Epilepsy & Seizure
Journal of Japan Epilepsy Society
Vol.4 No.1 (2011) pp.9-14

Case Report

Pyridoxine-dependent statusepilepticus diagnosed
during infancy
George Imataka 1) , Ryouta Kuribayashi 1), Keiko Tsukada1), Tatsuo Tsuboi 1),
Hideo Yamanouchi 2), Osamu Arisaka1)
1

Department of Pediatrics, Dokkyo Medical University School of Medicine

2

Department of Pediatrics, Saitama Medical University School of Medicine

Key words: Pyridoxine, inborn error of the metabolism, infant, status epilepticus
Published online: July 4, 2011

Abstract
Pyridoxine dependence is a very rare inborn error of metabolism. The disorder develops mainly during the early neonatal period,and cases diagnosed in infants are even rarer.
We herein report a case of a 77-day-old boy
with status epilepticus diagnosed with pyridoxine dependence. On day 2 after birth, theboy required respiratory management after entering a partial convulsive state. The convul-sions did not respond to phenobarbitals andwere temporarily controlled by continuous intravenous administration of midazolam. Subsequently, partial seizures occurred frequently,
and the patient was observed under treatment
with oral phenobarbital and phenytoin, andintravenous midazolam. However, at 65 daysof age, partial convulsions of the right upperand lower limbs lasting for one minute oc-George Imataka MD, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
Tel: +282-86-1111, Fax: +282-86-2947, E-mail: geo@dokkyomed.ac.jp

9George Imataka, et al.

Pyridoxine-dependent status epilepticus in an infantcurred episodically in clusters every few to tenminutes. A high dose of phenobarbital wasadministered and the blood concentration increased to 42 μg/ml, but convulsions were notcontrolled. At 77 days of age, when 100 mg ofpyridoxine was slowly injected intravenously
during electroencephalography, the background activity flattened and spikes disappeared. Pyridoxine dependence was diagnosed and all antiepileptic agents were discontinued. Oral administration of pyridoxine
at 10 mg/kg/day was started and seizures nolonger occurred. Pyridoxine dependence is atreatable inborn error of metabolism. To obtain a diagnosis of pyridoxine dependence,trial administration of pyridoxine is essential,
and the pyridoxine test for a definitive diagnosis should also be conducted in cases ofstatus epilepticus during infancy.

Case report
The male infant had a gestational age of 40
weeks and 2 days, weighed 3,414 g, and wasborn by Cesarean section with no asphyxial
signs. Forty-eight hours after birth, clonicpartial convulsions occurred mainly in theright upper and lower limbs. Blood glucose,electrolytes, lactic acid, pyruvic acid, vitamin
B6, amino acid, and organic acid were all
normal. Brain computed tomography andmagnetic resonance imaging findings of theinfant showed normal findings. Auditory
brainstem response also showed no abnormalities. Electroencephalography exhibited
spikes in the left frontal and right parietooccipital regions. The convulsive states did
not respond to midazolam or Phenobarbital.
Artificial respiratory management was nolonger required at 7 days of age. The partial
convulsions were temporarily controlled byphenobarbital at 7.5 mg/kg/day (blood concentration 35.6 μg/ml) and phenytoin at 10Introduction
Pyridoxine dependence is a form of epilepsy caused by a very rare inborn error ofmetabolism [1]. Onset is usually manifested as
intractable epilepsy during the early newborn
period [2]. We examined the partial convulsive state of an infant who had been under
treatment for epilepsy since the neonatal period. We then suspected pyridoxine dependence and conducted an intravenous pyridoxine
test. After pyridoxine was injected intravenously, the electroencephalography and seizure symptoms of the infant improved drastically. Based on this case, pyridoxine dependence in infants is discussed.

mg/kg/day (blood concentration 5.8 μg/ml).
At 56 days of age, a partial convulsive state of
the right upper and lower limbs occurred.
When the blood concentration of phenobarbital was increased to 44.1 μg/ml, the convulsions were stopped. At 65 days of age, partial
convulsions of the right upper and lower limbs
lasting one minute occurred episodically inclusters every few to ten minutes. The bloodconcentration of phenobarbital during the seizures was 42 μg/ml. Electroencephalogram
exhibited spikes predominantly in the occipital area of the left hemisphere (Figure 1). On10

