CME Course Director and Content Development

CME Course Director and Content Development
Faculty CME Course Director and Content Development Michael C. Smith, MD Director, Rush Epilepsy Center Professor, Department of Neurological Sciences Rush University Medical Center Chicago, Illinois Content Development John DeToledo, MD Professor and Chair Department of Neurology Texas Tech University Health Sciences Center Lubbock, Texas 2

CME Objectives I plan to incorporate the following objectives into my current practice of medicine: Utilize specific diagnostic testing in patients with uncontrolled epilepsy Determine seizure type based on symptoms Employ treatment options for patients (AEDs, surgery, VNS) with refractory complex partial seizures based on their efficacy and durability Prescribe appropriate AEDs in patients with refractory complex partial seizures

Refractory Epilepsy This section discusses approaches for diagnosis of patients with refractory epilepsy

Definition and Potential Predictors of Refractory Epilepsy
Definition ─ failure of ≥2 drugs and occurrence of ≥1 seizure/month over 18 months Factors that may predict refractory epilepsy Type of epilepsy Underlying syndrome Etiology History of seizure frequency, density, and clustering Environmental factors Trauma Prior drug exposure Genetic factors that influence a drug’s PK/PD The generally accepted definition of refractory seizures is failure of 2 or more drugs and occurrence of one or more seizures per month over 18 months Treatment resistance is a multifaceted phenomenon; there are a number of factors that may predict whether or not a patient will respond favorably to treatment or become refractory, such as Type of epilepsy Underlying syndrome Etiology Patient’s history of seizure frequency, density, and clustering Environmental factors Trauma Prior drug exposure Genetic factors that influence a drug’s pharmacokinetics/pharmacodynamics French Epilepsia 2007, abstract PD = pharmacodynamics; PK = pharmacokinetics Accessed May 8, 2011. French JA. CNS Epilepsia. 2007;48:3-7.

Epidemiology > 7.5 million people worldwide with refractory epilepsy ~ 50% of patients are seizure-free with current antiepileptic drugs (AEDs) ~ 33% of patients do not have seizure control with current AEDs Of the remaining 67% who do achieve remission, ~ 15% have recurrence of seizures over time Patients with refractory seizures incur a cost many times higher than those with controlled epilepsy Treiman Neuropsych Dis & Treat 2010, p298 There are more than 7.5 million people worldwide with refractory epilepsy About half of these patients are seizure-free with currently available antiepileptic drugs (AEDs) However, approximately 33% of patients do not have seizure control with currently available AEDs Of the remaining 67% of patients who do achieve remission, approximately 15% have recurrence of seizures over time Interest in the economic impact of epilepsy has been growing, and studies confirm that patients with refractory seizures incur a cost many times higher than those with controlled epilepsy Granata Expert Rev Neurother 2009, p1791 Treiman DM. Neuropsych Dis and Treat. 2010;6: Accessed May 8, 2011. Granata T, et al. Expert Rev Neurother. 2009;9:

Approximately One-Third of Patients Are Refractory to AEDs
Response rate, % A landmark, prospective, observational study by Kwan and Brodie evaluated the success of AED therapy in previously untreated patients; response to therapy was defined as being free of seizures for at least 1 year Among the 470 previously untreated patients evaluated, 47% (n = 222) became seizure-free during treatment with their 1st AED, 13% (n = 61) during treatment with their 2nd AED, and only 1% (n = 6) during treatment with their 3rd AED For 3% (n = 12) of patients, epilepsy was only controlled when a 2-drug combination approach was used Despite treatment, 36% (n = 169) of patients were refractory Patients who failed to respond to their 1st AED because of lack of efficacy had the lowest probability of future success (11%) compared with those who failed to respond because of intolerable side effects (41%) or idiosyncratic reactions (55%), suggesting that some patients have refractory epilepsy at the outset rather than developing resistance over time Kwan-Brodie NEJM 2000, p314 Kwan-Brodie NEJM 2000, p318 Treatment regimen Kwan-Brodie NEJM 2000, p314 Kwan P, Brodie MJ. N Engl J Med. 2000;342:

Mortality Patients with epilepsy have a 2- to 3-fold higher risk of mortality than the general population Increased risk varies by etiology, seizure type, degree of seizure control, and extent of coexisting neurological impairment Patients with refractory epilepsy have a 4- to 7-fold higher risk of mortality than patients in remission SUDEP accounts for up to 50% of deaths Majority of remaining deaths are caused by accidents, suicide, pneumonia, and cerebrovascular disease Patients with epilepsy have a 2- to 3-fold higher risk of mortality than the general population This increased mortality rate varies by etiology, seizure type, degree of seizure control, and extent of coexisting neurological impairment Although multiple factors influence mortality rate, lack of seizure control appears to be the major factor contributing to the increased mortality seen in patients with epilepsy Patients with refractory epilepsy have a 4- to-7-fold higher risk of mortality than patients in remission Sudden unexplained death in epilepsy (SUDEP) accounts for up to 50% of these deaths The majority of the remaining deaths are caused by accidents, suicide, pneumonia, and cerebrovascular disease Sperling CNS Spectr 2004, p4 SUDEP = sudden unexplained death in epilepsy Sperling MR. CNS Spectr. 2004;9:98-101,

Impact on Quality of Life
Quality-of-life parameter Wheless Epilepsy & Behavior 2006, p756 Epilepsy is associated with substantial day-to-day social and health-related consequences A survey by Wheless was conducted to obtain current insights into the experiences, attitudes, and quality of life of US patients with refractory epilepsy and their caregivers To participate in the survey, respondents had to currently be experiencing seizures or treatment-related side effects and have tried at least 2 different AEDs Both patients (n = 503) and their caregivers (n = 200) reported adverse effects of epilepsy on quality of life such as having a reduced chance of a fulfilling personal life and work success, low expectations of others, and hampered daily and future activities Both patients and their caregivers also felt that there is a stigma associated with epilepsy, felt that they are a burden to others, and suffered from depression Wheless Epilepsy & Behavior 2006, p757 Wheless Epilepsy & Behavior 2006, abstract Respondents agreeing, % Wheless Epilepsy & Behavior 2006, p761 Wheless JW. Epilepsy Behav. 2006;8:

Possible Reasons for Refractory Epilepsy
Errors in diagnosis Failure to identify a seizure syndrome Incorrect seizure classification Nonepileptic seizures Errors in AED choice or management Incorrect drug for the seizure type or syndrome Inadequate drug dose/timing Drug-drug interactions Noncompliance Inadequate patient education Too frequent or complex dosing schedule Poor tolerability There are several possible reasons why a patient may be experiencing refractory epilepsy, including diagnostic errors, errors in AED choice or management, and noncompliance Seizure medicines will not be effective for episodes that are not seizures; reasons for refractory epilepsy due to errors in diagnosis may include Failure to identify a seizure syndrome Incorrect seizure classification Nonepileptic seizures Determining the correct AED and most appropriate dose and duration of treatment is challenging; reasons for refractory epilepsy due to errors in AED choice or management may include Incorrect drug for the seizure type or syndrome Inadequate drug dose or timing Drug-drug interactions when 2 or more AEDs are used in combination Up to half of patients with epilepsy may not take their AEDs as directed, and more than half of patients seen in emergency departments because of recurrent seizures are noncompliant; reasons for refractory epilepsy due to patient noncompliance may include Inadequate patient education Too frequent or complex dosing schedule Poor tolerability “wrong diagnosis”, “correct AED, but inadequate treatment”, and “noncompliance” tabs Accessed May 8, 2011.

