Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis
Multiple sclerosis is an inflammatory neurological disease of young adults that leads to numerous therapeutic problems and to severe disability. Glatiramer acetate (GA) is a diseasemodifying drug used frequently for long-term treatment of the disease. We investigated the impact of GA treatment on...
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| Zitieren: | Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis / Z.Z. Major, V. Văcăraş, A.D. Buzoianu, D.F. Mureşanu // Нейрофизиология. — 2013. — Т. 45, № 3. — С. 264-272. — Бібліогр.: 26 назв. — англ. |
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irk-123456789-1480982019-02-17T01:26:33Z Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis Major, Z.Z. Văcăraş, V. Buzoianu, A.D Mureşanu, D.F. Multiple sclerosis is an inflammatory neurological disease of young adults that leads to numerous therapeutic problems and to severe disability. Glatiramer acetate (GA) is a diseasemodifying drug used frequently for long-term treatment of the disease. We investigated the impact of GA treatment on the parameters of reversal-pattern visual evoked potentials and event-related P300 wave (reflecting visual acuity and cognitive dysfunction). Relapsingremitting multiple sclerosis patients either subjected to one-year-long continuous treatment with GA or without any disease-modifying therapy and also healthy controls were involved in the study. The above-mentioned parameters were analyzed at two time points, at the first recording and after one year. It was found that GA did not exert a significant influence on the phenomena studied at least during the one-year follow-up. This finding is in contrast to most of the clinical observations. Розсіяний склероз – запальне неврологічне захворювання, від якого страждають молоді люди, яке спричиняє численні терапевтичні проблеми і призводить до тяжкої інвалідизації. Глатирамер ацетат (ГА) є одним із препаратів, що модифікують захворювання, і використовується часто для впливають на захворювання; він часто використовується для лікування пацієнтів із такою патологією. Ми досліджували вплив лікування із застосуванням ГА на параметри зорових ВП, які виникали після пред’явлення реверсивного патерну, та пов’язаного з подією потенціалу P300 (що відбивають гостроту зору та когнітивну дисфункцію відповідно). Пацієнти, які страждали від розсіяного склерозу (ті, що пройшли однорічний безперервний лікувальний курс із застосуванням ГА, та ті, що не піддавалися такій терапії, модифікуючій захворювання), і здорові суб’єкти (контроль) брали участь у дослідженні. Згадані параметри аналізували у двох моментах часу – при першій реєстрації та через рік. Виявлено, що ГА не демонстрував істотних ефектів щодо параметрів, що вивчалися, в усякому разі в межах одного року. Цей факт супер 2013 Article Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis / Z.Z. Major, V. Văcăraş, A.D. Buzoianu, D.F. Mureşanu // Нейрофизиология. — 2013. — Т. 45, № 3. — С. 264-272. — Бібліогр.: 26 назв. — англ. 0028-2561 http://dspace.nbuv.gov.ua/handle/123456789/148098 616.00.4:547.466 en Нейрофизиология Інститут фізіології ім. О.О. Богомольця НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| description |
Multiple sclerosis is an inflammatory neurological disease of young adults that leads to
numerous therapeutic problems and to severe disability. Glatiramer acetate (GA) is a diseasemodifying drug used frequently for long-term treatment of the disease. We investigated the
impact of GA treatment on the parameters of reversal-pattern visual evoked potentials and
event-related P300 wave (reflecting visual acuity and cognitive dysfunction). Relapsingremitting multiple sclerosis patients either subjected to one-year-long continuous treatment
with GA or without any disease-modifying therapy and also healthy controls were involved
in the study. The above-mentioned parameters were analyzed at two time points, at the first
recording and after one year. It was found that GA did not exert a significant influence on the
phenomena studied at least during the one-year follow-up. This finding is in contrast to most
of the clinical observations. |
| format |
Article |
| author |
Major, Z.Z. Văcăraş, V. Buzoianu, A.D Mureşanu, D.F. |
| spellingShingle |
Major, Z.Z. Văcăraş, V. Buzoianu, A.D Mureşanu, D.F. Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis Нейрофизиология |
| author_facet |
Major, Z.Z. Văcăraş, V. Buzoianu, A.D Mureşanu, D.F. |
| author_sort |
Major, Z.Z. |
| title |
Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis |
| title_short |
Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis |
| title_full |
Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis |
| title_fullStr |
Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis |
| title_full_unstemmed |
Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis |
| title_sort |
glatiramer acetate treatment-related effects on visual eps and p300 wave in patients suffering from multiple sclerosis |
| publisher |
Інститут фізіології ім. О.О. Богомольця НАН України |
| publishDate |
2013 |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/148098 |
| citation_txt |
Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis / Z.Z. Major, V. Văcăraş, A.D. Buzoianu, D.F. Mureşanu // Нейрофизиология. — 2013. — Т. 45, № 3. — С. 264-272. — Бібліогр.: 26 назв. — англ. |
| series |
Нейрофизиология |
| work_keys_str_mv |
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| first_indexed |
2025-07-12T18:20:05Z |
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2025-07-12T18:20:05Z |
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| fulltext |
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3264
UDC 616.00.4:547.466
Z. Z. MAJOR1, V. VĂCĂRAŞ2, A. D. BUZOIANU1, and D. F. MUREŞANU2
GLATIRAMER ACETATE TREATMENT-RELATED EFFECTS ON VISUAL EPs AND
P300 WAVE IN PATIENTS SUFFERING FROM MULTIPLE SCLEROSIS
Received November 30, 2012.
