A 15-year epileptogenic period after perinatal
brain injury
Francesco Pisani, MDa
Elena Pavlidis, MDa
Carlotta Facini, MDa
Chiara La Morgia, MD, PhDb,c
Carlo Fusco, MDd
Gaetano Cantalupo, MDa,e

a Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Parma, Italy
b IRCCS Institute of Neurological Sciences of Bologna,
Bellaria Hospital, Bologna, Italy
c Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
d Child Neurology and Psychiatry Unit, Department of
Pediatrics, Arcispedale Santa Maria Nuova, IRCCS,
Reggio Emilia, Italy
e Child Neuropsychiatry, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy

Correspondence to: Elena Pavlidis
E-mail: elena.pavlidis2@gmail.com
Summary

Seizures are a frequent acute neurological event in the
neonatal period. Up to 12 to 18% of all seizures in newborns are due to perinatal stroke and up to 39% of affected children can then develop epilepsy in childhood.
We report the case of a young patient who presented
stroke-related seizures in the neonatal period and then
developed focal symptomatic epilepsy at 15 years of
age, and in whom the epileptic focus was found to co-localize with the site of his ischemic brain lesion.
Such a prolonged silent period before onset of remote
symptomatic epilepsy has not previously been reported.
This case suggests that newborns with seizures due to
a neonatal stroke are at higher risk of epilepsy and that
the epileptogenic process in these subjects can last
longer than a decade.
KEY WORDS: children, EEG, epilepsy, neonatal
seizures, perinatal stroke, seizure.
Introduction

Seizures occur more often in the neonatal period than at
all other ages and they are a frequent neurological complication in the neonatal intensive care unit. Populationbased studies indicate an incidence rate of neonatal
seizures (NSs) of 1.8 to 3.5 per 1000 live births (Chapman et al., 2012). Newborns with seizures carry an increased risk of long-term morbidity such as developmental delay, cerebral palsy and post-neonatal epilepsy
(PNE) (Pisani et al., 2012). Estimates on rates of PNE

Functional Neurology 2017; 32(1): 49-53

after NSs vary widely, ranging from 17 to 56%, depending on selection criteria and the duration of follow-up
(Pisani et al., 2012; Pisani et al., 2015; Mizrahi and
Watanabe, 2005). Perinatal stroke accounts for 12 to
18% of all etiologies causing seizures in this age group
(Walsh et al., 2011) and affected newborns seem to be
at increased risk of childhood epilepsy, with a rate of up
to 39% (Sehgal, 2012). Most children with NSs experience early spontaneous recurrent epileptic seizures. Almost 3/4 of seizures occurred within the first year of life
(Ellenberg et al., 1984; Fox et al., 2016) and the others
usually before the age of 5 (Pisani et al., 2012).
We report the case of a young boy with onset of epilepsy at the age of 15 years, found to be related to an ischemic lesion due to a perinatal stroke with seizures in
the neonatal period.
This observation suggests that whilst the risk for PNE is
maximal in the first 5 years of life, in some patients
seizures can appear much later in life.
Case report

This patient is the only child of unrelated parents, born
at term by physiological delivery after an uneventful
pregnancy. On the second day of life he started to present recurrent hemiclonic seizures, with alternating lateralization. At this age, video-EEG recordings documented focal ictal discharges in the right centro-parietal area
and, less frequently, in the homologous region of the
contralateral hemisphere. The seizures continued after
both intravenous pyridoxine and diazepam administration and were controlled with phenobarbital. Blood and
cerebrospinal fluid analysis were unremarkable and
cerebral magnetic resonance imaging (MRI) did not reveal abnormalities. Drugs were then gradually discontinued and the patient was discharged at 1 month of
age. Neurological follow-up was carried out through periodic evaluations until 24 months of age, disclosing only a slight language delay.
At 15 years of age, the patient experienced an unprovoked episode characterized by a sudden painful paresthesia of his left arm and shoulder followed by vision
blurring, loss of responsiveness for a few minutes, then
left head and eye deviation, and finally a brief convulsive
phase. During the post-ictal period he presented repeated vomiting and anterograde amnesia. He was admitted
to the emergency department where he underwent a
head computerized tomography scan and an EEG during wakefulness, both reported as normal. Therefore,
the patient was discharged without treatment.
He was then referred to our service and underwent a full
diagnostic work-up. Neurological examination showed a
slight asymmetry of deep tendon reflexes (predominant
on the left side). The cutaneous plantar reflex was silent
on the left side. A sleep-deprived EEG revealed spo-

