SUPPLEMENT ARTICLE Clinically indicated electrical stimulation strategies to treat patients with medically refractory epilepsy †1Ali Izadi, †‡1Katelynn Ondek, †Amber Schedlbauer, †§Inna Keselman, †‡Kiarash Shahlaie, and †‡*Gene Gurkoff Epilepsia Open, 3(s2):198–209, 2018 doi: 10.1002/epi4.12276 SUMMARY Focal epilepsies represent approximately half of all diagnoses, and more than one-third of these patients are refractory to pharmacologic treatment. Although resection can result in seizure freedom, many patients do not meet surgical criteria, as seizures may be multifocal in origin or have a focus in an eloquent region of the brain. For these indi- viduals, several U.S. Food and Drug Administration (FDA)–approved electrical stimu- lation paradigms serve as alternative options, including vagus nerve stimulation, responsive neurostimulation, and stimulation of the anterior nucleus of the thalamus. All of these are safe, flexible, and lead to progressive seizure control over time when used as an adjunctive therapy to antiepileptic drugs. Focal epilepsies frequently involve significant comorbidities such as cognitive decline. Similar to antiepilepsy medications and surgical resection, current stimulation targets and parameters have yet to address cognitive impairments directly, with patients reporting persistent comorbidities asso- ciated with focal epilepsy despite a significant reduction in the number of their sei- zures. Although low-frequency theta oscillations of the septohippocampal network Ali Izadi has a PhD in are critical for modulating cellular activity and, in turn, cognitive processing, the coor- neuroscience and is dination of neural excitability is also imperative for preventing seizures. In this review, focused on applying we summarize current FDA-approved electrical stimulation paradigms and propose novel DBS paradigms that theta oscillations of the medial septal nucleus represent a novel neuromodulation to treat neurologic target for concurrent seizure reduction and cognitive improvement in epilepsy. Ulti- disorders mately, further advancements in clinical neurostimulation strategies will allow for the efficient treatment of both seizures and comorbidities, thereby improving overall quality of life for patients with epilepsy. KEY WORDS: Epilepsy, Electrical stimulation, Deep brain stimulation, Theta oscilla- tions, Medial septal nucleus. Epilepsy, as defined by the presence of spontaneous 1–5% globally, making it the fourth most common neuro- recurrent seizures, has an estimated lifetime prevalence of logic disorder.1–5 Within the United States alone, there are approximately 3 million adults and 470,000 children cur- Accepted September 11, 2018. 6 †Department of Neurological Surgery, University of California, Davis, rently diagnosed with epilepsy. As of 2017, epilepsy syn- California,, U.S.A.; ‡Center for Neuroscience, University of California, dromes are operationally classified as focal (partial), Davis, California,, U.S.A.; and §Department of Neurology, University of generalized, or unknown onset.7 The origin of focal seizures California, Davis, California, U.S.A. *Address correspondence to Gene Gurkoff, Department of Neurological can be subdivided by topographic location (i.e., subcortical, Surgery, UC Davis School of Medicine, 4860 Y Street, Suite 3740, Sacra- temporal, frontal, occipital, or parietal lobe epilepsy). Col- mento, CA 95817, U.S.A. E-mail: [email protected] 1 lectively, focal-onset epilepsies represent more than half of Co-First Authors. all diagnoses8; among these, temporal lobe epilepsy (TLE) © 2018 The Authors. Epilepsia Open published by Wiley Periodicals Inc. is the most prevalent. on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Pharmacoresistance is most common in focal epilepsies Attribution-NonCommercial-NoDerivs License, which permits use and dis- such as TLE.8 In fact, ~40% of patients with TLE are refrac- tribution in any medium, provided the original work is properly cited, the tory to medical intervention and have persistent seizures.8,9 use is non-commercial and no modifications or adaptations are made. 198 199 Electrical Stimulation for Epilepsy synaptic excitation and inhibition.15,16 Approximately 47% Key Points of patients achieve seizure freedom with one AED; how- ever, if ineffective, adding a second drug (serially or in com- • Electrical stimulation is indicated for patients with bination) yields only an additional 11% remission rate, and medically refractory epilepsy who do not qualify for subsequent addition of drugs contributes less than a 3% surgical resection improvement in efficacy.9,17 Ultimately, only ~60% of • Vagus nerve stimulation, responsive neurostimula- patients respond to AEDs. Epilepsy is considered