effects of antiepileptic monotherapy on hematological and
Post on 20-Mar-2022
4 Views
Preview:
TRANSCRIPT
1
Effects of antiepileptic monotherapy on
hematological and biochemical parameters
Yuri Yoshimura1, Keiko Hara2,3, Miho Akaza3, Kaseya Ohta4, Yuki Sumi3, Motoki Inaji1, Eriko Yanagisawa5,
Taketoshi Maehara1
Purpose: Severe cytopenia and liver dysfunction are character ized as antiepileptic drug (AED)
adverse effects dependent upon an idiosyncrasy. However, in clinical practice, we often find hemato-
logical and biochemical changes during AED treatment with causes other than an idiosyncrasy. This
study aims to investigate the effect of antiepileptic monotherapy on hematological and biochemical
parameters.
Methods: We retrospectively recruited 480 patients untreated with AED at baseline. Changes in
hematological and biochemical parameters before and after initiation of medication were investigated,
and correlation with plasma concentrations of AED was analyzed.
Results: Sixty-six of 480 patients treated with carbamazepine (CBZ: n = 27), sodium valproate (VPA:
n = 19) or levetiracetam (LEV: n = 20) monotherapy were eventually selected for analysis. After CBZ
treatment, decreased white blood cell (WBC) count and increased gamma-glutamyltransferase (GGT)
and alkaline phosphatase (ALP) activities were recorded at high frequencies. Decreased WBC count
tended to correlate with elevated serum CBZ level. Elevated GGT activity was observed in all patients
treated with CBZ. In patients treated with VPA, platelet (PLT) counts decreased. In patients treated
with LEV, there were no significant differences in the measured parameters before and after medica-
tion.
Discussion: We considered that the reduction in WBC count might be dose-dependently related to
AEDs. Elevated GGT activity was observed in all patients treated with CBZ, but the average increase
in GGT activity was 35.19 ± 33.08 U/L. In patients undergoing VPA treatment, decreased PLT counts
were also observed at high frequency. Thus, hematological and biochemical parameters should be
closely monitored in patients receiving AED, especially in patients treated with high doses of AEDs.
Corresponding author: Keiko Hara
Department of Respiratory and Nervous System Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and
Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Tel: +81-3-5803-5077; Fax: +81-3-5803-5077; E-mail: hrkebi@tmd.ac.jp
Epilepsy & Seizure Journal of Japan Epilepsy Society
Vol. 11 No. 1 (2019) pp. 1-13
1Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental
University 2Hara Clinic 3Department of Respiratory and Nervous System Science, Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University 4Onda-Daini Hospital 5Medical Technology, School of Health Care Sciences, Faculty of Medicine, Tokyo Medical and Dental
University
Abstract
Received: August 19, 2018 ; Accepted: December 10, 2018
Key words: Antiepileptic drug; Hematological; Biochemical; effect; Monotherapy; Leukocyte reduction
Original Article
2
Introduction Antiepileptic drugs (AEDs) are frequently
used for several conditions including epilep-
sy, psychiatric disorders, and neuropathic
pain. In particular, AEDs are essential for the
treatment of patients with epilepsy. The goal
of AED treatment is to optimize seizure con-
trol and quality of life while minimizing
treatment toxicity [1]. Appropriate pharmaco-
logical management can result in freedom
from seizures in 60%–70% of the patients,
with more than 90% of them being controlled
by monotherapy [2].
However, various AED side effects have
been reported. Commonly occurring side ef-
fects of AEDs are drowsiness, dizziness,
weight changes, nausea, memory problems,
drug eruption, tremors, impaired liver func-
tion, pancytopenia, gastrointestinal symp-
toms, osteoporosis, depression, among other
symptoms. In 10% of the patients treated
with carbamazepine, adverse reactions are
noted, including allergic rashes or leukopenia
[3]. AEDs are associated with 8.3% of reports
of drug-induced liver injury, which is the ma-
jor reason for their withdrawal from thera-
peutic use [4]. The “Patients with Epilepsy
Practice Guideline 2018 in Japan” describes
the mechanism of AED side effects as usually
divided into three types: depending on an idi-
osyncrasy, dose-dependence, and long-term
pharmacotherapy [5]. Cytopenia and liver
dysfunction are classified as adverse effects
depending on an idiosyncrasy. However, in
clinical practice, hematological and biochem-
ical changes caused by AEDs are encoun-
tered more often than reported. Several previ-
ous reports have described the hematological
and biochemical changes caused by AEDs,
but these reports included patients on AED
polytherapy and compared the hematological
and biochemical parameters between control
patients and patients with epilepsy. There are
few reports that analyzed hematological and
biochemical changes caused by AEDs includ-
ing only patients who were initially untreated
with AED and then treated with AED mono-
therapy. In our longitudinal study, we ana-
lyzed the effects of AEDs on hematological
and biochemical parameters of patients un-
treated with AEDs at baseline.
