recent investigation in epilepsy

RECENT
INVESTIGATION IN
EPILEPSY
Osama Ragab

introduction
 Epilepsy is a common, chronic neurologic
disorder characterized by recurrent,
unprovoked seizures .
 The aim of investigation
 1- Diagnoses an exclude DD.
 2- Help to plan way of management.
 3- Research ( exploring pathology, novel
treatments)

introduction
Investigation in epilepsy include
 neuro-imaging
 electro-physiological.
 lab.

Neuro-imaging
 Neuroimaging techniques play a major role in
epileptogenic focus localization, and are
particularly effective in high definition structural
studies, which allow for the localization of
epileptogenic focus in almost 90% of patients
with temporal lobe epilepsy (TLE).
 CT brain and MRI is out of scope in this talk.

Neuro-imaging
 Functional magnetic resonance
imaging

Functional magnetic resonance imaging
 The fMRI technique is BOLD, (blood oxygen level
dependent )which relies on the signal changes
that occur in the venous flow as a result of
excessive deoxyhaemoglobin following a rise in
perfusion during brain activation.
 Signal changes occurring during brain activation
are very subtle, and thus it is advisable to use
high-field MRI systems.
 In clinical practice, most fMRI studies can be
performed on a 1.5-T scanner, although 3-T
scanners are the best.

 when a seizure is generated, giving rise to
excessive brain activity, there will be changes
in the BOLD signal of the areas involved.
 It has been demonstrated that there is a
significant increase at ictal onset that co-
occurs with the electrical changes.
 Increases in BOLD signal spread to other
brain areas, helping to identify the seizure
propagation pattern.

 performance of ictal fMRI is complex.
 The image artifacts produced by motion of
patients during seizure are a major drawback.
 In fact, only patients with partial and non-
motor seizures are candidates for this
technique.
 Furthermore, an electroencephalography
(EEG) recording is necessary during the fMRI
acquisition period to correlate functional data
with electrical brain activity.

Ictal SPECT and pre-ictal BOLD.
SPECT images on the left and fMRI
images on the right.
Top row Pre-ictal BOLD increases in
the left premotor/prefrontal area at
the grey–white junction (arrows)
correspond with ictal hyperperfusion
near these sites with SPECT
(arrowheads).
Bottom row Pre-ictal BOLD signal
increases (arrow) in the left caudate
nucleus, have a similar location to
ictal ECD SPECT hyperperfusion
(arrowhead)

 BOLD signal changes in
response to ictus.
 Activation in the thalamus
bilaterally, superior and
middle frontal gyrus
bilaterally, occipital cortex
bilaterally, and posterior
cingulate.
 deactivation in the caudate
nucleus bilaterally ,uncus
bilaterally , middle frontal
gyrus and posterior cingulate
bilaterally, and brainste

 fMRI studies have also been used for the
anatomical localization of language areas.
 Exact localization of the regions that control
language functions varies significantly between
subjects, and should be determined prior to
surgery .
 It should be noted that there is a high incidence
of atypical language lateralization in epilepsy
patients, and particularly, in child-onset epilepsy
patients.
 Therefore, in epilepsy surgery language areas,
fMRI can help in the localization of these cortical
fMRI and determination of language hemispheric
dominance.

dominance.
 in pediatric patients with hemispheric lesions,
such as cerebral infarction and encephalitis, brain
functions may be reorganized or transferred to the
non-affected hemisphere. For this reason,
dominant hemisphere determination is critical for
functional hemispherectomy.
 Some authors have reported interesting cases in
which Broca’s area of certain patients is located in
one hemisphere and Wernicke’s area is located in
the contralateral one,This condition, known as
‘‘interhemispheric dissociation of frontal and
temporal regions’’.

Language functional MRI with a
word-generation pradigm.
 (A) Right-handed subject.
Activation is observed in the left
inferior frontal gyrus (Broca’s
area) (arrow) and in the left
posterior temporal gyrus
(Wernicke’s area) (filled arrow)
demonstrating left-hemispheric
language dominance.
 (B) Lefthanded subject. Activation
is obtained in the right inferior
frontal gyrus and dorsolateral right
cortex, showing right-hemispheric
language dominance.
dominance.

