By Adam N. Mamelak, MD and Ajay Ananda, MD

Epilepsy is the most common disorder of the brain and the second leading cause of neuropsychiatric disability worldwide. The prevalence of epilepsy in developed countries is estimated to be 0.3-4 percent of the population, making epilepsy as common a disorder as Type I diabetes. This prevalence is probably much higher in less developed countries. Due to the social ostracism and negative stigma often associated with seizures, many people with epilepsy either hide their disorder or become removed from the mainstream of society by choice resulting in poor socio-economic status, high levels of unemployment and less satisfying interpersonal relationships than many other discords, which lack these stigmata.

Well over half of all cases of epilepsy are characterized by partial seizures, generally indicating a discrete (and potentially removable) seizure focus or zone of ictal onset within the brain. Unfortunately, approximately 30 percent of patients with epilepsy will continue to have seizures despite aggressive treatment with multiple antiepileptic drugs (AEDs) and other interventions. The untoward cognitive side effects of AEDs coupled with the long-term effects of recurrent seizures result in shorter life spans, reduced quality of life and increased co-morbidities for the majority of patients. For these patients, surgery to excise the seizure focus or diminish the frequency and/or severity of seizures is often the best option available.

As a general rule, patients without clear-cut lesions such as brain tumors or malformations are not considered for seizure surgery unless they have failed a good trial of AED rational polytherapy. This typically implies that at least two (often many more) AEDs and/or a combination of such drugs have failed to control the seizures. Depending on the seizure type and the goals of the surgery, patient for whom surgery can be considered fall into two broad categories: intent to cure or palliation. Of note, age is only a relative contraindication for epilepsy surgery. Data suggests that the younger a patient with refractory seizures is rendered seizure-free, the more likely they will complete their schooling, become viable members of the work force and have healthy social interaction. Similarly, there is no absolute age limit above which seizure surgery cannot be performed, even though the risk of surgical complications is clearly higher for patients above age 45 and the impact of rendering such patients seizure-free is probably diminished from a socio-economic perspective.

"Intent to cure" procedures include operations such as temporal lobectomy, amygdalo-hippocampectomy, hemispherectomy, or neocortical excision of a seizure focus. These operations are performed via craniotomies and are usually limited to those patients with localization-specific epilepsy (LSE). LSE implies that all, or at least the majority of the seizures arise from a well-defined region in the brain, for whom there is a concordant amount of data from a variety of non-invasive and invasive tests that indicate that the seizure focus has been reliably identified. A typical example of this would be a patient with medically refractory complex partial seizures arising from the mesial temporal lobe structures (e.g.amygdala, hippocampus). Such a patient might be an ideal candidate for an anterior temporal lobectomy or selective removal of the amygdala and hippocampus. For patients in this category surgical resection has been demonstrated to carry a 60-85 percent chance of rendering the patient seizure-free, compared to a less than 8 percent chance with medications. The chances of a patient becoming seizure-free from an extratemporal resection are less, but still in the range of 60-70 percent, far higher than with any combination of AEDs.

In some cases, a very large volume of a patient's brain may be involved in seizure generation. For these patients who often have a catastrophic form of epilepsy, removal of large portions of the diseased hemisphere may be needed. Dramatic operations such as hemispherectomy (removal of half the brain) and functional hemispherectomy, while large, have an excellent track record for controlling seizures in these patients. Typical patients undergoing hemispherectomy include children with Rasmussen's encephalitis, hemimegaloencephaly or those suffering from seizures as a byproduct of a hemispheric stroke. More recently, hemispherotomy (otomy rather than ectomy) has been reported and popularized by several epilepsy surgeons. In these surgeries all of the major white matter pathways connecting the lobes of the hemisphere to each other and the contralateral hemisphere are divided, but the bulk of the brain tissue is left in place. These procedures have gained popularity to avoid the many complications associated with massive surgical resections such as infection, hydrocephalus, hemosiderosis and brain shift. These procedures require an excellent understanding of the brain functional anatomy and have not yet been proven to provide superior results compared with more standard procedures. Nonetheless, these creative approaches are quite appealing and with the development of sophisticated white matter fiber tracing for intraoperative use with surgical navigation system, it may gain further acceptance as a less destructive option for these patients.

For patients in whom a discrete seizure focus does not exist or for whom surgical removal of the zone of seizure origin is felt to be too risky, there are some palliative surgical options. These surgeries do not aim to eliminate all seizures but to reduce the frequency and severity of the most disabling ones, and hopefully permit reduction in the amount of AEDs.

For patients with secondary generalized epilepsy due to congenital or acquired brain injury (e.g. Lennox-Gastaut syndrome, tuberous sclerosis) surgical excision of a discrete seizure focus is rarely warranted. However, these patients often suffer frequent life-threatening generalized seizures or drop attacks in, which they injure themselves or are hospitalized. For these patients, corpus callosotomy or surgical division of the corpus callosum can be used with great success. Corpus callosotomy typically results in a greater than 90 percent reduction in drop attack seizures, and a 60-70 percent reduction in generalized seizures. While not curative, these procedures can have a dramatic impact on the quality of life for both patient and caregiver. The utilization of intra-operative MRI or intra-operative surgical navigation to ensure division of at least the front 2/3rd of the corpus callosum is a recent adjunct that has improved outcomes for the patients.

