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- Intractable Epilepsy
- Supporting Information
Epilepsy is a chronic disorder characterized by recurrent and unprovoked seizures (Dreifuss, 1987; Hauser & Hesdorffer, 1990). It is one of the most common neurologic disorders in the adult. The lifetime risk of developing epilepsy is 3.2% (Mattson, 1992). Approximately 90% of the incident cases in adults have symptomatic partial or localization-related epilepsy (Camfield & Camfield, 1996; Hauser & Hesdorffer, 1990; Hauser, 1992). The medial temporal lobe is the most epileptogenic region of the brain (Luby et al., 1995; Jeong et al., 1999; Wiebe et al., 2001). Pathologic lesions underlying the epileptogenic zone include mesial temporal sclerosis (MTS), tumor, vascular anomaly, malformations of cortical development (MCDs), and head trauma (Cascino et al., 1993; Radhakrishnan et al., 1998). The initial response to medication is of prognostic importance (Hauser, 1992). Patients with a remote symptomatic neurologic disease, foreign-tissue lesion, developmental delay, or abnormal neurologic examination are less likely to be rendered seizure-free. The goals of treatment are to render the individual seizure-free without producing antiepileptic drug (AED) toxicity, allowing the individual to become a participating and productive member of society (Engel & Ojemann, 1993). Despite the introduction of “newer” AEDs, nearly one-half of patients with partial epilepsy will not attain a seizure remission with pharmacotherapy (Kwan & Brodie, 2003). This discussion focuses on management of the adult patient with intractable partial seizure disorders that are medically refractory and may not be surgically remediable. It is estimated that 400,000 of the 2 million individuals with partial epilepsy in the United States have a medically refractory partial seizure disorder (Hauser & Hesdorffer, 1990; Hauser, 1992). An estimated 1,500 patients in the United States undergo epilepsy surgery each year. A UK study indicated that 30,000 patients develop epilepsy each year and approximately 6,000 have medically refractory seizures (Lhatoo et al., 2003). However, there are only about 400 epilepsy surgeries performed annually in the UK. Therefore, the number of patients with intractable partial epilepsy that is both medically refractory and possibly not a surgically remediable epileptic syndrome is significant.
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- Intractable Epilepsy
- Supporting Information
The criteria required for the diagnosis of an intractable seizure disorder include medically refractory seizures and impairment in the quality of life of the individual (Hauser, 1992). It is important to note that the seizure-type(s), seizure frequency, and the specific disabling effect of the disease need to be considered when tailoring a diagnostic evaluation and therapeutic intervention. Approximately 30–40% of newly diagnosed patients have a difficult to control seizure disorder (Kwan & Brodie, 2003). A minority of patients who fail to respond to first-line antiepileptic drug (AED) therapy will be rendered seizure-free with newer medical treatments introduced in the last decade (Kwan & Brodie, 2003).
Epilepsy surgery is an effective and safe alternative form of therapy for selected patients with intractable partial epilepsy (Palmini et al., 1991; Cascino, 1996; Jeong et al., 1999; Wiebe et al., 2001; Siegel et al., 2004, 2006; Cohen-Gadol et al., 2006; Spencer et al., 2007). Patients with medial temporal lobe epilepsy and lesional epilepsy may be favorable candidates for epilepsy surgery and have a surgically remediable epileptic syndrome (Radhakrishnan et al., 1998) (Table 1). The hallmark pathology of medial temporal lobe epilepsy is mesial temporal sclerosis (Luby et al., 1995; Cascino et al., 1996; Jeong et al., 1999). The surgically excised hippocampus in these patients almost invariably shows focal cell loss and gliosis. The putative beneficial effect of successful surgery in improving the quality of life of the patient has been confirmed (Spencer et al., 2007).