Potential Consequences of Refractory Epilepsy
Accidents and physical injuries Brain injury and cognitive impairment Psychological disorders Social isolation and poor self-image Lower educational accomplishment Decreased employment Sperling CNS Spectr 2004, p1 There are several potential consequences of refractory epilepsy that are often unpredictable and, at times, can be quite severe Accidents and physical injuries Data suggest that people with epilepsy experience a higher rate of injury than the general population and that frequent seizures are associated with the greatest injury rates Brain injury and cognitive impairment Data show an association between persistent seizures and hippocampal volume loss and an increased probability of developing further seizures Recurrent seizures are also associated with an increasing degree of cognitive impairment leading to deficits in general intellectual ability, verbal and spatial learning, executive control, and motor speed Psychological disorders People with epilepsy have a higher incidence of psychological disorders than the general population; for example, suicide risk is 5 to 10 times higher Social isolation and poor self-image There is a stigma associated with epilepsy, which, in addition to other consequences of the disease, can lead to social isolation; for example, people with epilepsy are less likely to marry and have offspring Lower educational attainment People with epilepsy more often have learning disabilities and ultimately attain lower educational levels Decreased employment Unemployment and underemployment rates for people with epilepsy are high, ranging between 40% and 300% higher than the general population Sperling CNS Spectr 2004, p3 Sperling CNS Spectr 2004, p4, 6 Sperling MR. CNS Spectr. 2004;9:98-101, Sperling CNS Spectr 2004, p6 Sperling CNS Spectr 2004, p4, 6 Sperling CNS Spectr 2004, p7 Sperling CNS Spectr 2004, p8

Diagnosis This section discusses approaches for diagnosis of patients with refractory epilepsy

Review of Patient’s Medical History
Careful assessment of history fundamental to clinical diagnosis Important in search for etiology In adults 35 − 64 years, main etiologies are head trauma, vascular insults, and tumors In adults > 65 years, main etiologies are cerebrovascular disease and degenerative disorders May allow for identification of possible risk factors Seizure calendars or diaries Treiman Neuropsych Dis & Treat 2010, p Because epilepsy is in essence a clinical diagnosis, obtaining a detailed medical history of the patient and attempting to correlate history with seizure semiology is a fundamental step in the multi-pronged approach to diagnosing refractory epilepsy A patient’s medical history is critical in the search for the etiology of his or her epilepsy Across all age groups, the etiology cannot be determined in more than half (55% − 89%) of all individuals with epilepsy In adults aged 35 − 64 years, head trauma, vascular insults, and tumors are all important etiologies In adults > 65 years of age, cerebrovascular disease and degenerative disorders account for most of the identifiable etiologies A careful review of a patient’s medical history may allow for identification of possible risk factors for epilepsy; this is especially important if the etiology is one that itself requires treatment and ideally can be corrected Encouraging patients keep track of their seizures, medication intake, other epilepsy treatments, and side effects through seizure calendars or diaries can be valuable in helping to access whether they have refractory seizures and, if so, possible reasons and treatment approaches Treiman Neuropsych Dis & Treat 2010, p298 Treiman DM. Neuropsych Dis and Treat. 2010;6: Accessed May 9, 2011.

Localization-Related Epilepsy
Simple Partial Complex Partial Partial Onset With Secondary Generalization No impairment of consciousness Clinical features reflect localization of seizure focus Engage portions of opposite hemisphere Some impairment of consciousness Spread from cortical focus to diencephalon and opposite hemisphere Complete impairment of consciousness Generalized tonic-clonic convulsions Although all start from a cortical seizure focus, localization-related epilepsies manifest as 1 of 3 types of seizures with distinct features Simple partial seizures are sufficiently localized so that consciousness is not impaired. Clinical features of these seizures reflect the localization of their focus Complex partial seizures spread to engage portions of the brain hemisphere opposite the localization of seizure focus, resulting in at least some impairment of consciousness, such as decreased contact with the environment Seizures of partial onset with secondary generalization begin from a cortical focus but spread to the diencephalon and opposite hemisphere. Individuals experience complete impairment of consciousness and generalized tonic-clonic convulsions Seizure type in individuals with localization-related epilepsy is influenced by many factors, including the agent and dose of AED(s) used to treat the patient, and can vary in the same individual based on changes in his or her internal and external environment Treiman Neuropsych Dis & Treat 2010, p299 Treiman DM. Neuropsych Dis and Treat. 2010;6: Treiman Neuropsych Dis & Treat 2010, p298

Clinical Semiology of Complex Partial Seizures
Dependent upon location of cortical seizure focus Common Characteristics of CPS Temporal Lobe Frontal Lobe Occipital Lobe Parietal Lobe Aura, viscerosensory sensations, oro-alimentary automatisms Postictal confusion with gradual recovery Commonly nocturnal Abrupt onset and short duration, with little/no postictal confusion Explosive or bizarre behavior possible Visual hallucinations, forced blinking/ eyelid flutter Sensory alterations, visuospatial disorientation, apraxias Ipsilateral eye movement possible The clinical semiology of complex partial seizures is related to the location of the cortical seizure focus The temporal lobe is the most common site of origin, accounting for 80% of patients with complex partial seizures. Clinical signs common to temporal lobe seizures include aura; viscerosensory sensations; and oro-alimentary automatisms, such as lip smacking or chewing. Individuals experience postictal confusion usually lasting for several minutes with gradual recovery Complex partial seizures that originate in the frontal lobe commonly occur at night. Typical frontal lobe seizures have an abrupt onset and short duration and are followed by little or no postictal confusion. Associated behavior changes can be explosive or bizarre, sometime leading to a misdiagnosis of psychogenic nonepileptic seizures Seizures originating from the occipital lobe are far less common than those originating from the temporal and frontal lobes. Occipital lobe seizures are characterized by visual hallucination. Some individuals display forced blinking/eyelid flutter at seizure onset Parietal lobe epilepsy is least common. These seizures consist of sensory alterations, visuospatial disorientation, or apraxias. Ipsilateral eye movement is possible in patients who experience seizures arising from or spreading to the parietal eye field Temporal lobe most common site of origin (~80%); parietal lobe least common Treiman Neuropsych Dis & Treat 2010, p299 Treiman DM. Neuropsych Dis and Treat. 2010;6:

Neurologic Examination
To identify Presence of abnormalities, even subtle, to add support that events are epileptic seizures Potential lateralizing abnormalities for predicting location of epileptic focus Can be augmented by Detailed history of seizure semiology Video recordings of the seizures The purpose of the neurologic examination in evaluating the patient with possible epileptic seizures is 2-fold First, neurologic examinations can be used to identify the presence of abnormalities, even subtle ones, that can add support to the likelihood that the patient’s events are epileptic seizures Second, neurologic examinations can be used to identify potential lateralizing abnormalities that can allow prediction, to some extent, of the location of the epileptic focus Neurologic examination can be augmented by obtaining a detailed history regarding seizure semiology and reviewing video recordings of the seizures, either from home videos or on an epilepsy monitoring unit (EMU) Recently, a highly reliable sign was identified to differentiate between epileptic seizures and psychogenic nonepileptic events; almost all (94%) patients with epileptic seizures keep their eyes open during the seizure, whereas almost all (99%) patients with nonepileptic events close their eyes during the seizure Treiman Neuropsych Dis & Treat 2010, p300 Treiman DM. Neuropsych Dis and Treat. 2010;6:

Neuroimaging — MRI MRI Most sensitive and specific imaging technique for partial- related epilepsy Resolution improved by introduction of increasingly powerful magnets T1- and T2-weighted imaging FLAIR Neuroimaging has become increasingly important in assessing refractory epilepsy, and there are several techniques available to aid in diagnosis Magnetic resonance imaging (MRI) continues to be the most sensitive and specific imaging technique for partial-related epilepsy Resolution has been further improved with the introduction of increasingly powerful magnets For example, hippocampal atrophy can best be seen using T1-weighted imaging, whereas increased signal brightness can best be detected with T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences Treiman Neuropsych Dis & Treat 2010, p301 FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging Treiman DM. Neuropsych Dis and Treat. 2010;6: Image courtesy of Dr. Travis Stoub, High Resolution Epilepsy Protocol, Rush University Medical Center (personal communication)

Identifying Malformations of Cortical Development With 3T MRI
This slide illustrates focal cortical dysplasia as detected by 3T MRI. 3T = 3 Tesla Image courtesy of Dr. Michael Stein, Alexius Medical Center (personal communication)

Neuroimaging — Nuclear Medicine
Positron emission tomography (PET) — metabolic activity Single-photon emission computed tomography (SPECT) — ictal and interictal blood flow Interictal SPECT Ictal SPECT Nuclear medicine procedures, such as positron emission tomography (PET) scanning and single-photon emission computed tomography (SPECT), have also played an important role in diagnosis PET is useful for assessing metabolic activity SPECT is useful for assessing ictal and interictal blood flow Treiman Neuropsych Dis & Treat 2010, p301 Treiman DM. Neuropsych Dis and Treat. 2010;6: Image courtesy of Dr. Marvin Rossi, Rush University Medical Center (personal communication)

Neuroimaging — SISCOM SISCOM Subtraction ictal SPECT coregistered to MRI (SISCOM) — improved the power of SPECT Treiman Neuropsych Dis & Treat 2010, p301 Subtraction ictal SPECT coregistered to MRI (SISCOM) is the most recent imaging modality that has improved the power of SPECT Treiman DM. Neuropsych Dis and Treat. 2010;6: Image courtesy of Dr. Marvin Rossi, Rush University Medical Center (personal communication)

