Epilepsy, a common chronic neurological disorder, is a

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1 10 SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61 Epilepsy: Diagnostic Evaluation JMK Murthy* Epilepsy, a common chronic neurological disorder, is a potentially treatable condition. The determinants of seizure remission and long-term outcome include: seizure type, type of epilepsy and epilepsy syndrome, and etiology. The diagnostic evaluation of patients with epilepsy involves essentially these aspects. In patients with drug resistant epilepsy, pre-surgical work-up involves evaluation for the substrate for possible surgery. Electroencephalography Electroencephalography (EEG) records electrical current (changing voltage) generated in the large pyramidal neurons of the superficial layers of cerebral cortex. Only synchronized electrical activity occurring across large areas of layered cortex is recorded. Normal rhythmic EEG activity represents the current flow from rhythmic changes in resting membrane potentials (excitatory post-synaptic potentials and inhibitory post-synaptic potentials). In most normal adults, the awake EEG pattern consists of 8-12 Hz alpha activity which is most prominent in the occipital area with attenuation (block) on eye opening (Figure 1). Scalp EEG Inteictal EEG aids: (1) in establishing whether epilepsy is present, (2) in classifying seizure type, (3) in localization of irritative zone and epileptogenic zone, (4) in defining specific epilepsy syndrome, and (5) in selecting appropriate antiepileptic drug (AED) and also helps while withdrawing AEDs. However, EEG is not specific to etiology. Epileptiform discharges (IEDs) are specific for epilepsy (Table 1). 1 The duration of spikes is less than 70 msec and that of the sharp waves is between msec. Combination of spikes, sharp waves, and slow waves are also epileptiform discharges. Interictal spike or sharp wave is the summated postsynaptic excitatory and inhibitory potentials associated with hypersynchronous neuronal firing with paroxysmal depolarization shift and aftergoing hyperpolarization. A large area of cortex, approximately 6 cm, 2 must be involved in a spike discharge for that spike to be apparent with scalp recording. 2 The epileptiform activity in deep brain structures may not be seen with superficial scalp electrodes. IEDs are rarely seen normal children ( %) and adults ( %). 3-6 The EEG may be normal in people with epilepsy. In serial EEG recording, 50% of patients with epilepsy were found to have epileptiform discharges on the first EEG, 84% by the third EEG, and in 92% by the fourth EEG. 7 While reviewing interictal EEG particular attention is paid to sharp waves or spikes, focal or generalized slow activity, inappropriate response to stimuli (hyperventilation, photic stimulation), and EEG correlates to changes in state or behavior in addition to background rhythm. Methods that increase the chances of detecting IEDs in the EEG include sleep deprivation, hyperventilation, photic stimulation, and placement of special electrodes like e.g., sphenidal electrodes. Photoparoxysmal response (PPR) consists of spikes or spike waves in response to intermittent photic stimulation. The epileptiform discharge may persist after the end of photic stimulation and majority of the patients have stable photosensitivity range (Figure 2). The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has redefined generalized and focal seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). 8 EEG has an important role to distinguish between generalized from focal epilepsy. Focal spike and sharp activity generally suggests focal epilepsy and the irritative zone is the area of the cortex that generates interictal focal spike activity. The irretative zone does not coincide but frequently overlaps with epileptogenic zone (Figure 3). 9 However, sometimes focal (mesial frontal) onset seizures rapidly generalize, giving the EEG appearance of generalized onset. Spike and sharp wave location indicates the probability of epilepsy. Spikes in the anterior and mid temporal location have high probability of epilepsy. Frontal, central, and occipital spikes have moderate probability of epilepsy. 10 Fig. 1 : Normal awake EEG showing Hz alpha with attenuation (block) on eye opening Table 1: Characteristics of interictal epileptiform discharges1 Paroxysmal with spiky configuration standing out from the background Duration for spike msec and for sharp wave msec Abrupt change in polarity and surface negative polarity Should have a physiological field * Chief of Neurology, Institute of Neurosciences, Continental Hospitals, Hyderabad Fig. 2 : EEG showing photo-paroxysmal response at 15 Hz photic stimulation