 (A) Language functional MRI with
an auditory comprehension
paradigm. Structural axial images
fused with the activation maps in
the frontotemporal region in an
epilepsy patient with a history of
meningitis at the age of three.
Activation is obtained in the
posterior temporal region,
demonstrating right-hemispheric
language dominance.
 (B) Structural axial T2-weighted
images show cortical atrophy of
left hemisphere and signal
changes of the left temporal lobe.
dominance.

 Language functional MRI
with a word-generation
paradigm in an epilepsy
patient with a partially
resected left astrocytoma in
the insular region of the
brain.
 Structural axial images
fused with the activation
maps in the frontotemporal
region. Activation is
observed in the left inferior
frontal region adjacent to
the mass.
dominance.

Functional magnetic resonance for memory evaluation
 there is a large number of different fMRI
experiments for memory assessment using
different stimuli, including words, faces,
objects, scenes and routes, memory functions
(retrieval and encoding).
 The majority of these studies have shown
activation of the prefrontal cortex and mesial
temporal structures.
 The posterior body of the hippocampus, the
parahippocampal and fusiform gyri are the
mesial temporal regions that show higher
activation.

 Memory functional MRI
with a retrieval paradigm.
Group study in patients
with right temporal epilepsy.
Structural coronal images
fused with the activation
map show unilateral
activation in left mesial
temporal structures (arrow)
and bilateral though right-
predominant activation of
the prefrontal cortex.
Functional magnetic resonance for memory evaluation

MRI morphometric analysis
 MRI volumetry and morphometry are involved in
comparing the size and shape of brain structures.
 In the case of voxel-based morphometry (VBM), this
is done by spatially normalizing all images,
segmenting gray matter from images, and then
performing voxelwise parametric statistical tests to
produce a parametric map of structural regions .
 A voxel (volumetric pixel or Volumetric Picture
Element) is a volume element, representing a value
on a regular grid in three dimensional space. This is
analogous to a pixel, which represents 2D image
data.

 MRI volumetry has revealed smaller
ipsilateral thalamic volumes in TLE
patients with febrile seizures than in those
without.
 patients with TLE exhibit gray matter
volume reduction and other structural
abnormalities in the hippocampus and
thalamus. These abnormalities were more
severe in those who also had MTS .
MRI morphometric analysis

Proton magnetic resonance
spectroscopy

Proton magnetic resonance
spectroscopy
 Proton magnetic resonance spectroscopy
(PMRS) and imaging (PMRSI) are noninvasive
techniques for exploring the metabolic status
of the brain in health and in disease .
 The four major metabolites detected by PMRS
at long times are N-acetylaspartate (NAA),
creatine (Cr), choline-containing phospholipids
(Cho) and lactate (Lac).

spectroscopy
 NAA is a neuronal and axonal marker that
decreases with neuronal loss or dysfunction.
 Cr, either alone or as phosphocreatine, is a
marker for intact brain energy metabolism.
 Cho is a marker for membrane synthesis or
repair, inflammation, or demyelination.
 Lac is a metabolite of anaerobic glycolysis .

 Using PMRS to measure in vivo temporal lobe
metabolite concentrations in patients with TLE
there is a bilateral reduction of N-acetyl
aspartate (NAA) to creatine plus
phosphocreatine (Cr) ratio (NAA/Cr) in the
temporal lobe.
 normalization of NAA/Cr in the contralateral
temporal lobe was seen following successful
temporal lobe resection .
spectroscopy

Diffusion tensor imaging
 Diffusion tensor imaging (DTI) measures
diffusion properties of water protons in tissue
and can detect subtle white matter changes in
the pathological state .
 Apparent diffusion coefficient (ADC) is an
average measure of water diffusion .
 fractional anisotropy (FA) measures the
degree of alignment of cellular structures
within a tissue (e.g., white matter fiber tracts),
with 0 being the least anisotropic and 1 being
highly anisotropic .