EEG: complex partial seizure
EEG Monitoring EEG: complex partial seizure Determine seizure type Finding epileptiform discharges not essential for diagnosis Recording off medication can precipitate seizure Advantages of recording 30 minutes of sleep in an EMU Increases likelihood of observing interictal spikes Recorded behavior can be correlated to EEG changes Almost all patients evaluated in an EMU have refractory seizures EEG monitoring is used to determine the seizure type and is an essential element in the evaluation of patients with possible epilepsy Two types of EEG monitoring are generally used Daytime monitoring, which is an outpatient procedure with a duration of 6 to 8 hours Inpatient monitoring, which has a duration of 24 hours or more Finding epileptiform discharges on the EEG, however, is not essential for the diagnosis Even in adults with established epilepsy, only 29% to 55% have interictal spikes on their first EEG, although 80% to 90% eventually show interictal spikes on repeated EEG examinations Recording off medication can precipitate seizures In addition to EEG monitoring, there are several advantages to recording 30 minutes of sleep in an epilepsy monitoring unit (EMU) For example, this significantly increases the likelihood of observing interictal spikes or sharp waves Also, seizures recorded in an EMU have the advantage that behavior recorded on video can be correlated with EEG changes Almost all patients with localization-related epilepsy evaluated in an EMU have medically refractory seizures EMU = epilepsy monitoring unit Treiman DM. Neuropsych Dis and Treat. 2010;6: Accessed May 9, 2011. Image courtesy of Elaine Wylie’s Principles of Epilepsy Treiman Neuropsych Dis & Treat 2010, p300

MEG Detection of Structural Abnormality Not Previously Seen on MRI
This slide illustrates example cases where magnetoencephalography (MEG) detected structural abnormalities that were not previously observed on MRI scans. MEG = magnetoencephalography Image courtesy of Dr. Michael Stein, Illinois MEG Center Alexian Brothers Medical Center

Common Diagnostic Errors
It is essential to consider diagnostic errors in every case Disorders commonly misdiagnosed as epilepsy Psychogenic nonepileptic seizures Syncope REM sleep behavior disorder Despite several different approaches and techniques available to diagnose refractory epilepsy, it is essential to consider the possibility of diagnostic errors in every case There are several disorders that are commonly misdiagnosed as epilepsy, including Psychogenic nonepileptic seizures: psychological manifestations or a form of conversion disorder These episodes are distinguished from epilepsy only in that they are not associated with abnormal, rhythmic discharges of cortical neurons In several clinical series of patients with possible epilepsy, the relative frequency of psychogenic nonepileptic seizures ranged from 10% to 40% Syncope: fainting because of a sudden, usually temporary, loss of consciousness generally caused by a fall in blood pressure Diagnosing syncope is very challenging because patients typically do not have signs or symptoms REM sleep behavior disorder (RBD): episodes of motor agitation arising during REM sleep due to the absence of muscular atonia They occur often in elderly men In addition to being misdiagnosed as epilepsy, they can also be misdiagnosed as neurodegenerative disorders like Parkinson’s disease html REM = rapid eye movement Accessed May 9, 2011.

Diagnosis and Implications of Epilepsy in the Elderly
Symptoms of epilepsy in the elderly differ from younger patients Elderly often present with vague symptoms: confusion, altered mental status, memory loss Lack of clinical signs in the elderly may lead to delayed diagnosis and treatment Parameter Young Elderly Number of seizure types Multiple Singular Most common seizure type Tonic-clonic Complex partial Seizure frequency High Low Postictal state Brief Prolonged Injury potential Waterhouse Cleve Clin J Med pS27 The elderly represent the fastest-growing segment of the US population. By 2050, the elderly are expected to number over 85 million persons. Although the incidence of seizures in persons ≥75 years old exceeds that of all other age groups, seizures in this age group may present with unique nuances rarely seen in younger patients. Elderly can present with vague symptoms, including confusion, altered mental status, memory loss. Lack of clinical signs in the elderly may lead to delayed diagnosis and treatment The differential diagnosis of seizures in the elderly should rule out spells due to other causes, such as syncope, transient ischemic attack, transient global amnesia, or episodic vertigo. Garnett. Ann Pharmacol 2005, p1852 AND Waterhouse Cleve Clin J Med pS28 Waterhouse Cleve Clin J Med pS28 Waterhouse Cleve Clin J Med pS28 Waterhouse E, et al. Cleve Clin J Med. 2005;72(Suppl 3):S26-S37. Garnett WR. Ann Pharmacother. 2005;39:

Treatment This section discusses approaches for treatment of patients with refractory epilepsy

Overview of Treatment Approaches for Refractory Partial Seizures
Pharmacologic Classic AEDs New AEDs Nonpharmacologic Surgery Ablative therapy Gamma Knife radiosurgery Laser-induced thermal ablation Electrical stimulation Vagus nerve stimulation Deep brain stimulationa Ketogenic diet Modified Atkins diet Treiman Neuropsych Dis & Treat 2010, p297 The goal of treatment is to make the patient completely seizure-free without intolerable drug-induced side effects In a study by Callaghan et al, 246 patients with treatment-refractory epilepsy (defined as having ≥ 1 seizure/month and not having responded to ≥ 2 AEDs) were followed up for 3 years Overall, 15% of patients (approximately 5% per year) obtained a 6-month terminal seizure remission, suggesting that there is always hope for meaningful remission in this population There are several treatment approaches available for patients with refractory epilepsy Pharmacologic interventions include classic as well as new AEDs Nonpharmacologic interventions include surgery, ablative therapy (Gamma Knife radiosurgery and laser-induced thermal ablation), electrical stimulation (vagus nerve stimulation and deep brain stimulation [not approved by US Food and Drug Administration]), and ketogenic diet, which is a modified Atkins/low-glycemic diet Callaghan Ann Neurol 2007, p 382 Treiman Neuropsych Dis & Treat 2010, p297 a. Not approved by United States Food and Drug Administration. Treiman DM. Neuropsychiatr Dis Treat. 2010;6: Régis Y, Roberts DW. Stereotact Funct Neurosurg. 1999;72 Suppl 1:11-21. Tovar-Spinoza Z, et al. Childs Nerv Syst Jun 4. Epub ahead of print. Granata T, et al. Expert Rev Neurother. 2009;9: Accessed June 8, 2011. Granata Expert Rev Neurother 2009, p ; Regis Stereotact Funct Neurosurg 1999, Abstract; Tovar-Spinoza Childs Nerv Syst, Abstract

Pharmacologic Treatment Approaches
This section discusses the use of nonpharmacologic treatment approaches for patients with refractory epilepsy

Currently Approved AEDs for Partial-Onset Seizures
Classic AEDs Phenobarbital Phenytoin Primidone Carbamazepine Valproate Newer AEDs Felbamate Gabapentin Lamotrigine Topiramate* Tiagabine Levetiracetam Oxcarbazepine* Zonisamide Pregabalin Lacosamide Vigabatrin Clobazam† Ezogabine (retigabine) Perampanel Eslicarbazepine Treiman Neuropsych Dis & Treat 2010, p301; Potiga PI, p 1; Fycompa PI, p 2 Currently, there are 5 classic AEDs and 15 newer AEDs available in the US and many other countries for the treatment of localization-related epilepsy The AEDs currently available exert their action through a somewhat limited range of molecular targets, which include sodium and calcium channels, as well as inhibitory and, to a lesser extent, excitatory neurotransmission The newest AEDs approved for the treatment of partial-onset seizures have different mechanisms of action. Ezogabine activates KCNQ potassium channels to enhance voltage-gated M current, whereas parempanel is a noncompetitive antagonist of AMPA-mediated glutamate receptors. Eslicarbazepine blocks voltage-gated sodium channels, inhibiting sodium channel-dependent release of neurotransmitters with a potency similar to that of carbamazepine and oxcarbazepine Some of the newer AEDs represent modifications to classic compounds and were developed with the goal of improving safety and tolerability Unfortunately, there are limited data comparing the relative effectiveness of the currently available AEDs Multiple individual drug comparisons have failed to show consistent superiority of the newer AEDs over the classic ones, or of 1 newer AED over another in the treatment of either new-onset or refractory seizures Stephen CNS drugs 2011, p 90; Bialer Epilepsy Res 2010, p101 *Extended-release formulations available. †Approved for Lennox-Gastaut syndrome. NOTE: Drugs are listed in order of approval in United States except extended-release formulations. Treiman DM. Neuropsychiatr Dis Treat. 2010;6: ; Onfi [package insert]. Deerfield, IL: Lundbeck Inc.; 2011; Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013; Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; Oxtellar XR [package insert]. Rockville, MD: Supernus Pharmaceuticals, Inc.; 2012. Luszczki Pharmacol Rep 2009, p 200 Granata Expert Rev Neurother 2009, p1793 Treiman Neuropsych Dis & Treat 2010, p