2 SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL Epileptogenic Zone Area of the cortex generating seizures, the removal of which is necessary to abolish seizures Symptomatic Zone Ictal-onset Zone Irritative Zone Functional Deficit Zone Epileptogenic Lesion Fig. 6 : Awake interictal EEG showing predominantly right occipital transient of sharp-wave activity Fig. 3 : Shows the concept of epileptogenic zone and different zones (Table 4) and their congruence in a patient with left mesial temporal lobe epilepsy Fig. 4 : Awake inteictal EEG showing left anterior temporal sharp wave transients with phase reversal at left anterior temporal leads Fig. 5 : Awake interictal EEG showing left frontal spike activity with a field Localization of the focus can be determined by principles of polarity: (1) in the bipolar montages by reversal of polarity, isopotentiality, and end of the chain and (2) in the referential montages by voltage maxim. Interictal EEG abnormalities commonly observed in temporal lobe epilepsy are focal arrhythmic slowing (either theta or delta) and focal IEDs that are often restricted to anterior temporal leads (Figure 4). Bilateral independent discharges are not uncommon. Clear laterality of spikes in patients with mesial temporal lobe epilepsy provides a reliable guide to epileptogenesis and significant improvement Fig. 7 : Awake interictal EEG showing generalized polyspike, spikewave activity with normal background activity in a patient with juvenile myoclonic epilepsy or cure has been reported in 74-92% of such patients following surgical resection.10 The interictal EEG is less useful in localizing the extratemporal epilepsy. In patients with frontal lesions, the IEDs was exclusively frontal in 27.5% (Figure 5) and in patients with parieto-occipital lobe lesions it was exclusively over the lesional lobe in only 12.1% (Figure 6). 11 Generalized or multifocal spikes or sharp waves, generalized spike and wave complexes and poly--spikes are reliable indicators of epilepsies with generalized seizures. In combination with a normal awake and sleep background, generalized 3-4 hz and wave complexes and polyspikes are typical for generalized genetic (idiopathic) generalized epilepsies: childhood absence epilepsy (CAE), juvenile absence epilepsy (IAE), juvenile myoclonic epilepsy (JME) (Figure 7), and idiopathic epilepsy with GTC only. Video-EEG Video-EEG monitoring refers to continuous EEG recorded for a prolonged period with simultaneous video recording of the clinical manifestations. This permits having correlation of the recorded behavior and the EEG activity. The indications for video-eeg include: (1) to establish the epileptic nature of the attack, (2) to characterize the seizure semiology and thus seizure type, particularly in children; (3) diagnostic evaluation of patients with drug resistant seizures; (4) presurgical evaluation of potential surgical candidates (non-invasive and invasive)

3 12 SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61 (a) (b) Fig. 8 : Magnetic resonance imaging (a) FLAIR sequence showing right hippocampal atrophy with hyperintense signal changes suggesting sclerosis and (b) T1-weight sequence showing changes in the floor architecture Fig. 9 : Magnetic resonance imaging, FLAIR sequence showing right frontal focal cortical dysplasia with transmantal sign Invasive EEG Invasive EEG is two types: intracranial EEG recording and intraoperative electrocorticography (ECoG). Intracranial EEG (iceeg) is a technique in which the electrodes are directly implanted on to the surface and depths of the brain. This approach is used in the presurgical evaluation of patients with drug resistant epilepsy, particularly in non-lesional extratemporal, bilateral temporal, and dual pathology. Electrocorticography (ECoG) refers to intraoperative recording of cortical activity, interictal abnormalities, with subdural and less commonly with depth electrodes. ECoG helps in delineating the irritative cortex and thus helps in delineating the extent of surgical resection. Table 2: Structural MR imaging in epilepsy Hippocampal sclerosis (mesial temporal sclerosis) Malformation of cortical development Focal cortical dysplasia Lessencephaly Hetrotopia (band hetrotopia, nodular hetrotopia) Polymicrogyria Schizencephaly Hemimegalencephaly Tuberous sclerosis Tumors Dysembryoplastic neuroepithelial tumor Ganglio-glioma Gangliocytoma Oligodendroglioma Low grade