Disorders causing INLE
Histopathologic anomalies of neocortical architecture are frequently
observed in patients with chronic epilepsy. Meencke and Janz [1, 2] noted
minor histological changes ("microdysgenesis" ) in the frontal cortex
of patients with primary generalized epilepsy, including increased ectopic
neurons in white matter. While similar abnormalities appear in the molecular
layer of normal brains and dyslexic patients [3, 4], microdysgenesis is
regarded as being intrinsically epileptogenic. In a study that compared
fifty patients undergoing superficial temporal resections with 33 control
autopsy specimens, severe neuronal ectopia was identified in 42% of epilepsy
patients but not in controls .
The histological features of microdysgenesis result from disordered
neuronal proliferation and migration. Nissl-stained tissue sections reveal
abnormal dendritic morphology including pyramidal and non-pyramidal neurons
with vertically oriented basal dendrites, and abnormally shaped apical
dendrites . Scattered neurons in subcortical white matter are common.
In the absence of major malformation, these features suggest some form
of neurochemical alterations as a basis for the lowering of seizure threshold.
The benefit of surgery for seizures due to microdysgenesis is controversial.
While microscopic disorders of cortical development often have a poor
response to therapy, , neuronal ectopia and neuronal clustering are
linked to more favorable clinical outcome . This diversity may reflect
differences in case selection or surgical protocols.
Meningitis and encephalitis
Bacterial and viral infections of the central nervous system increase
the risk of seizures and typically begin within five years. A general
retrospective cohort study identified an 11-fold increase in the risk
for seizures  that was non-uniform for different infections. The risk
was sixteen-fold for encephalitis, four-fold for bacterial meningitis,
and two-fold for aseptic meningitis. Viral encephalitis was the most significant
risk factor for partial seizures.
Central nervous system infection before age 4 years is also a risk factor
for hippocampal sclerosis, but does not account for all cases of post-infectious
epilepsy, even seizures of temporal lobe origin. The Herpes simplex virus,
for example, classically attacks insular and temporal neocortex leading
to atrophy without hippocampal sclerosis .
Chronic focal encephalitis (Rasmussen syndrome)
The syndrome of partial seizures due to chronic focal encephalitis (CFE)
is a rare but well recognized cause of medically refractory epilepsy [10,
11]. Rasmussen syndrome is associated with relentless inflammatory unilateral
hemispheric destruction. Seizures are often the presenting feature, most
commonly simple or complex partial events. Status epilepticus is the initial
presentation in 20% of patients. Seizure patterns often vary as the disorder
progresses, but remain frequent, severe and drug-resistant.
CFE patients exhibit progressive unilateral ventricular dilatation and
cortical atrophy although anomalous courses are not rare. A patient reported
by Zupanc et al.  had repeatedly normal MR imaging studies
for several months after seizure onset, and a 12 year old boy manifested
a focal area of increased signal in the left frontal lobe one year after
seizure onset . It appears likely that an unknown proportion of patients
exhibit uncontrolled partial epilepsy prior to neuroimaging abnormalities.
Functional imaging may be more sensitive in the early detection of Rasmussen
syndrome. MR spectroscopy reveals decreased NAA signal intensity throughout
the affected hemisphere . Both PET and SPECT demonstrate regions of
abnormal metabolism and blood flow according to the severity of the involvement
Metabolic and degenerative disorders
Seizures are the rule in most neurodegenerative and metabolic disorders,
and serial seizures or status epilepticus are common. While generalized
seizures such as myoclonic or tonic attacks occur commonly, localization-related
features are also frequent, especially in younger patients. Their clinical
features may be indistinguishable from other causes of partial epilepsy
and must be excluded by virtue of other clinical signs. It must be emphasized
that neuroimaging studies tend to be normal in the early stages of a degenerative
illness, furthering diagnostic certainty.
Idiopathic partial epilepsy
The idiopathic partial epilepsies are common childhood-onset partial
seizure disorders, accounting for approximately 25% of epilepsy in pre-adolescent
patients. The benign evolution is well known, with seizure-freedom and
disappearance of epileptiform EEG features before the end of the second
decade. The favorable prognoses mandate restraint with regard to antiepileptic
drug therapy .
A small proportion of children with idiopathic benign partial epilepsy
experience a fulminant course that is medically resistant. Panayiotopoulos
 reported on a late-onset variant of childhood onset occipital paroxysms
with predominantly simple partial diurnal seizures consisting of visual
symptoms (hallucinations) followed by hemiclonic movements, automatisms
and migraine headaches. The EEG was indistinguishable from the benign
early-onset group in revealing asymmetric repetitive occipital or posterior
temporal spikes or sharp and slow waves that attenuated with eye opening.