Patients and Methods Participants
This study was approved by the Ethics
Committee of Tokyo Medical and Dental
University (#556). We retrospectively recruit-
ed 480 patients untreated with AED at base-
line in the Department of Neurosurgery, To-
kyo Medical and Dental University between
April 2012, and December 2017, and in the
Hara Clinic between January 2000 and De-
cember 2017. Both facilities were accredited
by The Japan Epilepsy Society. All the pa-
tients selected for this study were untreated
with any AED at the first medical examina-
tion blood sampling. In six patients, a mean
of 1945 ± 3135 (73–8269) days had elapsed
since the discontinuation of AED medication;
the remaining patients were never exposed to
AEDs previously. All enrolled patients were
subsequently treated with AED monotherapy.
Data
We longitudinally investigated hematological
and biochemical parameters twice in each
patient receiving AED monotherapy. Initial-
ly, we collected data of a patient within 3
Effects of antiepileptic monotherapy Yuri Yoshimura et al.
3
months before AED initiation. From the same
patient, we collected hematological and bio-
chemical parameters and AED plasma con-
centrations from 2 weeks to 3 months after
AED initiation. Hematological parameters
included white blood cell count (WBC), red
blood cell count (RBC), hemoglobin (HGB),
hematocrit (HCT), and platelet count (PLT).
Patients taking folic acid were excluded from
hematological analysis because folic acid is
associated with the production of blood cells.
Biochemical parameters included measure-
ments of aspartate aminotransferase activity
(AST), alanine aminotransferase activity
(ALT), gamma-glutamyltransferase activity
(GGT), alkaline phosphatase activity (ALP),
lactate dehydrogenase level (LDH), blood
urea nitrogen concentration (BUN), and cre-
atinine (CRE). Patients aged 18 years and
under were excluded from liver function
evaluation of AST, ALT, GGT, ALP and
LDH analysis because these reference values
differ between adults and children. Hemato-
logical and biochemical parameters were
compared between before and after admin-
istration of AED. For the hematological and
biochemical parameters that showed signifi-
cant differences, the rates of change (post-/
pre-medication) were calculated, and we ana-
lyzed whether these differences correlated
with AED plasma concentrations.
Statistics
Data were analyzed using SPSS version 25
(IBM Corp., Armonk, NY, USA). Paired t-
test was used for the analyses of continuous
data, comparing pre- with post-medication
data. Correlation between the rates of change
in parameters and AED plasma concentra-
tions was assessed using Pearson’s correla-
tion coefficient. For non-normally distributed
data, Wilcoxon signed rank test, and
Spearman’s correlation coefficient were used.
A two-sided P < 0.05 was considered statisti-
cally significant.
Epilepsy & Seizure Vol. 11 No. 1 (2019)
Figure 1 Patient flow char t. AED: antiepileptic drug.
4
Results A flow chart of patient selection is pre-
sented in Figure 1. A total of 480 patients
were recruited, who were not treated with
AED at baseline and began AED monothera-
py at the beginning of this study period.
Three hundred of the 480 patients (63%)
were excluded because of comorbidities com-
prising cancer (n = 130), traumatic brain inju-
ries (n = 128), cerebrovascular disease (n =
11), convulsive attacks (n = 11), cerebral
fracture (n = 5), cerebral abscess (n = 5), liver
or renal dysfunction (n = 4) and other comor-
bidities (n = 6). The reason for exclusion is
that blood cell counts or liver enzyme levels
may be influenced by chemotherapy, immu-
nosuppressive drugs, acute stress, surgical
wound infection, or co-administered drugs.
Thirteen of the 480 patients (3%) were fur-
ther excluded because of discontinuation of
AED or change in AED within two weeks
after initiation of the first AED: carbamaze-
pine (CBZ, eight patients), sodium valproate
(VPA, three patients), levetiracetam (LEV,
one patient) and lacosamide (LCM, one pa-
tient). Six of 13 patients discontinued AED
treatment for reasons other than side effects,
such as discontinuation of hospital visit and
poor adherence. The remaining seven patients
changed to another AED because of side ef-
fects. Hypacusis (n = 1), drowsiness (n = 1),
or dizziness (n = 3) were reported in five pa-
tients treated with CBZ, while drug eruption
(n = 1) and decreased WBC count (n = 1)
were reported in two patients initiated with
VPA. The blood sampling time points before
and after AED medication were designated
“pre-medication” when sampled within three
months from initiation of AED medication
and “post-medication” when sampled from 2
weeks to 3 months after initiation of AED
therapy. The case of increasing AED dosage
was regarded as an exception in this criterion
related to the blood sampling time points.
