Download ADPE02B0805 - Piracetam

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ADPE02B0805
Clinical Neuvopharmacologv
Vol 24, No. 6, pp 352–357
02001
Lippincott Williams & Wilkins, Inc., Phila(ielphla
Controlled Pilot Study of Piracetam for Pediatric Opsoclonus–
Myoclonus
Michael
National
Pediatric
R. Pranzatelli,
M,voclonas
Center,
Elizabeth
Departments
D. Tate,
of Neurolo~
Sprin@eld,
Isabel
and Pediatrics,
Illinois,
Galvan,
Southern
and Alisa
Illinois
Wheeler
Universi&
School
of Medicine,
USA
Summary: Piracetam is an effective symptomatic treatment for some types of myoclonus in adults. To survey the efficacy and safety ofpiracetam in pediatric opsoclonus–
myoclonus, we conducted an open, randomized, two-period, dose-ranging, doubleblind, crossover, clinical trial of five children comparing the antimyoclonic properties of
oral piracetam to placebo. We devised and validated a new rating scale, specifically for
pediatric opsoclonus–myoclonus. Two parents while blinded were able to identib the
active phase by improvement in behavior, but another thought the behavior was worse.
None of the patients showed improvement in myoclonus, The adult-equivalent dose of
piracetam used in this study, which is threefold higher than that used in previous pediatric studies, was well tolerated and safe. We found our rating scale to be a reliable and
useful tool for future studies of opsoclonus–myoclonus in children. Key Words: Dancing eyes syndrome-Kinsbourne
syndrome—Opsoclonus–my
oclonus—Subcortical
myoclonus-Myoclonus
rating scale
Piracetam
(2-oxo- 1-pyrrolidine
acetamide, Nootropil) is the serendipitous
prototype of a “nootropic”
class of antimyoclonic
drugs (1). A reduction of myoclonus in progressive myoclonus epilepsy, posthypoxic
myoclonus, and other myoclonic disorders has been reported in adults, Oral piracetam is rapidly absorbed,
achieving peak plasma levels in 30 minutes with a halflife of about 5 hours before it is excreted unchanged in
the urine (2). Brain levels exceed plasma levels several
hours afier oral administration.
Although piracetam is a
cyclic derivative
of y-aminobutyric
acid, its action
does not seem to be mediated by y-aminobutyric
acid,
and the mechanism of its antimyoclonic
properties is
unknown (3).
Although piracetam is efficacious for certain types
of myoclonus in adults, it has not been evaluated in the
pediatric age group. With a median lethal dose of more
than 10 g/kg (2) and a European reputation of being
virtually nontoxic, it is ideal for study in the pediatric
population.
Children with opsoclonus–myoclonus,
a
putative autoimmune reaction to remote neuroblastoma
or certain viral infections (4), are especially in need of
more effective treatment. Despite conventional immunotherapy, many are left with significant motor and
cognitive impairment, and there are limited alternative
treatments. This is a pilot study ofpiracetam
for myoclonus in pediatric opsoclonus–myoclonus.
Although more than one evaluation scale has been
developed to evaluate myoclonus in adults, they are not
well suited for use in young children, who cannot comply with the required tasks. Previously, we designed
and validated a pediatric myoclonus scale (5), which
we used in the present study to evaluate the clinical
types of myoclonus.
However,
in the presence
of
ataxia, evaluation of action myoclonus can be difficult.
As a more global measure of motor dysfunction
in
childhood opsoclonus–myoclonus,
we now introduce a
new scale that includes parameters affected by opsocIonus, myoclonus, tremor, and ataxia, the major motor
manifestations ofopsoclonus–myoclonus.
This scale is
well suited to scoring from videotapes, which is the
documentation
standard for drug trials in patients with
movement disorders.
———
Address correspondence and
reprint requests to Michael R. Pranzatelli, National Pediatric Myoclonus Center, SIU School of Medicine, PO
Box 19658, Springfield, IL 627949658,
USA.
3.52
..
---
T’-.
