Epilepsy Research (2009) 86, 232—236

journal homepage: www.elsevier.com/locate/epilepsyres

SHORT COMMUNICATION

Na VPA-induced acute ischemic stroke in an
epileptic patient with methylenetetrahydrofolate
reductase gene polymorphism
Asuman Orhan Varoglu ∗
Department of Neurology, Medical School, Ataturk University, 25240 Erzurum, Turkey
Received 8 January 2009; received in revised form 19 June 2009; accepted 28 June 2009
Available online 30 July 2009

KEYWORDS
Methylenetetrahydrofolate reductase
(MTHFR);
Na-Valproic acid
(VPA);
Acute ischemic
stroke;
Homocysteine (Hcy);
Epilepsy

Summary A 23-year-old man using Na-Valproic acid (VPA) was admitted to our clinic due to
convulsion. The neurological examination revealed right hemiparesis. From the exitus notes,
we learned that his two siblings had died from status epilepticus. Magnetic resonance imaging
(MRI), MRI spectroscopy, and diffusion-weighted investigations (DWI) showed acute—subacute
ischemic stroke in the left temporo-parieto-occipital region. The patient had an ischemic stroke.
Heterozygote methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism was determined on genetic examination. The homocysteine (Hcy) level was 18.2 mmol/l (5—15 mmol/l).
So VPA treatment was stopped and oxcarbazepine treatment was started. MTHFR 677C/T
polymorphism is associated with the risk of vascular diseases due to hyperhomocysteinemia.
Heterozygote (MTHFR) 677C/T polymorphism has not been reported to be associated with
epilepsy. In patients with heterozygote (MTHFR) 677C/T polymorphism and under long-term
use of certain drugs the determination of Hcy plasma levels may be useful to prevent the
development of atherothrombotic disease.
© 2009 Elsevier B.V. All rights reserved.

Introduction
Methylenetetrahydrofolate reductase (MTHFR) plays essential roles in DNA synthesis, repair, and methylation. MTHFR
irreversibly converts 5,10-methylenetetrahydrofolate,
which is the predominant form of folate in plasma, to
5-methylenetetrahydrofolate. Then 5-methylenetetrahydrofolate catalyzed by methionine synthesis uses Vit B (12) as

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E-mail address: asumanorhan@yahoo.com.

a cofactor for the remethylation of homocysteine (Hcy) to
methionine (Wang et al., 2009). It has been demonstrated
that 677C/T and A1298C are common polymorphisms in
MTHFR deficiency. In the literature, the rate of the C677T
mutation of MTHFR varies from 5 to 22% (Cattaneo et al.,
1997). According to a previous report, homozygotes and
heterozygotes have an approximately 70 and 35% reduction
of MTHFR activity in vitro, respectively (Zetterberg, 2004).
MTHFR deficiency, which is an autosomal recessive disorder,
results in hyperhomocysteinemia. Hyperhomocysteinemia
is a possible risk factor for occlusive vascular diseases and
epilepsy (Xu et al., 2008; Ono et al., 2002).

0920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2009.06.009

Na VPA-induced acute ischemic stroke in an epileptic patient

233

MTHFR polymorphisms are associated with elevated Hcy
concentrations in epileptic patients receiving anticonvulsants (Caccamo et al., 2004; Yoo and Hong, 1999). Vilaseca
et al. (2000) showed that plasma total Hcy concentration was high in epileptic children with the MTHFR 677C/T
mutation who are taking Na-Valproic acid (VPA) as monotherapy. Another report showed that chronic VPA treatment
decreased methionine adenosyltransferase activity in the
rat brain (Carl, 1986). We found no previous reports of
epileptic patients with heterozygote MTHFR deficiency.
We report a patient with heterozygote MTHFR polymorphism and epilepsy associated with acute ischemic brain
stroke. To our knowledge this is the first case of its kind
in the literature.

tinued more than two months. Computed tomography (CT)
obtained two weeks before VPA therapy was unremarkable.
The patient was hospitalized in another clinic for uncontrolled seizures before coming to our clinic. In this hospital,
CT and MRI were evaluated as normal. There was neither
stroke history in the early ages of life, nor genetic epilepsy
in the family. According to the hospital documents, specifically the exitus notes, his two siblings had epilepsy and had
died from seizures, but we did not have access to any document on these siblings, so there is no information available
regarding the presence of the mutation in these two siblings.
At admission, the patient’s neurological examination
revealed loss of consciousness, right hemiparesis. Additionally, the plantar reflex was also extensor. Body temperature
was 38.0 ◦ C. The slow activity appeared as commonly in
the electroencephalography. After the stroke episode, CT
showed a hypodense lesion (Fig. 1A), MRI showed T2hyperintense lesion (Fig. 1B), and DWI showed hyperintense
lesion (Fig. 1C) in the left temporo-parieto-occipital region.
However, CT and MRI findings performed 10 days before the
present radiologic evaluation were unremarkable. MRI spectroscopy showed a decreased N-acetylaspartate (NAA) peak

