Abbreviations
CT — computed tomography
MRI — magnetic resonance imaging
MEG — magnetoencephalography
SPECT — single photon emission computed tomography
PET-FDG — positron emission tomography with fluorine-8-fluoro-2-deoxy-D-glucose
Stereo-EEG — invasive stereo-electroencephalography
FCD — focal cortical dysplasia
ECoG — invasive electrocorticography
EEG — electroencephalography
FLAIR — fluid-attenuated inversion recovery
T1WI — T1-weighted image
T2WI — T2-weighted image
SISCOM — subtraction ictal SPECT co-registered to MRI
Epilepsy is a chronic disease caused by brain damage and manifested by recurrent motor, sensitive, autonomic, behavioral and convulsive attacks, various personality changes and global social stigmatization of patients.
In accordance with the guidelines of the International League Against Epilepsy (ILAE), the diagnosis of epilepsy is confirmed by the following criteria: a) at least 2 spontaneous seizures with an interval ≥24 hours. b) 1 spontaneous seizure and confirmed epileptogenic structural brain changes or persistent EEG changes.
Uncontrolled epilepsy is associated with significantly increased risk of mortality compared with general population [1]. According to various researchers, hazard ratio is 1.4—3.6 [2—4]. The main causes of mortality are status epilepticus and its complications, injuries and sudden unexpected death in epilepsy (SUDEP). Early adequate treatment prevents abnormal personality changes and improves quality of life [5]. Unfortunately, medication does not result complete control over seizures in 30% of patients and pharmacoresistance occurs in these cases. This term implies the absence of control over seizures under two or more adequate schemes of anticonvulsants administration as monotherapy and their combination [6—8]. Each this patient should be considered as a candidate for surgical treatment of epilepsy.
Effectiveness and safety of surgical treatment of epilepsy have been proven in various studies [7, 9—13]. For example, surgical treatment of MR-positive temporal lobe epilepsy is followed by complete disappearance of seizures in more than 80% of patients. At the same time, extra-temporal epilepsy and the absence of MRI-confirmed structural pathology (MR negativity) are associated with worse outcomes of surgical treatment. According to various authors, postoperative freedom from seizures is only 40—50% [1,14]. This is due to simple localization of epileptogenic zone in patients with MR-positive temporal lobe epilepsy and difficult analysis in those with extra-temporal MR-negative forms of disease.
Preoperative examination and surgery for epilepsy
The main goal of preoperative examination is localization of epileptogenic zone, since the main objective of surgery is complete resection of this area or dissection of epileptic network with preservation of patient’s functional status (H.O. Lüders). This strategy improves quality of life and ensures complete freedom from seizures in a large number of patients [7,9,11,12,15].
The following parts of epileptic network are distinguished considering Luders concept of cortical zones [16, 17]:
1. Symptomatogenic zone — area of cerebral cortex responsible for clinical manifestation of seizures after stimulation. In other words, this zone is responsible for specific semiology of seizures. As a rule, a thorough analysis of clinical manifestations allows you to determine this area.
2. Irritative zone — zone of cerebral cortex generating interictal epileptiform activity. The last one may be registered using scalp EEG, invasive electrocorticography (ECoG), stereo-EEG and magnetoencephalography (MEG). It is important that irritative zone is not always a part of epileptogenic zone. Determination of interictal activity is not enough to make a decision about surgery.
3. Seizure onset zone — cerebral cortex initiating seizure. This zone is located within epileptogenic zone or at the border with it. Seizure onset zone should be resected together with epileptogenic zone to achieve complete control over attacks [18]. Video EEG monitoring, ECoG, stereo-EEG, single-photon emission computed tomography (SPECT, SISCOM) are used to verify this area.
4. Epileptogenic anatomical lesion — visible structural brain lesion (CT, MRI). It is customary to divide patients with epilepsy into 2 groups: MR-positive with confirmed structural brain lesion (tumor, cavernous angioma, arteriovenous malformation, focal cortical dysplasia (FCD), post-traumatic and post-ischemic zones of cystic-gliosis transformation, etc.) and MR-negative without clear structural lesion. At the same time, MRI- or CT-confirmed structural cerebral lesion is not always a cause of epileptic seizures. Multiple brain lesions are diagnosed in some patients that significantly complicates searching for epileptogenic focus. For example, in patients with multiple cavernous angiomas or foci of tuberous sclerosis, epilepsy may be caused by only one focal lesion. The objective of epileptologist, neurosurgeon and radiologist is to determine the epileptogenic focus.
5. Functional deficit zone — cerebral zone demonstrating certain neurological or neuropsychological deficit (hemiparesis, hemihyposthesia, homonymous hemianopsia, memory loss, speech impairment, etc.) within interictal period. Comprehensive neurological and neuropsychological examination, PET-FDG (positron emission tomography with 18F-fluorodeoxyglucose), functional MRI and Wada test are used for verification of this zone.
6. Epileptogenic zone — cerebral area generating epileptic seizures. Determination of this zone is theoretical, its boundaries and localization are recognized considering aggregated information about five previous zones. Identifying of this zone is the main goal of preoperative examination and "target" of surgeon, since total resection of this segment ensures freedom from seizures.
