Kısa süreli oral metilfenidat kullanımı ile ilişkili iskemik inme

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Giriþ
Methylphenidate (MP) is a piperidine-derived central nervous system (CNS) stimulant (1). It is commonly used for the treatment of
attention deficit hiperactivity disorder (ADHD) among children and of
narcolepcy in adults (1). Some studies suggest possible therapeutic uses
for methylphenidate in elderly patients with depression (2), patients
with post-stroke depression (3), those with human immunodeficiency
virus infection (4), those with traumatic brain injury (5), and cancer
patients (6). This drug is related to amphetamine and other psychostimulants.
In the brain, MP increases the extracellular levels of dopamine and
norepinephrine in a manner similar to cocaine and amphetamine (7).
MP blocks the dopamine transporters in the presynaptic cell membrane,
leading to increased extracellular levels of dopamine, and affects the cortex, medulla and bulbus. However, unlike the other two psycho-stimulants (cocaine and amphetamine), MP does not affect the serotonergic
system (8,9), and hence, it has been used as a tool in animal experiments
for characterizing dopamine-behavior relationship without a serotonin
effect (9). MP's behavioral profile in rats, including induction of locomotor activity and stereotypes, resembles those of cocaine and amphetamine. Chemically similar to cocaine and other simulants, MP presents
a pragmatic paradox (10); it decreases activity and increases the ability to
concantrate in children with ADHD. Despite decades of experience with
methylphenidate, however, limited information is available regarding
the incidence of neurologic complications with use as a stimulant.
Neurologic complications following long term oral methylphenidate
therapy have been reported (10). This report describes a child who suffered from a rare neurologic complication, ischemic stroke following the
use of short term oral methylphenidate for ADHD.
Case Report
A 9-year-old boy suddenly developed left-sided weakness without
loss of consciousness while having breakfast. His weakness progressed
*S.B. Bakýrköy Kadýn Doðum ve Çocuk Hastalýklarý
Eðitim ve Araþtýrma Hastanesi, Çocuk Nörolojisi Ünitesi, Ýstanbul
Ayrý basým isteði: Dr. Olcay Iþýk, Büyükþehir Mah., Bahçeli
Sok. A/18A Kat: 5, Daire: 22, Beylikdüzü, Büyükçekmece,
Ýstanbul
E-mail: isik_orkun@hotmail.com
Makalenin geliþ tarihi: 15.08.2005
Kabul tarihi: 28.04.2006
Gülhane Týp Dergisi 2006; 48: 169-171
OLGU SUNUMU
© Gülhane Askeri Týp Akademisi 2006
Summary
Methylphenidate is a central nervous system
stimulant used for the treatment of attention
deficit hyperactivity disorder and narcolepsy.
In this report, a 9-year-old boy with cerebral
ischemic stroke developing after the short
term use of oral methylphenidate is presented.
The experience of our patient and a review of
the literature suggest that consumption of oral
methylphenidate may be a potential predisposing factor for stroke.
Key words: Methylphenidate, ischemic stroke,
short term use
Özet
Kýsa süreli oral metilfenidat kullanýmý ile
iliþkili iskemik inme
Metilfenidat, dikkat eksikliði-hiperaktivite
hastalýðý ve narkolepside kullanýlan bir santral
sinir sistemi stimülanýdýr. Bu makalede, kýsa
süreli oral metilfenidat kullanýmýný takiben
serebral iskemik inme geliþen 9 yaþýnda bir
erkek çocuðu sunulmaktadýr. Bizim hastamýzdaki deneyimimiz ve literatür incelemesi, oral
metilfenidat kullanýmýnýn inme için potansiyel
predispozan bir faktör olabileceði fikrini
desteklemektedir.
Anahtar kelimeler: Metilfenidat, iskemik
inme, kýsa süreli kullaným170 · Eylül 2006 · Gülhane TD Kocaman ve ark.
over the next one hour. He was in
good general health before the incident. He had no significant medical
history. His prenatal, natal and postnatal histories were normal. He had
no similar symptoms in the past. His
family members had no risk factors
for any vascular disease. He had used
methylphenidate hydrochloride tablets (60 mg per day by mouth) for the
last 6 months. It had been started by a
pediatric psychiatrician for the attention deficit.
General physical examination
with emphasis on the cardiovascular
system showed no abnormalities. His
blood pressure was 100/70 mmHg on
admission and it was normal during
hospitalization. There was no evidence of needle puncture, superficial
venous thromboses over the extremities, nasal mucosal ulceration or septum perforation. At neurologic examination, mental state and speech were
normal. There was a left central facial
palsy. Other cranial nerves were
intact. Funduscopic examination
showed a normal vascular pattern and
optic disc. There was no visual field
defect. Right upper and lower
extremites had normal muscle tone
and strength, whereas the left
extremities had decreased muscle
tone. Left upper extremity strength
was 2/5 both proximally and distally.
Left lower extremity strength was 1/5
and 2/5 at proximal and distal, respectively. Muscle bulk was normal.
