Long term prognosis of symptomatic occipital lobe epilepsy ... - sepeap

Epilepsy Research (2010) 88, 93—99
journal homepage: www.elsevier.com/locate/epilepsyres
REVIEW
Long term prognosis of symptomatic occipital lobe
epilepsy secondary to neonatal hypoglycemia
Hesham Montassir a,∗ , Yoshihiro Maegaki a , Kousaku Ohno a , Kaeko Ogura b
a Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago,
683-8504, Japan
b Information Center for Persons with Developmental Disabilities, Research Institute, National Rehabilitation Center for Persons
with Disabilities, 4-1 Namiki, Tokorozawa, Saitama, 359-8555, Japan
Received 13 March 2009; received in revised form 13 July 2009; accepted 4 October 2009
Available online 14 November 2009
KEYWORDS
Occipital lobe
epilepsy;
Neonatal
hypoglycemia;
Status epilepticus;
MRI;
Prognosis
Summary
Purpose: To report on long-term clinical course in patients with symptomatic occipital lobe
epilepsy secondary to neonatal hypoglycemia.
Methods: Six patients with neonatal hypoglycemia and symptomatic occipital lobe epilepsy
were studied in our hospital through reviewing their medical records retrospectively.
Results: The median onset age of epilepsy was 2 years 8 months and median follow-up period
was 12 years and 4 months. Initial seizure types were generalized convulsions in 4 patients,
hemiconvulsion in 1, and infantile spasms in 1. Ictal manifestations of main seizures were
identical to occipital lobe seizures, such as eye deviation, eye blinking, ictal vomiting, and
visual hallucination. Seizure frequency was maximum during infancy and early childhood and
decreased thereafter with no seizure in 2 patients, a few seizures a year in 3, and once a month
in 1. All patients had status epilepticus in the early course of epilepsy. EEGs showed parietooccipital
spikes in all patients. MRI revealed cortical atrophy and T2 prolongation parietooccipitally
in 4 patients, hippocampal atrophy in 1, and unremarkable in 1.
Conclusion: This study indicates that epilepsy secondary to neonatal hypoglycemia is intractable
during infancy and early childhood with frequent status epilepticus but tends to decrease in
older age.
© 2009 Elsevier B.V. All rights reserved.
Contents
Introduction............................................................................................................... 94
Subjects and methods ..................................................................................................... 94
Results .................................................................................................................... 94
∗ Corresponding author. Tel.: +81 859 38 6777; fax: +81 859 38 6779.
E-mail address: hishammontassir@gmail.com (H. Montassir).
0920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2009.10.001

94 H. Montassir et al.
Perinatal history and neurological sequelae (Table 2)................................................................. 94
Characteristics of epileptic seizure and clinical course of epilepsy (Table 3 and Figs. 1 and 2)........................ 95
EEG and MRI findings (Table 4 and Figs. 3—5) ......................................................................... 97
Discussion ............................................................................................................... 97
References .............................................................................................................. 99
Introduction
Glucose is essentially important for brain metabolism. It
is well known that severe neonatal hypoglycemia results
in posterior cerebral injury. The neurological sequelae
of severe neonatal hypoglycemic encephalopathy include
developmental delay, learning or behavioral problems,
epilepsy, and visual impairment. Although the prevalence
of epilepsy in neonatal hypoglycemic encephalopathy was
quite high, studies about epilepsy secondary to neonatal
hypoglycemia are sparse (Norden, 2001). Caraballo et
al. (2004) reported that prognosis of symptomatic occipital
lobe epilepsy following neonatal hypoglycemia was
mostly good. In our own experience, symptomatic occipital
lobe epilepsy secondary to neonatal hypoglycemia is
intractable to treatment with high prevalence of status
epilepticus in infancy but remits in late childhood. Longitudinal
clinical course of epilepsy secondary to neonatal
hypoglycemia are not fully described. In this study, we
sought to examine the long-term prognosis and longitudinal
clinical course of symptomatic occipital lobe epilepsy
secondary to neonatal hypoglycemia.