Complete seizure control is achieved in approximately 60% of patients
[18, 19]. Patients with this variant are more likely to have an abnormal
perinatal history, neurological examination and EEG background .
Benign partial epilepsy with centrotemporal spikes is the most common,
and best-delineated form of benign partial epilepsy . Prognosis for
remission is excellent . DNA analysis in some families implicates
linkage to chromosome 15q14 associated with potential dysregulation of
the alpha 7 AchR subunit gene or a closely linked region .
An atypical non-benign evolution occurs in children who have a younger
age of onset and multiple seizure types, including partial or generalized
atonic drop attacks, and generalized continuous spike-wave complexes during
sleep . Status epilepticus is rare . One family with typical centro-temporal
epileptiform discharges was reported to have a dominantly inherited pattern
of oral and speech dyspraxia .
The presence of brain lesions in patients with BECTS suggests that some
patients suffer from a symptomatic disorder mimicking an idiopathic syndrome.
Malformations of cortical development, anaplastic tumors and hippocampal
sclerosis occur in rare patients [27-30]. Patients with atypical evolution
of BECTS must therefore be evaluated for the presence of a structural
lesion indicative of symptomatic partial epilepsy.
The EEG is critical to the presurgical evaluation of children with INLE.
EEG data help classify the epilepsy and exclude non-surgical syndromes.
As discussed above, EEG data help to identify the idiopathic partial epilepsies
or an underlying progressive disturbance such as Alpers' syndrome. After
surgical candidacy is established, the EEG further assists in the localization
of the seizure focus and predicts surgical outcome.
Newer techniques such as magnetoencephalography, 3-D dipole source localization
algorithms and computerized processing add additional information to the
raw EEG [31-33] but their impact remains to be determined.
The scalp EEG helps define the overall extent of epileptogenic involvement.
It is usually adequate to lateralize or regionalize the seizure focus,
but due to complexities in the generation and propagation of epileptic
discharges, detects only 10 to 50% of interictal spikes at the scalp.
Ictal onsets characterized by focal low amplitude fast activity are easily
The yield of scalp EEG is enhanced through additional electrodes (supraorbital,
anterior temporal, etc.). Unlike adults, sphenoidal electrodes have little
utility in children who have a lower incidence of hippocampal sclerosis
and mesial temporal seizure foci. However, children referred for monitoring
are more likely to have frequent seizures, and their length of stay is
often less than one week. The child with infrequent seizures should have
antiepileptic drugs (AEDs) withdrawn and placed in activating situations
EEG interpretation must allow for rapidly changing patterns that indicate
dynamic postnatal processes including myelination, synaptic connectivity,
dendritic pruning and neuronal dropout. The immature neonatal cortex cannot
support sustained or widespread hypersynchronized cortical discharges,
even with diffuse pathological changes. As a consequence, the EEG may
de-emphasize the extent of epileptogenic region in the very young child.
This limitation is compounded by spatio-temporal dissociation of clinical
and electrographic seizures.
In contrast, infants are more prone to bilaterally synchronous or generalized
discharges. Generalized discharges in patients with partial epileptic
disorders occur during a narrow time window and are therefore a developmental
phase. With advancing chronological age, the EEG and clinical semiology
of partial seizures is more easily classified into standardized patterns.
The task of defining consistent focality is particularly challenging
when focal epileptiform activity propagates rapidly. Seizures in children
are generally easier to lateralize, but more difficult to localize compared
to adults. Not uncommonly, focal epileptiform patterns are identified
interictally prior to the phase of generalization . Focality may be
determined by alterations of EEG background including polymorphic slowing
or attenuated fast frequencies. In some cases, focal intermittent fast
activity is the only clue to primarily localized epileptogenic dysfunction
Intracranial EEG monitoring
With advances in non-invasive technology, fewer patients require chronic
intracranial monitoring. Its contribution to the presurgical evaluation
has been challenged, particularly in adults with lesional epilepsy in
the temporal lobe. As surgical candidacy shifts towards younger age groups
however, invasive recording has regained its utility, especially for children
with normal imaging studies and subtle malformations of cortical development.
The main goal of IEM in the INLE patient is to generate a "surgical
diagram" that accurately depicts the location and extent of the epileptogenic
region (ER), its relationship to eloquent cortex and the planned resection.
This approach is mandatory when the location and extent of the ER cannot
be adequately determined through non-invasive means. However, IEM is costly
and associated with increased morbidity. It should therefore be utilized
on an individual basis. IEM is not an "exploratory procedure" if the non-invasive
evaluation provides no information about side or approximate location
of the ER. Due to limitations of sampling and interpretation, IEM may
not always successfully define a discrete ictal onset or alter the ultimate
surgical strategy and outcome .
