Functional neuro-imaging techniques are helpful in the pre-surgical evaluation of epilepsy for localization of the epileptogenic zone as ancillary tools to electroencephalography (EEG) and magnetic resonance imaging (MRI) or when other localization techniques are normal, non-concordant or discordant. Positron emission tomography (PET) and ictal single photon emission computed tomography (ictal SPECT) imaging are traditional tests that have been reported to have good sensitivity and specificity although the results are better with more expertise as is true for any technique. More recently magnetoencephalogram/magnetic source imaging (MEG/MSI), diffusion tensor imaging and functional magnetic resonance imaging (fMRI) have been used in localization and functional mapping during the pre-surgical work-up of epilepsy. Newer techniques such as fMRI-EEG, functional connectivity magnetic resonance imaging and near infra-red spectroscopy, magnetic resonance spectroscopy and magneto nanoparticles hold promise for further development that could then be applied in the work-up of epilepsy surgery. In this manuscript, we review these techniques and their current position in the pre-surgical evaluation of epilepsy.
Diffusion tensor imaging; functional connectivity magnetic resonance imaging; functional magnetic resonance imaging; functional magnetic resonance imaging-electroencephalography; magnetoencephalogram; positron emission tomography; single photon emission computed tomography; temporal lobe epilepsy
Temporal lobe epilepsy (TLE) is the most commonly encountered medically refractory epilepsy. It is also the substrate of refractory epilepsy that gives the most gratifying results in any epilepsy surgery program, with a minimum use of resources. Correlation of clinical behavior and the ictal patterns during ictal behavior is mandatory for success at epilepsy surgery. Video electroencephalogram (EEG) telemetry achieves this goal and hence plays a pivotal role in pre-surgical assessment. The role of telemetry is continuously evolving with the advent of digital EEG technology, of high-resolution volumetric magnetic resonance imaging and other functional imaging techniques. Most of surgical selection in patients with TLE can be done with a scalp video EEG monitoring. However, the limitations of the scalp EEG technique demand invasive recordings in a selected group of TLE patients. This subset of the patients can be a challenge to the epileptologist.
Temporal lobe epilepsy; video electroencephalogram; presurgical evaluation
Refractory status epilepticus is a potentially life-threatening medical emergency. It requires early diagnosis and treatment. There is a lack of consensus upon its semantic definition of whether it is status epilepticus that continues despite treatment with benzodiazepine and one antiepileptic medication (AED), i.e., Lorazepam + phenytoin. Others regard refractory status epilepticus as failure of benzodiazepine and 2 antiepileptic medications, i.e., Lorazepam + phenytoin + phenobarb. Up to 30% patients in SE fail to respond to two antiepileptic drugs (AEDs) and 15% continue to have seizure activity despite use of three drugs. Mechanisms that have made the treatment even more challenging are GABA-R that is internalized during status epilepticus and upregulation of multidrug transporter proteins. All patients of refractory status epilepticus require continuous EEG monitoring. There are three main agents used in the treatment of RSE. These include pentobarbital or thiopental, midazolam and propofol. RSE was shown to result in mortality in 35% cases, 39.13% of patients were left with severe neurological deficits, while another 13% had mild neurological deficits.
Midazolam; pentobarb; propofol; refractory status epilepticus; status epilepticus
The elderly are generally defined as those over 60 or 65 years old, but they are a heterogeneous group and may be subdivided into categories based on age and health status. The incidence of epilepsy is highest in the elderly. With a progressive increase in life expectancy, this is the fastest growing segment of patients with epilepsy. Older patients most often have focal seizures, with less prominent auras and automatisms, and longer duration of postictal confusion compared to younger patients. Status epilepticus is common and has a high mortality. The most common specific etiology is cerebrovascular disease, but the cause remains unknown in many patients. Diagnosis can be challenging because of several patient-related, physician-related and investigation-related factors. Over-diagnosis and under-diagnosis are common. Treatment is complicated by the presence of physiological changes related to aging, co-morbidities and cognitive problems as well as concerns regarding drug interactions and medication adherence. Seizures can be controlled in most patients with low doses of a single anti-epileptic drug (AED). Tolerability is an important factor in selection of an AED, as elderly patients tend to be highly sensitive to side effects. Drug-resistant epilepsy is uncommon. Epilepsy surgery, especially temporal lobectomy, can be performed in older patients with good results. More studies addressing the pathophysiological mechanisms of epilepsy in this age group, and greater inclusion of the elderly in clinical trials, as well as development of comprehensive care models are needed to provide optimal care to these patients.