Epilepsy & Seizure Vol.4 No.1 2011

doxine dependence. The main etiology has
been proposed to be the absence of the inhibitory neurotransmitter GABA in the cerebrum.
Glutamate dehydrogenase is an enzyme that isrequired when GABA is synthesized fromglutamic acid. Pyridoxal phosphate, which isan active metabolite of pyridoxine, is a coenzyme of glutamate dehydrogenase that is
likely to be associated with pyridoxine dependence [5]. However, in this case of pyridoxine dependence, the concentrations ofpyridoxine in the blood are normal, andtherefore the condition cannot be diagnosed
from the clinical conditions of epilepsy orbiochemical data obtained from screening ofblood, urine, and spinal fluid. Therefore, trial
administration of pyridoxine is the most important test for an early diagnosis.
The infant who had been treated for epilepsy since the neonatal period developed apartial convulsive state, and we suspected thepossibility of pyridoxine dependence. We
performed a pyridoxine test by intravenous
injection of a total of 100 mg/kg of pyridoxine
in three step-wise increasing doses. Subsequently, the abnormal waves on electroencephalogram of the infant were improved andthe seizures were well controlled. Many of theinitial symptoms of pyridoxine dependence
lead to the development of partial convulsions
in the early postnatal period. Occasionally,
convulsive seizures develop in utero duringlate pregnancy and are perceived by themother [6, 7]. In addition, some cases are diagnosed as pyridoxine dependence after theneonatal period as in our case, or even after

77 days of age, a total of 100 mg of pyridoxine
was slowly injected intravenously during
electroencephalography, with an initial doseof 20 mg increasing to 30 mg after 3 minutes
and 50 mg after a further 3 minutes. After 5
minutes, the background activity of the electroencephalography flattened and spikes disappeared (Figure 2). From the electroencephalographic findings, pyridoxine dependence was diagnosed, and all of the antiepileptic agents were discontinued. Oral administration of pyridoxine was started at 10 mg/kg/
day and continued. Thereafter, the patient has
had no seizures for more than 5 years withnormal mental and physical development.

DiscussionPyridoxine dependence is known to manifest
as early-onset seizures in neurologically normal newborns. In an epidemiological study byBaxter et al. [1], the incidence is 1 out of
783,000 newborns, which is very rare. Some
recent papers reported new genes associatedwith pyridoxine-dependent seizures. For example, Cormier-Daire et al. [2] identified agene for pyridoxine-dependent epilepsy
mapped to chromosome 5q31 region, while
Mills et al. [3] reported mutations in antiquitin
in individuals with pyridoxine-dependent seizures. Kanno et al. [4] reported allelic andnon-allelic heterogeneities in pyridoxinedependent seizures revealed by ALDH7A1
mutational analysis. In addition, Kure et al. [5]reported that GAD65 and GAD67 genes wereinvolved in two family lines in a case of pyri-11

George Imataka, et al.

Pyridoxine-dependent status epilepticus in an infantFig. 1. Electroencephalogram recorded at 65 days of age. Spikes were observed in
the occipital area of the left hemisphere.

F3‐A1
F4‐A2
C3‐A1
C4‐A2
P3‐A1
P4‐A2
O1‐A1
O2‐A2
F7‐A1F8‐A2T3‐A1T4‐A2Resp.
ECDAFigure 2: Electroencephalogram recorded after the injection a total 100 mg of pyridoxine
at 77 days of age. Background activity flattened and focal occipital spikes disappeared

F3‐A1F4‐A2C3‐A1C4‐A2P3‐A1P4‐A2O1‐A1O2‐A2F7‐A1
F8‐A2T3‐A1T4‐A2Resp.
ECD

B
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Epilepsy & Seizure Vol.4 No.1 2011

the first year of life [8-10]. In a review of 63
cases of pyridoxine-dependent seizures inNorth American, seizures were observed during the neonatal period in only 70% of thecases [11]. Moreover, it has been reported thatpyridoxine-dependent epilepsy after the age of
1 year commonly manifests status epilepticus[12]. Therefore it is very important to exclude
pyridoxine-dependent seizure even in patientswith convulsions during the infantile period.
Trial administration of pyridoxine is the mostuseful method for diagnosing pyridoxine dependence. However, including our case, one
cannot distinguish pyridoxine-responsive seizures from pyridoxine-dependent seizures
only from the observation that convulsions arestopped by prescribing pyridoxine. Ohtsuka etal. [13] reported relapse of seizure by discontinuation of pyridoxine. Our patient has continued pyridoxine treatment. Since pyridoxine
dependence can be treated by administeringpyridoxine, early diagnosis of pyridoxine dependence can prevent intellectual impairmentof an infant [9]. The present case highlightsthat although very rare, it is very important tosuspect pyridoxine dependence in infants withstatus epilepticus.

[3]

[4]

[5]

[6]

[7]

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