Table 1. Surgically remediable epileptic syndromes
|Selected epileptic syndromes|| MRI (%)||Ictal SPECT (%) ||Pathology|
|Medial temporal lobe epilepsy||>90||–||MTS|
|Lesional epilepsy: tumor||100||–||Ganglioglioma, glioma, DNET|
|Lesional epilepsy: vascular||100||–||Cavernous hemangioma, AVM|
|Lesional epilepsy: malformation||80–90||–||FCD|
|Neocortical (extrahippocampal)||0||75||Gliosis, focal cell loss, none|
Patients with lesional epilepsy may have a primary brain tumor, vascular anomaly, or a malformation of cortical development (MCD) (Cascino et al., 1993). The common surgical pathologies encountered in patients with lesional epilepsy include a low-grade glial neoplasm, cavernous hemangioma, and focal cortical dysplasia (Cascino et al., 1993). Individuals with mesial temporal sclerosis and lesional pathology usually have an abnormal structural magnetic resonance imaging (MRI) study, and the seizure types are classified as substrate-directed partial epilepsy (Cascino et al., 1996). The MRI in these individuals may detect a specific intraaxial structural abnormality that may suggest the likely site of seizure onset and the surgical pathology. MRI plays a pivotal role in the selection and evaluation of patients for alternative forms of therapy (Luby et al., 1995; Radhakrishnan et al., 1998). The majority of these patients experience a significant reduction in seizure tendency following surgical ablation of the epileptic brain tissue (Jeong et al., 1999; Wiebe et al., 2001; Cohen-Gadol et al., 2006). The rationale for the presurgical evaluation is to identify the site of ictal onset and initial seizure propagation, that is, the epileptogenic zone, and determine the likely pathologic findings underlying the epileptic brain tissue (Wiebe et al., 2001) (Table 2). In patients with an MRI-identified foreign-tissue lesion or unilateral mesial temporal sclerosis, the purpose of the electroclinical correlation is essentially to confirm the epileptogenicity of the structural abnormality (Engel & Ojemann, 1993; Cascino et al., 1996).
Table 2. Presurgical evaluation
|Performed invariably||Performed variably||At selected centers|
|History and examination||Video-EEG (intracranial)||SISCOM|
|MRI head||FDG–PET||PET receptor studies|
|Video-EEG (extracranial)||Interictal-lictal SPECT||Functional MRI|
|Neuropsychology||Sodium amobarbital study||MRI volumetry|
Approximately 60–80% of patients with unilateral mesial temporal sclerosis, a low-grade glial neoplasm, or a cavernous hemangioma are seizure-free following surgical treatment (Radhakrishnan et al., 1998; Jeong et al., 1999; Wiebe et al., 2001). Demonstration of concordance between the pathologic substrate and the ictal onset zone indicates a highly favorable operative outcome in selected individuals (Jeong et al., 1999). In one study, more than 90% of patients with temporal lobe epilepsy and with a focal pathologic finding underlying the epileptogenic zone will experience an excellent surgical outcome, that is, auras only or rare nondisabling seizures (Radhakrishnan et al., 1998).
The operative outcome is distinctly less favorable in individuals with focal cortical dysplasia and nonlesional partial epilepsy (Palmini et al., 1991; Mosewich et al., 2000; Siegel et al., 2006). The potential reasons for the reduced efficacy of surgical treatment in these patients include the extratemporal onset of seizures and the inadequate localization of the epileptic brain tissue using neuroimaging techniques (Mosewich et al., 2000). The most common operative strategy in patients with intractable partial epilepsy involves a focal cortical resection of the epileptogenic zone with an excision of the pathologic lesion (Radhakrishnan et al., 1998). The seizure types in patients with localization-related seizure disorders and “normal” MRI studies are often classified as non–substrate-directed partial epilepsy. The most frequent site of seizure onset in patients with neocortical nonlesional partial epilepsy is the frontal lobe (Mosewich et al., 2000). The surgical pathology in these patients includes gliosis, focal cell loss, MCD, or no histopathologic alteration (Mosewich et al., 2000). The MRI may rarely be indeterminate in selected lesional pathology, for example, in focal cortical dysplasia. Only a minority of patients with neocortical, extratemporal seizures are rendered seizure-free following surgical treatment (Mosewich et al., 2000). An estimated 20–30% of these patients with extratemporal, mainly frontal lobe, seizures will enter a seizure remission following a focal cortical resection (Mosewich et al., 2000). An important reason for the unfavorable operative outcome in patients with non–substrate-directed partial epilepsy is the inherent difficulty in identifying the epileptogenic zone. The potential limitations of interictal and ictal extracranial and intracranial electroencephalography (EEG) monitoring in patients with partial seizures of extratemporal origin have been well-defined (Mosewich et al., 2000). The anatomic region of seizure onset may represent a continuum in these patients that lends itself to an incomplete focal resection of the epileptogenic zone. A large resection increases the likelihood of rendering the patient seizure free, but it also increases the potential for operative morbidity. Advances in periictal imaging have assisted the selection of operative candidates with non–substrate-directed partial epilepsy, altered the preoperative evaluation, and tailored the surgical excision (O’Brien et al., 2000).