Ninety-one of 480 patients (19%) were ex-
cluded because of no blood sampling at the
designated time points. Four patients were
excluded due to other factors such as preg-
nancy (n = 2), hemolysis (n = 1), and abnor-
mal AST level before AED medication. (n =
1). Seventy-two of 480 patients (15%) re-
mained for further analysis. Eventually, we
selected 66 patients treated with CBZ, VPA
or LEV monotherapy for final analysis (CBZ:
n = 27, VPA: n = 19, LEV: n = 20) (Table 1).
Six patients were excluded from analysis be-
cause of insufficient patient numbers for
AED monotherapy (phenytoin: n = 1,
lamotrigine: n = 3, zonisamide: n = 2). Of 66
patients, 36 patients had localization-related
epilepsy, 18 exhibited generalized epilepsy,
five patients were unknown, one patient was
diagnosed with bipolar disorder, and six pa-
tients were treated with AED for convulsion
prevention. According to patient medical rec-
ords, 28 of 66 patients were prescribed medi-
cations other than AED, which included med-
ications administered only occasionally. All
patients included were deemed otherwise
healthy at blood sampling.
CBZ
One patient taking folic acid was excluded
from analysis. Finally, hematological param-
eters were analyzed in 26 patients. Post-
medication WBC counts were significantly
lower compared with pre-medication WBC
counts (pre-medication 6.24 ± 1.90×103/µL,
post-medication 5.28 ± 1.56×103/µL, P <
Yuri Yoshimura et al. Effects of antiepileptic monotherapy
5
0.001) (Table 2). In 18 of 26 patients treated
with CBZ (69%), WBC counts decreased fol-
lowing treatment compared with pre-
medication counts. The decrease in WBC
count was 1.48 ± 1.10×103/µL in these 18
patients. None of the patients had WBC count
decreased below the lower limit of reference
values (3.5×103 to 9.7×103/µL). Six patients
aged 18 years or younger were excluded from
analysis of the following parameters: AST,
ALT, GGT, ALP, and LDH, and these pa-
rameters were analyzed in 21 patients. Post-
medication GGT and ALP activities were sig-
nificantly higher compared with pre-
medication levels (GGT: pre-medication
28.38 ± 17.94 U/L, post-medication 63.57 ±
Epilepsy & Seizure Vol. 11 No. 1 (2019)
Total CBZ VPA LEV
Number of patients 66 27 19 20
Gender, n (%)
Male 37 (56) 16 (59) 11 (58) 10 (50)
Female 29 (44) 11 (41) 8 (42) 10 (50)
Age of drug initiation, year
mean ± SD 37.1 ± 19.0 39.3 ± 21.1 30.2± 14.3 40.8± 19.0
range 10-78 10-78 12-59 16-74
≤18 years, n (%) 12 (18) 6 (21) 3 (16) 3 (15)
Duration from AED initiation to post-
medication blood-draw, days
mean ± SD 83.4±83.9 95.1±94.6 72.9±88.5 77.7±64.1
range 14-381 14-381 14-342 14-259
Number of patients treated with folic acid, n (%) 5 (7) 1 (4) 3 (16) 1 (5)
Table 1 Demographic character istics of patients analyzed.
AED: antiepileptic drug, CBZ: carbamazepine, VPA: sodium valproate, LEV: levetiracetam
Table 2 Compar ison of pre- and post-medication values of hematological and biochemical parameters in patients treated with carbamazepine (CBZ).