7. Functionally significant zones — cerebral areas responsible for certain functions. These zones usually include primary motor and somatosensory cortex, speech zones (Broca and Wernicke’s areas), primary visual cortex. Preoperative and intraoperative determination of these zones is mandatory to prevent irreversible neurological deficit.
The concept of epileptogenic zone is determined by multidisciplinary team of specialists including epileptologist, neurosurgeon, neuropsychologist, neuro-linguist, neuro-radiologist, neurophysiologist, etc. These specialists conduct comprehensive preoperative examination and evaluate treatment outcomes.
Standard mandatory preoperative examination of patients with intractable epilepsy includes analysis of anamnestic data, neurological status and seizures, prolonged scalp video EEG monitoring, MRI in accordance with epilepsy-oriented protocol, comprehensive neuropsychological examination. These methods are sufficient to formulate the concept and conduct surgical procedure with favorable clinical outcome if diagnostic data completely coincide and unambiguously indicate certain localization of epileptogenic zone [19]. Additional non-invasive examination including PET, MEG, ictal and interictal SPECT, functional MRI, etc. is indicated if diagnostic data are insufficient or contradictory. Invasive video EEG monitoring (ECoG, stereo-EEG) is performed if previous diagnostic data are unclear [20]. Wada test is applied in some patients prior to neurosurgical interventions on the dominant speech hemisphere. This method is useful to predict functional postoperative outcomes. Considering all preoperative data, multidisciplinary team determines the concept of epileptogenic zone, features of resection or palliative surgery.
Semiology of seizures
Careful assessment of seizure semiology, preceding aura and, especially, initial clinical manifestations is essential to localize symptomatic zone (Table) [21—26].

Video monitoring of scalp EEG
EEG is crucial to localize epileptogenic zone [18, 23]. EEG is also valuable for differential diagnosis of epilepsy with other diseases.
EEG allows recording abnormal epileptiform activity of the cerebral cortex in ictal and interictal periods. Interictal epileptiform activity (spikes, spike waves, etc.) is valuable to determine irritative zone [18]. Registration of abnormal epileptiform activity preceding seizures indicates seizure onset zone [27]. However, it is not always possible to register this activity. For example, seizures may be incorrectly interpreted as originating from convexital surface of the frontal or temporal lobes or not be recorded at all due to deep localization if epileptiform focus is localized within interhemispheric fissure, orbito-frontal cortex, etc. [18, 28].
Magnetic resonance imaging
MRI should be performed in each patient with epilepsy in order to rule out symptomatic seizures. Standard MRI can detect epileptogenic lesions in only 50% of cases. MRI in accordance with epileptological protocol is characterized by the greatest sensitivity and specificity in identifying structural epileptogenic lesions [22, 29]. Differences in standard MRI and MRI with epileptological protocol are shown on the example of a patient with hippocampal sclerosis (Fig. 1).

Epileptological protocol of MRI includes the following sequences: T2WI and FLAIR in axial and coronal projections along the hippocampus plane, DWI in axial plane, isotropic 3D T1WI, T1WI inversion-recovery in coronal projection in hippocampi plane, SWI (susceptibility weighted images), etc. We report an example of sequence protocol. However, certain differences and features may be observed. Functional MRI is useful to analyze lateralization of speech functions and memory [21, 23, 29—35], localize motor, sensory and speech centers on the surface of cerebral cortex [36—39].
Neuropsychological testing
The goal of neuropsychological testing is determining of functional deficiency zone. Basic survey includes assessment of verbal and non-verbal memory, intelligence. These measures are valuable to assess the risk of postoperative deficiency [24, 40].
We have previously noted that standard examination is usually sufficient to verify epileptogenic zone and determine optimal treatment strategy. The methods described below are optional and may be useful to localize epileptogenic zone in difficult cases.
Magnetoencephalography
MEG is an additional non-invasive survey based on analysis of magnetic fields generated by cerebral electrical activity [41]. Survey ensures localization of irritative zone in analysis of interictal activity. However, complexity and cumbersomeness of equipment complicate registration of ictal activity and verification of seizure onset zone compared with 24-hour video monitoring of EEG [42]. MEG has one significant advantage over standard scalp EEG. Magnetic fields are almost independent on the obstacles created by surrounding tissues. Therefore, abnormal activity may be registered from all cerebral zones without any interference [43].
Positron emission tomography with glucose
PET is an additional diagnostic method for localizing zone of functional deficiency through registration of zones of metabolic disturbance. PET with fluorine-8-fluoro-2-deoxy-D-glucose (18F-fluorodeoxyglucose) is applied in diagnosis of epilepsy. Epileptogenic zone is characterized by hypometabolism in interictal period and hypermetabolism during seizure [21]. PET-confirmed hypometabolic zones are of great diagnostic importance in MR-negative patients with temporal lobe epilepsy. Sensitivity of PET-FDG is maximum (87—90%) for temporal lobe epilepsy and decreases for extra-temporal epilepsy (38—55%) [44—46]. PET is valuable to determine advisability of surgery in 53% of cases with normal or controversial MRI data [47]. According to large trials, PET-FDG should be also preferred over SPECT in interictal period [48] (Fig. 2).