PIRA CETAM FOR OPSOCLONUS–MYOCLONUS
MATERIALS
AND METHODS
Subjects
We recruited
six children
with opsoclonus–
myoclonus through the National Pediatric Myoclonus
Center. Consent for this Institutional
Review Board–
approved study was obtained by the principle investigator. Patients had action-induced
and spontaneous
myoclonus. Subjects ranged in age from 2 to 6 years,
and paraneoplastic
and nonneoplastic
etiologies were
equally represented (Table 1). The sixth and youngest
subject was dropped from the study in the second phase
when he refused piracetam because of its bitterness. He
could not swallow pills, so the tablet had to be crushed.
Despite whatever the parents used to try to camouflage
the taste, he spit it out.
Establishing
an Etiology
A thorough search for occult neuroblastoma,
including urinary catecholamines,
serum ferritin, neuronspecific enolase, paraneoplastic
autoantibody
panel
(anti-Hu, antiRi, antiYo), body computed tomography
scan, and 1231-meta-iodobenzyl
guanidine scan, was
completed before enrollment in the study because the
treatment of choice was removal of the tumor (4). Most
often, however, referrals were made after tumor removal and immunotherapy.
Experimental
Design
The drug trial was a double-blind, two-period, doseranging, crossover study separated by a drug washout.
The enrollment of patients into the study was ongoing
and sequential. The order of drug treatment (piracetam
or placebo) was assigned randomly and coded. All patients were treated for 4 weeks with piracetam and with
placebo, beginning with one and crossing over to the
other after a 2-week washout. The first week was a
dose-finding period (incremental dose), after which the
patient stayed on the “best dose” for the following 2
weeks. The fourth week was a tapering period (decremental dose).
Drug Dosage
and Administration
UCB supplied piracetam
Secteur Pharmaceutical
(Braine-L’Alleud,
Belgium) in 800-mg caplets, the
coating of which eases swallowing and prevents identification by bitter taste. The optimum dosage of piracetam was determined by gradual titration according
to adverse and therapeutic effects in each patient. Although the dosage of piracetam in adults is not based on
body weight, we scaled the pediatric dose accordingly,
353
making the ceiling dose 400 mg/kg and the starting
dose 80–1 30 mglkg for a 5-kg and 45-kg child, respectively. The total daily starting dose was 2 g, which was
increased stepwise to 8–1 O gld.
For small children, the scored caplet could be broken
once or twice as necessary. We opted against the use of
liquid formulations of piracetam so as not to introduce
a variable in comparisons with adults taking pills. The
liquid form is not very palatable for children and is associated with mild gastrointestinal
symptoms.
Clinical
Data Collection
Epidemiologic
and historical data included patient’s
birth history, age of onset of myoclonus, chronologic
and developmental
age at start of study, and details of
myoclonus, such as distribution and temporal pattern.
Patients were examined once during periods 1 and 2.
Patient vital signs were obtained at the end of week 1
and 3. Data as to sleeping patterns, personality changes,
and drug compliance were also obtained. While they
were still blinded, parents were asked to answer yes or
no to each of a 10-item questionnaire.
The responses
were used to generate Table 2.
Videotaping
and Evaluation
Videotapes were made by the research nurse practitioner according to a written set of instructions so that
each item to be used for scoring was included. As a
semiquantitative
measure of myoclonus, we used the
Myoclonus
Evaluation Scale (MES), which we validated previously (5). As a more global measure of motor dysfi.mction, we used the Opsoclonus–Myoclonus
Scale (OMS) (Table 3). Our trained research assistant,
who had been included in the validation procedures
mentioned in the next section and who was blinded to
patient information, scored videotapes.
Validation
of the Opsoclonus–Myoclonus
,,.
.
,
Scale
We determined interrater reliability by a judge panel
of two blinded observers (child neurologist
and research assistant)
independently
scoring videotapes
(one for each scale item) made at baseline before the
start of the study. Correlations and paired t tests were
used to analyze the data. Test–retest reliability was calculated by having the research assistant score the same
five videotapes twice, and paired ttests were used to
analyze the data. Having two neurologists review a few
videotapes and determine whether the scale adequately
gauged the patients’ motor problems assessed face validity. Discriminate validity was assessed by having the
Clln. Neuropharmacol.,
,!
Scales
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F’01. 24, No
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6, 2001
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-
.