Parameter n Pre Post P-value T value Z value
WBC (×103/μL) 26 6.24±1.90 5.28±1.56 <0.001* 3.83
RBC (×104/μL) 26 448.58±59.50 449.27±47.87 0.920 -0.10
HGB (g/dL) 26 13.71±1.55 13.75±1.22 0.845 -0.20
HCT (%) 26 41.89±4.54 42.22±3.83 0.607 -0.52
PLT (×104/μL) 26 24.16±5.89 23.46±5.84 0.451 0.77
AST (U/L) 21 21.71±5.05 30.29±26.13 0.130 -1.58
ALT (U/L) 21 19.48±8.30 28.95±27.23 0.154 -1.48
GGT (U/L) 21 28.38±17.94 63.57±42.49 <0.001* -4.02
ALP (U/L) 20 237.50±110.50 267.35±107.57 0.006* -3.06
LDH (U/L) 20 230.30±74.36 247.50±103.89 0.279 -1.11
BUN (mg/dL) 25 13.62±3.44 14.54±4.57 0.135 -1.55
CRE (mg/dL) 25 0.74±0.15 0.75±0.19 0.210 -1.25
WBC: white blood cell, RBC: red blood cell, HGB: hemoglobin, HCT: hematocrit, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyltransferase, ALP: alka-line phosphatase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRE: creatinine Data are presented as mean ± SD. *: P < 0.05
6
42.49 U/L, P < 0.001; ALP: pre-medication
237.50 ± 111.50 U/L, post-medication 267.35
± 107.57 U/L, P = 0.006). In all patients treat-
ed with CBZ (100%), GGT activities were
increased on average by 35.19 ± 33.08 U/L
following CBZ commencement. In seven of
21 patients (33%), GGT levels were higher
than the upper limit of the reference values
(reference: females ≤ 48 years, males ≤ 79
years; females: n = 4, pre-medication 23.75 ±
3.59 U/L, post-medication 90.75 ± 47.52 U/
L; males: n = 3, pre-medication 68.67 ± 6.43
U/L, post-medication 131.33 ± 34.44 U/L). In
17 of 20 patients treated with CBZ (85%),
ALP levels were higher after CBZ therapy
was initiated. The increase in ALP activity
averaged 40.47 ± 37.62 U/L in 17 patients
after CBZ was prescribed. Two of 17 patients
(12%) had ALP levels higher than the upper
limit of the reference values (reference: 104
to 338 U/L; pre-medication 463.50 ± 284.96
U/L, post-medication 532.00 ± 192.33 U/L).
The mean post-medication plasma CBZ con-
centration was 5.05 ± 1.71 µg/mL in 26 pa-
tients, not including those taking folic acid.
The rates of change in WBC count tended to
Yuri Yoshimura et al. Effects of antiepileptic monotherapy
Figure 2 Cor relation between CBZ plasma concentration and WBC reduction. CBZ: carbam-azepine, WBC: white blood cell
Parameter n Pre Post P-value T value Z value
WBC (×103/μL) 16 6.39±1.67 5.82±1.63 0.141 1.55
RBC (×104/μL) 16 486.75±58.92 473.56±68.71 0.139 1.56
HGB (g/dL) 16 14.90±1.80 14.69±2.12 0.347 0.97
HCT (%) 16 45.58±5.14 14.69±2.12 0.237 1.23
PLT (×104/μL) 16 24.17±6.87 20.71±6.31 0.006* 3.17
AST (U/L) 16 23.50±7.06 21.88±8.52 0.249 1.20
ALT (U/L) 16 21.13±9.35 20.44±15.37 0.774 0.29
GGT (U/L) 16 31.88±30.89 33.81±57.17 0.232 -1.20
ALP (U/L) 12 234.75±57.46 215.33±86.34 0.152 1.54
LDH (U/L) 13 190.38±35.93 190.77±35.83 0.953 -0.06
BUN (mg/dL) 17 13.51±3.13 14.15±2.77 0.406 -0.85
CRE (mg/dL) 17 0.72±0.16 0.77±0.18 0.133 -1.50
WBC: white blood cell, RBC: red blood cell, HGB: hemoglobin, HCT: hematocrit, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyltransferase, ALP: alka-line phosphatase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRE: creatinine Data are presented as mean ± SD. *: P < 0.05
Table 3 Compar ison of pre- and post-medication values of hematological and biochemical parameters in patients treated with sodium valproate (VPA).
7
correlate with post-medication plasma con-
centration, but this effect was not significant,
as shown in Figure 2 (Pearson’s correlation
coefficient, R = -0.38, P = 0.056). As CBZ
plasma concentration increased, WBC count
tended to decrease. On the other hand, the
rates of GGT and ALP changes did not corre-
late with post-medication plasma CBZ con-
centration.
VPA
Post-medication PLT count was signifi-
cantly lower (pre-medication 24.17 ±
6.87×104/µL; post-medication 20.71 ±
6.31×104/µL, P = 0.006) (Table 3). In 14 of
16 patients treated with VPA (88%), PLT
counts were lower after VPA treatment was
initiated. The decrease in PLT count averaged
4.21 ± 4.14×104/µL in 14 patients. Two of the
14 patients (14%) had PLT counts lower than
the lower limit of reference values (reference:
15.8×104 to 34.8×104/µL; pre-medication
16.85 ± 1.20×104/µL, and post-medication
11.25 ± 2.62×104/µL). Mean post-medication
plasma VPA concentration was 36.29 ± 25.90
µg/mL. The rate of PLT change did not cor-
relate with post-medication plasma concen-
tration. There were no other significant
changes between pre- and post-medication
parameters.
