Correspondence

Serotonin Syndrome Induced by

Tramadol Intoxication in an
8-Month-Old Infant
To the Editor:
I read with interest the case presented by Marchal et al. [1].
They reported, for the rst time, on moderate serotonin
syndrome in an 8-month-old girl after tramadol intoxication,
and concluded that pediatricians should be aware of specic clin-
ical manifestations of serotonin syndrome, to avoid any delay in
management. Interestingly, the management used by the authors
for their patients remains unclear. As is well known, patients
who develop serotonin syndrome and present with agitation or
neuromuscular hyperactivity (similar to the patient of Marchal
et al. [1]) should initially be managed with benzodiazepines
[2]. Furthermore, the administration of cyproheptadine may
improve the patients condition sooner. Cyproheptadine is
a rst-generation, histamine-1 receptor blocking agent with
nonspecic antagonist properties at the 5HT-1A and 5HT-2A
receptors. Patients with mild to moderate signs of serotonin
syndrome, and who are not hyperthermic, typically respond to
this pharmacologic agent within 30 minutes to 2 hours of admin-
istration [2,3]. Although this medication is not available in an
intravenous form, tablets may be crushed and administered by
nasogastric tube in pediatric patients. Moreover, despite the
authors statement in their Discussion about the association of
tramadol with selective serotonin reuptake inhibitors in the
development of serotonin syndrome, an overdose of a single
serotonin-potentiating agent such as tramadol may also produce
serotonin syndrome [2].
References
[1] Marchal C, Honorat R, Claudet I. Serotonin syndrome induced by tramadol
intoxication in an 8-month-old infant. Pediatr Neurol 2011;44:72e4.
[2] Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with
cyproheptadine. N Engl J Med 1994;331:1021e2.
[3] Graudins A, Stearman A, Chan B. Treatment of serotonin syndrome with
cyproheptadine. J Emerg Med 1998;16:615e9.
Hossein Sanaei-Zadeh, MD
Department of Forensic Medicine and Toxicology
Tehran University of Medical Sciences
Hazrat Rasoul Akram Hospital
Tehran, Iran
E-mail address: h-sanaiezadeh@tums.ac.ir
doi:10.1016/j.pediatrneurol.2012.01.004
Response:
I thank Dr. Sanaei-Zadeh for his accurate and expert
comments about our case report. The management of this
patient was not specied because it was mainly supportive.
We did not need to use benzodiazepines because the girl man-
ifested episodic agitation alternating with drowsiness. Her
agitation was moderate at hospital, compared with her
described neurologic status on the preceding night at home.
Cyproheptadine was not prescribed because the staff pediatri-
cian in the emergency unit did not recognize serotonin
syndrome during the patients admission, and did not know
that cyproheptadine was recommended for patients with
severe toxicity, including children. The diagnosis was rendered
the next morning during the clinical case review by a pediatri-
cian experienced in toxicology. We experienced a delayed diag-
nosis because serotonin syndrome is rare in pediatric patients,
and is often misdiagnosed. We published this case report
because we hoped that sharing such an experience could
increase the recognition of serotonin syndrome and reduce
the delay of its management in children.
Isabelle Claudet, MD, MSc
Pediatric Emergency Department
Childrens Hospital
31059 Toulouse, France
E-mail address: claudet.i@chu-toulouse.fr
doi:10.1016/j.pediatrneurol.2012.01.005
Idursulfatase Therapy in
Mucopolysaccharidosis Type II:
After 2.5 Years of TreatmentdNo
Benet for Older Patients With
Multisystem Involvement
To the Editor:
We were intrigued by the article of the Hoffman et al. [1]. We
have observed three patients treated with Hunter syndrome with
idursulfatase (0.5 mg/kg/weekly) for 2.5 years (ages at initiation
of treatment: 5.5, 6, and 12.5 years). All three children were
mentally retarded (intelligence quotients, 34-80) and manifested
a coarse face, hepatosplenomegaly, and stiff joints. Kyphosis,
epilepsy, and stunted growth were evident in one child. No patient
demonstrated myocardiopathy, deafness, or corneal opacities.
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One new mutation was discovered, i.e., p.K236N (c.708G>C) in
a child with a moderately severe phenotype (who later emigrated
and was lost to follow-up). One patient died at age 15 years from
respiratory insufciency (carrying the same S333L mutation as
the deceased uncle of the other patient, who also died at age 11
years). The calculated incidence and prevalence rates for mucopoly-
saccharidosis type II in Macedonia involve 0.36 and 3.6/1,000,000
boys, respectively [2].
In total, eight infusion-related reactions occurred in two
patients. The size of the liver and spleen were signicantly
reduced during treatment, as observed by Muenzer et al. [3].
Because the treatment did not affect the mental status and
joint stiffness of our patients (two children underwent
surgical corrective procedures), discussion of the possible
outcomes with the parents is very important, because they
may harbor unrealistic expectations. Moreover, the pretreat-
ment existence of neurologic impairment poses a major disad-
vantage. Contrary to the opinion of Hoffmann et al. [1], in
older patients with severe multisystem impairment, the treat-
ment of mucopolysaccharidosis type II with idursulfatase does
not seem to be indicated, because no clear benet has been
observed.