Factors to Consider When Choosing an AED
Adverse reactions AED(s) Hirsutism, gum hyperplasia Phenytoin Alopecia, tremor Valproate Weight gain Valproate, gabapentin, pregabalin Weight loss Felbamate, topiramate, zonisamide Hyponatremia Carbamazepine, oxcarbazepine Teratogenicity Hypersensitivity All AEDs Other factors Once-daily dosing possible Phenobarbital, phenytoin, topiramate, zonisamide, extended-release AEDs Time needed for dose escalation Lamotrigine, zonisamide Formulary status/cost* Because the current state of evidence is that no AED is clearly superior to other AEDs in the management of refractory epilepsy, the choice of which AED to use in an individual patient has to be based on other considerations For example, factors such as previous success or failure of a given drug, cost, and the drug side effect profile matched to the individual patient’s characteristics must be considered when determining the appropriate treatment option For instance, drugs associated with significant weight gain, such as valproate, gabapentin, and pregabalin, might best be avoided in patients who are already overweight In women of childbearing age, AEDs with a significant risk of teratogenicity, such as valproate, should be avoided Hypersensitivity is seen with all AEDs In patients for whom compliance is an issue, AEDs that can be taken once daily or have an extended-release form should be considered Time for dose titration is a concern primarily with lamotrigine and zonisamide; time to titration is typically 6 weeks or longer In addition, formulary status/cost of the AED should also be considered. A drug that is not affordable is neither safe nor effective (because patients will not take it at all or may take it incorrectly) Treiman Neuropsych Dis & Treat 2010, p302 *A drug that is not affordable is neither safe nor effective Treiman DM. Neuropsych Dis and Treat. 2010;6:

Efficacy of Classic AEDs in Patients With Partial Seizures
100 80 60 Percent continuing 40 Phenytoin Carbamazepine Mattson et al conducted a double-blind study to compare the efficacy and toxicity of 4 classic AEDs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults Patients were randomly assigned to treatment with either phenytoin, carbamazepine, primidone, or phenobarbital and were followed up for 2 years or until the drug failed to control seizures or caused unacceptable side effects The number of patients remaining active in the study was assessed with life table analyses; the decreasing retention of patients over time represented an inability to manage seizures, unacceptable toxicity, or both There was a higher retention rate among patients with partial seizures given carbamazepine or phenytoin compared with those given phenobarbital or primidone (P < .02) Differences in failure rates of the drugs were explained primarily by side effect profile 20 Primidone Phenobarbital Mattson NEJM 1985, p145, 147 3 6 9 12 15 18 21 24 27 30 33 36 Months Mattson RH, et al. N Engl J Med. 1985;313:

Newer AEDs as Add-on Therapy in Patients With Refractory Epilepsy
60 50% 51% 50 43% 40% 40 36% 34% % of patients with ≥50% seizure reduction 30 26% 27% 27% 20 25% 22% 20% 20% A number of studies have reported responder rates for the newer AEDs when they were used as add-on therapy for the treatment of refractory complex partial seizures Responder rates ranged from 8% to 51% depending on the AED used Of the drugs tested in this setting, gabapentin was associated with the lowest responder rates, whereas oxcarbazepine and topiramate have yielded the highest responder rates However, it is difficult to compare these results across studies because of heterogeneity of the patient populations and different dosing regimens used 10 French Neurology 2007, p and Nadkarni Neurology 2005, pS2 8% Tiagabine1,2 Oxcarbazepine1,2 Zonisamide1,2 Gabapentin1 Lamotrigine1,2 Topiramate1,2 Levetiracetam1 NOTE: Patient follow-up in these studies varied, but maximum follow-up period studied was 3 months. 1. French JA , et al. Neurology. 2004;62: Nadkarni S, et al. Neurology. 2005;64(suppl 3):S2-S11.

Efficacy of Felbamate in Patients With Refractory Complex Partial Seizures
Eligible patients (N = 56) had ≥ 4 seizures/month on phenytoin and carbamazepine Mean age = 31 years Gender = 32 male; 24 female Seizure frequency Mean P value Felbamate Placebo Over 8 weeks 34.9 40.2 ─ Reduction over 8 weeks 4.95 - 0.36 0.046 Percent reduction 4.24 0.018 Truncated percent reduction 7.60 - 9.90 0.007 A double-blind, placebo-controlled study investigated the efficacy of felbamate (mean dose = 2,300 mg/day), a newer AED, versus placebo in 56 patients with refractory complex partial seizures Eligible patients were required to have at least 4 partial seizures per month despite therapeutic blood levels of phenytoin and carbamazepine The mean seizure frequencies for the 8-week periods analyzed were approximately 35 for felbamate and 40 for placebo Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction Adverse events associated with felbamate treatment consisted primarily of nausea and central nervous system effects Leppik Neurology 1991, p1785 Leppik IE, et al. Neurology. 1991;41:

Efficacy of Pregabalin in Patients With Refractory Complex Partial Seizures
Three randomized, placebo-controlled, 12-week studies of pregabalin (50 to 600 mg/day), a newer AED, as add-on therapy in patients with refractory complex partial seizures have reported percent reduction in seizure frequency ranging from 12% to 54% In a large multicenter study reported by French et al, 453 patients on 1 to 3 AEDs were randomized to adjunctive therapy with either placebo or pregabalin at doses ranging from 50 to 600 mg/day administered in 2 divided doses Percent reduction in seizure frequency was dose proportional Responder rates were 14% in the placebo group, 15% at 50 mg, 31% at 150 mg, 40% at 300 mg, and 51% at 600 mg/day However, 24% of patients treated with 600 mg/day discontinued due to adverse events (primarily dizziness and somnolence) In a study reported by Arroyo et al, 287 patients were randomized to either placebo or pregabalin at doses of 150 or 600 mg/day given in 3 divided doses As in the previous study, percent reduction in seizure frequency was dose related In addition, the responder rate in the 600 mg/day pregabalin group (43.5%) was statistically superior to that observed in the 150 mg/day pregabalin group (14.1%) Based on this and the previous study, 150 mg/day does not appear to be an optimal dose In the study reported by Beydoun et al, patients randomized to pregabalin all received a daily dose of 600 mg, which was divided into either 2 (BID) or 3 (TID) doses Both dosing schedules were effective, but the TID schedule was slightly better than BID dosing in terms of efficacy and safety Responder rates were 9% in the placebo group, 43% for BID schedule, and 49% for TID schedule In all these studies, the most common adverse events were dizziness, somnolence, weight gain, and amblyopia French Neurology 2003, p1631 Doses (mg/day) given as 2 divided doses Doses (mg/day) given as 3 divided doses Doses (mg) French et al Arroyo et al Beydoun et al French JA, et al. Neurology. 2003;60: Arroyo S, et al. Epilepsia. 2004;45:20-27. Beydoun A, et al. Neurology. 2005;64: Arroyo Epilepsia 2004, p20 Beydoun Neurology 2005, p475

Median percent reduction in seizure frequency per 28 days
Efficacy of Lacosamide in Patients With Refractory Complex Partial Seizures *P < .05 vs placebo * * * * * * Median percent reduction in seizure frequency per 28 days Three randomized, placebo-controlled studies of lacosamide (200 to 600 mg/day), a newer AED, as adjunctive therapy in patients with refractory complex partial seizures have reported approximately 40% median reduction in seizure frequency over 28 days among patients receiving 400 or 600 mg/day In these studies, patients were taking up to 3 concomitant AEDs In the study reported by Ben-Menachem et al, 418 patients were randomized The 50% responder rates were 22% in the placebo group compared with 33%, 41%, and 38% for patients receiving lacosamide at doses of 200, 400, and 600 mg/day, respectively In the study recently reported by Chung et al, 405 patients were randomized, and the results were similar to those reported by Ben-Menachem et al The median percent reduction in seizure frequency achieved with 400 or 600 mg/day was similar and significantly superior to placebo In addition, responder rates were 38% and 41% at these doses compared to 18% in the placebo group The authors also reported that patients treated with lacosamide had large reductions in generalized tonic-clonic seizures with median percent reductions in seizure frequency of 59% and 93% for 400 and 600 mg/day, respectively, compared with 14% for placebo In contrast to the study reported by Ben-Menachem et al, the study reported by Halasz et al in 485 patients receiving up to 3 concomitant AEDs showed that addition of lacosamide (200 mg/day) was significantly more effective than placebo and yielded a similar reduction in seizure frequency as 400 mg/day However, the responder rate at 200 mg/day was lower (35%) compared with 400 mg/day (40.5%) and was not significantly superior to placebo The most common dose-related adverse events in these studies were dizziness, nausea, vomiting, fatigue, ataxia, vision abnormal, diplopia, and nystagmus Ben-Menachem Epilepsia 2007, p1308 Doses (mg/day) Doses (mg/day) Doses (mg/day) Ben-Menachem et al Chung et al Halasz et al Ben-Menachem E, et al. Epilepsia. 2007;48: Chung S, et al. Epilepsia. 2010;51: Halasz P, et al. Epilepsia. 2009;50: Chung Epilepsia 2001, p958 Halasz Epilepsia 2009, p443