Case report
A 23-year-old male epileptic patient was admitted to our
clinic, presenting with an abnormal mental status and convulsions. VPA was started following the fifth episode. These
episodes began two months before VPA was started and con-

Figure 1 (A) Computerize tomography. (B) Axial T2 MR image showing a lesion spreading at the left temporo-parieto-occipital
region. (C) DW imaging showing hyperintensity observed at the left temporo-parieto-occipital region. (D) MRI spectroscopy showing
decreasing NAA peak and the presence of lactate peak at the lesion.

234
and the presence of a lactate peak at the lesion (Fig. 1D).
The CSF study was normal. Finally, the present case was
diagnosed as ischemic stroke. Acyclovir was stopped and
platelet inhibitor treatment was started. Transthoracic
and transesophageal echocardiography and carotid artery
Doppler were normal. The markers of collagen tissue diseases were negative. Some hematological markers such as
fibrinogen, antithrombin, and protein C and S were also in
normal ranges. Factor V Leiden and prothrombin G20210A
gene mutations were not detected. The genetic analysis revealed that the patient had the heterozygote gene
for 677C/T in the MTHFR enzyme. Both siblings were also
heterozygotes. In our case, plasma Vit B (12) and folic
acid were normal and plasma Hcy level was 18.2 mmol/l
(5—15 mmol/l). In his siblings, plasma Vit B (12), folic acid,
and Hcy level were normal. In the follow-up, we determined
that his fourth sibling, who is still living, has also epilepsy.
Before the acute ischemic stroke episode, the neurological
examination was also completely normal. The first seizures
were generalized tonic—clonic type. After the ischemic
stroke, secondary generalized seizures began. Therefore,
VPA was stopped and oxcarbazepine (1200 mg/day) was
started. In addition, folic acid (174 mg) was given three
times a day. Finally, the patient’s neurological status was
improved and the patient was discharged.
After two months, the patient was assessed in an outpatient clinic. The level of Hcy was 10 mmol/l (5—15 mmol/l)
and plasma Vit B (12) and folic acid were normal.

Discussion
MTHFR
catalyzes
the
reduction
of
5,10methylenetetrahydrofolate to 5-methyltetrahydrofolate for
the remethylation of homocysteine to methionine. In 1988,
Kang et al. described a thermolabile variant (677C/T) of
MTHFR, which is associated with decreased enzyme activity
and mildly elevated Hcy plasma levels. Consequently,
MTHFR deficiency may cause hyperhomocysteinemia and
occlusive vascular diseases.
In the literature, there are some reports concerning the
relationship between MTHFR 677C/T mutation and epilepsy
(Wang et al., 2009; Yoo and Hong, 1999; Xu et al., 2008). In
all of these reports, the MTHFR 677C/T mutation occurred as
homozygote. Although there is some speculation about this
association, the underlying pathophysiologic mechanism of
the relationship between the MTHFR 677C/T mutation and
epilepsy has not yet been identified. In the literature, there
are two main speculations (Ono et al., 2000; Dean et al.,
2008; Marangos et al., 1990). The first one, Ono et al. (2000)
reported that seizures are related to cystathionine beta synthase deficiency in homocysteinuric patients, especially in
the early infant period. In the second speculation, which
was described by Dean et al. (2008), suggested that the
production of increasing brain-derived neurotrophic factor
for DNA hypomethylation may be responsible for the development of epilepsy in individuals with the MTHFR 677C/T
polymorphism.
As mentioned above, living siblings have carried the same
mutation and have a normal Hcy level, but one of them also
developed epilepsy. The epilepsy in this family is associated
with MTHFR 677C/T deficiency. Apart from hyperhomocys-