Multiple sclerosis is an inflammatory neurological disease of young adults that leads to
numerous therapeutic problems and to severe disability. Glatiramer acetate (GA) is a disease-
modifying drug used frequently for long-term treatment of the disease. We investigated the
impact of GA treatment on the parameters of reversal-pattern visual evoked potentials and
event-related P300 wave (reflecting visual acuity and cognitive dysfunction). Relapsing-
remitting multiple sclerosis patients either subjected to one-year-long continuous treatment
with GA or without any disease-modifying therapy and also healthy controls were involved
in the study. The above-mentioned parameters were analyzed at two time points, at the first
recording and after one year. It was found that GA did not exert a significant influence on the
phenomena studied at least during the one-year follow-up. This finding is in contrast to most
of the clinical observations.
Keywords: multiple sclerosis, visual evoked potentials, P300 wave, glatiramer acetate.
1 Pharmacology Department of the University of Medicine and Pharmacy
“Iuliu Haţieganu,” Cluj-Napoca, Romania.
2 Neurology Department of the University of Medicine and Pharmacy “Iuliu
Haţieganu,” Cluj-Napoca, Romania.
Correspondence should be addressed to Z. Z. Major
(e-mail: zoltan.major@umfcluj.ro).
INTRODUCTION
Multiple sclerosis (MS) is one of the most debilitating
inflammatory neurological diseases of young adults.
Patients gradually lose their ability to deal with
common daily activities; as an end-point, they become
totally dependent and, sadly, a burden to society. From
this viewpoint, an early proper diagnosis of the disease
is mandatory in order to delay, as long as possible,
major disability. A valuable tool in fulfilling this task
is testing evoked potentials (EPs). Introduced into
practice in the 1950s, some of these neurophysiological
methods constitute a useful diagnostic and prognostic
tool.
One can define EPs as EEG-derived responses of
the CNS to external stimuli. Stimuli are differentiated,
according to the involved sensory system, visual,
auditory, or somatosensory. The EPs recorded over
different body regions are classified as near-field or
far-field potentials, according to the distance of the
neural generator from the recording place. Another
classification involves as a criterion the cognitive
participation of the subject; if present, we refer to
it as event-related potentials (ERPs), if not, then as
stimulus-related evoked potentials (EPs). We have
used both categories, visual EPs (VEPs), as stimulus-
related, and the P300 wave as an ERP.
Through demyelination, MS affects the conductivity
in the CNS, this being mirrored by the EP latencies.
When nerve fibers are affected, amplitude changes can
also be assumed. The disease starts quite frequently
under the form of a clinically isolated syndrome, with
visual symptoms in most cases. For this reason, VEP
recording might be helpful, revealing pathological
findings even under circumstances when the sensitivity
of imaging techniques is not enough. As the disease
progresses and the extent of tissue loss becomes
important, a variable degree of cognitive dysfunction
might install. A feasible approach to characterize the
effect is theoretically the P300 wave, an objective
measure for certain cognitive processes.
Visual EPs are the most commonly used evoked
brain responses among the diagnostic procedures for
MS. When retrobulbar optical neuropathy is present
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3 265
GLATIRAMER ACETATE TREATMENT-RELATED EFFECTS ON VISUAL EPs
(as the basis of a clinically isolated syndrome or a
relapse), VEPs are impaired. These changes are either
prolongation of the latency (a part of the revised
McDonald criteria [1]), or decrease in the amplitude
[2], or even changes in the component morphology [3].
A key issue when assessing the efficacy of a
disease-modifying drug is to find objective measures
of the corresponding pharmacological effect .
Recording of VEPs were proposed for this. According
to a study using interferon beta-1a for MS treatment,
there was no impact observed on these potentials
[4], while other researchers reported significant
changes [5]. Natalizumab showed an even better
profile observed after one year of treatment, this was
ameliorating the electrophysiological parameters of
VEPs, somatosensory EPs, and motor EPs [6]. For a
drug used in the treatment of MS, such as glatiramer
acetate (GA), the available data are poor and indirect
[7], and this explains the need to evaluate GA’s impact
on VEPs.
Event-related potentials, similarly to other EPs,
are conditioned for normality by the integrity of
conduction in the CNS; the state of the white matter
is crucially important. Even the smallest degree of
demyelination can influence the conductance in the
CNS, causing, at least theoretically, different degrees
of cognitive dysfunction. According to the initial
viewpoint, the cognitive EPs allow us to identify
even the slightest changes before relevant results of
standard neuropsychological tests [8].
The P300 (P3) is a positive EEG-derived (also
by the averaging technique) deflection observed
approximately 300 msec after triggering; it can be
elicited by either visual, auditory, or somatosensory
stimuli. It includes two main components, P3a and P3b,
which are not always identifiable separately. These are
waves corresponding to the main supposed generators,
the dopaminergic frontal and noradrenergic temporal
ones [9]. The investigated parameters of P300 usually
are the latencies; the amplitudes are characterized by
high inter- and intrapersonal variability.
Latency changes of P300 in MS were reported in the
literature (prolongation when compared with normal
[10, 11]), and the test was even used for evaluation
of evolution of the disease and response to therapy
[12, 13]. The wave was even investigated as a tool to
predict treatment responses to a symptomatic approach
with modafinil and found to show such a role [14].
The P300 test was proposed recently as an objective
method for evaluation of cognitive dysfunction also
for pediatric patients [15].
As was mentioned above, we have only indirect data
with respect to ERPs in the case of GA [14]. There
is only one prospective study stating a positive effect
of a one-year-long interferon beta-1b treatment on
the P300 parameters in MS patients [16]. Considering
these, we have tried to evaluate the effects of GA
treatment on VEPs and cognitive ERPs (P300).
METHODS
Our study was performed on relapsing-remitting
multiple sclerosis (RRMS) patients admitted to the
Neurology Clinic of the Cluj County Emergency
Hospital (Romania).
The impact of GA treatment on the parameters of
two EEG phenomena, the reversal-pattern VEPs and
event-related P300 wave (reflecting visual acuity
and cognitive dysfunction), was investigated in three
groups of participants. Group 1 (hereafter, GA-treated,
n = 21) consisted of patients with RRMS diagnosis.
TABLE 1. Examined Groups 1-3 Consisted of Relapsing-Remitting Multiple Sclerosis (RRMS) Patients and Healthy Individuals
(Control)
Т а б л и ц я 1. Досліджені групи 1-3, сформовані з пацієнтів, які страждали від розсіяного склерозу, та здорових суб’єктів
(контроль)
Indices
Groups
1 (glatiramer acetate-treated
RRMS patients,
n = 21)
2 (untreated RRMS patients,
n = 14) 3 (control, n = 12)
Age, years 36.67 ± 2.15 37.36 ± 2.05 35.83 ± 2.82
Men 6 (28.6%) 4 (28.6%) 4 (33.33%)
Women 15 (71.4%) 10 (71.4%) 8 (66.7%)
EDSS 2.59 ± 0.18 2.50 ± 0.27
Footnote. Means ± s.d. are shown.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3266
Z. Z. MAJOR, V. VĂCĂRAŞ, A. D. BUZOIANU, and D. F. MUREŞANU
The above-mentioned parameters were analyzed
at inclusion (when the first recording took place)
and after one year of continuous treatment with GA
(20 mg per day, subcutaneous daily injections); these
time points of the analysis are designated below as
time points I and II, respectively. Group 2 (hereafter,
untreated, n = 14) also included RRMS patients
examined at inclusion in the study (time point I
of examination) and after one year but without any
disease-modifying treatment (time point II). Group 3
(control, n = 12) was composed of healthy individuals
(with only one evaluation of the investigated
parameters).
Patients with mental retardation, diabetes mellitus,
dyselectrolytemias, and psychiatric comorbidities were
not included in the tested groups, and the presence of
any sight or hearing disturbance was also an exclusion
criterion.
Age was comparable in the groups; as for the sex
of the participants, the distribution was identical for
both RRMS groups (GA-treated and untreated) and
somewhat different for the controls. Another key
parameter for two former groups was the EDSS score
at inclusion, which showed no statistical differences at
the beginning of the study (Table 1).
After groups had been formed, evaluation started
using reversal-pattern VEP and auditory-induced
P300 recordings. A Medtronic Keypoint 4 device
(Medtronic-Dantec, Denmark) was used to trigger
and record VEPs, with 12×16 sized checkers, using
a resolution of 30 msec, 20 mV per division, low-pass
filter at 1 Hz, high-pass filter at 0.2 kHz, maximum
tolerated impedance of recording electrodes 5 kW, and
stimulation frequency 1 sec–1. An active electrode was
placed in Oz, a reference in Fz, and a grounding one
in Cz, according to the 10-20 system. Each eye was
stimulated twice, with an average of 50 stimuli. The
latency and amplitude of the N75, P100, and N135
components were measured; waveforms were also
compared.
The same device was also used to record the
P300 wave. Acoustic stimuli were presented through
earphones according to the oddball paradigm, using a
resolution of 100 msec, 50 mV per division, low-pass
frequency at 0.2 Hz, high-pass at 0.1 kHz, maximum
tolerated impedance of the electrodes 1 kW, variable
stimulation frequency between 0.3 and 1 sec–1,
percentage of the odd stimuli 15%, frequency of these
stimuli 2,000 Hz, and that of frequent ones 1,000 Hz.
Recordings were made with electrodes placed in Fz,
Cz, and Pz of the 10-20 system; reference electrodes
were positioned in A1 and A2, and a grounding one
in Fpz. The percentage of hits and number of false
hits were recorded using a neurofeedback setting;
the reaction time was also recorded. Two evaluations
were performed for each subject, with a total of
150 averages and 22-23 odd sounds/evaluation. The
recorded parameters were the latency and amplitude
of P300, the percentage of hits, number of false hits,
and reaction time.