Syl]drolnc
Gc!ldcr
onset
(Y)
M’2
LI
1 ]7
M
t“
g
4
5
2.91
3.66
F
F
Etl(>l[)gy
83
I
I H3
Act!on
myoclonus
Spontaneous
myoclo!lus
Ataxta
Dysathrla
Cogn]t]>e
]rnpa]rntent
Amhulatt)ry
Impa]rmcnt
(gillt)
overall
ftlnctlc]n:il
]mpl]rtnent
other
medtcal
problems
Head
MRI
EEG
SSEPS
v
+
+
None
N
N
N
NN
+
+..
,,
+
++
+
4+4,
.
v
++
+A-
+++
Norlc
S
N
N
NB
++
II
+++
-++
++
++
+..
Mild
ret:lrdatlon
Mild tonsllar
Kctop!a
[hair] I
N (small
plneal
cyst)
N
N
s
N
NN
N
—
NN
N13
v
++
++
++
+
+.+
+
++
+
+
4
()
+++
+
++
+
None
N<)IIC
Ciln!cal ratltlg scald. (), n,,rmal or tr:ice: -, mild; -+, moderate, -+-, severe, \B, neumhlast[]m:l; V, viral ‘Ideopathlc: S, slow]ng, N, r>or!nal.EtG, clcctrocncephalogram;
auditoty evoked potentials; VERS, visual evoked responses.
VERS
FLAER\
Increased
applitude
p2/p4
(R
hctnisphere)
N
N
—
SSF.P\, sc>m:ltosensoty evoked potentials; BAERs, bralnstem
g
>
TABLE 2.
Patient
I
Phase of
active drug
2—
Summa~
Max dose
reached
(mg/kg/d)
Dose of
first drug
effects
(mg/kg/d)
Drug side effects reported
at maximum dose
400
400
Sleepinterrttpted, increased
nocturnal myoclonus
5
2
364
364
Difficulty sleeping, violent
aggressive behavior,
diarrhea
400
240
Decreased appetite, bed
wetting increased
400
400
None
400
300
Increased myoclonus
ofresponses
reported
by patients
Placebo effects
reported
$
~
and/or parents
Parents
identified
drug
Improvement
on drug
Overall parents
assessment
Behavior improved
at school
Yes
85% improved on
the drug
Yes
Gait, eating,
moods, personality
worse,
Headaches,
stomachache,
drooling 60-75
worse
Hyperactive
No
Worse on drug
than placebo
No
Yes
Yes
No
More steady and
better moods on
the drug
No difference
No
No
No difference
No
Hyperactive,
restless, talking
more, increased
vocabulary
Less myoclonus,
improved speech,
coordination
—
Type of improvement
250A, behavior and
social skills; 500/0
attention span,
drooling decreased
10YO,more confident
—
Behavior is better with
drug, worse with
placebo
PIRACETAM FOR OPSOCLONUS–MYOCLONUS
TABLE 3.
Opsoc[onus-myoclonus
motor performance
evaluation
scale of
1. Walking: side-to-side imbalance
&normal
l-mild
2–moderate
3–severe
2. Walking: front-to-back imbalance
O-normal
1–mild
2–moderate
3–severe
3. Walking: wide base
O–normal
1-mild
2–moderate
3–severe
4. Instability while standing (feet apart)
O–normal
l–mild
2–moderate
3–severe
5. Difficulty achieving standing position
O–achieves standing normally
1–achieves with jerks, but no support
2–achieves with self-support
3–tmable to reach standing without assistance
6. Truncal instability wh]le sitting
O–sits with no supporI from arms and no jerking
l–sits with minimal support from arms and occasional jerking
2–sits with total support from arms or trunk to maintain balance
3–unable to sit in chair
7. Targeting difficulty
&reaches target with no jerks
l–reaches target with minimal jerks
2–reaches target with moderate to severe jerks
3–unable to reach target
8. D]fticulty grasping with one hand
O–grasps object (cup, crayon, etc.) with one hand
I–grasps object with two hands
2–grasps object with two hands, but has difficulty holding it
3–unable to grasp object
9. Difficulty with pincer grasp
O–grasps with thumb and tip of digit (pincer)
l-grasps with thumb and digit but unstable hold
2–grasp with closed fist
3–unable to grasp object
10. Abnormal eye movements while tracking (fixation)
O<yes track smoothly and do not jerk
I<yes have infrequent/small amplitude jerks
2<yes have frequentllarge amplitude jerks
3<yes cannot track
11. Abnormal eye movements while resting
O<yes do not jerk
I<yes have infrequenti’small amplitude jerks
2<yes have frequent/small amplitude jerks
3<ye have frequent’large amplitude jerks
12. Speech abnormality (dysarthria)
Wnomal
l–mild
2–moderate
3–severe
Videotapes were made to include a segment of each item needed for
scoring.
research assistant score videotapes from 10 children
with opsoclonus-myoclonus
and the same number of
normal children of similar age. These data were analyzed by an independent t test on each item.
,,
,.. . .
355
Laboratory
Blood Tests
Complete blood count and metabolic panel (chem20) were obtained before the study and four times during the study: twice on drug A and twice on drug B. The
first blood drawing was at the end of week 1 and the
second was in week 3.
Statistical
Analysis
Scores on placebo and drug were compared statistically by two-tailed paired t tests as implemented
on
SAS, a statistical analysis computer software program
for the PC (6).
RESULTS
Efficacy
Blinded parents reported subjective responses. Of
five children with opsoclonus–myoclonus,
blinded parents of two correctly identified the active drug phase
because of isolated improvement in behavior and attention span, not effects on myoclonus (Table 2). Another
parent, however, reported aggressive
behavior with
the drug.
Objective responses were scored from videotapes.
Piracetam had no significant
effect on MES scores
compared to placebo (Table 4).
Performance on the OMS was analyzed both by individual components
and by total scores (Table 5).
There were no significant drug effects.
Safety
No abnormalities
were found in vital signs, blood
cell counts, or blood chemistries.
No one withdrew
TABLE 4.
Scores on the myoclonus
evaluation
scale (A4ES)
Type
Dmg
Placebo
Spontaneous myoclonus score
Frequency
Intensely
Distribution
Action myoclonus score
Frequency
Intensity
Distribution
Total score (spontaneous + action)
6.0 + 0.8
6.2 + 0.8
2.0 * 0.4
1.6+ 0.2
2.4 * 0.2
8.2+ 0.8
3.0 + 0.3
2.4 + 0.2
2.8 + 0.4
14+ 1.2
2.0 * 0.3
1.8+0.2
2.4 * 0.4
6.8 + 0.86
2.6 + 0.4
2.0 * 0.3
2.2 + 0.2
13+1.6
The MES (action-induced, spontaneous, sensoryevoked)
as scored
by a blinded observer from videotapes. For each of the three categories of
the scale (frequency, distribution, intensity), the scorer assigned a score
of O to 4 (O, normal; 1, rare myoclonic jerk; 2, some/occasional myoclonus; 3, &any/intermittent myoclonic jerks; 4, continuous myoclonus).
Because there was no consistent sensory-evoked myoclonus, scores for
it were dropped from the scale. The maximum abnormality (total for
spontaneous myoclonus plus total for action myoclonus) was a score of
24. Data are expressed as the mean* SEM, N = 5.
M. R, PRANZA TELLI ET AL.
356
TABLE 5.
Scores
on the
opsoclottus-myoclonus
scale
Test
item no.
2
3
4
5
6
8
9
10
11
12
Total score
Drug
Placebo
1.8 +0,2
1.4 + 0.2
1.8 * 0,2
1.4 i 0.2
1.8+ 0.4
1.4* 0.2
1.2 * 0.4
0.8 + 0.2
1.4 * 0.2
0.0 * 0,0
1.0● 0.4
1.0+ 0,0
0.5 + 0.3
1.8+ 0.6
13.2%1.2
1.8+ 0.4
1,4i 0.2
2,0 * 0.0
0.4 * 0.2
1.0+ 0.0
0.2 *
1.0 +
1.0 *
0.8 +
2.0 +
14.4 +
0.2
0.4
0.0
0.4
0,4
1.4
Data are means + SEM, N =5. See Table 3 for an explanation of test
items.
from the study because of drug side effects. All but one
of the children reached the maximum dose studied.