refractory tion, and stimulation of the anterior nucleus of the tha- or pharmacoresistant when administration of 2 AEDs, either lamus reduce seizures by 50–70% serially or combined, fails to achieve seizure freedom after • Theta stimulation of the medial septum represents a 2 years.8,17,18 Patients experiencing years of seizures, and potential therapy to reduce seizures and improve cog- those who develop structural abnormalities, are 50% more nition in temporal lobe epilepsy likely to become refractory to medication. Refractory patients account for 80% of the total (direct plus indirect) Patients whose seizures cannot be controlled have higher cost of epilepsy in the United States, which is estimated to rates of morbidity and mortality, including trauma, suicide, be over $15.5 billion annually.19,20 and sudden unexpected death in epilepsy.10,11 For refractory Pharmacoresistance is most common in focal epilep- patients, resection of the seizure focus is a potential treat- sies8,21 and is frequently associated with cognitive decline. ment option. However, eligibility for resection depends on For example, approximately 70% of patients with TLE exhi- location of the seizure focus, including the surgeon’s ability bit memory impairment.14 Furthermore, unmanaged epi- to identify and safely remove the epileptic tissue. Further- lepsy can result in increased rates of morbidity/mortality more, of those patients receiving resective surgery, only 50– and decreased quality of life, as patients may be legally 70% become seizure-free.12,13 Therefore, there is a clear unable to drive and socially unable to conduct normal voca- need to develop additional adjunctive therapies for the treat- tional and recreational activities.11,22,23 Even in cases of ment of refractory epilepsy. pharmacoresponsive epilepsy, the adverse side-effects of Over the last 50 years, neurostimulation has been estab- AEDs can impair quality of life, as drugs that reduce lished across multiple preclinical and clinical trials as a safe excitability and seizures are associated with exacerbation of and reversible surgical option that can be combined with tra- cognitive and mood comorbidities.24–27 Moreover, drug– ditional medical interventions to significantly reduce sei- drug interactions with other important medications, such as zures. Currently, there are 3 U.S. Food and Drug birth control,28 can impair quality of life, even in the context Administration (FDA)–approved neurostimulation para- of reduced seizures.27 Over 80% of patients taking more digms: vagus nerve stimulation (VNS), responsive nerve than one AED report an average of 6–7 medication-related stimulation (RNS), and deep brain stimulation (DBS). How- adverse effects,26 leading to a 20% noncompliance rate.29– ever, there is still room for optimization of neurostimulation 31 Ultimately, noncompliance can result in uncontrolled sei- for epilepsy, specifically in terms of improving seizure zures in patients who choose to discontinue AED use. reduction and treating common comorbidities of epilepsy, such as cognitive dysfunction.14 This review will address Resection current FDA-approved neurostimulation treatment strate- The only curative option for focal epilepsy is resection, gies. Furthermore, we will discuss evidence supporting the which is effective in 50–70% cases, depending upon epi- hypothesis that driving theta oscillations via stimulation of lepsy type, focus, and patient age.12,13 Among all epilepsies, the medial septal nucleus (MSN) has the potential to both surgical treatment is most commonly used for and effica- reduce seizures and improve cognitive outcome. Ultimately, cious in treating TLE. However, surgically eligible patients the development of a range of tools, including neurostimula- often wait more than 20 years for resection, during which tion, maximizes our ability to achieve seizure freedom and time they continue to have seizures.32,33 In addition, some improve quality of life for patients with refractory epilepsy patients, such as those with generalized or multifocal epi- disorders. lepsy, or those with an epileptic focus in a key language area, are ineligible for resection.34 Even when surgery is curative, removal of temporal lobe tissue can have deleteri- Primary Treatment Strategies 35–39 for Focal Epilepsies ous effects on cognitive function. Therefore, too many patients taking AEDs for focal epilepsy, and particularly Anti-epileptic drugs TLE, continue to experience uncontrollable seizures, persis- The first line of treatment for epilepsy is administration tent comorbidities, and drug-related side effects. This of antiepileptic drugs (AEDs). There are multiple pharma- emphasizes a clear need for alternative therapies, such as cologic strategies