Thus, although removal of the entire region of significant electroencephalographic
abnormalities is generally required for seizure-freedom in non-lesional
epilepsy [37, 38], not all patients do require invasive studies. One-
stage resections based on interictal PET data in conjunction with intraoperative
ECoG have been performed on a limited number of patients with a single
hypometabolic region at one center. It is probably too early to know whether
this approach will ultimately prove successful . One-stage procedures
are indicated in children with partial seizures arising from the anterior
temporal lobe when scalp EEG and PET/SPECT data are congruent .
IEM may be necessary in otherwise straightforward cases of temporal
lobe epilepsy if non-invasive studies suggest seizure origin in the posterior
temporo-occipital base/convexity or if the ER is encroaching upon language
cortex in the dominant hemisphere . IEM is also indicated if tailored
procedures such as selective amygdalo-hippocampectomy or lateral neocorticectomy
rather than lobectomy are contemplated. In children with non-lesional
extra-temporal epilepsy where the role of functional imaging is still
uncertain [40, 42-44], invasive recording may be the only means to determine
the true extent of the ER.
The electrographic patterns that define the extent of optimal resection
are not universally agreed upon. Regions of active spiking on the pre-excision
ECoG are used to define the epileptogenic zone and resection plane in
patients undergoing one-stage excisional procedures . Prominent interictal
spiking is considered significant if it shows consistent focality or rhythmic
features, occurs in trains of focal "fast" activity, or is associated
with focal attenuation of background. Focal burst suppression is always
regarded as significant. In contrast, infrequent spikes, spikes without
consistent focality or "rim" spikes recorded on the post-resection ECoG
In subdurally implanted patients, the ictal onset zone is the single
most critical factor in defining the ER [36, 46, 47]. Secondary foci that
consistently activate intra-ictally  (during a seizure) are included
in the resection if they appear in proximity to the primary ictal focus.
Similar to the ECoG data, regions of prominent interictal spiking and
background abnormalities are also considered significant.
Talairach and colleagues  pioneered depth recording of the EEG to
localize seizure origin in surgical candidates. The use of depth electrodes
is particularly valuable in temporal lobe epilepsy , but may also
contribute useful information about deeply seated foci in other lobes
as well [51, 52]. When depth electrodes are placed accurately and targeted
strategically, delineation of seizure onset is well defined and improves
seizure outcome. The combined use of subdural and depth electrodes in
the preoperative evaluation of epilepsy has been reported, and MR imaging
of both depth and subdural electrodes is a safe procedure .
By definition, patients with "non-lesional" epilepsy have a normal routine
CT/MRI exam. However, more detailed analysis using novel MRI sequencing
techniques can often identify subtle abnormalities of gyral architecture
or the gray-white matter interface. Additional surface phased-array coils
improve signal-to-noise ratio and spatial resolution in superficial cortex
and the hippocampus . In a study employing three-dimensional reconstruction,
gyral abnormalities were detected in 6/16 patients with extratemporal
seizures and unremarkable routine MRI exams . High field strength
magnets enhance the yield in INLE , and volumetric acquired sequences
on T1 weighted MR imaging permit co-registration with abnormalities on
functional imaging studies.
Over-diagnosis may result from inadequate normative data in the first
few years of life. For example, incomplete myelination decreases gray-white
matter contrast on T2 weighted images and compromises the identification
of cortical abnormalities. Special MRI sequences are effort-intensive
and impractical. We generally utilize special sequences only in regions
of interest identified on other non-invasive studies.
Magnetic resonance spectroscopy (MRS) assesses cerebral metabolites
and neurotransmitters in epileptogenesis. Anatomical specificity is lacking
as MRS is based on the chemical properties of protons in magnetic fields.
Concentrations of N-acetyl aspartate (NAA), creatinine (Cr), and choline
are estimated through proton H MRS. Epileptogenic foci show a decreased
ratio of NAA/Cr and choline due to neuronal loss and gliosis . High-energy
phosphate compounds, inorganic phosphate, and pH are assessed using phosphorus
MRS; in general, epileptic foci are associated with increased pH and inorganic
phosphate, and decreased phosphate monoesters [58, 59].
Positron emission tomography (PET)
PET scans define focal metabolic abnormalities at resolutions as low
as 5 mm , with the type of abnormality varying according to the ligand
used. Multiple metabolic tracers are available including fluoro 2-deoxyglucose
(FDG), tracers specific for cerebral blood flow such as oxygen and dihydrogen
oxide (O H2O), and receptor density ligands such as in opiates or flumazenil.
In children, INLE, subtle malformations of cortical development are more
sensitive to flumazenil PET than FDG PET.