An alternative for many patients is the use of the Vagus Nerve Stimulator (VNS). VNS is an FDA-approved device consisting of an electrode coil that is wrapped around the left Vagus nerve in the neck and a pulse generator implanted in the chest wall. Electrical stimulations of the nerve are transmitted to the brain stem via afferent fibers in the Vagus nerve and induce a neuromodulatory affect on the brain that can reduce seizures. VNS implant is a much smaller procedure than all of the other surgical procedures discussed. It typically takes 45 minutes, and is performed on an outpatient basis. The device is well-tolerated and very easy to program. A large database of over 8,000 patient implanted in the US indicates that seizure reduction is observed in almost 2/3rds of patients, with a greater than 50 percent reduction seen in over half the patients. The frequency and intensity of seizures is also reduced in many patients and improvements in mood and alertness are also frequently reported, especially if AEDs are reduced. Unfortunately, very few patients become seizure-free following VNS implant, and 25 percent will experience no change in their seizures. Finally, patients who are potential candidates for more definitive excision surgery are still far more likely to benefit from resection than VNS and should be evaluated for candidacy before considering VNS as a palliative option. Nonetheless, the VNS is an attractive surgical alternative to AEDs or more invasive epilepsy surgery in appropriately selected candidates.

For many patients with LSE the exact location of the seizure focus cannot be demonstrated convincingly by non-invasive tests. For these patients, video-EEG monitoring utilizing intracranial electrodes is often needed to confirm the seizure focus, better define the extent of a resection or potentially indicate that surgical resection might not be a safe option. Often, these invasive electrodes are used to perform cortical stimulation mapping, a technique wherein electrical current is delivered to the individual electrodes to map out higher cortical functions such as language, motor, sensory and memory specific regions. By combining information regarding the zone of seizure origin with a detailed patient-specific map of the cortical surface anatomy, very precise and tailored removal of epileptic tissue can be removed. Both surface electrode arrays such as subdural grids and electrodes that penetrate into the brain parenchyma such as depth electrodes can be utilized. Depth electrodes are particularly useful in confirming that seizures arise from the medial temporal lobe region, to more accurately lateralize the seizure site and to identify patients with multiple independent zones of seizure onset. In contrast, subdural grid electrodes are ideal for providing a detailed map of a complex zone of seizure origin over a broad cortical region such as the frontal or parietal lobes.

While surgical excision of an epileptic focus and the techniques for invasive electrode monitoring are quite sophisticated and involved, they are not really very new ideas. Pioneers such as Wilder Penfield originally defined similar methods in the 1940's and with some technical improvements have been a core tool of epilepsy surgery since the 1980's. The development of more sophisticated methods for seizure localization that avoid or minimize the use of invasive intracranial recordings has been the focus of heavy research ever since the potential surgical complications of invasive monitoring such as infection or brain injury became apparent. Non-invasive methods have clear advantages for patient safety, cost, and convenience. The use of imaging methods such as 18FDG PET and Magnetic Resonance Spectroscopy (MRS) can be a useful adjunct to identifying a seizure focus in a subset of patients. 18FDG is measure of brain glucose utilization and areas of brain scarring may have diminished glucose utilization, providing an indirect but concordant test for localizing a seizure focus. Similarly MRS can detect brain areas with diminished number of neurons, again suggesting a region of brain injury. Ictal SPECT has been used in a similar fashion to detect regions of increased metabolism during a seizure. Unfortunately, these methods do not directly measure brain electrical activity and as such are concordant tools.

Recently, there has been interest in the use of Magnetoencephalography (MEG) to help localize a seizure focus. MEG detects the magnetic dipole equivalents of electrical current in the brain. Because of the unique properties of magnetic dipoles, major issues affecting EEG dipole modeling such as volume conduction of electrical currents in the brain are avoided. However, MEG is very expensive and requires significant technical expertise to perform and interpret the studies accurately. Better methods of dipole mapping are also needed to correctly identify the sources of activity in many cases. Nonetheless, several investigators have demonstrated MEG to be a useful tool for directing placement of intracranial electrodes, modifying surgical planning and performing non-invasive brain mapping. Ongoing efforts in this arena will likely improve our ability to correctly localize more patients, resulting in more surgical "cures".

Surgery continues to represent the most viable opportunity to cure epilepsy for most patients with localization-specific, medically refractory epilepsy. This is a bold statement when one considers the fact that in the past decade over eight new AEDs have been introduced in the U.S. While a useful adjunct, these drugs have had a relatively minor impact on the control of seizures in this patient population. Unfortunately, the majorities of these patients are never referred to a comprehensive epilepsy program and suffer the life-long effects of seizures. The careful work-up and evaluation of a patient with epilepsy is one of the most detailed and investigative work-ups in all of medicine. For this reason, successful surgery is critically dependent not just on the surgeon, but the entire epilepsy team comprised of neurologists, neuropsychologist,s EEG technicians, nurses, and others. Close interaction between the surgeon and neurologist and meticulous review of all data collected remain the core feature of successful epilepsy surgery. With increased physician awareness of the significant benefits and relatively low risks of epilepsy surgery there is a greater chance that patients will be referred to centers that can more definitively treat their seizures.

(Figure 1) A 33 year old woman with a life-long history of medically refractory complex partial seizures had pre-surgical work-up indicating a probable right mesial temporal lobe onset to her seizure, but without clear localization by scalp EEG. A-C) MEG revealed multiple interictal spikes in the right posterior temporal lobe. D) Depth electrodes were placed, with extra electrodes placed in the posterior temporal lobe at the region of MEG spikes. Continuous video-EEG demonstrated onset in this region, with rapid spread to the mesial temporal lobe. E) A subdural grid electrode array was placed over this area and further localized the seizure onset zone (red) to the posterior inferior temporal lobe with rapid spread (2 seconds) to the mesial temporal lobe. A tailored removal of the temporal lobe to include the area of seizure onset and the mesial temporal lobe was carried out. The patient has now been seizure-free for over three years, is currently driving and has discontinued all AEDs.

Ajay Ananda, MD is an attending neurosurgeon at the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles.