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Long-term Efficacy and Safety of Piracetam in the Treatment of Progressive Myoclonus Epilepsy
Marco Fedi, MD;
David Reutens, MD, FRACP;
François Dubeau, MD, FRCPC;
Eva Andermann, MD, PhD, FCCMG;
Daniela D'Agostino, MD;
Frederick Andermann, MD, FRCPC
Arch Neurol. 2001;58:781-786.
ABSTRACT
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Background Piracetam has been proven to be effective and well tolerated in the
treatment of myoclonus in short-term studies.
Objective To assess its long-term clinical efficacy, 11 patients with disabling
myoclonus due to progressive myoclonus epilepsy were treated with piracetam
in an open-label study.
Methods Neurologic outcome (at the 1st, 6th, 12th, and 18th month of treatment)
was assessed by an adjusted sum score of the following 3 indices: motor impairment,
functional disability, and global assessment of disability due to myoclonus.
Severity of other neurologic symptoms (seizure frequency and severity, dysarthria,
and gait ataxia) also was assessed. Treatment with piracetam was initiated
at a dose of 3.2 g/d that was gradually increased until stable benefit was
noted (maximal dose in the trial was 20 g/d). Concomitant antiepileptic drugs
were maintained at their previous dose.
Results Statistically significant improvement in the total rating score was
observed after introduction of piracetam at the 1st, 6th, and 12th month of
treatment. Severity of other neurologic symptom scores did not improve significantly.
Two patients reported drowsiness during the first 2 weeks of treatment.
Conclusions Piracetam given as add-on therapy seems to be an effective, sustained,
and well-tolerated treatment of myoclonus. In patients with progressive myoclonus
epilepsy, the efficacy of the drug increased during the first 12 months of
treatment and then stabilized.
INTRODUCTION
MYOCLONUS consists of sudden, irregular muscle jerks unassociated with
loss of consciousness.1 Progressive myoclonus
epilepsy (PME) represents an uncommon epilepsy syndrome caused by a large
number of rare specific genetic disorders. In its fully developed form, the
syndrome consists of myoclonic jerks, tonic-clonic seizures, mental retardation,
and ataxia.2 Myoclonic jerks are often difficult
to control in these conditions and usually are an important cause of disability
in activities of daily living.
Piracetam (2-oxo-1-pyrrolidine-acetamide) a nootropic drug with broad
indications and few transient adverse effects has been shown to be an effective
antimyoclonic agent with a dose-related effect. Since the first report by
Terwinghe et al3 in 1978 in a patient with
action myoclonus due to Lance-Adams syndrome, several short-term studies have
suggested that piracetam may have a beneficial effect in the treatment of
cortical myoclonus regardless of the underlying cause.4, 5, 6, 7, 8, 9, 10, 11
We performed a long-term, open-label study of 11 patients who had intractable
myoclonus to evaluate the efficacy and the safety of piracetam treatment over
an 18-month period.
PATIENTS AND METHODS
Eleven patients (8 males and 3 females; age range, 17-36 years; mean
± SD age, 24.5 ± 5.8 years) who had severe chronic disabling
action and spontaneous myoclonus were treated with piracetam added to their
previous drug regimen between November 1994 and November 1998. Before the
introduction of piracetam treatment control of myoclonus was poor, despite
the use of other antimyoclonic agents. Exclusion criteria included pregnancy,
breastfeeding, and severe renal impairment.
Myoclonus was secondary to Unverricht-Lundborg disease in 2 patients,
Lafora disease in 3 patients, mitochondrial encephalomyopathy with ragged
red fibers in 3 patients, and sialidosis type I in 1 patient. In 2 patients
with typical clinical features of PME, a specific diagnosis could not be reached
despite extensive investigation. Mean ± SD age at onset was 10.7 ±
6.4 years (age range, 2-26 years), duration of disease ranged between 4 and
22 years (mean ± SD duration, 13 ± 8 years). All patients had
action and spontaneous myoclonus; stimulus sensitivity was noted in 3. Generalized
tonic-clonic seizures were present in 8 and absent in 3. Two patients with
Lafora disease also had focal occipital seizures. Electroencephalograms were
obtained for all patients; somatosensory evoked potentials were obtained in
5 patients and jerk locked back averaging of electroencelphalographic activity
preceding jerks in 4 patients.