PET scanning is usually performed in the interictal state. Ictal studies
are more difficult due to short tracer half-life and the need for steady
state mathematical modeling. Postictal metabolic changes may be evident
up to 48 hours. Scalp EEG is obtained during and after the tracer injection
to look for interictal discharging and subclinical seizures. While scalp
electrodes do not affect PET scanning, intracranial electrodes can produce
erroneous regional hypometabolism on FDG PET.
The focal areas of hypometabolism commonly seen interictally are believed
to represent reduced blood flow and inhibition or deafferentation of neurons
surrounding the epileptogenic focus. The degree of hypometabolism usually
varies across regions with more severe hypometabolism in the ictal onset
zone (figure 1a) .
The more profound the hypometabolism, the better the prognosis, especially
in temporal lobe epilepsy. In children with cortical dysplasia, areas
of very active spiking may reveal hypermetabolic interictal states.
PET data can identify focal dysfunction in INLE due to infantile spasms
and anterior temporal foci . Hypometabolism is most often observed
in temporo-parieto- occipital regions; partial seizures and focal EEG
findings in these regions may antedate the onset of spasms. More recent
studies recognize the limitations of PET imaging. Hypometabolic regions
may be non-specific or reflect secondary sites that revert to normal once
the primary seizure focus is removed. Furthermore, the size and location
of observed focalities may vary during interictal, ictal and postictal
states. These considerations become especially critical with frequent
seizures or near-continuous epileptiform EEG activity. Thus, PET data
could easily mischaracterize the extent of the ER, resulting in failure
or unnecessarily large resections. These concerns suggest caution in relying
too heavily on PET data for surgical planning in INLE. Newer PET ligands
such as flumazenil or serotonin may, pending validation, be more specific
than FDG .
Single photon emission tomography (SPECT)
The major strength of SPECT lies in its ability to document peri-ictally
increased blood flow. SPECT images are formed from injected radiotracer
photons in the cortex. Ligands include Tc hexamethylpropleneamine oxime
(HMPAO) and Tc ethylcysteinate dimer (ECD) that are fixed in brain for
up to 6 hours. SPECT also measures neurotransmitter systems including
benzodiazepines and muscarine cholinergic receptors .
Variable SPECT results in the same patient are unrelated to interictal
spike or seizure frequency . Similar to PET, interictal SPECT demonstrates
regional hypoperfusion over a region of cortex larger then regions of
MRI or EEG abnormality . Cortical dysplasia may reveal increased perfusion
in the interictal state reflecting the heightened metabolic demand of
almost continuous discharges.
Ictal SPECT scans demonstrate regional hyperperfusion (figure
1b), higher sensitivity and greater specificity than interictal
SPECT . Improved yield is possible with seizures of 90 seconds or
more; injection must occur within 30 seconds for best results. The yield
is lower for simple partial seizures or secondarily generalized seizures
whereas simple partial seizures rarely lateralize. The origin of secondary
generalized seizures is often the most hyperperfused region .
Ictal SPECT is particularly useful for characterizing syndromes such
as hypothalamic hamartomas or tuberous sclerosis complex where positive
findings may obviate the need for invasive monitoring. There are limitations
however, as hyperperfusion often extends well beyond the ictal onset zone
to regions involved in propagation. While secondary propagation sites
usually demonstrate hyperperfused "blushes", the primary epileptogenic
focus often has a configuration that does not conform morphologically
to an anatomic gyrus.
Subtraction imaging of ictal and interictal SPECT may be used if the
ictal images are inconclusive. However, ictal hyperperfusion may persist
for variable periods of time, and compromise the interictal study if obtained
too soon after the ictal scan. There is relatively poor spatial resolution
with the subtraction SPECT scans but co-registration to volumetric MRI
scan using a surface matching technique improves anatomical localization
Comparison between modalities
There is no definitive comparison of the relative sensitivities of MRI,
peri-ictal SPECT and interictal PET . MRI assessment is solely visual
and subjective as it must account for the normal variation of gyral morphology.
PET and ictal SPECT assist the localizing process in INLE, or lesional
cases with discordant ictal EEG and MRI data. Interictal SPECT has a high
rate of hypoperfusion contralateral to the ictal onset zone (10%), and
poor correlation with the epileptogenic zone . PET and ictal SPECT
show low sensitivity and high specificity for extratemporal foci and higher
sensitivity and moderate specificity for temporal lobe epilepsy .
Ictal SPECT is less sensitive than PET for nonlocalized extratemporal
lobe seizures. PET is more sensitive than ictal SPECT for temporal lobe
epilepsy as judged by subdural EEG ictal localization, and correlation
with surgical outcome . PET's main problem is its cost and availability.
Although SPECT is a less sensitive technique for determining the epileptogenic
zone compared to PET, it is the only modality that has the capacity to
image during a seizure and therefore, complements PET data .
Received September 15, 2000 / Accepted November 10, 2000