astrocytoma Hemispherical syndromes Rasmussen encephalitis Sturge-Weber syndrome HHE syndrome Others Cavernoma Hypothalamic hamertoma Vascular malformations Atrophic scars Imaging in Epilepsy Magnetic Resonance Imaging Advances in neuroimaging particularly with continuous evolution of magnetic resonance imaging (MRI) techniques in the last one decade have a great impact on the management of epilepsy. The application of neuroimaging extends beyond the identification of epileptogenic lesions and refinement of surgical interventions. Presence of structural abnormality and widespread, bilateral abnormalities detected on structural and functional imaging studies are associated with likely antiepileptic drug (AED) resistance. High resolution MRI should be the imaging modality to detect structural lesions in patients with chronic epilepsy. MRI has been

4 SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL Table 3 : Indications for MRI in epilepsy 14 Onset of seizures at any age with evidence of a partial onset on history or EEG Onset of unclassified or apparently generalized seizures in the first year of life or in adulthood Evidence of focal fixed deficit on neurological or neuropsychological examination Difficulty in obtaining control of seizures with first-line antiepileptic drug treatment Loss of control of seizures with antiepileptic drugs or a change in the seizures pattern that may imply a progressive underlying lesion Fig. 10 : Interictal PET showing left temporal hypometabolism shown consistently superior to computed tomography (CT) in identifying the etiology of epilepsy. It identifies mesial temporal sclerosis (Figure 8 a and b) small lesions and abnormalities of malformation of cortical development (Figure 9) (Table 2). Focal structural pathology is identifiable on MRI in 12.7% to 14% patients with newly diagnosed epilepsy. 12,13 The reported sensitivity of MRI in identifying surgical proven pathological substrates is approximately 86%. 12 However, CT may be useful as complementary imaging technique in the detection of cortical calcification. The indications for MRI in patients with epilepsy are given in Table MR-spectroscopy (MRS), functional-mri (fmri), and diffusion tensor imaging (DTI) are the other adjunctive MRI techniques used in the presurgical evaluation of patients with drug resistant epilepsy. MRS provides measurement of brain metabolites. In patients with hippocampal sclerosis 1H MRS shows decrease in the ratio of N-acetylaspartate (NAA, neuronal and axonal marker) to creatine (marker of brain energy metabolism) and lateralizes seizure focus in 80-90% of the patients. 15,16 Functional MRI (fmri) is based on the principle that neuronal activity produces regional changes in cerebral blood flow, volume, and oxygenation, therefore leading to variation in the ratio of diamagnetic oxyhemoglobin and paramagnetic deoxyhemoglobin which can be detected as bloodoxygen-level-dependent (BOLD) contrast. fmri is being used for lateralizing language dominance and also memory deficits thus avoiding the need for invasive intracarotid amobabrbital test (Wada s test). DTI provides the structural integrity of brain tissue. Tractography is a post-acquisition processing extension of DTI in which the directional information of the diffusion of water in each voxel is used to infer the orientation of specific white matter tracts. Tractography is the only currently available technique for tracing white matter pathways in vivo. Understanding the configuration of white matter-tracts is fundamental in understanding cerebral function. Tractography can be combined with functional activation studies to delineate white matter tracts connecting eloquent cortex which can assist pre-operative planning to reduce the risk of damaging eloquent cortical function. 17 Functional Imaging Functional imaging with single photon emission tomography (SPECT) and positron emission tomography (PET) reflects seizurerelated changes in cerebral perfusion, glucose metabolism, and neuroreceptor status and thus help in localizing epileptogenic foci even in areas that are morphologically inconspicuous. Neither SPECT nor PET information independently makes the case for surgery in a particular brain area in lesion negative epilepsy and the information from other investigations has to be considered. Ictal SPECT and interictal PET (Figure 10) are useful imaging modalities in the presurgical evaluation of patients with drug resistance epilepsy. The usefulness of interictal SPECT for preoperative localization of ictal onset zone is limited because of low sensitivity, where as ictal SPECT is more sensitive in localizing ictal onset zone. The sensitivity in temporal lobe epilepsy ranges between 73 97% and 66% for extratemporal lobe epilepsy. 