Subjects and methods
We retrospectively extracted subjects from the database of outpatients
who were referred to our child neurology clinic at Tottori
University Hospital from 1980 to 2006 (12,463 patients). We
extracted the data of 2028 epileptic patients from our database.
Then, 81 patients with occipital lobe epilepsy were extracted.
Patients with symptomatic occipital lobe epilepsy who had neonatal
hypoglycemia were the subjects of this study. Occipital lobe
epilepsy was defined as having ictal semiology identical to occipital
lobe seizures, which include eye deviation or eye blinking with
staring, ictal vomiting, or visual hallucination (Williamson et al.,
1992), and interictal paroxysmal waves in the posterior derivation.
Patients with occipital lobe epilepsy who had occipital lobe
injuries other than neonatal hypoglycemia were excluded. Severe
hypoxic-ischemic brain injury is a high risk for the occurrence of
epilepsy regardless of hypoglycemia, while the mild to moderate
type is not (Zafeiriou et al., 1999; Pisani et al., 2009). Therefore,
patients with severe cerebral palsy who are not able to walk independently
were excluded, while those with mild cerebral palsy were
included. Epilepsy patients with preterm birth (less than 35 weeks
gestation) or those with inborn errors of metabolism, congenital
anomalies, brain malformation, or chromosomal abnormality were
also excluded, even if they had histories of neonatal hypoglycemia
(Table 1).
Neonatal hypoglycemia was defined as whole-blood glucose concentration
below 35 mg/dL, 40 mg/dL, and 45 mg/dL during 0—3 h,
3—24 h, and after 24 h after birth, respectively (Srinivasan et al.,
1986).
Onsets of epilepsy, major seizure types, and clinical course of
epilepsy, EEG and neuroimaging findings were studied from their
medical records. Status epilepticus was defined as clinical seizure
lasting more than 30 min. MRI (1.5 T or 3.0 T recently) was performed
repeatedly and included T1-, T2-, and FLAIR imaging. Mental
or intellectual status was evaluated using the Wechsler intelligence
scale for children or the Enjoji development scale. ‘‘Normal’’ was
defined when IQ or DQ was more than 70, ‘‘mild’’ mental retardation
(MR) or developmental delay was defined when it was between
50 and 70, ‘‘moderate’’ when it was between 20 and 50, and
‘‘severe’’ when it was below 20. We also reviewed clinical and
laboratory data during perinatal periods.
This study was approved by the ethical committee in Tottori
University.
Results
The most common epileptic syndrome of occipital lobe
epilepsy was idiopathic childhood occipital epilepsy
(Panayiotopoulos syndrome and Gastaut type) and this was
found in 54 of the patients. Twenty-one patients with occipital
lobe epilepsy were excluded and finally 6 patients (5
males and 1 female) were the subjects of the study (Table 2).
Perinatal history and neurological sequelae
(Table 2)
Perinatal histories and neurological sequelae are shown in
Table 2. Patients 1—4 were taken care of in our neonatal
intensive care unit and Patients 5 and 6 were treated in other
hospitals. Perinatal histories closely correlated with neonatal
hypoglycemia were highly present: low birth weight for
gestational age in 5, low Apgar score after 1 min in 3, and
neonatal seizure in 5. Severe neonatal hypoglycemia with a
serum glucose level of less than 15 mg/dL was reported in
3 patients and hypoglycemia was prolonged more than 10 h
Table 1
Inclusion and exclusion criteria.
Inclusion criteria (no. of patients)
Exclusion criteria
Outpatients (12,463)
OLE with occipital
injuries other than
neonatal
hypoglycemia
Epilepsy patients (2028)
Severe CP with
inability to walk
Occipital lobe epilepsy (81) LBW (less than 35
weeks of gestation)
Neonatal hypoglycemia (6) Inborn errors of
metabolism
Congenital anomalies
Brain malformations
Chromosomal
abnormalities
CP: cerebral palsy; no.: number; OLE: occipital lobe epilepsy;
LBW: low birth weight.

Longitudinal clinical course 95
Table 2
Perinatal histories and neurological sequelae.