Statistical analysis was performed using Microsoft
Excel, SPSS 17, and Statistica 4.5 software. After
calculation of means and s.e., the paired t-test and
variance analysis (ANOVA) were used, followed by
post-hoc analysis, with the Scheffé or Dunnett T3
test, depending on the variance equality. For other
circumstances, when parametric testing was not
allowed, nonparametric tests were chosen (such as
Wilcoxon, Mann–Whitney U, and Kruskal–Wallis).
For multiple comparisons, log-linear analysis was
used. The threshold P value for significance for each
test was P < 0.05.
RESULTS
VEP Testing. First, it should be mentioned that
normal and W-shaped VEP waveforms were observed
in groups 1 and 2 of RRMS patients (Fig. 1).
Raw data were tested first using the Kolmogorov–
Smirnov test (all groups demonstrated normal
distributions; not shown). Still, considering the
small number of participants, both parametric and
nonparametric tests were performed.
Statistical analysis began with the evaluation of the
obtained latencies. We measured differences between
the left and right latencies of the VEP components for
RRMS patients and found that some asymmetry might
be present, but its degree was quite comparable in all
three groups (GA-treated, untreated, and control; not
shown). There were no significant differences after the
one-year follow-up in the individual groups.
The next aspect was to check if significant changes
appeared between the groups compared with the
parameters of the control group. Variance analysis
and the Levene test for the homogeneity of variances
were used, and it was found that equal variances could
not be assumed. Therefore, we applied ANOVA and
post-hoc analysis with the Dunnett T3 test doubled
by their nonparametric equivalences, the Kruskal–
Wallis and Mann–Whitney U tests (taking into account
the small number of patients/controls; Fig. 2). As
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3 267
GLATIRAMER ACETATE TREATMENT-RELATED EFFECTS ON VISUAL EPs
this diagram demonstrates, the latencies of all VEP
components in both RRMS groups were significantly
longer, as compared with those in healthy controls,
independently of the time points of the analysis. At
the same time, there were no significant differences
between the GA-treated (after one-year-long treatment
with GA) and untreated groups.
The next step was to check the variation in the
amplitudes of VEP components using the same
paradigm. The Kolmogorov–Smirnov test proved
the normality of the groups for this parameter also.
Then, descriptive statistics and asymmetry testing
were performed; changes in the treated group and
differences after one year of therapy were detected
for components P100 and N135. Similar significant
changes were found also for N75 after one year in
the untreated group. Another noticeable difference
was the amplitude reduction on both sides in the N75
n=108
Left OzFz
Left OzFz
Right OzFz
Right OzFz
A B
n=100
n=106
n=104
2 μV 2 μV
30 msec 30 msec
F i g. 1. Examples of visual evoked potentials observed in patients of groups 1 and 2; normal (A) and W-shaped (B) P100 waveforms are
shown.
Р и с. 1. Приклади зорових викликаних потенціалів, спостережуваних у пацієнтів груп 1 та 2; показано нормальні та W-подібні
форми хвилі потенціалу P100 (А та B відповідно).
40
60
80
100
120
140
160
msec
N75L
* * * * * * * *
*
*
* * * * * *
*
*
*
*
*
1
*
2 1 2 3
* *
N75R
P100L
P100R
N135L N135R
F i g. 2. Mean latencies of the components of the visual EP in relapsing-remitting multiple sclerosis (RRMS) patients treated with glatiramer
acetate, GA, in time points I and II of the analysis, i.e., at the first recording and after one year of continuous treatment with GA (1), in
untreated RRMS patients in time points I and II, i.e., at the first recording and after one year (2), and in healthy individuals (control, 3).
* Significant difference from the control.
Р и с. 2. Середні величини латентних періодів компонентів зорових ВП у пацієнтів із розсіяним склерозом (РС), котрі проходили
лікувальний курс із застосуванням глатирамеру ацетату (ГА), у моменти часу I і II, тобто під час першої реєстрації та за рік
безперервного лікування (1), у пацієнтів із РС, котрі не отримували лікування, у моменти часу I і II, тобто під час першої реєстрації
та за рік (2) та у здорових людей (контроль, 3).
I II
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3268
Z. Z. MAJOR, V. VĂCĂRAŞ, A. D. BUZOIANU, and D. F. MUREŞANU
component after one year of treatment.
The intragroup analysis was followed by the
intergroup comparison, using the same tests as for the
latencies (Fig. 3).
The morphology of the VEPs was tested using log-
linear analysis. The crosstab used and the results are
shown in Table 2.
Observing the frequencies, one can notice the
differences at inclusion in the study between the
GA-treated and untreated groups. Because VEP
morphology was not a selection criterion, different
frequencies were found at the start of the study.
Evaluation continued for one year; so, the initial data
had no impact on the treatment-induced variability.
For each principal effect (treatment, time point, and
morphology), the observed frequencies differed from
the expected values. As a result, the three-dimensional
frequency analysis revealed a model with high
adequation of the observed and anticipated frequencies
in the case of association of the principal effect of
time point (at inclusion vs one-year follow-up), and
the interaction between treatment and morphology.
The latter interaction fits the model with even higher
adequation, but it is bi-dimensional.
The most constant effect was given by the moment
of examination; the impact of GA treatment over the
frequency of the W-like morphology is significant, the
latter index being increased.