Single-photon emission computed tomography
SPECT is a diagnostic method for assessing distribution of radionuclides in brain tissue. SPECT with technetium-99m is used for diagnosis of epilepsy. Ictal SPECT confirms increased perfusion in seizure onset zone associated with increased metabolism. Ictal SPECT is quite time-consuming, since it requires coordinated work of many specialists. Epileptologist must register seizure on time, inject radiopharmaceutical drug within 10 seconds after that and perform SPECT as soon as patient's condition will be stabilized. Interictal SPECT is performed with the same dosage of radiopharmaceutical drug. Combination and mathematical analysis of ictal and interictal SPECT data with their “overlay” on MRI data (the so-called SISCOM protocol) significantly increase sensitivity and specificity up to 90% [19, 21, 49—52]. Ictal SPECT is the most informative for verification of seizure onset zone. However, certain difficulties of this survey limit selection of suitable patients. SPECT may be the only informative non-invasive method in verifying the epileptogenic focus in patients with multiple structural lesion (for example, tuberous sclerosis). Moreover, SPECT data may be used to schedule insertion of electrodes for invasive monitoring in case of MR-negative epilepsy.
Wada test
Initially, intracarotid Wada test was used to lateralize speech function. This method began to be used for analysis of memory later. Memory lateralization is of great importance in prediction of cognitive postoperative disorders after temporal lobectomy or hemispherotomy. Selective cerebral angiography is performed prior to Wada test for assessment of collateral blood flow. Next, selective catheterization of one of the internal carotid arteries is followed by bolus injection of barbituric anesthetic. Amobarbital and propofol are the most common drugs applied in Wada test. The next stage is neuropsychological testing and assessment of motor status of contralateral limbs. Video monitoring of EEG is simultaneously carried out to assess reliability of the study (there is significant slowdown of EEG rhythms after administration of the drug). Memory is analyzed after restoration of hemispheric function. This is made to assess the ability to remember on the background of anesthesia. Next, contralateral examination is carried out in similar fashion. These data are valuable to lateralize speech and memory functions and predict postoperative aphatic and mnestic disorders [53—55].
Invasive EEG monitoring
Prolonged invasive monitoring of EEG is carried out in some cases if data of non-invasive survey are insufficient and localization of epileptogenic zone is unclear [11, 22, 41, 56, 57]. This method implies intracranial implantation of electrodes. Their positions are previously determined considering data of non-invasive examination.
There are several types of invasive electrodes:
1. Subdural electrodes as flat membranes with integrated electrodes ("strips" and "gratings") are placed on the brain surface. The advantages of this method are covering of large areas of one hemisphere, neurophysiological mapping outside the operating theatre (in a ward) via stimulation of certain electrodes and scheduling surgical strategy. The disadvantages are need for craniotomy for insertion of the electrodes and redo surgery for their removal. These procedures are associated with increased risk of cerebrospinal fluid leakage and infectious complications. Quality of survey is significantly reduced if epileptogenic focus is located in the depth of gyri, interhemispheric or lateral fissures.
2. Alternative method of invasive monitoring is stereo EEG. This method implies registration after percutaneous installation of deep electrodes. Implantation of these electrodes mandatory requires specialized navigation systems from basic stereotactic frames and neuronavigation to modern robotic systems. Stereo EEG requires careful analysis of the concept of possible seizure onset zone and propagation pathways.
Any invasive monitoring is limited by registration of electrical activity within a small space around the electrode. Incorrect hypothesis and inadequate arrangement of the electrodes may be followed by illusion of focality in case of bilateral and diffuse epileptiform activity [58—60]. Risk of hemorrhagic complications associated with implantation of deep electrodes is up to 4% and directly correlates with the number of electrodes (10—14 electrodes on the average), dimensions of craniotomy and duration of invasive monitoring [61, 62].
Stimulation of electrode contacts and cortical mapping may be valuable to schedule boundaries of resection if electrodes are placed on the brain surface (“grid”) or in the structure (deep electrode) of functionally significant zone [63, 64].
Conclusion
Correct localization of epileptogenic zone is essential to obtain good surgical outcomes in patients with intractable focal epilepsy. Seizure semiology, video EEG and MRI data are fundamental to localize this zone. These data are sufficient to make a decision or to refuse resection in approximately 60% of cases. Additional diagnosis including PET, SPECT (SISCOM), MEG, Wada test and invasive monitoring in various combinations is required in 40% of cases.
The most informative preoperative examination is based on personalized approach to each patient. Multidisciplinary team of specialists (epileptologist, neurosurgeon, neuropsychologist, radiologist) ensures development of individual survey design in patients with various forms of epilepsy depending on previously obtained diagnostic data. This approach is useful to avoid "unnecessary" financial costs for additional survey.
Careful selection of patients, comprehensive preoperative diagnosis and multidisciplinary approach in the treatment of each patient ensure favorable treatment outcomes in patients with intractable epilepsy.
The authors declare no conflicts of interest.