 DTI tractography and electron
microscopy of the fimbria-fornix.
Histological fields of the fimbria-
fornix resected during surgery
from two patients with TLE are
shown with their corresponding
FA maps (A and D, with the left
fimbria-fornix marked as green)
and tractography of the fimbria-
fornix (B and E). The patient
withMTS shows lower diffusion
anisotropy of the fimbria-fornix
(B) than the patient without MTS
(E).
 This corresponds to lower axonal
density for the patient with MTS
(C) than for the patient without
MTS (F).
Diffusion tensor imaging

 Nuclear medicine functional
examination techniques in
epilepsy

Nuclear medicine functional
examination techniques in
epilepsy

SPECT
 Brain perfusion SPECT imaging is a functional
brain examination technique that relies on
tracers that have the ability to cross the blood-
brain barrier and distribute inside brain cells in
proportion to cerebral blood flow.
 These tracers are hexamethylpropyleneamine
oxime (HMPAO) and ethylcysteinate dimer
(ECD), both labeled with technetium-99m
(Tc99m).

SPECT in temporal epilepsy
 Interictal SPECT involves injecting the tracer
with the patient in baseline condition, at rest,
and seizure-free for over a 24-h period.
 Interictal SPECT shows the EZ as a
hypoactive focal area, which means a low-
perfusion region.

 Ictal SPECT involves tracer injection during the
epilepsy seizure and the images can be acquired
up to 2 h later, once the seizure has been
controlled.
 SPECT shows an increase in
radiopharmaceutical uptake in the EZ secondary
to an increase in the regional cerebral blood flow
during the seizure.
 Comparison of brain perfusion between ictal and
interictal SPECTs performed on the same patient
in two different situations may assist in localizing
the EZ with a diagnostic sensitivity > 90%.
 postictal SPECT usually shows the EZ as focal
tracer hyperperfusion and diffuse lateral
hypoperfusion.

 (A) interictal SPECT of a patient
with complex partial seizures in the
right temporal lobe.
 (B) SPECT image shows an
increase in perfusion in the right
temporal lobe, exactly where the
EZ is located.
 (C) Images showing fusion of the
ictal-interictal SPECT subtraction
coregistered to the MRI of the
same patient. An increase in
perfusion in the anterior pole of the
right temporal lobe with mesial
region predominance is observed.

SISCOM
 SISCOM (Subtraction Ictal Spect Co-registered to
Magnetic Resonance Imaging) has been recently
implemented to optimize surgical outcomes by
combining SPECT and MRI images.
 A SISCOM image results from fusing the
difference image between ictal SPECT and
interictal SPECT with the MRI image of the same
patient.
 SISCOM plays a crucial role in treating patients
with malformations of cortical development
(MCD), since it has been demostrated that the
dysplastic area is not entirely epileptogenic.


Positron emission tomography.
 The basis of fluorine-18-labeled fluorodeoxyglucose
(18FFDG) PET is that intracranial glucose distribution
equals cerebral metabolism.
 ictal studies are difficult to obtain due to slow brain
glucose uptake and the short decomposition time of
18F.
 Interictal PET detects a focal decrease in glucose
uptake, which is described as hypometabolism
reflecting a focal functional brain deficit associated
with the EZ.
 PET sensitivity in mesial temporal epilepsy ranges
from 80% to 90%, and can detect focal temporal
hypometabolism in patients free of MRI-positive
mesial sclerosis.

 Nine-year-old boy with
frontal seizures secondary
to left frontal focal cortical
dysplasia with normal MRI
findings.
 Fluorine-18-labeled
fluorodeoxyglucose PET
image and PET/MRI fusion
image show
hypometabolism in the
anterior frontal region
(arrow).
Positron emission tomography.

 Imaging of Specific
Neurotransmitter Systems

Imaging of Specific
 Neurochemical characterization of the different
cortical zones in the epileptic brain with the use of
specific receptor ligands is also of high interest.
 GABA acts on 2 types of receptors: GABAA and
GABAB. Imaging of the GABAA receptor can be
done using either 11Cor 18F-labeled flumazenil
(FMZ).
 11C-labeled FMZ binding was found to be
abnormal in gray and white matter in the brain of
75% of patients with different types of refractory
neocortical focal epilepsy.