Muscle stretch reflexes were diminished throughout on the left side in
comparison to right. There was no
sensory loss or extinction. The plantar reflex was upgoing on the left.
There were no primitive reflexes.
There was no evidence of limb incoordination or cerebellar ataxia out of
proportion to weakness. He was not
able to walk at the time of presentation.
The following laboratory tests or
investigations showed normal results:
complete blood count with differential, sedimentation rate; blood chemistry and electrolytes, plasma homocystein level, C-reactive protein and
lipid profile; serum protein electrophoresis; serum VDRL, anti-HIV,
anticardiolipin, antinuclear and dsDNA antibodies; serum protein C,
protein S, antithrombin III, 20210 A
gen mutation, factor V Leiden and
activated partial thromboplastin time;
liver enzymes; urinalysis; CSF analysis including electrophoresis; ECG,
chest X-ray and transesophageal
echocardiography.
Brain MR scan showed acut
infarction involving the caput of right
caudate nucleus, putamen and adjacent anterior limb of the internal capsule (Figure 1). Magnetic resonance
angiography was normal. His recovery stage was uneventful. However,
convulsion appeared 3 months later,
and anticonvulsion therapy was started. The medical therapy was only salisilat preparation after this acut
infarction. Physiotherapy program
was continued approximately 3
months. After this therapy program,
his neurological deficit was minimal.
His convulsion did not recur later.
He is under follow-up program of
the Department of Pediatric Neurology.
Discussion
Stroke is relatively rare in childhood. Incidence of ischemic stroke in
pediatric population is 0.6 to 3.3 in
100 000 children. Ratio of ischemic to
hemorrhagic stroke is 1/1.5 in childhood (11). Many strokes in children
do not have a known etiology or a
complication of a disease originating
outside the central nervous system
(CNS). Congenital heart disease,
sickle cell disease, vasculitis, infection, hypercoagulable states, trauma
and drugs are the usual causes of
childhood stroke (11).
In the etiology, after eliminating
all the causes, the main cause of
stroke may be use of a drug, especially psychostimulant agents as in our
case. Amphetamine has been implicated in the etiology of cerebral vasFigure 1. Cranial magnetic resonance scans show acut infarction in the caput of right caudate
nucleus, putamen and adjacent anterior limb of the internal capsule on the T1 and T2 sequencesCilt 48 · Sayý 3 · Gülhane TD Ischemic stroke and methylphenidate · 171
culitis and stroke. MP, which is
structurally and pharmacologically
similar to amphetamine and cocain, is
widely used in the treatment of
hyperactivity and attention deficit
disorder in children. Although psychiatrists and pharmacologists have
used it to treat ADHD for 40 years,
they have never known completely
how it worked (10). Earlier research
has shown that cocain blocks about
50% of dopamine transporters, leading to a surfeit of dopamine in the
synapse and a hit of pleasure. Because
of MP's chemical similarities to
cocaine, pharmacologists thought
that it might work in the same way,
only less potently, blocking fewer
transporters. Animal studies with
high doses of MP indicated that this
could be the case (10).
Amphetamine-induced vasculitis
was first described in drug abusers in
1970 (12); the pathophysiology and
pathology of the vascular abnormalities, particularly in the central nervous system, remain poorly understood. Lymphocytic infiltration
around brain arterioles has been produced experimentally in monkeys
with repeated intravenous administration of methamphetamine (13).
Intravenous MP, like methamphetamine, can produce angiographic
changes including decreased vessel
calibre and absence of filling in small
middle cerebral artery branches (14).
Recent clinical reports have reported
associated irregularity and partial
occlusion of small cerebral vessels
with oral amphetamine use in nondrug abusers (15). Given its pharmacological similarity to amphetamine,
the association of MP with cerebral
arteritis is not unexpected, yet has not
been previously reported.
A clinical report by Trugman
described an 12-year-old patient with
hemidystonia, few years after experiencing ischemic cerebral infarction.
The patient was diagnosed to have
ADHD at age five and treated with
MP 20 mg per day until age 12 when
right hemiparesis and aphasia suddenly developed. Cerebral angiography showed occlusion of the left
anterior cerebral artery and a branch
of the left middle cerebral artery.
Brain MRI confirmed infarction in
the left striatum and internal capsule
(16).
Schteinschnaider et al. reported
an eight-year-old boy with ADHD,
who developed repeated episodes of
hemidystonia and ataxia, while
receiving MP 20 mg daily for 18
months. An MRI showed thalamic
infarction, and an angiogram revealed
occlusion of both cerebral arteries
(17).
The occurence of acut infarction
involving the caput of right caudate
nucleus, putamen and adjacent anterior limb of the internal capsule following the use of short term oral
methylphenidate in our patient who
did not have any known risk factor
for cerebrovascular disease, suggests
an association between this drug and
cerebral infarction. It seems justified
to consider the use of short term oral
methylphenidate as a potential predisposing factor for stroke in this
patient.
We draw your attention to the risk
of using oral MP, which is taken by
many children in recent years.
Although the pathogenesis of this
cerebral infarction is unclear, we
believe that physicians who prescribe
this drug should be aware of this
potential possibility.