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

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


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 area.

fMRI and determination of language hemispheric 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.


(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.


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.


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 .


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).


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 .


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).


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.

SPECT in temporal epilepsy

(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.

SPECT in temporal epilepsy

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


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.


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)


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


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.


Magnetoencephalography (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.



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).

Serological investigation in

epilepsy

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.


http://en.wikipedia.org/wiki/Glia

http://en.wikipedia.org/wiki/Astrocyte

http://en.wikipedia.org/wiki/Neurite

http://en.wikipedia.org/wiki/Central_nervous_system

http://en.wikipedia.org/wiki/Neurotrophic_factor

http://en.wikipedia.org/wiki/Neurotrophic_factor

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.


http://en.wikipedia.org/wiki/Phosphopyruvate_hydratase



http://en.wikipedia.org/wiki/Neuron

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

Long-term monitoring (LTM)

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.

Long-term monitoring (LTM)

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.


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recent investigation in epilepsy

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