Validation
of OpsocIonus–Myoclonus
Scale
We found the OMS to be reliable and easy to use.
Interrater reliability (0.90 correlation) and test–retest
reliability (0.87 correlation)
were high. Discriminate
validity for patients versus controls was also statistically significant @ = 0.001).
DISCUSSION
Implications
for Opsoclonus–Myoclonus
Subcortical Myoclonus
and
The reason that piracetam
was not efficacious
against myoclonus in our children with opsoclonus–
myoclonus may be because the myoclonus is subcortical in origin, as first suggested by Kinsbourne (7). An
electrophysiologic
study in three adults with opsoclonus–myoclonus
found no cortical correlate using backaveraging (8). Most adults with cortical myoclonus
benefit from piracetam at a dose of 16.8-24 g/d (9-1 1),
but it is not effective (9) or less effective(11)
for subcortical myoclonus
in open-label
studies. However,
given the lack of controlled trials of piracetam in children and in subcortical myoclonus of various etiologic
subtypes, we believed a pilot study in opsoclonus–
myoclonus was worth doing. Although a larger sample
size conceivably might have identified responders, the
lack of motor improvement in five consecutive children
was not deemed sufficiently promising to warrant further study.
Perhaps piracetam is ineffective against subcortical
myoclonus
because
it acts selectively
on cortical
mechanisms (12). However, correlation between elec-
C/in
,,
,.
,Vc>urouhurmucol
.. . . .
trophy siologic and clinical responses
to piracetam
has not been a uniform finding (11), especially during monotherapy
(13). In one study, 25°A of adults
with cortical myoclonus
did not improve with piracetam (13).
Monotherapy
may have put our patients at a disadvantage if a synergistic effect with antiepileptic drugs
explains greater piracetam efficacy in cortical myoclonus (14). Piracetam monotherapy had no effect on myoclonus in one study (13), but was effective in two
others (10, 11).
An argument could also be made for pharmacokinetic differences
affecting regional distribution
of piracetam. In the rat, the concentration
of piracetam 4
hours after an oral dose of 500 mg/kg was lowest in the
pens–medulla
and highest in cortex, but the differences
between any brain region, including other subcortical
structures, were less than 40°/0 (2). The significance of
these differences and their occurrence in humans is unknown.
Safety of Piracetam
in Children
We found no adverse effects of piracetam on blood
parameters. In a piracetam study of adults with myocIonus, two of 60 patients developed reversible hematologic abnormalities (thrombocytopenia
or leukopenia),
which were attributed to interactions with antiepileptic
drugs (11 ). No abnormalities were found in 24 patients
in another study (1 O).
We identified
no pediatric
studies of the adultequivalent piracetam dose used in our study. Low doses
of 3.3 gld, or approximately
80–170 mgfkg, have been
used safely in hundreds of school-aged
children for
dyslexia ( 15–20), attention deficit disorder (21), nocturnal enuresis (22), sensorineural
hearing loss (23),
and to study brain electrical potentials in normal children (24). Our study supports the use of 2.5–3 times
higher doses of piracetam in studies of children.
Suggestions
for Future Pediatric
Studies
A smaller dose preparation
will be necessary for
studies of piracetam in young children old enough to
swallow pills. The liquid preparation, which has been
used in all trials to date, is not palatable to youngsters
and produces gastrointestinal
disturbances.
Given the
lack of side effects, higher doses could be entertained.
Also, the study of putative cognitive or behavioral
properties of piracetam would require a different paradigm than ours, which focused on motor responses.
Myoclonus is an important problem in infants and toddlers, who deserve the benefit of therapeutic trials. A
study of piracetam for cortical myoclonus of pediatric
onset is in progress at our center.
L’ol 24, A(O 6, 200/
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PIRA CETAM FOR OPSOCLONUS–A4YOCLONUS
Acknowledgments: This work was supported by grants from
the Food and Drug Administration, Orphan Products Development Program (FD-U-000955
) and UCB Pharmaceutical
Sector
to M.R.P. and E.T, UCB donated piracetam and placebo for the
study. The authors thank Janice Vines for typing the manuscript
12.
13,
and all the families who participated in the study.
14,
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