A.O. Varoglu
teinemia, we thought that there might also be different
mechanisms involving the MTHFR 677C/T mutation and the
development of epilepsy.
A high rate of the MTHFR 677C/T polymorphism is
observed in epileptic patients (Yoo and Hong, 1999). From
the literature, we know that the Hcy level increases in
homozygote patients but not in heterozygote ones (Yoo and
Hong, 1999). In a retrospective study on 55 Systemic Lupus
Erythematosus patients, Afeltra et al. (2002) reported that
levels of Hcy in plasma are in the normal range in five
heterozygote cases. To our knowledge, there is no report
concerning an elevated Hcy level in heterozygote MTHFR
677C/T deficiency. Our patient is the first case with epilepsy
and heterozygote MTHFR 677C/T deficiency that developed
acute ischemic stroke after VPA treatment.
It is well known that the use of antiepileptic drugs
(AEDs) may lead to hyperhomocysteinemia by reducing the
folic acid and Vit B (12) level. As previously reported,
phenytoin and carbamazepine (CBZ), but not VPA, induced
hyperhomocysteinemia with low folate status, probably by
inducing hepatic microsomal enzyme (Yoo and Hong, 1999).
The underlying mechanism for hyperhomocysteinemia due
to VPA is unknown (Yoo and Hong, 1999). The relationship between serum folate, Vit B (12), and Hcy levels
of patients receiving AEDs has been detailed in numerous reports of MTHFR 677C/T deficiency (Ono et al., 2000,
2002; Yoo and Hong, 1999; Vurucu et al., 2008). Ono et
al. (2002) reported that folate deficiency was not observed
in monotherapy patients, but hyperhomocysteinemia and
low folate status occurred in homozygote patients receiving multidrug therapy. Vurucu et al. (2008) reported that
low folate level and hyperhomocysteinemia were associated with the using of CBZ or VPA, and also C677T
variants of the MTHFR gene have no contribution in hyperhomocysteinemia in epileptic patients receiving CBZ or
VPA.
In the absence of other thrombophilic risk factors, the use
of VPA may elevate Hcy levels as a side effect in patients
without heterozygote MTHFR gene mutation (Sener et al.,
2006; Karabiber et al., 2003; Verrotti et al., 2000; Attilakos
et al., 2006; Vurucu et al., 2008).
The reduction of serum Vit B (12) and folate levels, and
hyperhomocysteinemia is common in the use of CBZ, phenytoin, or phenobarbital treatment. Few studies have shown
that there is a negative correlation between low folate
status and hyperhomocysteinemia in patients treated with
hepatic enzyme inductor AEDs such as CBZ, phenytoin, phenobarbital, or pirimidon. Some authors have suggested that
cofactors and Hcy levels do not usually change because
VPA is a hepatic enzyme inhibitor (Apeland et al., 2000;
Fernández-Miranda et al., 2005; Kishi et al., 1997).
Folic acid and Vit B (12) supplementation are suggested
in patients with low folate status, a low Vit B (12) level,
and hyperhomocysteinemia in order to prevent the development of occlusive vascular disease (Yoo and Hong, 1999).
In our case, we administered folic acid (174 mg) three times
a day, although the levels of folic acid and Vit B (12) were
within the normal range. After two months, the patient
was assessed in an outpatient clinic. His neurological examination and plasma Hcy level were normal. Therefore, we
thought that the cause of the reduced Hcy level in our case
may be ceasing the VPA treatment.

Na VPA-induced acute ischemic stroke in an epileptic patient
VPA is a widely used antiepileptic drug, but may have serious side effects. In the rat model, it was demonstrated that
the mechanism underlying VPA toxicity is the alterations in
the methionine cycle (Ubeda et al., 2002). In another report,
Hendel et al. (1984) showed that the absorption of folic
acid decreased but liver metabolism did not change due to
VPA therapy. However, several studies implicated that treatment with VPA was used safely to treat low folate and Vit B
(12) status and hyperhomocysteinemia in epileptic patients
(Vurucu et al., 2008; Gidal et al., 2005). In contrast, in our
case, hyperhomocysteinemia was observed with VPA use.
In the present case, we do not have any imaging findings of the vascular territories of intracranial vessels, but
we do have imaging findings of normal carotid arteries. Some
studies have reported that serum levels of Hcy were not correlated with the carotid intima—media thickness in patients
having this mutation with ischemic stroke (Ntaios et al.,
2008; Mousavi et al., 2006).
To our knowledge, there no information regarding the
decreased Hcy level leads to acute ischemic stroke. We
found no report about the relationship between the duration of exposure to hyperhomocysteinemia and the risk of
acute ischemic stroke in the literature.
Heterozygote MTHFR 677C/T polymorphism has not
been reported to be definitively linked to epilepsy. There
has not even been hyperhomocysteinemia due to heterozygote MTHFR 677C/T polymorphism reported. In our
case, although heterozygote MTHFR 677C/T polymorphism was determined, hyperhomocysteinemia was found
(18.2 mmol/l). We present a case with epilepsy and heterozygote MTHFR polymorphism associated with acute
ischemic brain injury after using VPA.
In conclusion, we may suggest that heterozygote MTHFR
gene variant analysis should be taken into consideration
in patients with family history of epilepsy, especially in
the presence of hyperhomocysteinemia. It is important to
measure the homocysteine level, particularly when using
drugs for a long time period in patients with this deficiency,
because careful follow-up of patients with heterozygote
MTHFR 677C/T deficiency might be life-saving.

Conflicts of interest
The author has no conflict of interest to disclose.

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