All patients underwent high-resolution brain magnetic resonance imaging
using a 1.5-T scanner. Magnetic resonance spectroscopy was performed in 5
patients and fluorodeoxyglucose F 18–positron emission tomography in
1 patient. Diagnosis was confirmed by genetic analysis or biopsy in patients
having Lafora disease, Unverricht-Lundborg disease, and mitochondrial encephalomyopathy
with ragged red fibers. Grossly elevated urinary sialoliposaccharide levels
and the characteristic cherry-red spot in the fundus supported the diagnosis
of sialidosis type I. Patients were assigned to 1 of 3 stages according to
the duration of disease, level of disability, and clinical and electrophysiological
features: early, intermediate, and late.12, 13, 14
By dividing the baseline motor impairment due to myoclonus by the duration
of the disease in years, a quotient was calculated to reflect the rate of
progression. Myoclonus was the primary cause of disability in activities of
daily living leading to complete dependence requiring constant assistance
for 9 patients and slight assistance for 2 patients who needed some help.
Clinical features and findings are summarized in Table 1.
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Table 1. Clinical Features of 11 Patients Treated With Piracetam*
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Piracetam was obtained in 800-mg capsules, given in increasing dosage,
starting with 3.2 g/d divided in 3 doses, then increased by 2.4 g/d every
4 days up to a maximum dose of 20 g/d or until a stable therapeutic effect
was evident. The dosage of other antimyoclonic or antiepileptic drugs remained
constant.
CLINICAL EVALUATION
All patients were periodically examined by at least one of us before
and during treatment over an 18-month period. The presence, frequency, severity,
and degree of disability due to myoclonus was evaluated by clinical interviews,
neurologic examination, and analysis of videotape recordings obtained before
and during treatment. Clinical benefit was assessed using a modification of
the rating scales described by Truong and Fahn15
for motor impairment, functional disability, severity of other symptoms, global
impression of intensity of myoclonus by the investigator, the parents, or
the care giver, and global impression of efficacy of treatment by the investigator
and the patient. Measurements of these indices were performed on enrollment
in the study and after 1, 6, 12, and 18 months of treatment.
Myoclonus was clinically scored in 8 regions of the body (eyes, face,
neck, trunk, and all 4 limbs) for frequency (resting and action myoclonus)
and severity (action myoclonus). Functional disability in activities of daily
living was evaluated in 7 domains: eating (ability to use a fork and knife),
swallowing, dressing, speech, hygiene, balance, and presence of falling. Each
function was rated on a scale of 0 (worse) to 4 (best). In previous studies5, 6 "walking" was included in the functional
disability score. Since in patients with PME walking may be disturbed by either
ataxia or action myoclonus, we evaluated balance (ataxia) and falling (myoclonus)
separately to achieve a more sensitive result. Both scores were rated according
to severity and interference in activities of daily living on a scale of 0
(worse) to 4 (best). The global impression of intensity of myoclonus achieved
from the parents and the physician was rated as follows: 0, none; 1, mild;
2, moderate; 3, marked (causing interference and distress); and 4, severe
(causing great distress in activities of daily living). Since most patients
had additional neurologic dysfunction, the following accompanying neurologic
symptoms were also evaluated: seizure frequency and severity,16
dysarthria, and gait ataxia. Seizure frequency was scored as as follows: 0,
no seizures; 1, less than 1 seizure yearly; 2, at least 1 seizure yearly;
3, at least 1 seizure monthly; 4, at least 1 seizure weekly; 5, at least 1,
but less than 10 seizures daily; and 6, more than 10 seizures daily. Seizure
severity was defined according to different features: falls, loss of consciousness,
and duration of postictal effect in a score of 0 to 4. Dysarthria and ataxic
gait were scored as 0, none; 1, slight; 2, mild; 3, moderate; and 4, severe
anarthria or imbalance.
The global clinical impression of the efficacy of piracetam treatment
was deduced from parents and physician observers: marked control of myoclonus,
75% to 100%; moderate, 50% to 74%; slight, 25% to 49%; no reduction, 0% to
24%; and worsening, 0% worse than the baseline value.7
Detailed scores of myoclonus and associated symptoms are listed in Table 2. We did not assess stimulus sensitivity
and handwriting scores.
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Table 2. Summary of Method Used in Long-term Study to Score Myoclonus,
Disability, and Associated Symptoms
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STATISTICAL METHODS
The Friedman test was performed to assess statistical differences between
the baseline and the treatment followed by Wilcoxon 2-sample rank sum test
to evaluate the differences between the baseline and each follow-up period.
For the Wilcoxon 2-sample rank sum test (since we are comparing baseline against
other time measurements),  was corrected for multiple comparisons and
statistical significance was set at P<.01. SysStat
version 7.01 software (SPSS Science, Chicago, Ill) was used for the analysis.