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F. Pisani et al.
radic sharp waves over the left hemisphere, and right
fronto-central spikes, whose source was estimated to lie
in the peri-rolandic region of the right hemisphere. The
neuropsychological evaluation documented a borderline
cognitive level (IQ=79). Brain MRI disclosed signal abnormalities in the right peri-rolandic region, with a focal
ischemic lesion involving the right precentral operculum
(Fig. 1), compatible with the electrical source imaging of
the epileptiform abnormalities (Fig. 2).
A chronic treatment with lamotrigine was started. The
patient, now followed-up in another hospital, is still on
treatment and has been seizure free for 6 years.
Discussion

Our report raises an important issue: how long can the
epileptogenic latent period last? This patient had a history of perinatal stroke and NSs and presented with an
acute epileptic seizure at 15 years of age. In the perinatal period, imaging was interpreted as normal, and the
diagnosis of perinatal ischemic stroke was made only
retrospectively. Patients with perinatal stroke can present acute symptoms in the first week of life; these consist mainly of focal and repetitive acute symptomatic
seizures in an otherwise well-appearing neonate (Walsh
et al., 2011). As reported in the literature, a small and
peripheral ischemic lesion can be missed at the imaging
work-up and usually, in these subjects, NSs can recur,
mainly localized to one side, and the background EEG
activity can be normal (Rafay et al., 2009). This, as in
our case, can happen after an uneventful pregnancy
and peripartum period (Chabrier et al., 2011).
Perinatal stroke accounts for 12 to 18% of all seizures
during the neonatal period (Walsh et al., 2011) and the
majority of NSs are symptomatic markers of an underlying acute brain dysfunction. The NSs in our patient suggested an acute neurological event and, in view of his
perinatal history and the focal lesion shown on his MRI
images, they were very likely due to his perinatal stroke.
Thereafter, the patient became seizure free, as do most
newborns with this kind of lesion, and developed a mild
neurological impairment. Thus, his anticonvulsant therapy was discontinued early, in the first month of life. However, a late unprovoked seizure occurred, confirming
that children with perinatal stroke can have a good
short-term outcome, although, in up to 46% of them
(particularly after an arterial ischemic stroke), spontaneous seizures may recur even after a long latent period (Sehgal, 2012). Furthermore, the “practical clinical
definition of epilepsy” allows the diagnosis of epilepsy
after a single seizure in situations with a probability of
further seizures of at least 60% (Fisher et al., 2014).
This may include our child who presented with a single
seizure combined with a remote symptomatic etiology
and an epileptiform EEG study (Stroink et al., 1998). Although we cannot completely exclude the occurrence of
two independent events in this patient, his perinatal history and the area of the lesion, which is consistent with
the focus of the epileptic EEG abnormalities both in the
neonatal period and later in life, strongly suggest that he
suffered from PNE after a perinatal stroke.
Epilepsy is a common endpoint of many forms of acquired brain pathology (Goldberg and Coulter, 2013).
Brain injuries are often followed by a latent period of