Reduction in median monthly seizure frequency
Efficacy of Vigabatrin in Patients With Refractory Complex Partial Seizures * * * P ≤ vs placebo * Reduction in median monthly seizure frequency Two randomized, placebo-controlled studies of vigabatrin, a newer AED, as add-on therapy in patients with refractory complex partial seizures have reported reductions in the median monthly seizure frequency ranging from 2.8 to 4.5 seizures per month in patients treated with an optimal dose of 3 or 6 g/day The study reported by Dean et al enrolled 174 patients with previously uncontrolled complex partial seizures with or without secondary generalization Both 3 and 6 g/day were equally effective and showed a significant reduction in monthly seizure frequency compared with placebo, whereas 1 g/day was not effective Responder rates were 7% for placebo and 24%, 51%, and 54% for 1, 3, and 6 g/day, respectively, which were all significantly superior to placebo In the study reported by French et al, 182 patients were randomized to vigabatrin (3 g/day) or placebo Vigabatrin significantly reduced the median monthly seizure frequency by 2.8 seizures per month and yielded a responder rate of 43% compared with 19% in the placebo group (P < .001) The most common treatment-related adverse events were fatigue, drowsiness, and dizziness No clinically important visual field changes or changes in MRI or evoked potential were noted in these studies Dean Epilepsia 1999, p74 French et al Dean et al Dean C, et al. Epilepsia. 1999;40:74-82. French JA , et al. Neurology. 1996;46:54-61. French Neurology 1996, p54

Median percent reduction in seizure frequency
Efficacy of Ezogabine in Patients With Refractory Complex Partial Seizures * *P < .05 vs placebo * * * * Median percent reduction in seizure frequency In 3 randomized, placebo-controlled studies of ezogabine (600 to 1200 mg/day), an AED recently approved in the United States for adjunctive treatment of partial-onset seizures in adults, median reduction in seizure frequency over 28 days among patients receiving 600, 900, or 1200 mg/day was dose-dependent and ranged from 23% to 44%. In these studies, patients were taking 1 to 3 concomitant AEDs In the study reported by Porter et al, 399 patients were randomized The ≥50% responder rates were 16% in the placebo group compared with 23%, 32%, and 33% for patients receiving ezogabine at doses of 600, 900, and 1200 mg/day, respectively In the study reported by French et al, only 1 dose of ezogabine (1200 mg) was compared with placebo (N=306 randomized patients) The median percent reduction in seizure frequency achieved with ezogabine was significantly superior to placebo In addition, the responder rate was 44% with ezogabine 1200 mg/day compared with 18% in the placebo group Similar to the study reported by Porter et al, a dose-dependent reduction in seizure frequency was observed in the study reported recently by Brodie et al, which randomized 539 patients to treatment with either 600 or 900 mg/day of ezogabine or placebo However, in this study, the difference between placebo and the 600 mg/day dose was statistically significant for median percent reduction in seizure frequency from baseline (28% vs 16%, respectively; P = .007), possibly due to the larger sample size The responder rate also was significantly superior to placebo at both the 600 mg/day (37%) and the 900 mg/day dose (47%) Across all controlled clinical studies, the most frequently reported adverse reactions with ezogabine, reported by at least 5% of patients and occurring at approximately twice the placebo rate, were dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, disturbance in attention, memory impairment, asthenia, and blurred vision. In most cases, the reactions were of mild or moderate intensity Ezogabine PI, p2,p13 Porter Neurology 2007, p1199, p1200 French Neurology 2011, p1557, p 1558 Porter et al French et al Brodie et al Porter RJ, et al. Neurology. 2007;68(15): French JA, et al. Neurology. 2011;76(18): Brodie MJ, et al. Neurology. 2010;75(20): Brodie Neurology 2012, p1819, p1821, p1822 Ezogabine PI, p5

Efficacy of Perampanel in Patients With Refractory Complex Partial Seizures *P < .05 vs placebo * * * * * Median percent reduction in seizure frequency * The efficacy and safety of perampanel, recently approved for treatment of partial-onset seizures in individuals aged 12 years and older, was studied in 3 phase 3, randomized, placebo-controlled trials at doses ranging from 2 to 12 mg/day. Median percent reduction in seizure frequency over 28 days among patients receiving 4 to 12 mg/day perampanel ranged from 18% to 35%. Dose response was apparent at these doses, with little additional reduction in frequency with the 12 mg/day dose. In these studies, patients were taking 1 to 3 concomitant AEDs In the study reported by French et al published in the journal Neurology, 388 patients were randomized Although the percentage reduction in seizure frequency was greater with the 12 mg/day dose (35%) compared with the 8 mg/day dose (26%), the ≥50% responder rates with these 2 doses were similar (38% and 36%, respectively) and were not significantly greater than placebo (26%) A second study reported by French et al (published in the journal Epilepsia) also compared perampanel 8 and 12 mg/day with placebo (N=386 randomized patients) The median percent reduction in seizure frequency achieved with perampanel was greater with the 8 mg/day dose (31%) than with the 12 mg/day dose (18%) In addition, the responder rate was 33% with perampanel 800 mg/day compared with 34% for perampanel 12 mg/day and 15% in the placebo group In the study reported by Porter et al, 712 patients were randomized to treatment with 2 to 8 mg/day perampanel or placebo A dose-dependent reduction in seizure frequency from baseline was observed and ranged from 14% with the 2 mg/day dose to 31% with the 8 mg/day dose The ≥50% responder rate during the maintenance phase with perampanel was 21% for the 2 mg/day dose, 29% for the 4 mg/day dose, and 35% for the 8 mg/day dose compared with 18% for placebo Only the 4 and 8 mg/day doses showed results that were statistically significantly different from placebo for these end points Across the 3 phase 3 trials, the most frequently reported dose-related adverse reactions in patients receiving perampanel at doses of 8 mg or 12 mg (≥5% and occurring at least 1% higher than in the placebo group) included dizziness, somnolence, fatigue, irritability, falls, nausea, and ataxia. For almost every adverse reaction, rates were higher with the 12 mg/day dose and more often led to dose reduction or discontinuation Perampanel PI, p2,p13 French Neurology 2012, p591, p 592, p593 French et al Neurology French et al Epilepsia Krauss et al French Epilepsia 2012, p3, p4 French JA ,et al. Neurology. 2012;79(6): French JA, et al. Epilepsia. 2013;54(1): Krauss GL, et al. Neurology. 2012;78(18): Krauss Neurology 2012, p1410 PerampanelPI, p5

Efficacy of Eslicarbazepine in Patients With Refractory Complex Partial Seizures *P < .05 vs placebo * * * * * * Median percent reduction in seizure frequency Ben-Menachem Epilepsy Res 2010 AND Elger Epilepsia 2009 AND Gil-Nagel Acta Neurol Scand 2009 In 3 randomized, placebo-controlled studies of eslicarbazepine (400 to 1200 mg/day), median reduction in seizure frequency over 14 weeks in patients receiving 400, 800, or 1200 mg/day was dose-dependent and ranged from 19% to 45%. In these studies, patients were taking 1 to 4 concomitant AEDs In the study reported by Ben-Menachem et al, 395 patients were randomized The ≥50% responder rates were 13% in the placebo group compared with 17%, 40%, and 37% for patients receiving eslicarbazepine at doses of 400, 800, and 1200 mg/day, respectively In the study reported by Elger et al, 402 patients were randomized The ≥50% responder rates were 20% in the placebo group compared with 23%, 34%, and 43% for patients receiving eslicarbazepine at doses of 400, 800, and 1200 mg/day, respectively In the study reported by Gil-Nagel et al, 252 patients were randomized The ≥50% responder rates were 23% in the placebo group compared with 35%, and 38% for patients receiving eslicarbazepine at doses of 800 and 1200 mg/day, respectively In this study, the 400 mg/day dose was not tested Across all controlled clinical studies, the median percent reduction in seizure frequency achieved with eslicarbazepine was significantly superior to placebo at both the 800 and 1200 md/day doses The most frequently reported adverse reactions with eslicarbazepine, reported by at least 10% of patients on any dose in any one trial, were dizziness, somnolence, headache, nausea, diplopia, abnormal coordination, and vomiting. In most cases, the reactions were of mild or moderate intensity Ben-Menachem Epilepsy Res 2010, p280 Elger et al Ben-Menachem et al Gil-Nagel et al Ben-Menachem Epilepsy Res 2010, p280 AND Elger Epilepsia 2009, p458 AND Gil-Nagel Acta Neurol Scand 2009, pgs284, 285 Elger Epilepsia 2009, pgs457, 459 Ben-Menachem E, et al. Epilepsy Res. 2010;89: Elger C, et al. Epilepsia. 2009;50: Gil-Nagel A, et al. Acta Neurol Scand. 2009;120: Gil-Nagel Acta Neurol Scand 2009, pgs284, 285 Ben-Menachem Epilepsy Res 2010, p283 AND Elger Epilepsia 2009, p454 AND Gil-Nagel Acta Neurol Scand 2009, p281