18 Co-registration of the subtracted SPECT images to the patient s MRI (SISCOM) can provide further anatomical information on the location the seizure focus PET is of use in lateralizing rather than localizing epileptic focus. In patients with epilepsy the goal of a PET study is to detect areas of relative hypometabolisim, which are presumed to reflect focal functional disturbance of cerebral activity associated with the ictal onset zone. The sensitivity of PET in temporal lobe epilepsy ranges between 70-90%, where as in patients with extratemporal lobe epilepsy it varies between 30-60%. 18 Drug Resistant Epilepsy and Presurgical Evaluation Epidemiological data indicate that 20-40% of the patients with newly diagnosed epilepsy become drug resistant. Drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure sustained seizure freedom. Patients with drug resistant epilepsy should be investigated to determine whether the patient is a possible surgical candidate. 19 Presurgical evaluation in patients with drug resistant epilepsy aims at determining the epileptogenic zone. Epileptogenic zone is a theoritical concept and is defined as the area of the cortex generating seizures, the removal of which is necessary to abolish seizures.9 Determining the epileptogenic zone involves identification a number of other zones (Table 4) that if consistently indicative of the same brain area as abnormal (i.e. concordent ), provide the best indication of where the true epileptogenic zone might lie. 20 Several investigative techniques are done to define the epileptogenic zone. Prolonged video-eeg identifies irritative zone and also ictal onset zone. Analysis of seizure symptoms and signs of the seizures captured during video-eeg identifies the

5 14 SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61 Table 4 : Definitions of abnormal brain areas9 Zones Definitions Technique Irritative zone Area of the cortex that generates and interictal spikes Electophysiological invasive and noninvasive) Ictal onset zones Area of brain where Electrophsiological seizures are generated invasive and noninvasive) (including areas of early Epileptogenic lesion Structural abnormality Structural imaging of the brain that is MRI and tissue the direct cause of the pathology epileptic seizures Symptomatic zone Functional deficit Portion of the brain that produces the Initial clinical symptomatology Cortical area of nonepileptic Dysfunction symptomaticic zone which in turn can (1) lateralize the seizures to one hemisphere and (2) localize the seizures to a specific brain region in that hemisphere. A variety of neuroimaging techniques are used in the presurgical evaluation to identify various zones: high resolution MRI to determine epileptic lesion zone, fmri to map the eloquent cortex, EEG-fMRI and MEG to determine irritative zone, PET for functional deficit zone, SPECT to determine ictal onset zone, and fmri to determine language dominance and memory deficits. Basic preoperative testing includes interictal EEG, structural imaging usung high resolution MRI, video-eeg monitoring, and neuropsychological evaluation. Additional tests are done when the information obtained by these basic testing is insufficient to define the epileptogenic zone. When all the test results are congruent in localizing the epileptogenic zone, the patients can be considered for surgery (Figure 3). Basic preoperative testing (mostly non-invasive) often helps in identifying the epileptogenic zone (surgical substrate), in a significant proportion of patients, particularly in patients with mesial temporal lobe epilepsy. This approach is being used most widely in India while evaluating patients with drug resisting epilepsy for possible surgery. To conclude basic evaluation of a patient with epilepsy involves EEG to define the type of seizure and epilepsy and epilepsy syndrome, video-eeg to characterize the seizure semiology, particularly in patients with multiple seizure types and it also helps to exclude non-epileptic events, and structural imaging with high resolution MRI to establish the cause of epilepsy. Patient with drug resistant epilepsy may require multimodality investigations to determine the epileptogenic zone. References Behavioral observation (video-eeg) and patient report Neurological examination, fmri, neuropsychological examination, PET and SPECT 1. 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