References
[1] Hoffmann B, Schulze-Frenking G, Al-Sawaf S, et al. Hunter disease before and
during enzyme replacement therapy. Pediatr Neurol 2011;45:181e4.
[2] Gucev ZS, Tasic V, Sinigerska I, et al. Hunter syndrome (MPS II) in Macedonia
and Bulgaria: Novel gene alterations of iduronate 2-sulfatase and prevalence
rates. Prilozi 2011;XXXII:188e98.
[3] Muenzer J, Bodamer O, Burton B, et al. The role of enzyme replacement therapy
in severe Hunter syndrome: An expert panel consensus. Eur J Pediatr 2012;171:
181e8.
Zoran S. Gucev, MD, PhD
Velibor Tasic, MD, PhD
Medical Faculty
University Childrens Hospital
1000 Skopje, Macedonia
E-mail address: gucevz@gmail.com
doi:10.1016/j.pediatrneurol.2012.01.006
Response:
Gucev and Tasic report on their experience with idursulfa-
tase in the treatment of three patients with Hunter disease,
and conclude that no effects for older patients with multi-
system involvement are evident. Nevertheless, they describe
a signicant reduction of liver and spleen size during treatment
with enzyme replacement therapy, without providing informa-
tion about possible secondary effects of reduced organomegaly,
e.g., breathing and exhaustion may be improved. Based on the
fact that two children in their cohort had to undergo surgical
procedures, Gucev and Tasic also concluded that no effects
were evident regarding joint stiffness over a period of 2.5
years. Consecutive measures of height or information on
repeated measurements of joint range of motion were not
reported.
Among other effects we have observed [1], patients gained
height, demonstrated improved physical capacity, required fewer
antibiotics, and developed a reduction of abdominal girth, regard-
less of the degree of neurologic impairment.
In a cohort of 18 patients with Hunter disease, Schulze-
Frenking et al. described benecial effects on growth over a period
of up to 3 years [2]. Moreover, animal models of mucopolysacchar-
idosis type IV indicate that intravenously administered enzyme
replacement therapy penetrates growth plate cartilage and inu-
ences gene expression in human chondrocytes [3]. Although
similar studies of mucopolysaccharidosis type II are lacking,
Dvorak-Ewell et al. [3] demonstrated that enzyme replacement
therapy in principle may be able to improve bone and connective
tissue composition. As long as these studies remain to be reported,
the systematic evaluation of joint status before and during enzyme
replacement therapy in any of the mucopolysaccharidoses should
be mandatory.
We agree with Gucev and Tasic that the expectations of
patients and families regarding the possible effects of enzyme
replacement therapy often cannot be fullled. Enzyme replace-
ment therapy is no cure, and may exert limited effects on
central nervous system manifestations. Particularly among
patients with severely affected central nervous systems, fami-
lies and physicians, with the participation of psychologists if
possible, should discuss the possibilities and limitations of
enzyme replacement therapy before the initiation of treatment.
To dene individual outcome criteria for the continuation or
discontinuation of treatment may be helpful. Whether or not
the treatment of patients with neurologic impairment is indi-
cated may remain, at least for the present, an individual
decision.
The single patient reports that have been presented are helpful.
However, until further studies on the treatment of mucopolysac-
charidosis type II with idursulfatase are completed, nal conclu-
sions on the possible effects or lack of such effects should be
drawn with the highest caution.
References
[1] Hoffmann B, Schulze-Frenking G, Al-Sawaf S, Beck M, Mayatepek E. Hunter
disease before and during enzyme replacement therapy. Pediatr Neurol 2011;
45:181e4.
[2] Schulze-Frenking G, Jones SA, Roberts J, Beck M, Wraith JE. Effects of enzyme
replacement therapy on growth in patients with mucopolysaccharidosis type
II. J Inherit Metab Dis 2011;34:203e8.
[3] Dvorak-Ewell M, Wendt D, Hague C, et al. Enzyme replacement in a human
model of mucopolysaccharidosis IVA in vitro and its biodistribution in the carti-
lage of wild type mice. PLoS One 2010;5:e12194.
Bjrn Hoffmann, MD
Sulaiman Al Sawaf
Ertan Mayatepek, MD
Department of General Pediatrics and Neonatology
University Childrens Hospital
Heinrich-Heine University
40225 Dsseldorf, Germany
Department of General Pediatrics
Childrens Hospital
57072 Siegen, Germany
E-mail address: mail@kinderarzt-hoffmann.de
Gudrun Schulze-Frenking, MD
Michael Beck, MD
Division of Lysosomal Storage Diseases
University Childrens Hospital
Johannes-Gutenberg University
55122 Mainz, Germany
doi:10.1016/j.pediatrneurol.2012.01.007
Correspondence / Pediatric Neurology 46 (2012) 199e201 200