment in improving the sleep-disordered breathing in PWS, but a subset
of patients had worsening of symptoms 6 weeks after starting growth
hormone [10]. However, the apnea index of this patient did not meet the
diagnosis of sleep apnea.
We conclude that in PWS patients tryptophan might be a
useful pharmacologic treatment for excessive daytime sleepiness.
Contributors: All authors contributed to the
diagnosis, conceptualization, literature search, case management and
drafting of the report.
Funding: None.
Competing interests: None stated.
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