RESULTS
The total daily maintenance dose of piracetam, given in 2 or 3 doses,
ranged from 9.6 to 20 g/d (mean ± SD, 13.5 ± 7.2 g/d). Mean
± SD duration of treatment was 24.1 ± 3.7 months (range, 18-26
months). All patients completed the follow-up at 18 months. Piracetam was
given as an add-on therapy to the following previous drug regimens: valproate
sodium, 3 patients; valproate and clonazepam, 5 patients; gabapentin and lamotrigine,
1 patient; valproate, clonazepam, phenobarbital and lamotrigine, 1 patient;
and valproate and ethosuximide, 1 patient. Median and range of scores of motor
impairment, functional disability, severity of other neurologic symptoms,
global assessment of the intensity of myoclonus, and adjusted sum score during
the 4 follow-up periods are summarized in Table 3. The Friedman statistical test showed a significant effect
of piracetam treatment on the overall functions in the adjusted sum score
and the motor impairment index (P<.01). Significant
improvement was noted in the resting myoclonus frequency scale (P<.001), action myoclonus frequency scale (P<.003),
action myoclonus severity scale (P<.001), and
global impression of intensity of myoclonus scale (P<.001).
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Table 3. Effect of Piracetam in 11 Patients With Progressive Myoclonus
Epilepsy During 18 Months of Treatment*
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Functional disability score improved from the baseline, but this was
not statistically significant (P<.06). Among associated
neurologic symptoms no statistically significant difference was noticed between
baseline and the treatment period (P<.09). In
2 patients marked reduction of seizure frequency was observed; but when assessing
the effect of piracetam treatment on seizure frequency and severity, no statistical
significance was found in the group between the baseline and the treatment
period (P<.36). With regard to differences encountered
between baseline and each follow-up period, Wilcoxon 2-sample rank sum test
showed significant improvement (P<.01) between
baseline and the 1st, 6th, and 12th months of treatment in the following scores:
adjusted sum score, motor impairment index, resting myoclonus frequency scale,
action myoclonus frequency scale, action myoclonus severity scale, and global
impression of intensity of myoclonus (Table
3). The following scales showed a borderline significant difference
between the baseline and the 18th month of therapy with piracetam: adjusted
sum score (P<.04), motor impairment index (P<.05), resting myoclonus frequency scale (P<.07), action myoclonus frequency scale (P<.04),
and action myoclonus severity scale (P<.07). The
median percentage improvement for each period [(baseline score - treatment
score)/baseline score], ranged from 22.3% to 80.6% for the individual test
score.
The median improvement of the adjusted sum score improved by a median
of 16.6% (range, 1.2%-22.3%) at the first month of treatment, 21.7% (range,
13%-24.1%) at the sixth month, 37.6% (range, 14%-58.3%) at the 12th month,
and at 31.3% (range, 13.4%-46.3%) at the 18th month.
Both median improvements and statistical significance of the adjusted
sum score showed a trend toward a decrement of the efficacy of piracetam treatment
in controlling myoclonus after the 12th month. No significant correlation
was found between the degree of improvement or the motor impairment index
and the duration of disease or the rate of progression of the disease. The
impression of the effect of piracetam on myoclonus assessed by the parents
and physicians in the 11 patients, comparing the period before and after treatment,
indicated a marked reduction in 3, moderate reduction in 5, and mild reduction
in 4. Among those patients with mild reduction, there were 2 patients with
advanced Lafora disease and almost continuous myoclonic jerks.
Piracetam was well tolerated. Two patients reported drowsiness and dizziness
during the first 2 weeks of treatment. There was no positive relationship
between the dosage and the occurrence of adverse effects. No patient reported
diarrhea, a common adverse effect of piracetam when given at a high dosage.
COMMENT
This study demonstrates that piracetam is effective and well tolerated
for symptomatic treatment of myoclonus. Significant and clinically relevant
improvement was found in the mean sum score of myoclonus rating scales, and
particularly in motor impairment and global assessment of intensity of myoclonus
subscores. Since in some individuals only low doses were used (because of
the short supply of piracetam), increasing the dose may lead to further benefit
in some patients with PME. These results corroborate and extend those of previous
clinical trials of piracetam in which more than 158 patients with myoclonus
have been treated so far (Table 4).
Efficacy and safety of piracetam treatment was previously evaluated in Europe
and Japan, in short-term, open-label studies with daily doses ranging from
6 to 37 g for 2 and 24 weeks.4, 5, 7, 8, 9
In the 2 double-blind, placebo-controlled, crossover studies with piracetam
as add-on therapy reported, the drug was given at a dose of 9.6 to 24 g/d
for 2 weeks. In the first study, Brown et al6
observed significant improvement in motor performance during treatment with
piracetam compared with placebo in patients with cortical myoclonus. In the
second study, Koskiniemi et al4 noted significant
improvement in motor impairment with a dose-effect relationship, suggesting
that a dose of 24 g/d could be highly beneficial. Most patients in our study
achieved significant improvement in severity and frequency of myoclonus after
the introduction of piracetam treatment, but the motor impairment index did
not always reflect substantial clinical benefit. Motor performance in 3 patients
remained purposeless and ataxic although less jerky, and this was partly correlated
with the lack of improvement in functional ability for activities of daily
living. This result is in contrast with previous observations, since both
double-blind, placebo-controlled, open-label studies have shown significant
improvement in functional disability.4, 5, 6, 11
Most of our patients were at an advanced stage of PME and the disability was
secondary not only to the myoclonus but also to pyramidal and cerebellar deficits.