Safety of AEDs Drug tolerability important in selecting an AED
AEDs commonly associated with cognitive, behavioral, or sedative side effects Complicate use Negatively impact quality of life Side effects more common with classic AEDs Drug tolerability is one of the most important factors in selecting an AED These drugs are commonly associated with cognitive, behavioral, or sedative side effects that complicate their use and can have a significant detrimental effect on a patient’s quality of life These side effects tend to be slightly more common with the classic AEDs compared with the newer AEDs Asconape Neurol Clin 2010, p845 Asconape JJ, et al. Neurol Clin. 2010;28:

Most Common Side Effects of AEDs
Classic AEDs Confusion Diplopia, blurred vision Dizziness, ataxia Drowsiness Fatigue Headache Irritability Nausea Neutropenia Osteopenia Rash Thrombocytopenia Tremor Weight gain Newer AEDs Cognitive impairment Diplopia, blurred vision Dizziness, ataxia Drowsiness Fatigue Headache Hyponatremia Metabolic acidosis Mood swings, irritability Nausea Nephrolithiasis Oligohidrosis Paresthesia Weight gain or loss Asconape Neurol Clin 2010, p846 Shown here are the most common side effects associated with both classic and newer AEDs Asconape JJ, et al. Neurol Clin. 2010;28:

Incidence of AEs in Adults With Partial-Onset Seizures Treated With Adjunctive Ezogabine
Other reported adverse reactions include: Urinary retention Neuropsychiatric symptoms QT interval effect Skin discoloration Retina pigment changes, with potential vision loss Adverse Event Placebo (n = 427) 600 mg/d (n = 281) 900 mg/d (n = 273) 1200 mg/d (n = 259) (%) Dizziness 9 15 23 32 Somnolence 12 25 27 Fatigue 6 16 13 Confusional state 3 4 8 Vertigo 2 Tremor 10 Abnormal coordination 5 Diplopia 7 Attention disturbance <1 Memory impairment Asthenia Blurred vision Gait disturbance 1 Aphasia Dysarthria Balance disorder In clinical trials of ezogabine in adult patients with partial-onset seizures, the most frequently reported adverse events were dizziness, somnolence, fatigue, confusional state, vertigo, and tremor. Other reported adverse events in patients treated with ezogabine were urinary retention, neuropsychiatric symptoms, and effects on the QT interval. Ezogabine also can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina with potential vision loss. Potiga PI, pgs 12-13 FDA Safety Alert; Potiga PI pgs12-13 AE = adverse event. Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013; FDA Safety Alert. Accessed July 9, 2012.

Incidence of AEs in Adults With Partial-Onset Seizures Treated With Perampanel
AEs in Adults With Partial-Onset Seizures Treated With Perampanel in Phase 3 Trials Other reported adverse reactions include: Neurologic effects Falls Black box warning for serious psychiatric and behavioral reactions including aggression, hostility, irritability, anger and homicidal ideation Adverse Event Placebo (n = 442) 4 mg/d (n = 172) 8 mg/d (n = 431) 12 mg/d (n = 255) (%) Dizziness 9 16 32 43 Somnolence 7 18 Fatigue 5 8 12 Irritability 3 4 Falls 2 10 Nausea 6 Ataxia 1 Balance disorder Gait disturbance Vertigo Weight gain In clinical trials of perampanel in adult patients with partial-onset seizures, the most frequently reported adverse events were dizziness, somnolence, fatigue, and irritability. Other reported adverse events in patients treated with perampanel were neurologic effects and falls. Perampanel carries a black box warning for serious psychiatric and behavioral reactions, including aggression, hostility, irritability, anger, and homicidal ideation. Fycompa PI, pgs 1, 6-7 AE = adverse event. Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012

Incidence of AEs in Adults With Partial-Onset Seizures Treated With Eslicarbazepine
In a long-term safety study, additional reported adverse reactions (occurring in ≥5% of patients) included: Diastolic blood pressure increase Abnormal coordination Vomiting Nausea Nasopharyngitis Diarrhea Back pain Blurred vision AEs in Adults Treated With Adjunctive Eslicarbazepine in a Clinical Study Adverse Event Placebo (n = 102) 400 mg/d (n = 100) 800 mg/d (n = 98) 1200 mg/d (n = 102) (%) Dizziness 2 4 14 Headache 6 5 9 11 Diplopia 7 Somnolence 10 Vertigo 1 Elger Epilepsia 2009, p460 The most frequently reported adverse events in patients treated with adjunctive eslicarbazepine were dizziness, headache, diplopia, somnolence, and vertigo. Adverse events occurring in ≥5% of patients in a long-term safety study included diastolic blood pressure increase, abnormal coordination, vomiting, nausea, nasopharyngitis, diarrhea, back pain, blurred vision Hufnagel Epilepsy Res 2013, p267 AE = adverse event. Elger C, et al. Epilepsia. 2009;50: Hufnagel A, et al. Epilepsy Res. 2013;103:

Extended-Release Formulations of Oxcarbazepine and Topiramate
Extended-Release Oxcarbazepine 38% and 43%* median percent reduction in seizure frequency for and 2400-mg doses, respectively, vs 29% for placebo (*P < .01 vs placebo) The most frequently reported adverse events (>5% of patients): dizziness, somnolence, diplopia, headache, vomiting, fatigue, balance disorder, tremor, asthenia Extended-Release Topiramate Indicated as initial monotherapy in patients age ≥10 years with partial-onset or primary generalized tonic-clonic seizures Adjunctive therapy in patients age ≥6 years with partial-onset or primary generalized tonic-clonic seizures or Lennox-Gastaut syndrome Available in 25-, 50-, 100-, and 200-mg doses Generally well tolerated, with no serious or severe adverse events Extended-release Oxcarbazepine A multicenter, randomized, double-blind, placebo-controlled, 3-arm, parallel-group study assessed the efficacy and safety of extended-release oxcarbazepine 1200 or 2400 mg/day versus placebo in 366 adults with refractory partial epilepsy aged 18 to 65 years. Patients had at least 3 partial seizures per 28 days during an 8 week baseline period, were receiving treatment with at least 1 to 3 AEDs, and were on stable treatment for a minimum of 4 weeks prior to study entry. Median percent reduction in seizure frequency over 28 days ranged from 38% to 43%. Although the 1200 mg/day dose did not reach statistical significance versus placebo, concentration-response analyses revealed this dose is an effective dose. The most frequently reported adverse events (>5% of pateints) were dizziness, somnolence, diplopia, headache, vomiting, dizziness, somnolence, diplopia, headache, vomiting, fatigue, balance disorder, tremor, and asthenia. Extended-release Topiramate Extended-release topiramate is indicated as initial monotherapy in patients age ≥10 years with partial-onset or primary generalized tonic-clonic seizures, and as adjunctive therapy in patients age ≥6 years with partial-onset or primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. It is available in 25-, 50-, 100-, and 200-mg doses. Extended-release topiramate is generally well tolerated, with no serious or severe AEs Oxtellar XR PI Oxtellar XR [package insert]. Rockville, MD: Supernus Pharmaceuticals, Inc.; 2012; Trokendi XR Tentative Approval Letter. Accessed July 6, 2013; Braun T, et al. Neurology. 2013;80(Meeting Abstracts):P Trokendi XR Tentative Approval Letter. Braun. Neurology. Abstracts-Conclusion.