 Evidence suggest that serotonin (5-HT) may also
have an anticonvulsant effect through activation of
the 5-HT1A receptor, because activation of
this receptor affects the release and activity of
other neurotransmitters such as glutamate,
dopamine, and GABA.
 One study used 18F-FCWAY, a selective 5-HT1A
receptor antagonist, to study the receptor in
patients with TLE and demonstrated a reduced
serotonin receptor binding in temporal lobe
epileptic foci.
Imaging of Specific

Remember
 Ictal SPECT is the only imaging modality that
can define in a reliable and consistent manner
the ictal onset zone.
 The functional deficit zone is the part of the
cortex with an abnormal function in-between
seizures, due to morphological or functional
factors, or both.
 Interictal FDG-PET is probably the best
imaging method to assess the functional deficit
zone.

 Magnetoencephalography
(MEG)

 It measures magnetic fields generated by
interictal electrical dipoles tangentially oriented
to the cortical surface.
 This electrophysiologic data, when combined
with structural information from high-resolution
MRI, yields magnetic source imaging (MSI),
which helps in localizing the irritative zone
(and by inference, the epileptogenic zone)
Magnetoencephalography
(MEG)

 Magnetic fields are found whenever there is a
current flow, whether in a wire or a neuronal
element.
 The magnetic field passes unaffected through
brain tissue and the skull, so it can be
recorded outside the head .
 By analyzing the spatial distributions of
magnetic fields it is possible to estimate the
intracranial localization of the generator source
and superimpose it on an MRI
(MEG)

 In addition to defining the boundaries of the
epileptogenic zone, a common goal of the
presurgical evaluation of epilepsy patients is to
determine the spatial relationship of functional
cortex with the ictal focus, so as to anticipate
any potential deficits from a proposed
resection.
(MEG)

 Magnetoencephalograp
hy (MEG) is a technique
for mapping brain
activity by recording
magnetic fields
produced by electrical
currents occurring
naturally in the brain,
using very sensitive
magnetometers.
 Arrays of SQUIDs
(superconducting
quantum interference
devices) are currently
the most common
magnetometer.
(MEG)

(MEG)
 Utility of MEG/MSI in localizing
a potential epileptogenic focus.
 Axial MRI shows a gray
matter–lined cleft leading
toward the ventricle, typical of
closed-lip schizencephaly (left
panel).
 The child had other suspected
areas of dysplastic cortex in
the left hemisphere. MEG/MSI
study demonstrating that the
predominance of interictal
abnormalities in this patient
localize to the area of the
schizencephaly (right panel).

 Threre is a-relationship between serum S100ß
protein (S100ßP), neuron specific enolase
(NSE) and heat shock protein 70 (HSP70) in
epilepsy syndrome .
 Since HSP70, S100ßP, NSE, levels have
been shown to reflect central nervous system
damage, these biomarkers may be of
prognostic value in TLE patients from the
cognitive aspect.
Serological investigation in epilepsy

 Elevated serum NSE has been reported in
patients with status epilepticus, complex
partial status, in addition to TLE.
 serum S100ßP , NSE or HSP70 may be
useful biomarkers for central nervous system
damage. However, little data exists with
regards to these biomarkers and cognitive
performances in epilepsy.

 S 100 protein is a family of low molecular
weight protein found in vertebrates
 S100B is glial-specific and is expressed
primarily by astrocytes.
 This protein may function in neurite extension,
stimulation of Ca2+ fluxes and axonal
proliferation.
 In the developing CNS it acts as a
neurotrophic factor and neuronal survival
protein.

 neuron specific enolase (NSE) is a
phosphopyruvate hydratase ,found in mature
neurons and cells of neuronal origin.
 Heat shock proteins (HSPs) are a family of
constitutive and inducible molecular
chaperones that may possess anti-apoptotic
actions.
 Induction of HSPs following seizures is long
reported, although their efficacy to block cell
death has only been recently addressed.

 serum levels of inflammatory cytokines,
interleukin-6 (IL-6) and interleukin-1 receptor
antagonist (IL-1RA) are significant elevated in
patien with TLE regardless duration of epilepsy
or mediction.

Recent electrophysiological
studies

 The characteristic activities observed in the scalp
EEG of subjects with epilepsy are sharp transient
waveforms. Such transient waveforms include
spikes and sharp waves .
 Importantly, demonstration of epileptiform
abnormalities in the EEG does not in itself equate
to epilepsy or indicate that the patient has a
seizure disorder.
 Non-epileptic individuals show epileptiform
abnormalities in the EEG in a number of
circumstances.