P300 Testing. After raw data related to the P300
were recorded, we proceeded as with the VEP
parameters: every group was tested for normality
with the help of the Kolmogorov–Smirnov test, and
the distributions were found to be normal. Then,
descriptive statistics were performed, and the latency
values in the two time points were tested within groups
(not shown). There was a significant increase in the
latency values in the case of the GA-treated group
during the investigated period. For the intergroup
comparison, there was only one significant difference;
when the starting values in the GA-treated group were
compared with the control, slightly smaller values
were observed, but the difference disappeared during
the one-year-long treatment. In this case, we used the
Scheffé test for post-hoc analysis, since the Levene
TABLE 2. Crosstab of the Frequencies of Relapsing-Remitting Multiple Sclerosis Patients Treated with Glatiramer Acetate (GA)
and Untreated Patients (UT) According to the Treatment Status, Time Points I and II of Examination, and Morphology of the Visual
Evoked Potentials, and also the Analysis of the Models Containing Principal Effects and Interactions
Т а б л и ц я 2. Перехресна таблиця частотності пацієнтів, котрі страждали від розсіяного склерозу (РС), після лікування із
застосуванням глатирамеру ацетату (ГА) та пацієнтів з РС, які не приймали ГА згідно зі статусом лікування, моментів часу
I і II у перебігу обстеження та морфології зорових викликаних потенціалів, а також аналіз моделей, що містять у собі основні
ефекти та взаємодії
Models
Treatment Time point Morphology
1 2 3
χ2 df P χ2 df P χ2 df P
Max likelihood χ2 61.25 6 0.000 67.61 6 0.000 14.55 6 0.024
Pearson χ2 55.03 6 0.000 69.84 6 0.000 14.24 6 0.027
1 2 3 1 2 1 3 2 3 Treat Time Morph Freq %
χ2 df P χ2 df P χ2 df P χ2 df P
GA
I
W 4 9.52%
Max likelihood χ2 8.13 4 0.087 61.23 5 0.000 8.16 5 0.148 14.52 5 0.013 N 38 90.48%
Pearson χ2 8.15 4 0.086 54.93 5 0.000 8.21 5 0.145 14.18 5 0.015
II
W 6 14.29%
321 21 31 32 N 36 85.71%
χ2 df P χ2 df P χ2 df P χ2 df P
UT
I
W 9 32.14%
Max likelihood χ2 0.00 0 1 61.18 4 0.000 0.50 4 0.973 14.43 4 0.006 N 19 67.86%
Pearson χ2 0.00 0 1 54.97 4 0.000 0.50 4 0.974 14.17 4 0.007
II
W 8 30.77%
1 32 21 3 2 31 N 18 69.23%
χ2 df P χ2 df P χ2 df P
Max likelihood χ2 8.05 3 0.045 8.09 3 0.044 0.47 3 0.925
Pearson χ2 8.20 3 0.042 8.12 3 0.044 0.47 3 0.925
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3 269
GLATIRAMER ACETATE TREATMENT-RELATED EFFECTS ON VISUAL EPs
test proved that variances were comparable (the Sheffé
test being more robust than the Dunnett test) (Fig. 4).
In the GA-treated group, the P300 amplitude showed
a significant increase for the Cz and Pz recordings and
a marginally significant shift for Fz after one-year-long
therapy. In the untreated group, no such change was
detectable, although a trend toward an increase was
noticeable. Since normal distribution was the case for
the amplitudes too and the variances were comparable,
an ANOVA-Scheffé combination was used, doubled
with the nonparametric analogs. Slight differences
were detected for the Pz recording in the case of GA-
treated group vs controls. More interestingly, after the
one-year follow-up, both RRMS groups demonstrated
significantly higher amplitudes for Fz recordings
than the control, still without significant differences
between them (Fig. 5).
In the case of neurofeedback parameters (hits, false
hits, and reaction time), the Kolmogorov–Smirnov
test proved that the distribution was not normal for
some of the measures. As a consequence, we decided
to use nonparametric tests (Kruskal–Wallis and Mann–
Whitney U), since the Wilcoxon test criteria were also
not satisfactory due to the lack of correspondence. No
significant changes were detected for the investigated
measures, although it was noticeable that, after one-
year-long GA treatment, both the percentage of hits
and the reaction time became better, but only with
1
3
5
7
9
µV
N75L
N75R
P100L
P100R
N135L
N135R
1 2 1 2 3
F i g. 3. Mean amplitudes of the components of visual evoked potentials in the three examined groups. Designations are the same as in Fig. 2.
Р и с. 3. Середні величини амплітуд компонентів зорового ВП у трьох обстежених групах.
300
320
340
360
380
msec
GA I
UT I
GA II
UT II Ctrl
1 2 3
F i g. 4. P300 latencies in relapsing-remitting multiple sclerosis (RRMS) patients treated with glatiramer acetate (GA) in time points I and
II of examination, i.e., at the first recording and after one year of continuous treatment with GA, GAI and GAII, respectively), in untreated
RRMS patients in time points I and II, i.e., at the first recording and after one year, UTI and UTII), and in control healthy individuals (Ctrl.);
1-3 correspond to Fz, Cz, and Pz recordings, respectively.