50

variable duration before the appearance of epilepsy. In
fact, epilepsy is believed to be the result of epileptogenesis, or chronic changes in neural networks favoring excitation. The epileptogenic process has been classically
divided into 3 steps: inciting event, silent period, and onset of spontaneous recurrent seizures (Bender and
Baram, 2007). In the present case, the occurrence of
NSs, a sign of an acute brain injury, was followed by a
long silent period before symptomatic epilepsy began.
However, nearly 2/3 of newborns with NSs have their
first spontaneous epileptic seizure during the first year
of life (Pisani et al., 2012). It is also reported that up to
55% of hemiplegic patients with perinatal stroke can be
expected to develop epilepsy by 10 years of age (Wanigasinghe et al., 2010). Furthermore, a recent study
highlighted that, among children with a history of perinatal stroke and NSs, the 10-year cumulative incidence
of a first remote seizure was 69% (CI 48-87%) and of
active epilepsy 54% (CI 32-79%) (Fox et al., 2016).
Nevertheless, a seizure-free period lasting as long as 15
years, as in our patient, has not previously been described. Previously, the longest reported time before
epilepsy onset in patients with perinatal stroke was 13
years (Wanigasinghe et al., 2010). Whatever the specific mechanisms of injury in epileptic patients, the main
pathological features include either massive cell death
that starts the epileptogenesis process, or repetitive and
prolonged seizures that may alter the developing brain
early in life to create epileptic neuronal circuits (Bender
and Baram, 2007; Dudek et al., 2010). Both these conditions are absent in our case who presented only limited cortical brain injury and this can partially explain why
the epilepsy began after many years.
Our patient was treated with both diazepam and phenobarbital during the neonatal period. Studies regarding
the possible role played by antiepileptic drugs in neuroprotection and anti-epileptogenesis have given controversial results (Löscher and Brandt 2010; Radzik et al.,
2015), thus we cannot exclude a possible influence of
the treatment on the subsequent duration of the silent
period. However, phenobarbital at least, being the firstline treatment for NS, has been used in other, previous
patients reported in the literature on PNE after perinatal
stroke, without resulting in such a long silent period
(Golomb et al., 2007).
In our patient the EEG source analysis of interictal abnormalites indicated an epileptic focus that matched
with the site of the lesion seen on the brain MRI images.
Damage of the cerebral cortex is widely considered to
be a conditio sine qua non for the development of
epilepsy (Menon and Shorvon, 2009). Furthermore, a
higher incidence of epilepsy in hemiplegia is reported in
association with radiological evidence of cortical and
subcortical damage than with periventricular changes
only. This might also suggest that there is a need for
careful long-term supervision of these children in whom
there is also a cortical damage. The latter seems to determine the high morbidity in newborns with NSs and in
some cases can be considered to represent the onset of
a long epileptogenic process.
In conclusion, our report suggests that newborns with
NS due to a perinatal stroke have a higher risk of epilepsy, with an epileptogenic process that can last longer
than a decade.
Functional Neurology 2017; 32(1): 49-53

Perinatal stroke, neonatal seizures and epilepsy

Figure 1 - Brain MRI findings.

Magnetic resonance imaging showed focal cortical damage of the right peri-rolandic region, with a focal ischemic lesion involving the right precentral operculum in the form of a limited ulegyria. In T1-weighted images the morphological abnormality is evident, showing a “mushroom
shape” associated with a focal band of hyperintensity in FLAIR in the subcortical white matter. This pattern is due to focal vascular damage
with selective vulnerability of the sulcal portion of the gyri.
Functional Neurology 2017; 32(1): 49-53

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F. Pisani et al.

Figure 2 - EEG Source Analysis.

In A, a short 3-second fragment of sleep EEG in bipolar longitudinal montage is depicted, showing a paroxysmal focal epileptiform abnormality over the right fronto-central region. In B, the inspection of the same EEG fragment after Independent Component Analysis revealed that the
epileptiform abnormality could be represented by a single component (F10). C shows the same EEG interval in which only the F10 component
was back-transformed in order to emphasize the epileptic component, ignoring background oscillations. The topographic voltage scalp distribution of the paroxysmal abnormality is displayed in D and its source, estimated by means of LORETA algorithm, is illustrated in E. The estimated source of the interictal epileptiform abnormalities fits well with the lesion found on the patient’s magnetic resonance imaging (F).

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