Long-term monitoring (LTM)
 There is now substantial evidence that LTM
has a crucial role in the assessment of seizure
disorders, as indicated by a recent ILAE
Commission report.
 LTM methods comprise ambulatory and
video-EEG telemetry.
 Ambulatory EEG is more suited to clinical
problems which do not require concurrent
synchronised video to document clinical
features (though it can be combined with
hand-held camcorder).

 Methods to increase the likelihood of
paroxysmal events include reduction in dose
of anti-epileptic medication, sleep deprivation
and provocation techniques, such as saline
injections. However, the latter can result in
false positives, and there are ethical issues if
the patient is deliberately misled

 Optimal duration of LTM study depends on the
clinical problem, and frequency of attacks.
 Patients are unlikely to benefit from
monitoring if paroxysmal events occur less
than once per week.
 Duration of outpatient LTM is to some extent
limited by technical issues – the need to
replace data storage media and batteries
every 24−48 hours, and the potential for faulty
recording due to poor electrode contact.

Neural networks
 Neural networks and statistical pattern
recognition methods have been applied to
EEG analysis.
 results showed that the ability of specifically
designed and trained recurrent neural
networks (RNN), combined with epileptic
wavelet preprocessing, to predict the onset of
seizures both on scalp and intracranial
recordings.

 Basically, an artificial neural network is a
system. A system is a structure that receives
an input, process the data, and provides an
output.
 Commonly, the input consists in a data array
which can be anything such as data from an
image file, a WAVE sound or any kind of data
that can be represented in an array.
 Artificial neural Networks (ANN) have been
widely used for spike recognition.
Artificial neural networks
(ANNs)

 Transcranial magnetic
stimulation in epilepsy

TMS
 A reduced MT ( motor threshold MT refers to the
lowest TMS intensity capable of eliciting small motor-
evoked potentials (MEPs), and is usually defined as
more than 50 micV in amplitude in muscles at rest or
200 micV in active muscles in at least five out of 10
trials ) indicating cortical hyperexcitability was
observed only in subsets of untreated patients with
idiopathic generalized epilepsy (IGE) .
 In contrast, MT is usually increased in treated
patients with IGE or partial epilepsy, likely due to
antiepileptic treatment.
 MT is also increased in the 48 h after a generalized
seizure .

TMS
 Prolonged SP (single TMS pulses delivered
during voluntary muscle contraction produce a
period of EMG suppression known as the
silent period ) was reported in patients with
untreated IGE and in patients with partial
motor seizures, whether the lesion was
located within or outside the primary motor
cortex .
 These findings may be due to spread of
epileptic hyperexcitability to corticospinal
inhibitory networks.

Invasive Intracranial Monitoring
 situations in which invasive intracranial
monitoring may be required:
 Seizures are lateralized but not localized.
 Seizures are localized but not lateralized .
 Seizures are neither localized nor lateralized .
 Seizure localization is discordant with other data (eg,
EEG ictal scalp data are discordant with
neuroimaging.
 The relation of seizure onset to functional tissue must
be determined (eg, seizures with early involvement of
language or motor function).
 The relation of seizure onset to lesion must be
determined (eg, dual pathology or multiple intracranial
lesions).

 Depth, strip, and grid electrodes are
implantable intracranial devices used to record
the ECoG over an longer period and to
stimulate the cortex to determine function.

 The number of seizures required to consider
an intracranial study complete depends on the
specific issues involved with treating a
particular patient.
 In general, an arbitrary number of 3 typical
clinical seizures has been considered the
minimum number to be captured.

 in addition to defining the location of the
epileptogenic cortex, the surgeon must determine
its relationship to functional cortex. This requires
mapping the cortex underlying an implanted grid
electrode.
 During brain stimulation, brain mapping is
performed by a neuropsychologist or physician,
who may test language or motor function. A
clinical neurophysiologist reviews the ECoG
during stimulation to ensure that any disruption of
neurological function is due to the stimulation and
not an after discharge.

 Primary motor cortex is
located with use of
extraoperative
somatosensory evoked
potentials and
intraoperative cortical
stimulation, Penfield
instrument in field is
positioned over primary
motor cortex.

recent investigation in epilepsy

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