Р и с. 4. Латентні періоди потенціалу P300 у пацієнтів із розсіяним склерозом (РС), котрі проходили лікувальний курс із
застосуванням глатирамеру ацетату (ГА) у моменти часу I і II, тобто під час першої реєстрації та за рік безперервного лікування,
GAI та GAII відповідно, у пацієнтів із РС, котрі не отримували лікування, у моменти часу I та II, тобто під час першої реєстрації та
за рік, UTI та UTII відповідно), та у здорових людей (контроль); 1-3 відповідають локусам відведення Fz, Cz, та Pz.
I II
* *
* *
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3270
Z. Z. MAJOR, V. VĂCĂRAŞ, A. D. BUZOIANU, and D. F. MUREŞANU
a marginal significance. When comparing the three
examined groups, the reaction time showed significant
increases in the case of the RRMS groups during the
first recording (Fig. 6).
DISCUSSION
Evoked-potential techniques were applied in MS
diagnosis together with imagery, being a useful,
complementary, and objective measure oriented
toward the state of the function and the loss of it.
From this aspect, there is a wide consensus [1], at least
regarding the VEPs. Our findings enhance a series of
studies that led to the use of EPs for the diagnosis of
MS. The latencies of the most important components,
the N75, P100, and N135 waves, increase in the case
of all MS patients, regardless of the therapeutic status,
when compared with the control (in accordance with
the literature, both at the beginning and at the end of
the study). A one-year-long treatment with the disease-
modifying drug showed no significant beneficial effect
from this viewpoint, and there were no noticeable
symmetry differences between groups.
The VEP amplitudes showed increased variability,
otherwise true for all evoked responses, being
proportional to the section of the conductive tracts
and influenced by a multitude of factors, such as bone
thickness, fatty tissue presence [17], alpha rhythm
dominance, oxygenation response to visual stimuli, etc.
[18]. As a consequence, at least in the past, amplitudes
were neglected in evaluation of EPs. Still, for visual
responses, they have relevance, at least in acute and
subacute phases of retrobulbar neuropathy, when an
amplitude reduction is present [19]. This reduction,
combined with the usually unilateral presence of
retrobulbar optical neuropathy, lends support to our
findings [2] (overall, significant partial asymmetry of
the amplitudes for the N75 component in the RRMS
groups vs control). As a consequence, we observe that
the latency asymmetry recovers more rapidly than
the amplitude in the case of VEPs (remyelination vs
axonal loss, but without a quantifiable influence of the
applied treatment).
An intriguing aspect is the VEP morphology. The
normal aspect, one marked positive deflection, the
P100 wave, is sometimes bifid, forming either a
doubled wave if the interpeak latency difference is
under 10 msec, or a W-shaped one (the same difference
being between 10-50 msec), or individual waves,
even more than two, when the difference is longer
than 50 msec. The W shape appears in an increased
0
5
10
15
20
µV
GA I
UT I
GA II UT II
Ctrl.
1 2 3
F i g. 5. P300 amplitudes in the three examined groups. Designations are the same as in Fig. 4.
Р и с. 5. Значення амплітуди потенціалу P300 у трьох обстежених групах.
2.5 500
No/%
1
2
3
msec
400
300
200
100
0
GA I UT I GA II UT II Ctrl.
2.0
1.5
1.0
1.5
0
F i g. 6. Neurofeedback parameters (hits, false hits, and reaction
time, 1-3, respectively) in the three examined groups. Designations
are the same as in Fig. 5.
Р и с. 6. Параметри зворотного зв’язку (співпадіння, неспівпа-
діння та затримка реакції, 1–3 відповідно) у трьох обстежених
групах.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3 271
GLATIRAMER ACETATE TREATMENT-RELATED EFFECTS ON VISUAL EPs
proportion in MS patients [20]. This was observed
vs control in our study too, in accordance with the
literature [21]. A one-year-long treatment with GA
seems, quite interestingly, to increase the occurrence
of the mentioned morphology when compared with
untreated MS patients. We are lacking a feasible
explanation with respect to this point; we can only
suppose that GA might enhance the occurrence of
oscillatory responses, probably by inducing a function-
compensating mechanism. These changes, like the
gamma oscillatory response [22], can distort the VEP,
causing the abnormal waveform.
The P300 component of the auditory cognitive
EP was investigated in order to evaluate if cognitive
dysfunction is detectable by the method. The technique
has not enjoyed a wide clinical use but was used/
implemented already in other conditions also, such
as dementia [23], ADHD, and/or epilepsy [24], etc.
Our subjects were at the initial stage of the disease
(as the EDSS score showed), and it can be assumed
that cognitive changes were slight, if existent. The
situation is reflected also by the considerably reduced
latency values when compared with the control (in
contradiction, at least for now, with the literature
[10]). After one year of treatment with GA, an
increase in the latency was noticed (with an obscure
significance), contrasting with the untreated group
and accompanied by an increase in the amplitudes.
We can only hypothesize that a compensatory effect
was induced during the GA treatment, either by the
drug or by an intrinsic mechanism. On the one hand,
the number of recruited pathways required for the
response generation increases, and, due to this, the
amplitude increases. On the other hand, the latency
prolongation suggests that the treatment exerts a week
influence on the process of remyelination (probably
due to the relatively short period of evaluation, as
opposed to the literature [25]).
