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ISSN 0044-4588
KORSAKOV'S JOURNAL
OF NEUROLOGY
AND PSYCHIATRY
Volume 11
2004
STROKE
Journal Supplement
MediaSphera
CEREBROLYSIN IN ISCHEMIC STROKE TREATMENT
Randomized, Double-Blind, Placebo-Controlled Study of Cerebrolysin
Safety and Efficacy in Treatment of Acute Ischemic Stroke
V.I. SKVORTSOVA, L.V. STAKHOVSKAYA, L.V. GUBSKY, N.A. SHAMALOV, I.V. TIKHONOVA, A.S.
SMYCHKOV
A randomized, double-blind, placebo controlled study of Cerebrolysin safety and efficacy in
the treatment of acute ischemic stroke
V.I. SKVORTSOVA, L.V. STAKHOVSKAYA, L.V. GUBSKY, N.A. SHAMALOV, I.V. TIKHONOVA, A.S. SMYCHKOV
Chair of Fundamental and Clinical Neurology, Russian State Medical University, Moscow
36 patients with ischemic stroke aged 45-85 years, who were admitted to a hospital within the
first 12 hours of stroke onset, became subjects of a randomized, double-blind, placebo-controlled
study of Cerebrolysin safety and efficacy. Patients (12 persons in each group) were assigned
placebo or one of Cerebrolysin doses: 10 and 50 ml applied along with a unified baseline
therapy. By day 30 of stroke, there was revealed acceleration of regression of neurological
disorders according to used clinical scales in patient groups that received Cerebrolysin as
compared with a placebo patient group (р<0.05). Patients who received Cerebrolysin and had
the brain lesion volume of 7 to 64 сm 3 demonstrated decrease in the lesion growth on day 3 of
the disease (р<0.05). An acute pharmacological test revealed decrease in the size and
prevalence of θ- and δ-foci in 72.7% of cases in a patient group that received 50 ml of
Cerebrolysin (р<0.05 versus the placebo patient group). In no case Cerebrolysin treatment,
including in the dose of 50 ml, caused manifestation of symptoms of paroxysmal brain activity.
The performed study confirmed safety and efficacy of high-dose Cerebrolysin in treatment of
ischemic stroke patients.
Keywords: ischemic stroke, neuroprotection, cerebrolysin
The aim of the study was to assess safety and efficacy of the neuroprotective drug Cerebrolysin
in acute ischemic stroke. Thirty-six patients with ischemic stroke in carotid artery territory aged
45-85 years, were eligible for inclusion in the trial if they were admitted to the hospital within the
first 12h after stroke onset. Patients were randomly and blindly assigned to placebo (n=12) or 1
or 2 dosages of Cerebrolysin: 10 ml/d (n=12) and 50 ml/d (n=12) for 10 days with concomitant
standard basic treatment in each group. A quantitative time-related analysis of the dynamics of
neurological deficit revealed the tendency towards acceleration of improvement assessed by the
Clinical Global Impression Scale and NIHSS in both Cerebrolysin groups by 30 day of the
treatment. The significant reduction in the volume of MRI ischemic focus was shown in both
Cerebrolysin groups (p<0.05 vs. Placebo) on day 3. Acute pharmacological test revealed a
decrease (p<0.05 vs. Placebo) of the size and Spread of delta and theta foci in 72.7% patients,
receiving 50 ml/d of Cerebrolysin. In none of the cases, Cerebrolysin treatment provoked any
paroxysmal activity on EEG. The trial demonstrated safety, efficacy and good tolerability of highdose Cerebrolysin in the treatment of ischemic stroke.
Key words: ischemic stroke, neuroprotection, cerebrolysin
Therapy in an acute period of ischemic stroke is aimed mainly at reducing functional
disintegration of the central nervous system (CNS) and neurological deficit. In this case
metabolic therapy plays the leading role [1].
Due to the possibility of brain tissue survival in the penumbra zone within at least 48 - 72
hours of stroke onset, special emphasis is laid on elaboration of new efficient methods of
secondary neuroprotection directed to interruption of delayed mechanisms of cell death (long-
STROKE, No. 11, 2004
CEREBROLYSIN IN ISCHEMIC STROKE TREATMENT
term effects of ischemia): excessive synthesis of nitric oxide and oxidant stress; activation of
microglia and microglia-related cytokine imbalance, immune shifts, local inflammation,
disturbances of microcirculation and blood-brain barrier; trophic dysfunction and apoptosis [1,
2].
Neuropeptides, endogenous regulators of CNS functions, play especially important role.
Main mechanisms of action of Cerebrolysin, a neuropeptide-based drug, are a modulating effect
on energy metabolism (decrease in brain oxygen demand, intensification of aerobic metabolism,
reduction of the lactate level in neural tissue, optimization of mitochondrial processes), a
neurotrophic effect and modulation of activity of endogenous growth factors, as well as
interaction with neuropeptide and neuromediator systems [3, 4]. Cerebrolysin also has
antioxidant properties as a result of its ability to inhibit processes of free-radical oxidation and
lipid peroxidation [4].
In the late 80th of the last century, expediency of high-dose (more than 10 ml) Cerebrolysin
administration was substantiated for the purpose of implementation of its neuroprotective
properties [2, 5]. Outcomes of a Cerebrolysin trial carried out in several research centres in
Austria, which enrolled patients in an acute period of carotid ischemic stroke, demonstrated
advantages of a 30—50 ml day dose versus a 10—30 ml dose. Administration of high doses of
Cerebrolysin (up to 50 ml) led to more profound regression of neurological signs in patients by
the end of the acute period and to reliable improvement of functional recovery and daily living
activities over the long-term period [6].
The purpose of this study was to conduct a randomized, double-blind, placebo-controlled
trial of Cerebrolysin safety and efficacy in treatment of ischemic stroke patients in the acute
period.
Materials and Methods
The study was conducted with the permission of the Committee on Ethical Issues of the
Russian State Medical University (RSMU). All patients and their relatives signed an informed
consent form to participate in the study.
The study enrolled patients aged 45 - 85 years with the first ischemic stroke in their life that
happened in the system of the internal carotid artery, who were admitted to a neuroreanimation
unit within 12 hours of stroke onset. The following patients were excluded from the trial:
patients with complete regression of neurological symptomatology within 4 hours of its
occurrence; patients with hemorrhagic stroke or stroke in the vertebral-basilar system with
blood pressure of 200/100 mm of mercury; patients with disorders of consciousness to the state
of sopor or coma; patients with acute myocardial infarction, impaired cardial function, renal and
hepatic insufficiency, a priori marked dementia; pregnant female patients and patients who
participated in other trials.
The studied population was made up of 36 patients (19 male, 17 female; 69.1± 10.3 years of
age). Left-side localisation of the brain lesion was determined in 22 patients, right-side – in 14
patients. 10 patients were transported to a hospital within 6 hours of stroke onset, 26 patients –
within 6 - 12 hours.
All patients were randomly and blindly assigned to receive either placebo or Cerebrolysin at
a dose of either 10 ml or 50 ml (12 patients in each group). The medication, dissolved in 40 ml
of a physiologic saline, was administered intravenously dropwise during 1 hour for the first 10
days of the disease along with maximally unified baseline therapy that included acetylsalicylic
acid at a dose of 100 mg/day, hemodilution, pentoxifylline, low-dose heparin (if necessary).
STROKE, No. 11, 2004
CEREBROLYSIN IN ISCHEMIC STROKE TREATMENT
Calcium channel-blocking agents, pyracetam, medications with neurotrophic and modulator
properties were not used in the treatment.
Complementary NIH multiple point scales, the Modified Rankin Scale and the Clinical
Global Impression Scale were used to objectify severity of the disease condition, intensity of
focal neurological deficit and assessment of clinical indices dynamics. Functional recovery was
evaluated by the Barthel Index. The neurological status and the level of functional recovery were
evaluated at admission of patients (before commencement of therapy), on days 3, 6, 10 and 30 of
the disease. The death rate and side effects of the medication were traced during the whole
period of study (30 days).
Magnetic resonance imaging (MRI) of the brain was performed before commencement of
therapy within the first 12 hours of the disease occurrence and repeated on days 3, 10 and 30
(Ellipse 0.15 Т MR imaging system, Az Corporation, Russia). There were performed axial T2weighted images with fluid attenuated inversion recovery (FLAIR), coronal T2-weighted images
(ТSЕ) and sagittal T1-weighted images (GRЕ). Scanning was performed with 7 mm section
thickness and 1 mm spaces between sections. On FLAIR-images, the brain infarct area had a high
signal; therefore those images were used to determine the brain lesion volume with the help of a
package of Osiris 3.1 application programs (the Hospital of the University, Geneva).
To study Cerebrolysin effect on the brain functional status, EEG-monitoring was carried out
based on 19-channel paperless Neurocartograph electroencephalograph (MBN Ltd., Russia)
according to the standard procedure before the first Cerebrolysin infusion, during the infusion
and within 2.5 hours after the infusion, and then on days 3, 6, 10, 30 of stroke onset. Parameters
of intensity of α-, β-, δ- and θ-rhythms both in ischemic and intact cerebral hemispheres were
analysed. Dipole characteristics of EEG focal changes were assessed with the help of the Brain
Loc program.
Statistical treatment of data obtained was performed with the help of a package of Statistica6.0 and Biostat programs. Reliability of differences in average values was determined with the
help of the Mann-Whitney nonparametric t-test; Spearman's rank correlation coefficients were
calculated. A two-sided significance level of 5% was chosen for all tests.
Results and Discussion
Analysed groups were comparable by etiological agents and hospitalisation terms, age and
sex composition, severity of patients’ condition under NIH and Rankin Modified Scales. At
admission to a hospital, there were no differences revealed in patients in terms of the brain
lesion volume which was 7 to 64 cm3 in the majority of patients (Table 1).
The conducted study confirmed Cerebrolysin safety, however one female patient, who
received Cerebrolysin in a dose of 50 ml, had an attack of acute retrosternal pain and dyspnea
which was the basis for exclusion her from the study. One patient had an episode of
psychomotor agitation during infusion of 10 ml of Cerebrolysin. At the same time, in the
patient placebo group there was not only an analogous case of psychomotor agitation after the
first and the second placebo infusions, but also a generalised convulsive attack on day 30 of
stroke.
Analysis of stroke outcome by day 30 did not revealed reliable differences between the
groups in terms of mortality. Causes of death of 3 of 5 Cerebrolysin patients and one patient
from the placebo group were not related to stroke (pulmonary embolism, pneumonia,
pyelonephritis). 2 Cerebrolysin patients and 2 placebo patients died as a result of cerebral edema
and development of secondary compression of the brainstem structures.
STROKE, No. 11, 2004
CEREBROLYSIN IN ISCHEMIC STROKE TREATMENT
During assessment of the level of functional recovery of impaired neurological functions, a
tendency towards increase in the score by the Barthel Index was observed in both Cerebrolysin
patient groups. Among patients of those groups, as of day 30 of the disease 3 patients
demonstrated complete recovery of neurological functions (a variant of “minor” stroke, the NIH
score = 0, the Barthel Index was above 75), while in the group that received placebo such cases
were not observed.
Table 1. Demographic and Initial Clinical Characteristics of Acute Ischemic Stroke
Patients Enrolled in the Study
Placebo
(n=12)
Index
Sex:
male
9
female
3
Average age, years
69.4±9.5
Correlation of number of patients with
8/4
affection of left and right hemispheres
Time passed since stoke onset to admission to a
8.6±2.9
hospital, hours
Average NIH score at the moment of
12.2±2.8
admission
Average Rankin score at the moment of
3.8±0.9
admission
Number of patients with NIH score
3 (25%)
above 14 (severe stroke)
Number of patients with NIH score equal
9 (75%)
and below 14 (moderately severe stroke)
Average brain lesion volume, cm3
21.7±23.1
Number of patients with brain lesion volume of
7
7 - 64 cm3
Cerebrolysin
10 ml/day (n=12) 50 ml/day (n=12)
3
9
69.9±10.2
6
6
68.7±10.6
6/6 .
8/4
7.0±2.4
9.2±2.9
12.3±6.6
11.2±4.7
4.2±0.9
3.5±1.1
5 (42%)
3 (25%)
7 (58%)
9 (75%)
14.6±18.3
17.5±14.7
6
8
Lesion volume, cm3
Placebo
Cerebrolysin (10 and 50 ml)
Day 3
Day 10
Dynamics of the Brain Lesion Volume According to MRI Data
While analysing dynamics of a clinical score on NIH Scales and on the Modified Rankin
Scale, no reliable difference between groups was revealed. At the same time, comparison of
STROKE, No. 11, 2004
CEREBROLYSIN IN ISCHEMIC STROKE TREATMENT
indices on the Clinical Global Impression Scale revealed acceleration of regression of
neurological disorders in the 50 ml/day Cerebrolysin patient group on day 30 of the disease as
compared with the placebo patient group (p<0.05).
Assessment of regression dynamics of individual focal symptoms revealed reliable
improvement of the movement function during 10 ml/day Cerebrolysin treatment by day 30 of
that treatment (p<0.05), as well as a tendency towards more complete recovery of sensory
functions in the group of patients who received 50 ml of Cerebrolysin (p=0.063) versus the
placebo patient group.
Assessment of dynamics of morphometric indices did not reveal significant differences
between groups in terms of growth of the brain lesion volume in lacunar infarction patients and
in extensive infarction patients (with the lesion volume above 70 cm3). At the same time, the
majority of patients who received Cerebrolysin and had the lesion volume of 7 to 64 cm 3
demonstrated reliable slowing down of that volume’s growth on day 3 of the disease as
compared with patients from the placebo group (р<0,05). On day 10 of the disease, a tendency
towards decrease in the growth of the lesion volume was observed in Cerebrolysin patient groups
(see Figure).
Analysis of results of EEG-monitoring performed during an acute pharmacological test (see
Table 2) proved that more than 60% of Cerebrolysin patients showed a tendency towards
increase in intensity of the α-rhythm both in affected and intact hemispheres (only 25% of
placebo patients showed that tendency; p<0.1). At that, more than 10% decrease in the
hemispheric asymmetry ratio by the α-rhythm in 10 ml/day and 50 ml/day Cerebrolysin groups
occurred respectively in 50 and 54.5% of patients (in 16.6% of placebo patients; p<0.1).
Monitoring of bioelectrical brain activity revealed decrease in size and prevalence of θ- and δfoci, measured by MRI, in the brain infarct area projection in 72.7% of patients who received 50
ml Cerebrolysin, while in the placebo group positive developments were revealed only in 16.6%
of cases (р<0.05). Administration of Cerebrolysin, including in the 50 ml dose, did not provoke
any paroxysmal brain activity.
Research of α-rhythm intensity dynamics revealed a tendency towards growth of that
dynamics in both Cerebrolysin groups. However, in the 10 ml/day Cerebrolysin group increase
in intensity prevailed in the intact hemisphere, while in the 50 ml/day Cerebrolysin group it
happened in both hemispheres which was accompanied by decrease in the hemispheric
asymmetry ratio in that group up to 30% by day 30 of stroke onset (p<0.1).
Assessment of Cerebrolysin efficacy depending on time of therapy commencement (within 0 6 or 6 - 12 hours of stroke onset) revealed a tendency towards greater increase in the score on the
Barthel Scale by day 30 in case of Cerebrolysin infusion within a 6-hour therapeutic window
(38.8±11.3 points) versus the period of 6 to 12 hours (28±13.5 points; р<0.1).
Table 2. EEG-Monitoring Results During Acute Pharmacological Test
Index
Placebo
Increase in α-rhythm intensity (more
than 10%)
3/12 (25%)
STROKE, No. 11, 2004
Cerebrolysin
10 ml/day
50 ml/day
8/12 (66.6%)
7/11 (63.6%)
CEREBROLYSIN IN ISCHEMIC STROKE TREATMENT
Decrease in the hemispheric
asymmetry ratio (more than 10%)
Decrease in δ- and θ-foci, increase in αfocus
Paroxysmal activity
2/12(16.6%)
6/12 (50%)
6/1 1 (54.5%)
2/12 (16.6%)
5/12 (41.7%)
8/1 1 (72.7%)*
0
0
0
During the correlation analysis it was determined that there was close connection between
stroke initial severity (by the NIH Scale) at the moment of admission to a hospital and the brain
lesion volume on day 1 of the disease in the placebo group and in the 10 ml/day Cerebrolysin
group; also each of those indices and their changes were closely connected with dynamics of δ-, θand α-foci on the EEG on days 3, 10 and 30 of stroke onset. At the same time, the 50 ml/day
Cerebrolysin group maintained only correlation between initial clinical and MRI-indices on day 1,
while correlations with clinical indices dynamics, MRI- and electroencephalography data were
absent. Disappearance of correlation of basic patient characteristics with dynamics of these
characteristics during 50 ml/day Cerebrolysin treatment proves the effect of this medication on the
natural disease history and the ability of this medication to increase recovery possibilities for
morphological and functional processes. Thus, the conducted study has confirmed Cerebrolysin
safety in 10 ml and 50 ml doses in treatment of ischemic stroke patients. It has been determined
that this medication, especially in the dose of 50 ml, decreases growth of infarction focus and
normalises the brain functional status. Early commencement of therapy (within the first 6 hours of
the disease) favours more complete recovery of impaired neurological functions which permits to
use Cerebrolysin within a therapeutic window under emergency conditions and in
neuroreanimation units. Undoubtedly, it is worthwhile to continue this study enrolling more
patients in it.
LITERATURE
1. Gusev E.I., Skvortsova V.I. Cerebral ischemia. М: Medicine 2001.
2. Windisch M., Gschanes A., Hutter-Paier B. Neurotrophic activities and therapeutic experience
with a brain-derived peptide preparation, ageing and dementia. J Neural Transmis 1998: Suppl 53.
3. Boado R.J. Molecular regulation of the blood-brain barrier GLUT1 glucose transporter by brainderived factor, ageing and dementia. J Neural Transmis 1998: Suppl 53
4. Gonzalez ME, Francis-Turner L. et at. Antioxidant systemic effect of short-term Cerebrolysin
administration, ageing and dementia. J Neural Transmis 1998; Suppl 53.
5. Gusev E.I., Burd G.S., Gekht A.B. et al. Use of Cerebrolysin in neurological and psychological
practice. Collected works. Clinical-neurophysiologic study of Cerebrolysin effect on the brain functional
status in acute and early recovery periods of hemispheric ischemic stroke. М 1998;20—28.
6. STIPAS investigators. Stroke 1994 25: 418 - 423.
Note. * - p<0.05 versus the placebo group.
STROKE, No. 11, 2004