LEV
There were no significant differences in the
measured parameters between pre- and post-
medication values (Table 4) following LEV
treatment. The mean post-medication plasma
concentration was 10.68 ± 10.16 µg/mL (n =
16).
Discussion This study is retrospective. Therefore, the
number of patients varied in different param-
eters measured and the number of patients
Epilepsy & Seizure Vol. 11 No. 1 (2019)
Table 4 Compar ison of pre- and post-medication values of hematological and biochemical parameters in patients treated with levetiracetam (LEV).
Parameter n Pre Post P-value T value Z value
WBC (×103/μL) 18 6.85±2.62 6.06±1.50 0.140 1.55
RBC (×104/μL) 18 467.89±37.93 464.94±40.65 0.649 0.46
HGB (g/dL) 18 14.16±1.14 14.10±1.44 0.741 0.34
HCT (%) 18 43.65±3.37 43.35±3.67 0.626 0.50
PLT (×104/μL) 18 25.69±4.57 24.36±4.07 0.132 1.58
AST (U/L) 17 21.24±9.35 19.82±4.26 0.501 0.69
ALT (U/L) 17 15.18±4.85 15.41±8.22 0.892 -0.14
GGT (U/L) 17 36.71±37.78 39.71±47.42 0.836 -0.21
ALP (U/L) 12 207.42±61.04 200.42±46.61 0.584 0.56
LDH (U/L) 15 191.20±29.84 183.73±30.20 0.323 1.02
BUN (mg/dL) 19 11.54±1.96 11.00±2.63 0.416 0.83
CRE (mg/dL) 19 0.69±0.14 0.69±0.15 0.952 -0.06
WBC: white blood cell, RBC: red blood cell, HGB: hemoglobin, HCT: hematocrit, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyltransferase, ALP: alka-line phosphatase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRE: creatinine Data are presented as mean ± SD. *: P < 0.05
8
studied was not large. However, the subjects
included in this study were AED-untreated
patients who initiated AED monotherapy, and
did not possess complicating factors that
would affect liver function or blood cell
counts.
In our study, WBC counts significantly
decreased after CBZ treatment in 69% of the
patients. An observed WBC reduction in
3.7% of patients has been previously reported
[6]. However, this figure might indicate pa-
tients who had lower WBC counts than the
reference value. In this study, WBC count
decreased at a higher frequency than previ-
ously reported and none of the patients had
WBC count lower than the lower reference
limit (3.5×103 to 9.7×103/µL) after initiation
of CBZ treatment.
Bachmann et al. [7] showed a statistically
significant increase in WBC count in women
administered CBZ (P = 0.039) compared with
controls. Conversely, our study evaluated the
hematological changes before and after medi-
cation in identical patients. Moreover, we re-
vealed that the rate of WBC change tended to
correlate with post-medication plasma CBZ
concentration. Also, because we excluded
patients who discontinued AED within two
weeks after AED initiation, patients with side
effects depending on an idiosyncrasy may
have been excluded from our analysis. Our
results suggest a potential mechanism other
than allergy or drug toxicity to account for
these observations.
Huang et al. [8] suggested that the serum
levels of folate and vitamin B12 following
AED treatment were significantly lower than
those before AED treatment. It is well known
that folate and vitamin B12 are necessary for
DNA synthesis. In our study, hematological
changes other than blood cell counts were not
revealed. Also, the absence of measured fo-
late and vitamin B12 data impeded us from
investigating those changes. However, there
is a possibility that low serum levels of folate
and vitamin B12 caused by AED resulted in
the observed high frequency of WBC count
reduction. We found that decreased WBC
counts were frequently induced by CBZ treat-
ment. Because WBC subsets were not inves-
tigated, we should prospectively monitor
WBC subsets of patients treated with CBZ in
future studies.
CBZ has been described as a potent induc-
er of microsomal enzymes in the liver [9].
Liver enzymes induced by CBZ have been
previously documented [10]. However, there
are few reports of the relationship between
enzyme induction and a concrete upper limit
of elevated GGT activity. In our report, a pa-
tient with GGT level of 171 U/L showed no
clinical symptoms of liver dysfunction.
The frequency of elevated GGT has been
widely reported to be 34%-100% in patients
undergoing CBZ treatment [11-13]. Strolin et
al. [10] reported that increase in serum GGT
was generally observed in 75%–95% of pa-
tients treated chronically with enzyme-
inducing agents. In our study, GGT activities
were higher in all patients treated with CBZ
compared with pre-medication levels. Ac-
cording to Callaghan et al. [14], GGT and
ALP should not be regarded as indicators of
hepatocellular damage in patients taking anti-
convulsant drugs, because increased levels of
these enzymes may reflect enzyme induction
rather than lesions of the cells. We consid-
ered that the increased GGT and ALP activi-
Yuri Yoshimura et al. Effects of antiepileptic monotherapy
9
ties observed in our study resulted from liver
enzyme induction by CBZ treatment.
Isojärvi et al. [15] has reported that pro-
gressive increase in serum GGT activity dur-
ing the first five years of CBZ medication is
common. They also demonstrated that after
two months of CBZ treatment, significantly
elevated GGT activity was observed com-
pared with that measured before treatment,
which is consistent with our result. However,
they did not report whether GGT activity was
elevated to above normal value. In our study,
GGT activity was elevated in all patients
treated with CBZ, and GGT activity exceeded
the reference values in 33% of the patients
treated with CBZ. Isojärvi et al. [15] also re-
vealed that longer CBZ treatment resulted in
higher GGT activity. Therefore, patients un-
dergoing long-term treatment with CBZ re-
quire follow-up.
Nijhawan et al. [16] reported that among
13 patients on AED therapy (PHT, PB or
CBZ) with increased serum ALP activity, 12
had increased liver ALP isoenzyme activity,
but nine had normal bone ALP isoenzyme
activity. According to the authors, the induc-
tion of liver microsomal enzymes by AEDs
could include liver ALP, but not bone ALP
[16]. However, patients administered CBZ
exhibited significantly elevated ALP levels
accompanied by increased bone and liver iso-
enzyme activities compared with controls
[17]. Thus, in our study, elevated ALP may
occur not only in the liver but also in bone.
Previous studies found no correlation be-
tween dosage of CBZ and changes in bio-
chemical parameters [18], which is consistent
with the present finding. Rehimdel et al. [18]
also revealed that the duration of CBZ treat-
ment correlated with increased ALP activity.
However, in our study, the relation between
the duration of CBZ use and the changes in
biochemical parameters was not evaluated.
As patients with epilepsy often undergo long-
term AED therapy, we should regularly mon-
itor biochemical parameters of these patients
even in those prescribed a low dosage of
AED. In our study, 14 of 16 patients treated
with VPA (88%) demonstrated decreased
PLT counts after VPA therapy was initiated.
However, PLT counts were lowered to
13×104/µL in only one of 16 patients (6%). In
a previous study, thrombocytopenia was pre-
sent (PLT count ≤ 13×104/µL) in 12 of 60
patients (20%) [19]. Another report suggested
that 17.7% of patients experienced thrombo-
cytopenia (PLT count ≤ 10×104/µL) after ex-
posure to divalproex sodium [20]. Mean plas-
ma VPA concentration in this study was 36.3
µg/mL, which was lower compared with the
concentration of 79.6 µg/ml in a previous re-
port [20]. The PLT count may infrequently
decrease to lower than 13×104/µL because of
low VPA plasma concentration. However, a
study reported that prominent hematologic
abnormalities including thrombocytopenia,
macrocytosis, anemia, and leukopenia in-
creased to 55% in 22 patients with VPA lev-
els > 100 µg/mL compared with 33% of the
total number of patients treated with VPA
[19]. Thus plasma VPA concentration should
be carefully monitored particularly in patients
treated with high doses of VPA .
According to the literature, elevated serum
vitamin B12 and no change or elevated folate
concentrations occur after VPA treatment [21
-23]. Hauser et al. [21] reported thrombocyto-
penia, macrocytosis, increased serum vitamin
B12 and a significant downward trend in red
blood cell count after initiation of VPA thera-
Epilepsy & Seizure Vol. 11 No. 1 (2019)
10
py, and suggested the possibility that direct
toxic effect on hematopoietic precursor or
stem cell was responsible for these effects.
Acharya and Bussel [24] also reported that
VPA caused bone marrow suppression, re-
sulting in hematologic toxicity. However, in
our study, there was no other hematological
change apart from decreased PLT count, pos-
sibly because of the small number of patients
administered VPA.
In this study, there were no changes in
measured biochemical parameters in patients
after VPA treatment. There are several re-
ports of alterations in liver enzymes in pa-
tients treated with VPA. Cepelak et al. [12]
described increased AST, ALT, and GGT
activities in patients administered VPA com-
pared with healthy children. In vitro VPA
treatment has been demonstrated to induce
enzyme production [25]. In contrast, Hauser
et al. [21] reported no significant upward
trends in mean AST, ALT, GGT, and ALP
levels, but a significant decline in ALT at 3
and 6 months after VPA treatment. In the pre-
sent study, there were no changes in these
levels following VPA treatment, but this
might be due to the relatively small sample
size.