Patient no., sex,
current age
Gestational
age
(weeks)
Birth weight
(g)
APGAR
(1 min)
Neonatal
seizure
Neonatal hypoglycemia Neurological
sequelae
Lowest level Duration (h) (IQ/DQ,
examined age)
1, m, 13 years 39 2100 9 + 35 24 Normal
2, f, 17 years 42 2790 3 +

96 H. Montassir et al.
Table 3
Clinical characteristics of epilepsy.
Patient Onset of epilepsy Seizure type Seizure frequency Number of
status
epilepticus
First
seizure
type
Major
seizure type
Maximum
(age)
Present
(age)
Antiepileptic
drugs
1 2 years 9 months Generalized
tonic-clonic
convulsion
2 2 years 1 month Generalized
tonic-clonic
convulsion
3 2 years 7 months Generalized
clonic
convulsion
4 2 years 9 months Generalized
clonic
convulsion
5 10 months Infantile
spasms
6 3 years Left clonic
hemiconvulsion
Eye
deviation,
vomiting,
cyanosis,
visual hallucination
Eye blinking
and eye
deviation,
evolving to
hemiconvulsion
Eye
deviation
and
vomiting
Eye
deviation
10
times/year
(3—9
years)
8
times/year
(9—10
years)
2—4
times/year
(3—8
years)
4
times/year
(13 years)
Seizure free
since 13
years (17
years)
Seizure free
since 9
years (23
years)
1—5 Twice/year
times/month (14 years)
(3—5
years)
Staring 2—3 Once/month
times/month (4 years)
(2—3
years)
Eye
deviation,
vomiting,
and cyanosis
20
times/year
(7—10
years)
Once/year
(16 years)
8 times VPA, CBZ, ZNS,
NZP, CLB, ST
9 times PB, VPA, CBZ
16 times PB, CBZ, VPA,
ZNS, PHT(#),
AZA, CZP(#)
Twice
Once
VPA, CBZ,
ZNS(#), CZP(#)
VPA, ZNS, CBZ,
CLB
20 times PB, CBZ(#),
ZNS, CLB(#)
AZA: azathioprine; CBZ: carbamazepine; CLB: clobazam; CZP: clonazepam; NZP: nitazepam; PB: phenobarbital; PHT: phenytoin; VPA:
valproate; ZNS: zonisamide; #: effective.
clobazam was used in 3 patients and was effective (seizure
reduction >50%) in 1 (Patient 6); clonazepam was used and
was effective in 2 patients (Patients 3 and 4); nitazepam
was used but proved non-effective in 1 patient; phenobarbital
was used and was non-effective in 3 patients; phenytoin
was used and was partially effective in 1 patient (Patient
3); valproate was used and non-effective in 5 patients;
and zonisamide was used in 5 patients and was effective
in 1 (Patient 4). Antiepileptic drugs were effective in 3
patients (Patients 3, 4, and 6), while seizures decreased
spontaneously without any change of drugs in 2 patients
(Patients 1 and 2).
Table 4
EEG and MRI findings.
Patient Major EEG findings and evolution MRI findings
1 rt O spikes Cortical atrophy and white matter
T2 prolongation (bilateral O)
2 lt O spikes, rt and lt F spikes → Cz small spikes Cortical atrophy and white matter
T2 prolongation (bilateral O, left F)
3 rt O spikes → rt and lt F spikes → normalized Cortical atrophy and white matter
T2 prolongation (bilateral O, left F)
4 bilateral P—O spikes → rt F spikes Unremarkable
5 Hypsarrhythmia → lt O spikes Cortical atrophy and white matter
T2 prolongation (bilateral O and F)
6 lt and rt O spikes Hippocampal atrophy on both sides
F: frontal; O: occipital; P: parital.

Longitudinal clinical course 97
Figure 3 Sleep EEG recorded at the age of 5 years showing
frequent sharp waves in the right occipital region.
Figure 4 Sleep EEG recorded at the age of 5 years showing
frequent sharp waves in the right occipital region.
EEG and MRI findings (Table 4 and Figs. 3—5)
Interictal EEGs showed occipital or parieto-occipital spikes
in all patients (Figs. 3 and 4) during infancy and early childhood.