No significant clinical improvement in associated neurologic symptoms was
noted.
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Table 4. Open-Label and Double-Blind Efficacy Studies of Piracetam
in the Treatment of Myoclonus
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Ataxic gait and dysarthria did not improve and this might be explained
by the cerebellar origin of these signs. Two patients experienced dramatic
reduction of seizure frequency during treatment with piracetam. In patients
with PME repetitive myoclonic jerks frequently build up to a clonic-tonic-clonic-generalized
seizure and it is likely that improvement in controlling myoclonic jerks helped
suppress the initial phase of an attack of this type.
High doses of piracetam were well tolerated and adverse effects were
rare, mild, and transitory. They occurred early during treatment and did not
require discontinuing the medication. Piracetam treatment was also well tolerated
in larger series of patients with Alzheimer disease, although lower doses
were generally used.17 The most common adverse
effect was gastrointestinal discomfort, occurring in about one third of the
patients.6 This is probably explained by the
mild osmotic effect that piracetam may cause when high doses are reached quickly.
When giving 3.6 g at the beginning and increasing the dose gradually, none
of the patients developed diarrhea.
To our knowledge, no long-term trials have been published to date and
our report is the first open-label follow-up study of piracetam treatment
in patients with myoclonus. The efficacy of piracetam treatment in long-term
follow-up seemed to increase during the first year of treatment and then stabilized;
this may be due to progression of the underlying disease.
The progression of disease in the group studied varied considerably
with the causes.18, 19 The worst
prognosis was seen in Lafora disease that leads to relentless dementia. In
patients with Unverricht-Lundborg disease or with mitochondrial encephalomyopathy
with ragged red fibers the prognosis is slightly better but highly variable.20
Though the prognosis in PME remains poor, progression is nowadays much
slower and life expectancy better than in the past. Avoidance of phenytoin
or other agents potentially causing ataxia may be a major factor.21 In our study the beneficial effect of piracetam treatment
was long lasting and might suggest slowing progression of the underlying disease.
It is still unclear how piracetam treatment exerts its antimyoclonic
effect. Its similarity to  -aminobutyric acid (GABA) has suggested a
GABAergic action, but it has been demonstrated that it does not act on any
well-characterized receptor site and no interaction with known mechanisms
involved in inhibitory and excitatory neurotransmission or membrane excitability
has been shown.22, 23, 24, 25
Piracetam is present in the polar heads of phospholipid membrane models and
this interaction has been shown to alter the physical properties of the cell
membrane, increasing its fluidity.23
It has been proposed that it could exert its antimyoclonic effect by
potentiation of other antiepileptic drugs which in these conditions have been
successfully used to control the seizures but not myoclonus.22
The best associated drugs were valproate and clonazepam both of which have
antimyoclonic properties.26, 27
Carbamazepine, phenytoin, lamotrigine, and vigabatrin have been shown to worsen
myoclonus; hence, they should be avoided in the treatment of these disorders.28, 29 Our patients receiving lamotrigine
treatment were worse, but we were unable to do draw a firm conclusion because
of the few patients studied.
Piracetam given at high dosage in association with clonazepam and valproate
is an effective and well-tolerated treatment of myoclonus in patients with
PME. The favorable results reported here with piracetam treatment are long
lasting, suggesting an improved prognosis and quality of life in patients
with PME. Since most trials of piracetam treatment have been conducted in
patients with advanced disease, longitudinal studies in naive patients are
required to further assess a possible effect on the natural history of these
disorders.
AUTHOR INFORMATION
Accepted for publication Augutst 31, 2000.
Piracetam was obtained on a compassionate basis from UCB Pharma, Brussels,
Belgium.
From the Department of Neurology and Neurosurgery, Montreal Neurological
Institute and Hospital, McGill University, Montreal, Quebec. Dr Reutens is
now with the Department of Neurology, Austin and Repatriation Medical Centre,
University of Melbourne, Melbourne, Australia.
Corresponding author: Frederick Andermann, MD, FRCP(C), Montreal
Neurological Institute and Hospital, 3801 University St, Room 127, Montreal,
Quebec, Canada H3A 2B4 (e-mail: MIDA{at}MUSICA.MCGILL.CA).
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