The potential contraindications to surgical treatment include multifocal regions of seizure onset, “unsatisfactory” localization of the epileptic brain tissue, coexistence of the epileptogenic zone and functional zone(s), multifocal pathologic findings, and the patient’s inability to tolerate general anesthesia or a neurosurgical procedure.
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- Intractable Epilepsy
- Supporting Information
The management of the patient with a medically refractory seizure disorder who is not a candidate for a “curative” surgical procedure can be very challenging (Nguyen & Spencer, 2003). Most of the individuals continue to receive AED therapy, often as polypharmacy. Combinations of AED medication may reduce seizure tendency; however, the burden of increased adverse effects is a significant issue. Insidious drug toxicity, for example, cognitive impairment, sedation, and metabolic bone disease, may further impair quality of life. The evaluation and treatment of these individuals should begin with a comprehensive assessment of their seizure disorder. This includes a review of the neurologic history and prior AED and alternative therapy. Identifying “trigger factors” that may be proconvulsant may assist in reducing seizure frequency. A comprehensive epilepsy center approach would also include an MRI head seizure protocol and sleep–awake EEG recording. Inpatient video-EEG monitoring may be appropriate to confirm the diagnosis of a seizure disorder, classify seizure-type(s), and determine the localization of seizure onset (Jeong et al., 1999; Wiebe et al., 2001; Cohen-Gadol et al., 2006). Periictal imaging with subtraction ictal single proton emission computer tomography (SPECT) coregistered with MRI (SISCOM) may be considered depending on the review of the MRI study and the electroclinical correlation (O’Brien et al., 2000). Treatment options for these individuals include continued AED treatment; “palliative” surgical procedures, for example, subtotal resection of the epileptogenic zone; AED investigational studies; vagus nerve stimulation (VNS); investigational electronic stimulation; and the ketogenic diet. Several of these options will be considered in the following text. Ultimately, the healthcare team must remain empathetic to the patient’s needs and concerns, and highly motivated to identify a successful therapeutic maneuver.
Electronic stimulation and devices
Vagus nerve stimulation
VNS is a symptomatic add-on treatment for patients with medically refractory partial epilepsy. The electronic device was approved by the US Food and Drug Administration (FDA) for partial epilepsy in patients 12 years of age or older in 1997. It consists of intermittent electrical stimulation of the left vagus nerve by means of a helical electrode and an implantable, programmable pulse generator. Currently, more than 50,000 patients are treated with VNS worldwide (Ardesch et al., 2007; De Herdt et al., 2007). VNS is an adjunctive treatment for certain types of intractable epilepsy and clinical depression. This is a palliative therapeutic modality with a response rate similar to AED therapy (Cramer et al., 2001). A favorable outcome with VNS, that is, ≥50% reduction in seizure activity, occurs in approximately one-third to one-half of individuals (Cramer et al., 2001). Very rarely will patients achieve a seizure remission with this device. VNS uses a stimulator that sends electric impulses to the left vagus nerve in the neck via a lead implanted under the skin. One VNS-implanted device consists of a titanium-encased generator about the size of a pocket watch; a lithium battery to fuel the generator, with a battery life of ∼6–8 years; a lead system with electrodes; and an anchor tether to secure leads to the vagus nerve.
Implantation is usually done as an outpatient procedure. The procedure goes as follows: An incision is made in the upper left chest, and the generator is implanted into a little “pouch” on the left chest under the clavicle. A second incision is made in the neck, so that the surgeon can access the vagus nerve. The surgeon then wraps the leads around the left branch of the vagus nerve and connects the electrodes to the generator. Once successfully implanted, the generator sends electric impulses to the vagus nerve at regular intervals. The left vagus nerve is stimulated rather than the right because the right plays a role in cardiac function such that stimulating it could have negative cardiac effects. The effect of VNS on cardiovascular function has recently been evaluated (Stemper et al., 2008).
The exact method of therapeutic action is unknown, but VNS has been shown to affect blood flow to different parts of the brain, and affect neurotransmitters including serotonin and norepinephrine, which are implicated in depression. Some patients experience an alteration of voice quality and loudness during the time that the pulse is being delivered to the vagus nerve. Other common side effects include hoarseness, throat pain, cough, dyspnea, and paresthesia.