Diagnosis; elderly; epilepsy; treatment
Despite medications, resective surgery, and vagal nerve stimulation, some patients with epilepsy continue to have seizures. In these patients, other approaches are urgently needed. The biological basis of stimulation of anterior thalamic nucleus and epileptogenic focus is presented. Results from two large randomized controlled trials Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE) and Neuropace pivotal trial are discussed. Neuromodulation provides effective treatment for a select group of refractory epilepsy patients. Future investigations into the mechanism underlying ‘response’ to brain stimulation are desired.
Anterior thalamic nucleus; brain stimulation; epilepsy; neuromodulation; responsive neuromodulation
The association between neurocysticercosis (NCC) and epilepsy is well known and NCC is an important risk factor for epileptic seizures in many Taenia solium-endemic regions of the world. However, while the relationship between NCC and epilepsy is well known, the association between NCC and medically refractory (or surgically remediable epilepsy) has received little attention in the past. Our experience and review of the sparse literature available suggests that NCC is causally related to surgically remediable epilepsy albeit uncommonly so and that association derives its underpinnings from several different scenarios: (1) Medically refractory lesional epilepsy, in which seizures arise from the vicinity of the calcified neurocysticercus lesion (CNL), (2) Medically refractory epilepsy with dual pathology type of relationship between the hippocampal sclerosis (HS) and CNL in which both have been unequivocally demonstrated to give rise to independent seizures and (3) Mesial temporal lobe epilepsy due to HS with a distantly-located CNL, which is in itself not epileptogenic. A major point of controversy revolves around whether or not there exists a causal association between the CNL and HS. We believe that an association exists between NCC and HS and the most important factor influencing this association is the location of the CNL. Furthermore, NCC is a risk factor for medically-refractory epilepsy and that this might account for a considerable proportion of the intractable epilepsy population in endemic regions; the association has been largely ignored owing to the lack of availability of presurgical work-up facilities in these regions. Finally, from a clinical standpoint of presurgical evaluation, patients with CNL and HS should be evaluated on a case by case basis owing to disparate settings underlying the association.
Association; medically-refractory epilepsy; mesial temporal sclerosis neurocysticercosis
Magnetoencephalography (MEG) is the measurement of the magnetic field generated by the electrical activity of neurons. It is usually combined with a magnetic resonance imaging to get what is called magnetic source imaging. The technology that has helped record these minute magnetic fields is super-conducting quantum interference detector which is like a highly sensitive magnetic field meter. To attenuate the external magnetic noise the MEG is housed inside a magnetically shielded room. The actual sensors recording magnetic fields are magnetometers and/or gradiometers. MEG fields pass through the head without any distortion. This is a significant advantage of MEG over electroencephalography. MEG provides a high spatial and temporal resolution. The recording and identification information should be according to the American Clinical Magnetoencephalography Society guidelines published in 2011. MEG currently has two approved indications in the United States, one is for pre-operative brain mapping and the other is for use in epilepsy surgery. MEG studies have shown functional brain tissue inside brain tumors.
Cortical mapping; epilepsy; magnetic source imaging; magnetoencephalography
Surgical decision-making is a complex process. First, a medical decision is made to determine if surgery is necessary. Second, another medical decision is made to determine the type of surgery. Third, a corporate decision is made if such a surgery is financially feasible. Finally, a legal decision is made to proceed or refuse the chosen surgery. This paper examines these issues in the case of surgery for medically intractable epilepsy and proposes a method of decision analysis to guide epilepsy surgery.
Materials and Methods:
A stochastic game of imperfect information using techniques of game theory and decision analysis is introduced as an analytical tool for surgical decision-making.
Surgery for appropriately chosen patients suffering from medically intractable epilepsy may not only be feasible, but may be the best medical option and the best financial option for the patient, families, society and the healthcare system. Such a situation would then make it legally or ethically difficult to reject or postpone surgery for these patients.
A process to collect data to quantify the parameters used in the decision analysis is hereby proposed.
Decision-analysis; economics; epilepsy; game theory; surgery
Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In about 15% of these patients, the seizures are not adequately controlled with antiepileptic drugs; such patients are potential candidates for surgical treatment and the major proportion is in the pediatric group (18 years old or less). Epilepsy surgery in children who have been carefully chosen can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-thirds of children with intractable seizures. Advances in structural and functional neuroimaging, neurosurgery, and neuroanaesthesia have improved the outcomes of surgery for children with intractable epilepsy. Early surgery improves the quality of life and cognitive and developmental outcome and allows the child to lead a normal life. Surgically remediable epilepsies should be identified early and include temporal lobe epilepsy with hippocampal sclerosis, lesional temporal and extratemporal epilepsy, hemispherical epilepsy, and gelastic epilepsy with hypothalamic hamartoma. These syndromes have both acquired and congenital etiologies and can be treated by resective or disconnective surgery. Palliative procedures are performed in children with diffuse and multifocal epilepsies who are not candidates for resective surgery. The palliative procedures include corpus callosotomy and vagal nerve stimulation while deep brain stimulation in epilepsy is still under evaluation. For children with “surgically remediable epilepsy,” surgery should be offered as a procedure of choice rather than as a treatment of last resort.
Children; epilepsy surgery; temporal lobe epilepsy; extratemporal epilepsy; hemispherotomy
There are 50 million people living with epilepsy worldwide, and most of them reside in developing countries. About 10 million persons with epilepsy are there in India. Many people with active epilepsy do not receive appropriate treatment for their condition, leading to large treatment gap. The lack of knowledge of antiepileptic drugs, poverty, cultural beliefs, stigma, poor health infrastructure, and shortage of trained professionals contribute for the treatment gap. Infectious diseases play an important role in seizures and long-term burden causing both new-onset epilepsy and status epilepticus. Proper education and appropriate health care services can make tremendous change in a country like India. There have been many original researches in various aspects of epilepsy across India. Some of the geographically specific epilepsies occur only in certain regions of our country which have been highlighted by authors. Even the pre-surgical evaluation and epilepsy surgery in patients with drug-resistant epilepsy is available in many centers in our country. This article attempts to provide a complete preview of epilepsy in India.
Epilepsy in India; epilepsy surgery; hot water epilepsy; progressive myoclonic epilepsy; status epilepticus; treatment gap; women with epilepsy
A structural brain lesion in patients with drug-resistant epilepsy (DRE) greatly increases the likelihood of identification of the seizure focus and ultimately seizure-free outcome following resective epilepsy surgery. In contrast, surgical outcomes of true non-lesional DRE are less favorable. Therefore, discovery of an underlying lesion is paramount in the pre-surgical work-up of patients with DRE. Over the years, the surgical treatment of pharmacoresistant epilepsy has evolved from straightforward lesional cases to include cases with hippocampal sclerosis. With the advent of magnetic resonance imaging (MRI), most cases of mesial temporal sclerosis became more easily identifiable on pre-operative neuroimaging. With the widespread use of high-resolution MRI with epilepsy protocols over the last two decades, our ability to visualize subtle structural changes has been greatly enhanced. However, there are some cases of lesional epilepsy, which remain unidentified on these routine MRIs. In such “non-lesional” refractory epilepsies, further investigation with advanced neuroimaging techniques, including metabolic imaging, as well as electrophysiological studies may help to identify the previously non-visualized focal brain abnormalities. In this review, we outline the current status for evaluation of MRI-negative DRE.
Epilepsy surgery; investigations; medically refractory epilepsy; non-lesional epilepsy; pharmacoresistant seizures
Electroencephalography (EEG) remains a “gold standard” for defining seizures; hence identification of epileptogenic zone for surgical treatment of epilepsy requires precise electrographic localization of the seizures. Routine scalp EEG recording is not sufficient in many instances, such as extratemporal lobe epilepsy or non-lesional temporal lobe epilepsy. In these individuals EEG recording from proximity of the seizure focus is necessary, which can be achieved by placing electrodes on the surface or in the substance of the brain. As this process requires invasive procedures (usually necessitating surgical intervention) EEG obtained via these electrodes is defined as invasive electroencephalography (iEEG). As only limited areas of the brain can be covered by these electrodes in an individual, precise targeting of the presumed seizure onset location is crucial. The presurgical planning includes where to place electrodes, which type of the electrodes to choose and planned duration of the intracranial recording. Though there are general principles that guide such endeavor, each center does it slightly differently depending upon the various technologies available to them and expertise and preferences of the epilepsy surgery team. Here we describe our approach to iEEG recording. We briefly describe the background, types of iEEG recording and rationale for each, various electrode types, and scenarios where iEEG might be useful. We also describe planning of iEEG recording once the need has been established as well as our decision making process of deciding about location of electrode placement, type of electrodes to use, length of recording, choice of arrays, mapping of eloquent cortex and finally surgical planning and decisions.
Depth electrodes; electrocorticography; epidural peg electrodes; epilepsy surgery; intracranial electroencephalography; invasive electroencephalography; subdural electrodes
Status epilepticus (SE) is an emergency neurological problem, more common in the developing countries due to high incidence of infection, stroke and head injury. The protocol for management of SE is intravenous benzodiazepine, followed by phenytoin, valproate (VPA) and phenobarbitone and if uncontrolled general anesthesia (GA). World Federation of Neurology recommends special guidelines for resource poor countries. Use of GA results in hypotension and respiratory depression needing intensive care management. There is a paucity of intensive care facilities hence the recommended antiepileptic drugs (AEDs) which have inherent toxicity of hypotension and respiratory failure cannot be given safely. Under these situations AEDs such as VPA, levetiracetam and lacosamide may be evaluated in SE because of cardiovascular and respiratory safety profile. In this review, the limitations of existing guidelines in the developing countries have been discussed and a way forward has been suggested.
Anesthetic agent; antiepileptic drug; refractory status; status epilepticus; respiratory failure; hypotension
Magnetoencephalography (MEG) non-invasively measures the magnetic field generated due to the excitatory postsynaptic electrical activity of the apical dendritic pyramidal cells. Such a tiny magnetic field is measured with the help of the biomagnetometer sensors coupled with the Super Conducting Quantum Interference Device (SQUID) inside the magnetically shielded room (MSR). The subjects are usually screened for the presence of ferromagnetic materials, and then the head position indicator coils, electroencephalography (EEG) electrodes (if measured simultaneously), and fiducials are digitized using a 3D digitizer, which aids in movement correction and also in transferring the MEG data from the head coordinates to the device and voxel coordinates, thereby enabling more accurate co-registration and localization. MEG data pre-processing involves filtering the data for environmental and subject interferences, artefact identification, and rejection. Magnetic resonance Imaging (MRI) is processed for correction and identifying fiducials. After choosing and computing for the appropriate head models (spherical or realistic; boundary/finite element model), the interictal/ictal epileptiform discharges are selected and modeled by an appropriate source modeling technique (clinically and commonly used — single equivalent current dipole — ECD model). The equivalent current dipole (ECD) source localization of the modeled interictal epileptiform discharge (IED) is considered physiologically valid or acceptable based on waveform morphology, isofield pattern, and dipole parameters (localization, dipole moment, confidence volume, goodness of fit). Thus, MEG source localization can aid clinicians in sublobar localization, lateralization, and grid placement, by evoking the irritative/seizure onset zone. It also accurately localizes the eloquent cortex-like visual, language areas. MEG also aids in diagnosing and delineating multiple novel findings in other neuropsychiatric disorders, including Alzheimer's disease, Parkinsonism, Traumatic brain injury, autistic disorders, and so oon.
Epilepsy analysis; head and source model; Magnetoencephalography (MEG); MEG acquisition
A multidisciplinary approach is required to understand the complex intricacies of drug-resistant epilepsy (DRE). A challenge that neurosurgeons across the world face is accurate localization of epileptogenic zone. A significant number of patients who have undergone resective brain surgery for epilepsy still continue to have seizures. The reason behind this therapy resistance still eludes us. Thus to develop a cure for the difficult to treat epilepsy, we need to comprehensively study epileptogenesis. Till date, most of the studies on DRE is focused on undermining the abnormal functioning of receptors involved in synaptic transmission and reduced levels of antiepileptic drugs around there targets. But recent advances in imaging and electrophysiological techniques have suggested the role epileptogenic networks in the process of epileptogenesis. According to this hypothesis, the local neurons recruit distant neurons through complex oscillatory circuits, which further recruit more distant neurons, thereby generating a hypersynchronus neuronal activity. The epileptogenic networks may be confined to the lesion or could propagate to distant focus. The success of surgery depends on the precision by which the epileptogenic network is determined while planning a surgical intervention. Here, we summarize various modalities of electrophysiological and imaging techniques to determine the functionally active epileptogenic networks. We also review evidence pertaining to the proposed role of epileptogenic network in abnormal synaptic transmission which is one of the major causes of epileptiform activity. Elucidation of current concepts in regulation of synaptic transmission by networks will help develop therapies for epilepsy cases that cannot be managed pharmacologically.
Epilepsy surgery; epileptogenesis; epileptogenic networks; pharmaco-resistant epilepsy
Epilepsy is one of the most common serious neurological conditions, and 30 to 40% of people with epilepsy have seizures that are not controlled by medication. Patients are considered to have refractory epilepsy if disabling seizures continue despite appropriate trials of two antiseizure drugs, either alone or in combination. At this point, patients should be referred to multidisciplinary epilepsy centers that perform specialized diagnostic testing to first determine whether they are, in fact, pharmacoresistant, and then, if so, offer alternative treatments. Apparent pharmacoresistance can result from a variety of situations, including noncompliance, seizures that are not epileptic, misdiagnosis of the seizure type or epilepsy syndrome, inappropriate use of medication, and lifestyle issues. For patients who are pharmacoresistant, surgical treatment offers the best opportunity for complete freedom from seizures. Surgically remediable epilepsy syndromes have been identified, but patients with more complicated epilepsy can also benefit from surgical treatment and require more specialized evaluation, including intracranial EEG monitoring. For patients who are not surgical candidates, or who are unwilling to consider surgery, a variety of other alternative treatments can be considered, including peripheral or central neurostimulation, ketogenic diet, and complementary and alternative approaches. When such alternative treatments are not appropriate or effective, quality of life can still be greatly improved by the psychological and social support services offered by multidisciplinary epilepsy centers. A major obstacle remains the fact that only a small proportion of patients with refractory epilepsy are referred for expert evaluation and treatment.
Complementary and alternative medicine; diagnostic approaches; epilepsy surgery; ketogenic diet; neurostimulation; refractory epilepsy
The success of an epilepsy surgery program depends upon the early identification of potential surgical candidates and selecting from them, ideal candidates for surgery, who are destined to have a post-operative seizure-free outcome without any unacceptable neurological deficits. Since epilepsy surgery centers in resource-poor countries will lack the full range of state-of-the-art technologies usually available in resource-rich countries to perform pre-surgical evaluation, cost-effectively utilization of the locally available investigative facilities to select the surgical candidates becomes challenging. In the present era of rapid electronic communications and telemedicine, it has become possible for epilepsy surgery centers to pool their technological and human resources and to partner with centers nationally and internationally in implementing pre-surgical evaluation strategies.