Frequency and amplitude of spikes were gradually
decreased and disappeared in 1 patient (Patient 3). Frontal
spikes as well as occipital spikes were also seen in 1 patient
(Patient 2). Frontal or central spikes were seen in late childhood
or adolescence in 3 patients (Patients 2—4), while their
clinical seizure symptoms went unchanged.
MRI revealed cortical atrophy and T2 prolongation in the
parieto-occipital region in 4 patients, of whom additional
frontal lesions were present in 3 patients (Figs. 2, 3 and 5).
One patient (Patient 6) showed hippocampal atrophy on both
sides without temporal lobe seizures. MRI was unremarkable
in 1 patient (Patient 4).
Discussion
It is well known that hypoglycemic brain injury predominantly
involves the occipital lobe (Murakmi et al., 1999;
Caraballo et al., 2004; Filan et al., 2006; Yalnizoglu and
Halioglu, 2007). We reported on 6 patients who had a history
of neonatal hypoglycemia and occipital lobe epilepsy
later on. Our patients had ictal symptoms compatible with
occipital lobe epilepsy, such as eye deviation, eye blinking,
staring, visual hallucinations, and ictal vomiting (Williamson
et al., 1992). Interictal EEGs showed spike waves in the
posterior region during the active periods of epilepsy in all
patients. MRI also revealed posterior cerebral damage in 4
patients. These findings indicate that epileptic foci of the
patients could mainly be caused by neonatal hypoglycemia.
Although 2 patients (Patients 4 and 6) could not be identified
with posterior cerebral lesion on MRI, they showed
typical clinical symptoms and EEG findings for occipital
lobe epilepsy. They could not be diagnosed as having idiopathic
childhood occipital epilepsy coincidentally, because
the onset and clinical course of seizures were not compatible
with those of Panayiotopoulos syndrome or Gastaut type.
They may have had very mild occipital lesions which could
not be recognized on MRI.
Perinatal hypoxic-ischemic encephalopathy in term
infants also causes parieto-occipital lobe epilepsy (Gil-Nagel
et al., 2005; Oguni et al., 2008). It is sometimes difficult to
distinguish between perinatal hypoxic-ischemic brain injury
and neonatal hypoglycemic brain injury in clinical symptoms
and neuroimaging findings. The perinatal hypoxic-ischemic
brain injury in term infants usually involves the deeper sulcal
portion of the convolutions and spares the crowns, so
called ‘‘mushroom gyri’’ or ‘‘ulegyria’’. The brain lesions
are located in parasagittal watershed vascular territories,
such as frontal and parieto-occipital lobes. It is usually more
marked in the posterior regions at the watershed zone of
the 3 major cerebral arteries. Perinatal hypoxic-ischemic
encephalopathy in term infants usually causes moderate to
severe neurological deficit, including mental or developmental
delay, motor palsy, visual impairment, and epilepsy,
while milder cases have been reported (Oguni et al., 2008).
Although EEG abnormalities and epileptic foci may be multifocal
or widespread, parieto-occipital lobe epilepsy may be
common. These two conditions sometimes coexist simultaneously
and would enhance each other, creating more brain
injury. In the series of Oguni et al. (2008), 3 of the 10
patients with parieto-occipital lobe epilepsy as sequela of
perinatal asphyxia were reported to have hypoglycemia in
the neonatal period. In the reports of neonatal hypoglycemic
encephalopathy, other associated factors including perinatal
asphyxia and fetal distress were highly present (Murakmi
et al., 1999; Yalnizoglu and Halioglu, 2007; Montassir et
al., 2009). In the present study, additional perinatal factors
which were possibly associated with brain injury other than
hypoglycemia were highly present; low birth weight for gestational
age in 5, low Apgar score in 3, neonatal seizure in 5.