Responsive neurostimulation system (ongoing clinical investigation)
NeuroPace, Inc. is sponsoring an investigational device study of the Responsive Neurostimulation (RNS) System, a responsive brain stimulation system for treating refractory epilepsy (Fountas & Smith, 2007; Theodore & Fisher, 2007) (Supporting Information 1 and 2). The RNS System Pivotal Clinical Investigation is a randomized, double-blind, sham-stimulation controlled investigation being conducted at approximately 28 sites throughout the United States. The purpose of the RNS System Pivotal Clinical Investigation is to assess the safety and to demonstrate that the RNS System is effective as an add-on (adjunctive) therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures (those that start from one or two areas of the brain) that are refractory (resistant or hard to treat) to two or more AED medications. Participants in the trial will continue to receive their epilepsy medications.
The RNS System is designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms. The RNS is placed within the skull and underneath the scalp by a surgeon, and is then connected to one or two wires containing electrodes that are placed within the brain or that rest on the brain surface in the area of the seizure focus (where seizures start). The RNS System is designed to continuously monitor brain electrical activity from the electrodes and, after identifying the “signature” of a seizure’s onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure. This type of treatment is called responsive stimulation, but it is not yet known if it will work for the treatment of epilepsy.
A modified laptop computer known as a programmer communicates with RNS via a hand-held wand. The programmer collects information from the RNS about brain electrical activity and is used to program it to make detections and deliver responsive stimulation.
Study participation is expected to last approximately 2–3 years, depending on when the eligibility criteria are met for implantation of the RNS. After enrolling in the study, participants first complete the baseline period, which lasts a minimum of 3 months and a maximum of 15 months. During this part of the study, participants will be given a seizure diary to keep track of their seizures on a daily basis. The doctor in charge of the study will review the frequency and severity of seizures during monthly telephone calls or office visits. Study participants must have an average of three seizures for three consecutive months to be eligible for implantation of the RNS. Once the eligibility criteria have been met, participants will be implanted with the RNS. Study doctors will check on a participant’s physical and emotional health and manage the system during regularly scheduled follow-up visits. Participants will continue to keep a daily seizure diary.
The RNS System Pivotal Clinical Investigation is a randomized, double-blind, sham-stimulation controlled investigation. The double-blinded portion of the trial begins 28 days after the RNS is implanted and lasts about 4 months. Half of the participants will be randomly assigned (by chance) to have responsive stimulation turned ON and half will have responsive stimulation turned OFF (sham-stimulation). Participants and one doctor in the trial will not know whether stimulation is being delivered or not. Another doctor will program the RNS System. Five months after the RNS has been implanted, when the double-blinded portion of the trial is completed, all participants will be able to have stimulation turned ON.
Stimulation of the anterior nucleus of the thalamus in epilepsy trial (ongoing investigation)
Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial is a multicenter ongoing investigation for the treatment of intractable epilepsy (Graves & Fisher, 2005) (Supporting Information 3). Deep-brain stimulation (DBS) to reduce the frequency of seizures is being funded by Medtronic, Inc. Electrodes are implanted in the anterior nucleus of the thalamus on both sides of the brain, which will be connected to a single pacemaker-like device (operated by battery) implanted under the skin, near the collarbone. All study participants will be implanted with the devices; however, not all participants will receive stimulation right away. One month following implantation, participants will be selected randomly to either receive stimulation or receive no stimulation (the control group). During this time, participants will be asked to count any seizures that occur. Neither participants nor researchers will know who is receiving what treatment during this double-blind phase of the study. After the double-blind period, everyone will receive stimulation. Participants will remain in the study for a total of 13 months, with long-term follow-up. The results of this study are expected to be made available in 2008.
Diet therapy: Ketogenic diet and Atkins diet
There is some evidence that the ketogenic diet may be effective in reducing seizure tendency in adult patients with partial and generalized epilepsy (Sirven et al., 1999). The high-fat, low-protein diet has been used effectively in children with intractable seizure disorders. One study indicated that 6 of 11 adult patients experienced greater than a 50% reduction in seizure activity during 8 months of follow-up. A similar experience has been shown for adult patients receiving a modified Atkins diet (Kossoff et al., 2008). This is also high in fat and low in carbohydrates. Almost 50% of 30 patients had a greater than 50% reduction in seizures. The potential benefits of the diet therapy to produce ketosis in adults must be weighed against any adverse effect on overall health and patient compliance. It would be anticipated that these are palliative therapeutic interventions (Sirven et al., 1999).
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- Intractable Epilepsy
- Supporting Information
Supporting Information 1. Safety and preliminary efficacy of the RNS™ responsive neurostimulator for the treatment of intractable epilepsy in adults (abstract presented at 2006 annual meeting of the American Epilepsy Society).
Supporting Information 2. NeuroPace Inc., study of RNS.
Supporting Information 3. SANTE trial of deep brain stimulation for epilepsy.
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Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.