LEV is a drug widely used for treating pa-
tients with epilepsy because of its superior
tolerability and efficacy. Whether LEV caus-
es hematological changes is controversial.
Neutropenia, decreased lymphocyte count, or
thrombocytopenia induced by LEV has been
reported [26-30], while Dinopoulos et al. [26]
reported decreased lymphocyte count with no
decrease in total WBC count. In our study,
there were no significant differences between
pre- and post-treatment values in all the he-
matological parameters examined in patients
administered LEV. A larger study is required
to clarify the effects of LEV on hematologi-
cal parameters.
The major metabolic pathway of LEV
does not depend on the hepatic cytochrome
P450 system, and LEV does not induce he-
patic enzymes [31]. Therefore, LEV does not
influence liver function. In our study, there
were no changes in liver enzymes, consistent
with previous reports.
Conclusions
After CBZ treatment, WBC count de-
creased in 69% of patients while GGT and
ALP activities increased in 85%. Decreased
WBC count tended to correlate with elevated
serum CBZ level. Therefore, our results sug-
gest that hematological changes are dose-
dependently related to AED concentrations.
The high frequencies of elevated GGT and
ALP activities may be caused by induction of
liver microsomal enzymes by AEDs. De-
creased PLT count was observed in 88% of
patients who initiated VPA. Hematological
and biochemical parameters should be care-
fully monitored in patients undergoing AED
treatment, especially in those treated with
high AED doses.
Acknowledgements We thank all the participants and staff in-
volved in this study.
Conflicts of interest The authors declare that they have no con-
flicts of interest.
Yuri Yoshimura et al. Effects of antiepileptic monotherapy
11
References [1] Glauser T, Ben-Menachem E, Bour-
geois B, Cnaan A, Chadwick D, Guer-
reiro C, Kalviainen R, Mattson R, Pe-
rucca E, Tomson T. ILAE treatment
guidelines: evidence-based analysis of
antiepileptic drug efficacy and effec-
tiveness as initial monotherapy for epi-
leptic seizures and syndromes. Epilep-
sia 2006; 47: 1094– 1120.
[2] Stephen LJ, Brodie MJ. Antiepileptic
drug monotherapy versus polytherapy:
pursuing seizure freedom and tolerabil-
ity in adults. Current Opinion in Neu-
rology 2012; 25: 164- 172.
[3] Killian JM. Tegretol in trigeminal neu-
ralgia with special reference to hemato-
poietic side effects. Headache 1969; 9:
58- 63.
[4] Björnsson E. Hepatotoxicity associated
with antiepileptic drugs. Acta Neurol
Scand 2008; 118: 281- 290.
[5] Japanese Society of Neurology. Guide-
line of diagnosis and treatment for epi-
lepsy 2018; 2018: Japan.
[6] Nihoniyakuhinsyu Forum. Drugs In
Japan: Ethical Drugs 2018. 2017; Ja-
pan.
[7] Bachmann T, Bertheussen KH, Sval-
heim S, Rauchenzauner M, Luef G,
Gjerstad L, Taubøll E, Haematological
side effects of antiepileptic drug treat-
ment in patients with epilepsy. Acta
Neurol. Scand 2011; Suppl. 191: 23–
27.
[8] Huang HL, Zhou H, Wang N, Yu CY.
Effects of antiepileptic drugs on the se-
rum folate and vitamin B12 in various
epileptic patients. Biomed Rep 2016; 5:
413- 416.
[9] Braide SA, Davies TJ. Factors that af-
fect the induction of gamma glutamyl-
transferase in epileptic patients receiv-
ing anticonvulsant drugs. Ann. Clin.
Biochem 1987; 24: 391- 399.
[10] Strolin Benedetti, M, Ruty, B, Baltes,
E. Induction of endogenous pathways
by antiepileptics and clinical implica-
tions. Fundam Clin Pharmacol 2005;
19: 511- 529.
[11] Hoshino M, Heise CO, Puglia P, Al-
meida AB, Cukiert A. Hepatic en-
zyme’s level during chronic use of anti-
convulsant drugs. Arq Neuropsiquiatr
1995; 53: 719- 723.
[12] Cepelak I, Zanić Grubisić T, Mandusić
A, Rekić B, Lenicek J. Valproate and
carbamazepine comedication changes
hepatic enzyme activities in sera of epi-
leptic children. Clin Chim Acta 1998;
276: 121- 127.
[13] Hadzagic-Catibusic F, Hasanbegovic E,
Melunovic M, Zubcevic S, Uzicanin S.
Effects of carbamazepine and valproate
on serum aspartate aminotransferase,
alanine aminotransferase and gamma -
glutamyltransferase in children. Med
Arch 2017; 71: 239- 242.
[14] Callaghan N, Majeed T, O’Connell A,
Oliveria DB. A comparative study of
serum F protein and other liver function
tests as an index of hepatocellular dam-
age in epileptic patients. Acta Neurol
Scand 1994; 89: 237– 241.
[15] Isojärvi JI, Pakarinen AJ, Myllylä VV.
Basic haematological parameters, se-
rum gamma-glutamyl-transferase activ-
ity, and erythrocyte folate and serum
vitamin B12 levels during carbamaze-
Epilepsy & Seizure Vol. 11 No. 1 (2019)
12
pine and oxcarbazepine therapy. Sei-
zure 1997; 6: 207- 211.
[16] Nijhawan R, Wierzbicki AS, Tozer R,
Lascelles PT, Patsalos PN. Antiepilep-
tic drugs, hepatic enzyme induction and
raised serum alkaline phosphatase iso-
enzymes. Int J Clin Pharmacol Res
1990; 10: 319– 323.
[17] Voudris K, Moustaki M, Zeis PM,
Dimou S, Vagiakou E, Tsagris B,
Skardoutsou A. Alkaline phosphatase
and its isoenzyme activity for the evalu-
ation of bone metabolism in children
receiving anticonvulsant monotherapy.
Seizure 2002; 11: 377- 380.
[18] Rahimdel A, Dehghan A, Moghadam
MA, Ardekani AM. Relationship be-
tween bone density and biochemical
markers of bone among two groups tak-
ing carbamazepine and sodium
valproate for epilepsy in comparison
with healthy individuals in Yazd. Elec-
tron Physician 2016; 8: 3257- 3265.
[19] May RB, Sunder TR. Hematologic
manifestations of long-term valproate
therapy. Epilepsia 1993; 34: 1098-
1101.
[20] Nasreddine W, Beydoun A. Valproate-
induced thrombocytopenia: A prospec-
tive monotherapy study. Epilepsia
2008; 49: 438– 445.
[21] Hauser E, Seidl R, Freilinger M, Male
C, Herkner K. Hematologic manifesta-
tions and impaired liver synthetic func-
tion during valproate monotherapy.
Brain Dev 1996; 18: 105– 109.
[22] Linnebank M, Moskau S, Semmler A,
Widman G, Stoffel-Wagner B, Weller
M, Elger CE. Antiepileptic drugs inter-
act with folate and vitamin B12 serum
levels. Ann Neurol 2011; 69: 352– 359.
[23] Attilakos A, Papakonstantinou E,
Schulpis K, Voudris K, Katsarou E,
Mastroyianni, S, Garoufi A. Early ef-
fect of sodium valproate and carbamaz-
epine monotherapy on homocysteine
metabolism in children with epilepsy.
Epilepsy Res 2006; 71: 229- 232.
[24] Acharya S, Bussel JB. Hematologic
toxicity of sodium valproate. J Pediatr
Hematol Oncol 2000; 22: 62- 65.
[25] Rogiers V, Callaerts A, Vercruysse A,
Akrawi M, Shephard E, Phillips I. Ef-
fects of valproate on xenobiotic bio-
transformation in rat liver. In vivo and
in vitro experiments. Pharm Weekbl Sci
1992; 14: 127– 131.
[26] Dinopoulos A, Attilakos A, Paschali-
dou M, Tsirouda M, Garoufi A,
Moustaki M, Siafakas N, Papaevange-
lou V. Short-term effect of levetirace-
tam monotherapy on haematological
parameters in children with epilepsy: A
prospective study. Epilepsy Res 2014;
108: 820- 823.
[27] Bunnell K, Pucci F. Levetiracetam-
induced neutropenia following traumat-
ic brain injury. Brain Inj 2015; 29: 115-
117.
[28] Taberner Bonastre MT, Peralta Muñoz
S, Boza FM, Gumà I Padró J. Neutro-
penia secondary to exposure to le-
vetiracetam. Tumori 2015; 101: 145-
146.
[29] Oh SJ, Kwon HI, Moon SH, Ro YS, Ko
JY. Toxic epidermal necrolysis with
isolated neutropenia related to the use
of levetiracetam. J. Dermatol 2016; 43:
Yuri Yoshimura et al. Effects of antiepileptic monotherapy
top related