Epilepsy; pre-surgical evaluation; surgery
In pre-surgical evaluation of epilepsy, there has been an increased interest in the study of electroencephalogram (EEG) activity outside the 1-70 Hz band of conventional frequency activity (CFA). Research over the last couple of decades has shown that EEG activity in the 70-600 Hz range, termed high frequency oscillations (HFOs), can be recorded intracranially from all brain regions both interictally and at seizure onset. In patients with epilepsy, HFOs are now considered as pathologic regardless of their frequency band although it may be difficult to distinguish them from the physiologic HFOs, which occur in a similar frequency range. Interictal HFOs are likely to be confined mostly to the seizure onset zone, thus providing a new measure for localizing it. More importantly, several studies have linked HFOs to underlying epileptogenicity, suggesting that HFOs can serve as potential biomarkers for the illness. Along with HFOs, analysis of ictal baseline shifts (IBS; or direct current shifts) and infraslow activity (ISA) (ISA: <0.1 Hz) has also attracted attention. Studies have shown that: IBSs can be recorded using the routine AC amplifiers with long time constants; IBSs occur at the time of conventional EEG onset, but in a restricted spatial distribution compared with conventional frequencies; and inclusion of IBS contacts in the resection can be associated with favorable seizure outcome. Only a handful of studies have evaluated all the EEG frequencies together in the same patient group. The latter studies suggest that the seizure onset is best localized by the ictal HFOs, the IBSs tend to provide a broader localization and the conventional frequencies could be non-localizing. However, small number of patients included in these studies precludes definitive conclusions regarding post-operative seizure outcome based on selective or combined resection of HFO, IBS and CFA contacts. Large, preferably prospective, studies are needed to further evaluate the implications of different EEG frequencies in epilepsy.
Epilepsy; high frequency oscillations; infraslow activity; intracranial electroencephalogram; seizure
While there are over one million people with drug-resistant epilepsy in India, today, there are only a handful of centers equipped to undertake presurgical evaluation and epilepsy surgery. The only solution to overcome this large surgical treatment gap is to establish comprehensive epilepsy care centers across the country that are capable of evaluating and selecting the patients for epilepsy surgery with the locally available technology and in a cost-effective manner. The National Epilepsy Surgery Support Activity (NESSA) aims to provide proper guidance and support in establishing epilepsy surgery programs across India and in neighboring resource-poor countries, and in sustaining them.
Drug resistant epilepsy; epilepsy; epilepsy surgery
Successful epilepsy surgery depends on the localization of the seizure onset zone in an area of the brain that can be safely resected. Defining these zones uses multiple diagnostic approaches, which include different types of electroencephalography (EEG) and imaging, and the results are best when all of the tests point to the same region. Although EEG obtained with scalp recordings is often sufficient for the purposes of localization, there are times when intracranial recordings directly from the brain are needed; but the planning, use, value, and interpretation of the these recordings are not standardized, in part because the questions that are to be answered vary considerably across many patients and their heterogenous types of epilepsy that are investigated. Furthermore, there is a desire to use the opportunity of direct brain recordings to understand the pathophysiology of epilepsy, as these recordings are viewed as an opportunity to answer questions that cannot be otherwise answered. In this review, we examine the situations that may require intracranial electrodes and discuss the broad issues that this powerful diagnostic tool can help address, for identifying the seizure focus and for understanding the large scale circuits of the seizures.
Epilepsy surgery; electroencephalography; electrophysiology; intracranial electrodes
During the colloquium on drug-resistant epilepsy (DRE) at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore on August 16-18, 2013, a number of presentations were made on the surgically remediable lesional epilepsy syndromes, presurgical evaluation, surgical techniques, neuropathology of drug resistance focal epilepsy and surgical outcome. This pictorial essay with the illustrative case examples provides an overview of the various surgical techniques for the management of drug-resistant focal epilepsy.
Drug-resistant epilepsy; epilepsy surgery; epilepsy; surgical techniques
Extratemporal lobe epilepsies (ETLE) are characterized by the epileptogenic foci outside the temporal lobe. They have a wide spectrum of semiological presentation depending upon the site of origin. They can arise from frontal, parietal, occipital lobes and from hypothalamic hamartoma. We discuss in this review the semiology of different types of ETLE encountered in the epilepsy monitoring unit.
Extratemporal lobe epilepsies; lateralizing sign; localizing signs; semiology