Potential for Drug-Drug Interactions With AEDs
Inducers (1A2, 2C, 3A4, UGT) Phenytoin Carbamazepine Phenobarbital Primidone Negligible or no effect Ezogabine (retigabine) Gabapentin Lacosamide Lamotrigine Levetiracetam Perampanel Pregabalin Tiagabine Vigabatrin Zonisamide Cytochrome P450 Inhibitors (2C9, UGT, EH, 2D6) Valproate Felbamate Clobazam One of the clearest advantages of the newer AEDs is their more favorable pharmacokinetic and drug-drug interaction profiles Classic AEDs, such as phenytoin, carbamazepine, phenobarbital, and primidone, are potent inducers of the cytochrome P450 enzymatic system, resulting in significant drug-drug interactions with a long list of medications commonly used in clinical practice Many newer AEDs have much more favorable pharmacokinetics, with generally good oral bioavailability, low protein binding, linear kinetics, lack of active metabolites, and low potential for drug-drug interactions Exceptions include the AEDs clobazam and ezogabine (retigabine). Clobazam has an active metabolite (N-desmethylclobazam) and is associated with some drug-drug interactions as a result of its inhibition of CYP2D6 and induction of CYP3A4 Ezogabine also has an N-acetyl metabolite (NAMR) with antiepileptic activity. However, neither ezogabine nor NAMR are likely to affect the pharmacokinetics of substrates of the major CYP450 isoenzymes through induction or inhibition Asconape Neurol Clin 2010, p847 AND Fycompa PI, p 7, p 11 Mild inducers (3A4) or inhibitors (2C19) Oxcarbazepine Topiramate Clobazam Asconape JJ, et al. Neurol Clin. 2010;28: ; Onfi [package insert]. Deerfield, IL: Lundbeck Inc.; 2011; Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013; Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012. Onfi PI, p15 Potiga PI, p 20-21

Black Box Warnings of AEDs
Phenytoin Stevens-Johnson syndrome Carbamazepine Serious dermatologic reactions and HLA-B*1502 allele, aplastic anemia, and agranulocytosis Valproate, divalproex Hepatotoxicity, teratogenicity, pancreatitis Lamotrigine Serious skin rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death Felbamate Aplastic anemia and hepatic failure Vigabatrin Vision loss Perampanel Serious or life-threatening psychiatric and behavioral adverse reactions, including aggression, hostility, irritability, anger, and homicidal ideation Ezogabine Retinal abnormalities and potential vision loss Key Warnings and Precautions All Suicidal behavior and ideation Several AEDs specifically phenytoin, carbamazepine, valproate, lamotrigine, felbamate, and vigabatrin, are associated with serious adverse events that have triggered black box warnings in their label Unfortunately, these types of idiosyncratic reactions are rarely seen during drug development and only become apparent when the drug is more widely used Phenytoin is associated with Stevens-Johnson syndrome Carbamazepine is associated with serious dermatologic reactions and HLA-B*1502 allele, aplastic anemia, and agranulocytosis Valproate is associated with hepatotoxicity, teratogenicity, and pancreatitis Lamotrigine is associated with rare but potentially fatal serious skin rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death Felbamate is associated with rare but potentially fatal aplastic anemia and liver failure Vigabatrin is associated with peripheral visual field defects, which can be severe in rare cases and require frequent monitoring Perampanel is associated with life-threatening psychiatric and behavioral adverse reactions, including aggression, hostility, irritability, anger, and homicidal ideation and threats. Patients should be monitored for these reactions as well as for atypical changes in mood, behavior, or personality, particularly during the titration period and at higher doses Ezogabine can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. The rate of progression of retinal abnormalities and their reversibility are unknown. All patients taking POTIGA should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. All AED labels include a warning for suicidal behavior and ideation. Accessed May 14, 2011; Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012; Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. Fycompa PI/p 1 Potiga PI/p 1

ILAE Guidelines for Epilepsy
Class of study Seizure type or epilepsy syndrome I II III Level of efficacy and effectiveness evidence Adults with partial-onset seizures 4 1 34 Level A: CBZ, LEV, PHT, ZNS Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB Children with partial-onset seizures 19 Level A: OXC Level B: None Level C: CBZ, PB, PHT, TPM, VPA, VGB Elderly adults with partial-onset seizures 3 Level A: GBP, LTG Level C: CBZ Adults with generalized-onset tonic-clonic seizures 27 Level A: None Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA Level A = at least 1 randomized controlled trial (RCT) or meta-analysis of RCTs showing superiority (class I) or 2 RCTs or meta-analyses showing noninferiority with 21-30% margin (class II); level B = 1 class II RCT or meta-analysis; level C = at least 2 RCTs showing noninferiority with >30% margin (class III). CBZ = carbamazepine; GBP = gabapentin; ILAE = International League Against Epilepsy; LEV = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; TPM = topiramate; VGB = vigabatrin; VPA = valproic acid; ZNS = zonisamide. NOTE: AEDs with level A or B evidence of efficacy should be considered for first-line monotherapy. Glauser Epilepsia 2006 This slide summarizes the International League Against Epilepsy (ILAE) guidelines for the management of epilepsy Glauser TA, et al. Epilepsia. 2013;54:1-13.

Strategies for Optimizing AED Use
Verify diagnosis and classification; determine etiology if possible Match choice of AED to seizure type(s) and to a patient’s specific characteristics Use monotherapy if possible Use polytherapy if necessary When adding an AED start low and go slow, but push to maximum tolerated dose if necessary Consider changing timing of dosing to reduce toxicity Use pharmacokinetic principles to fine-tune dose Adjust dose for drug-drug interactions Do not give up There are a number of strategies for optimizing use of AEDs for the management of refractory seizures when a change in therapy is indicated First, it is essential to verify the diagnosis and classification of epilepsy and to determine the etiology if possible Based on guidelines and expert opinions, the choice of AED should be matched to the seizure type and to a patient’s specific characteristics Monotherapy should be used if possible, but polytherapy with multiple AEDs can be used if seizures are not adequately controlled with just one AED It is important to start with a low dose and titrate slowly when adding an AED to the treatment regimen Often potentially effective AEDs are abandoned because initial doses are too high or the rate of titration too fast so that early side effects develop that could have been avoided had the drug been started more slowly It is important to consider pharmacokinetic principles and the potential for drug-drug interactions when adjusting the AED dose For example, evaluating serum AED concentrations can help to monitor for compliance, establish a maximum tolerated dose, and identify early signs of adverse events Above all, it is important not to give up Data suggest that even after treatment with numerous ineffective AEDs, for example 6 to 7, at least 26.5% of patients will respond with a favorable outcome (> 50% reduction in seizure frequency) to a newly administered AED Treiman Neuropsych Dis & Treat 2010, p302 Treiman DM. Neuropsych Dis and Treat. 2010;6: Schiller Neurology -2008, p57-58

AEDs — Current Limitations and Future Perspectives
Antiseizure activity, but lack antiepileptogenic properties Considerable side effects, acute and chronic Rationale for polypharmacy mainly based on empirical evidence Future perspectives Shift to using models that identify disease- modifying agents Shift to delivering drug directly into the brain Despite the improvements in patient care enabled by the use of AEDs, these agents do have obvious limitations For example, currently available AEDs have antiseizure activity but lack antiepileptogenic properties Despite extensive research, the process of epileptogenesis remains poorly understood, hence no antiepileptogenic agents have been developed Current AEDs, including newer compounds, have considerable side effects, both acute and chronic The rationale for polypharmacy, especially for patients with refractory disease, is mainly based on empirical evidence rather than actual data In order to improve patient outcomes through future drug development, a paradigm shift may be necessary Current AEDs were all developed based on the same preclinical models of epilepsy; shifting from using models that identify therapies for the symptomatic treatment of epilepsy to those that may lead to identifying disease-modifying therapies will likely improve patient outcomes Moving away from systemic delivery of AEDs to delivery directly into the brain may be an attractive treatment option for epilepsy that can lead to higher drug levels at the target region and potentially decrease systemic side effects Boon Seizure 2011, p357 Boon PA. Seizure. 2011;20:

Nonpharmacologic Treatment Approaches
This section discusses the use of nonpharmacologic treatment approaches for patients with refractory epilepsy

Nonpharmacologic Treatment Approaches
Surgery Electrical stimulation Vagus nerve stimulation Deep brain stimulation Ablative therapy Gamma Knife radiosurgery Laser-induced thermal ablation Ketogenic diet Modified Atkins diet In addition to pharmacologic treatment with AEDs, there are also several nonpharmacologic treatment options for patients with refractory epilepsy For example, surgery, electrical stimulation (vagus nerve stimulation and deep brain stimulation), ablative therapy (Gamma Knife radiosurgery and laser-induced thermal ablation), and ketogenic diet (modified Atkins) are all approaches to treat patients with refractory epilepsy Granata Expert Rev Neurother 2009, p ; Regis Stereotact Funct Neurosurg 1999, Abstract; Tovar-Spinoza Childs Nerv Syst, Abstract Granata T, et al. Expert Rev Neurother. 2009;9: Régis Y, Roberts DW. Stereotact Funct Neurosurg. 1999;72 Suppl 1:11-21. Tovar-Spinoza Z, et al. Childs Nerv Syst Jun 4. Epub ahead of print. Accessed June 8, 2011.