Neurofeedback set t ings are represented by
the cognitive tasks and the resulting parameters,
when eliciting the auditory P300 using the oddball
paradigm. Multiple sclerosis patients demonstrate an
increased reaction time, which is used as a measure
of the information processing rate [26]. Under these
circumstances, our data suggest some beneficial effect
of GA treatment in clinical terms; the reaction time is
somewhat reduced, compared with the initial values,
and the number of hits increased (despite only with
marginal significance), which might increase with an
increased number of cases.
The limits of our study are the following. The
performed neurophysiological tests delivered an
impressive amount of data, which, combined with
the doubled statistical analysis, hopefully neutralized
one of the limits of our study, namely participation-
induced variability and the relatively small group
sizes. Another concern is the duration of treatment.
In order to establish whether a one-year-long follow-
up permits or not a proper validation of all potential
effects of GA in MS, further investigations are needed.
Thus, the VEP latencies in both RRMS groups are
longer when compared with healthy individuals, and
GA shows no impact from this aspect after one year
of continuous treatment. Partial amplitude variability
(N75 reduction) is noticeable in RRMS groups,
compared with the control, and W-like morphology of
VEPs is increased after GA treatment.
For the P300 wave, both latencies and amplitudes
(Cz and Pz recordings) increased after GA treatment.
Untreated RRMS patients showed also an amplitude
increase. A trend toward induction of the reaction time
is noticeable after one-year-long GA treatment.
Further research is needed to evaluate if this relative
lack of electrophysiological improvement is persistent
even in the case where the investigation period is
prolonged.
Informed consent was obtained from all persons involved
in the tests.
The authors, Z. Z. Major, V. Văcăraş, A. D. Buzoianu, and
D. F. Mureşanu, declare that they have no conflict of interests.
Z. Z. Major and V. Văcăraş, on the one hand, and A. D.
Bu zoia nuand D. F. Mureşanu, on the other hand, contributed
equally to the study.
Acknowledgments. This study was funded by the research
grant No. 27020/44/15.11.2011 of the University of Medicine
and Pharmacy “Iuliu Haţieganu,” Cluj-Napoca, Romania.
We thank Crăciun Horea and Balog Carmen for their kind
cooperation.
З. З. Майор1, В. Вакараш2, А. Д. Бузоіану1, Д. Ф. Мурешану2
ВПЛИВ ЛІКУВАННЯ ГЛАТИРАМЕРОМ АЦЕТАТОМ НА
ЗОРОВІ ВИКЛИКАНІ ПОТЕНЦІАЛИ ТА ХВИЛЮ P300 У
ПАЦІЄНТІВ, ХВОРИХ НА РОЗСІЯНИЙ СКЛЕРОЗ
1 Відділ фармакології Медичного і фармацевтичного
університету „Іуліу Хат’єгану” Клуж-Напока (Румунія).
2 Відділ неврології Медичного і фармацевтичного
університету „Іуліу Хат’єгану” Клуж-Напока (Румунія).
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 3272
Z. Z. MAJOR, V. VĂCĂRAŞ, A. D. BUZOIANU, and D. F. MUREŞANU
Р е з ю м е
Розсіяний склероз – запальне неврологічне захворювання,
від якого страждають молоді люди, яке спричиняє численні
терапевтичні проблеми і призводить до тяжкої інвалідизації.
Глатирамер ацетат (ГА) є одним із препаратів, що модифіку-
ють захворювання, і використовується часто для впливають
на захворювання; він часто використовується для лікуван-
ня пацієнтів із такою патологією. Ми досліджували вплив
лікування із застосуванням ГА на параметри зорових ВП,
які виникали після пред’явлення реверсивного патерну, та
пов’язаного з подією потенціалу P300 (що відбивають го-
строту зору та когнітивну дисфункцію відповідно). Пацієн-
ти, які страждали від розсіяного склерозу (ті, що пройшли
однорічний безперервний лікувальний курс із застосуван-
ням ГА, та ті, що не піддавалися такій терапії, модифіку-
ючій захворювання), і здорові суб’єкти (контроль) брали
участь у дослідженні. Згадані параметри аналізували у двох
моментах часу – при першій реєстрації та через рік. Вияв-
лено, що ГА не демонстрував істотних ефектів щодо пара-
метрів, що вивчалися, в усякому разі в межах одного року.
Цей факт суперечить багатьом описаним клінічним спосте-
реженням.
REFERENCES
1. C. H. Polman, S. C. Reingold, B. Banwell, et al., “Diagnostic
criteria for multiple sclerosis: 2012 revisions to the McDonald
criteria,” Ann. Neurol., 69, No. 2, 292-302 (2011).
2. I. P. Chatziralli, M. M. Moschos, D. Brouzas, et al.,
“Evaluation of retinal nerve fiber layer thickness and visual
evoked potentials in optic neuritis associated with multiple
sclerosis,” Clin. Exp. Optom., 95, No. 2, 223-228 (2012).
3. B. Weinstock-Guttman, M. Baier, R. Stockton, et al., “Pattern
reversal visual evoked potentials as a measure of visual
pathway pathology in multiple sclerosis,” Mult. Scler., 9,
No. 5, 529-534 (2003).