MRI demonstrated abnormalities in the frontal lobe as well
as the occipital lobe in 3 patients (Patients 2, 3, and 5). MRI
of Patients 2 and 5 showed ‘‘mushroom gyri’’ or ‘‘ulegyria’’
in the posterior regions. These findings indicate that not
only hypoglycemia but also perinatal hypoxia or ischemia
played an important role in the genesis of brain injury. The
vulnerability of the brain to hypoglycemia is enhanced by
concomitant other perinatal factors. In term infants, therefore,
hypoglycemic encephalopathy and hypoxic-ischemic
encephalopathy often overlap and sometimes cannot be distinguishable
in practice. There may be some difference in
response to treatment; epileptic patients with perinatal

98 H. Montassir et al.
Figure 5 A: patient 1, B: patient 2, C: patient 3, and D: patient 5. MRI images show parieto-occipital atrophies in both sides and
white matter T2 prolongation bilatrally. CBZ, carbamazepine.
hypoxia-ischemia often proved refractory to treatment but
those with neonatal hypoglycemia showed relatively good
prognoses (Villani et al., 2003; Caraballo et al., 2004; Gil-
Nagel et al., 2005; Oguni et al., 2008). The present study
agreed with this finding.
Although the prevalence of epilepsy in neonatal hypoglycemic
encephalopathy was greater than 50% (Murakmi
et al., 1999; Alkalay et al., 2005; Yalnizoglu and Halioglu,
2007), the characteristics and long-term prognosis were
not well known. Norden (2001) described 4 patients with
an epileptic syndrome secondary to neonatal hypoglycemia
characterized by complex focal seizures originating from
the occipital lobes, with magnetic resonance imaging
evidence of atrophic changes in the occipital cortices.
Seizures were refractory to antiepileptic drugs, and individuals
experienced pervasive delays in development. In
the series of Caraballo et al. (2004), on the other hand,
most patients with occipital lobe epilepsy had good prognoses.
In the present study we found that symptomatic
occipital lobe epilepsy secondary to neonatal hypoglycemia
was intractable and possessed quite a high risk of status
epilepticus in infancy and early childhood but remitted in
late childhood and adolescence.
It is unclear if epilepsy following neonatal hypoglycemia
has pharmaco-resistance and develops status epilepticus in
the early course of the disease. Panayiotopoulos syndrome,
early onset benign childhood occipital epilepsy, shows similar
ictal symptoms and interictal EEG findings to the present
patients, such as nocturnal seizures, ictal symptoms of
eye deviation and vomiting, liability to status epilepticus,
occipital spikes, and high remission in late childhood. In
the etiological study of status epilepticus in childhood,
Panayiotopoulos syndrome and symptomatic occipital lobe
epilepsy secondary to neonatal hypoglycemia were the
major cause and highest recurrence risk for status epilepticus
(Okanishi et al., 2008). Therefore, epileptogenecity
in the occipital lobe may be important for prolongation of
seizure activity in infancy.

Longitudinal clinical course 99
The posterior cerebral predilection of neonatal hypoglycemic
encephalopathy has been demonstrated by
computed tomography and magnetic resonance imaging
(Chiu, 1998; Traill et al., 1998; Kinnala et al., 1999). The
possible reasons for the pattern of damage may relate to the
high degree of axonal migration and synaptogenesis occurring
within the occipital lobe during the neonatal period and
the development of receptors for excitatory amino acids
which can be stimulated by elevated levels of aspartate.
This last mechanism could result in the selective death of
the postsynaptic neurons. It has also been hypothesized that
high metabolic turnover during early life predisposes this
area to injury as occurs in mitochondrial diseases (Dvorkin
et al., 1987).
A few limitations of this study can now be examined.
First, the small number of patients may affect the accuracy
of the results. Further studies with larger numbers
are needed. Second, occipital lobe epilepsy was based on
seizure semiology and interictal EEG. The possibility of
frontal or temporal lobe epilepsy cannot be completely
denied in patients with extra-occipital lobe abnormality.
Third, occipital lobe injuries could not be identified on MRI
in 2 patients. Brain injuries could be subtle, while nevertheless
we cannot deny the possibility of minor focal cortical
dysplasia.
In occipital lobe epilepsy in infancy and early childhood,
neonatal hypoglycemia should be considered as an important
possible etiology. Seizures are liable to be pharmacoresistant
and develop status epileptics in infancy and early
childhood, while they mostly decrease and are shortened in
late childhood and adolescence.
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