4. R. M. Liscic and J. Brecelj, “Visual evoked potentials in
multiple sclerosis patients treated with interferon beta-1a,”
Croat. Med. J., 45, No. 3, 323-327 (2004).
5. O. Anlar, M. Kisli, T. Tombul, et al., “Visual evoked potentials
in multiple sclerosis before and after two years of interferon
therapy,” Int. J. Neurosci., 113, No. 4, 483-489 (2003).
6. S. G. Meuth, S. Bittner, C. Seiler, et al., “Natalizumab restores
evoked potential abnormalities in patients with relapsing-
remitting multiple sclerosis,” Mult. Scler., 17, No. 2,198-203
(2011).
7. J. W. Chan, “Early diagnosis, monitoring, and treatment of
optic neuritis,” Neurologist, 18, No. 1, 23-31 (2012).
8. M. R. Newton, G. Barrett, M. M. Callanan, et al., “Cognitive
event-related potentials in multiple sclerosis,” Brain, 112,
No. 6, 1637-1660 (1989).
9. J . Polich and J. R. Criado, “Neuropsychology and
neuropharmacology of P3a and P3b,” Int. J. Psychophysiol.,
60, No. 2, 172-185 (2006).
10. J. C. Aminoff and D. S. Goodin, “Long-latency cerebral event-
related potentials in multiple sclerosis,” J. Clin. Neurophysiol.,
18, 372-377 (2001).
11. M. R. Piras, I. Magnano, E. D. G. Canu, et al., “Longitudinal
study of cognitive dysfunction in multiple sclerosis:
neuropsychological, neuroradiological and neurophysiological
findings,” J. Neurol. Neurosurg. Psychiat., 74, 878-885 (2003).
12. I. Magnano, I. Aiello, and M. R. Piras, “Cognitive impairment
and neurological correlates in multiple sclerosis,” J. Neurol.
Sci., 245, 117-122 (2006).
13. R. J. J. Gonzales, M. Vasquez, E. Vaquero, et al., “Differential
cognitive impairment for diverse forms of multiple sclerosis,”
BMC Neurosci., 19, 7-39 (2006).
14. G. Nagels, M. B. D’hooghe, L. Vleugels, et al., “P300 and
treatment effect of modafinil on fatigue in multiple sclerosis,”
J. Clin. Neurosci., 14, No. 1, 33-40 (2007).
15. S. Lori, E. Portaccio, V. Zipoli, et al., “Cognitive impairment
and event-related potentials in pediatric multiple sclerosis:
2-year study,” Neurol. Sci., 32, No. 6, 1043-1046 (2011).
16. S. Flechter, J. Vardi, Y. Finkelstein, et al., “Cognitive
dysfunction evaluation in multiple sclerosis patients treated
with interferon beta-1b: an open-label prospective 1 year
study,” Isr. Med. Assoc. J., 9, No. 6, 457-459 (2007).
17. P. Vogel, Kursbuch Klinische Neurophysiologie EMG-ENG-
Evozierte Potenziale, Thieme, Stuttgart (2006).
18. S. P. Koch, S. Koendgen, R. Bourayou, et al., “Individual
alpha frequency correlates with amplitude of visual evoked
potential and hemodynamic response,” Neuroimage, 41,
No. 2, 233-242 (2008).
19. D. Pojda-Wilczek, “Retrospective analysis of pattern VEP
results in different ocular and systemic diseases,” Klin. Oczna,
112, Nos. 7/9, 205-209 (2010).
20. R. T. Rousseff, P. Tzvetanov, and M. A. Rousseva, “The
bifid visual evoked potential-normal variant or a sign of
demyelination?” Clin. Neurol. Neurosurg., 107, No. 2, 113-116
(2005).
21. T. R. Marra, “The clinical significance of the bifid or
‘W’ pattern reversal visual evoked potential,” Clin.
Electroencephalogr., 21, No. 3, 162-167 (1990).
22. W. G. Sannita, S. Carozzo, M. Fioretto, et al., “Abnormal
waveform of the human pattern VEP: contribution from gamma
oscillatory components,” Invest. Ophthalmol. Vis. Sci., 48,
No. 10, 4534-4541 (2007).
23. J. M. Olichney, J. C.Yang, J. Taylor, et al., “Cognitive event-
related potentials: biomarkers of synaptic dysfunction across
the stages of Alzheimer’s disease,” J. Alzheimer’s Dis., 26,
Suppl. 3, 215-228 (2011).
24. Z. Z. Major, “Combined evoked potentials in co-occurring
attention deficit hyperactivity disorder and epilepsy,”
Ideggyogy. Sz., 64, Nos. 7/8, 248-256 (2011).
25. M. Kipp, M. Victor, G. Martino, et al., “Endogenous
remyelination: findings in human studies,” CNS Neurol.
Disord. Drug. Targets, 11, No. 5, 598-609 (2012).
26. L. I. Reicker, T. N. Tombaugh, L. Walker, et al., “Reaction
time: An alternative method for assessing the effects of
multiple sclerosis on information processing speed,” Arch.
Clin. Neuropsychol., 22, No. 5, 655-664 (2007).
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