Epilepsies That May Benefit Available Interventions
Surgery Epilepsies That May Benefit Available Interventions Mesial temporal lobe epilepsy Frontal lobe epilepsy Lesional partial epilepsy Focal encephalomalacia Tumor Vascular malformation Congenital developmental anomaly Neocortical cryptogenic epilepsy Resection of the seizure focus Multiple subpial transection when seizure focus is in eloquent cortex Destruction of seizure focus by gamma knife/lasera Corpus callosotomy Engel Epilepsia 2003, p741 AND Wiebe NEJM 2001, p311 AND Zimmerman Mayo Clin Proc 2003, p109 This slide shows the types of epilepsy that may benefit from surgery and the currently available surgical interventions There are several types of epilepsy that are amenable to surgery, such as: Mesial temporal lobe epilepsy Frontal lobe epilepsy Lesional partial epilepsy (such as focal encephalomalacia, tumor, vascular malformation, congenital development anomaly) Neocortical cryptogenic epilepsy Available surgical interventions include: Resection or removal of the seizure focus Multiple subpial transection when the seizure focus is in the eloquent cortex; this procedure stops seizure impulses by cutting nerve fibers in the outer layers of the brain, thereby sparing the vital functions concentrated in the deeper layers of brain tissue Destruction of seizure focus by gamma knife (not FDA approved) or radiosurgery Corpus callosotomy; although this procedure most effectively ameliorates tonic and atonic seizures, frontal lobe CPS also often respond a. Gamma knife is not FDA approved. Engel J, et al. Epilepsia. 2003;44: ; Wiebe S, et al. New Engl J Med. 2001;345: ; Zimmerman R and Sirven J. Mayo Clin Proc. 2003;78: ; Treiman DM. Neuropsych Dis and Treat. 2010;6: Asadi-Pooya AA, et al. Epilepsy Behav. 2008;13: Treiman Neuropsych Dis & Treat 2010, p306 Asadi-Pooya Epilepsy Behav 2008, abstract

Surgical Evaluation Candidates undergo extensive evaluation
EEG to determine seizure origin Neuroimaging tests to support EEG High probability of success if following conditions are true Area of seizure onset is consistently and repeatedly from same brain region Implicated region can be safety removed without creating intolerable deficits In ideal candidate, success rates are 70% ─ 90% Patients with refractory epilepsy who are considering surgery must undergo extensive evaluations to determine the likelihood that any specific surgical procedure will be effective in controlling seizures without unacceptable adverse effects Initially, EEG readings are used to determine the seizure origin within the individual’s brain; the ideal result is a consistent origin of the seizures Neuroimaging tests, including MRI, PET, and SPECT scans, are all extremely valuable in supporting the EEG data, especially when they provide localizing information that correlates with the EEG findings Surgical intervention may be performed with a high probability of success if the following two conditions are true based on the accumulated data The area of seizure onset is consistently and repeatedly from the same brain region, such as the frontal or temporal lobes The implicated region of the brain can be safety removed without creating intolerable deficits such as loss of speech, memory, or fine sensory or motor cortical function The ideal candidate for resective surgery is the patient with refractory complex partial seizures who has failed to respond to an adequate trial of at least 2 to 3 AEDs and who exhibits mesial temporal sclerosis on MRI In such patients, success rates of 70% ─ 90% for selective amygdalohippocampectomy or temporal lobectomy can be expected in the hands of an experienced surgeon page/Surgical_evaluation.html Accessed May 15, Treiman DM. Neuropsych Dis and Treat. 2010;6: Treiman Neuropsych Dis & Treat 2010, p306

Predictors of Surgical Outcome
Lesional vs nonlesional epilepsy Temporal vs extratemporal epilepsy Presence of hippocampal sclerosis or lack thereof Postoperative EEG In addition to the predictors of surgical outcome discussed on the previous slide, lesional versus nonlesional epilepsy and temporal versus extratemporal epilepsy, two more predictors of surgical outcome include the type of hippocampal sclerosis or lack thereof and a postoperative EEG Typical hippocampal sclerosis (HS) is defined as patterns of neuronal loss primarily involving both CA1 and CA4 subfield, while atypical HS involves focal or restricted neuronal loss A recent study by Thom et al correlated pathologic findings with clinical outcomes after surgery, defined as seizure freedom at 2-year follow-up Atypical patterns were seen in 30% of patients Patients with the poorest outcomes were those with CA1 subtype (33% seizure freedom) and with absence of HS (44% seizure freedom) Patients with the best outcomes included those with end folium sclerosis (100% seizure freedom), total HS (71% seizure freedom), and classic HS (69% seizure freedom) Postoperative EEG has also been used as a predictor of seizure freedom after surgery A recent meta-analysis by Rathore and Radhakrishnan pooled data from 18 published studies (n = 1,345) and 2 unpublished data sets (n = 503) of postsurgical patients with interictal epileptiform discharges (IEDs) on postoperative EEGs Mean prevalence of IEDs on postoperative EEGs was 31.5% Presence of postoperative IEDs was associated with a higher risk of seizures (odds ratio of 3.3) An abnormal postoperative EEG had a modest positive predictive value (52%) but a very good negative predictive value (71%), thereby suggesting that the absence of IEDs on a postoperative EEG was associated with good seizure outcome Rudzinski Neurol Clin Prac 2011, pS21-S22 Rudzinski LA , Meador KJ. Neurol Clin Prac. 2011;76:S20-S25.

Vagus Nerve Stimulation (VNS)
For treatment of patients who failed to respond to ≥ 3 AEDs and for whom surgery is not possible Pulse generator implanted subcutaneously and connected to left vagus nerve Stimulation parameters can be programmed Precise mechanism of action unknown VNS gained FDA approval in 1997 for the adjunctive treatment of patients with medically refractory seizures who have typically failed to respond to at least 3 AEDs and for whom surgery is not possible The VNS device consists of 2 electrodes, an externally programmable pulse generator, and a battery pack The stimulating electrode is implanted around the midcervical portion of the left vagus nerve while the impulse generator and battery pack are implanted in a subcutaneous pocket in the left infraclavicular region The pulse generator is programmed externally through the skin with a magnetic wand Different parameters of stimulation can be programmed, such as current strength, pulse width, pulse train frequency, current on and off times, and magnet current strength VNS sends electrical impulses via the left vagus nerve to the nucleus of tractus solitarius (NTS), from where there are outputs to the cortex and brain stem; however, the precise mechanism of action of VNS remains unknown Sethi The Internet J Neurol 2008 Sethi NK, et al. The Internet J Neurol. 2008;9.

Clinical Efficacy of VNS
> 50% reduction in seizure frequency in most patients In a long-term prospective study, mean seizure reduction at 1 ─ 6 years, respectively, was 14%, 25%, 29%, 29%, 43%, and 50% In an open-label, retrospective study, overall reduction in mean monthly seizure frequency was 51% and responder rate was 59% In a retrospective analysis of a randomized trial, 6 of 7 nonresponders had > 50% reduction in seizures after current was increased A greater than 50% reduction in seizure frequency rate is achieved in most patients with refractory epilepsy following VNS In a long-term prospective study from the Netherlands, Ardesch et al looked at the efficacy of VNS in patients with refractory epilepsy Patients (n = 19) had received between 3 and16 AEDs and were not surgical candidates Post-VNS follow-up ranged from 2 to 6 years Mean seizure reduction at 1 ─ 6 years, respectively, was 14% (n = 19), 25% (n = 19), 29% (n = 16), 29% (n = 15), 43% (n = 9), and 50% (n = 7) In an uncontrolled, open-label retrospective study, De Herdt et al evaluated the long-term outcome in patients (n = 128) treated with VNS for refractory epilepsy The mean number of AEDs before implantation was 3 The overall reduction in mean monthly seizure frequency was 51% and the responder rate (defined as the percentage of patients with a seizure reduction of at least 50%) was 59% In a retrospective analysis of a randomized trial, Bunch et al evaluated whether acute response to VNS in terms of reduction in seizure frequency correlated with the amplitude of the output current Sixty-one patients were randomized to one of 3 groups differing primarily by their on/off time No correlation was found between output current and reduction in seizure frequency or responder rates Six of the initial 7 nonresponders experienced > 50% reduction in seizures after the current was increased Sethi The Internet J Neurol 2008 Sethi NK, et al. The Internet J Neurol. 2008;9.

Adverse Events and Contraindications of VNS
Dyspnea, increased coughing, laryngismus, pharyngitis, nausea, throat pain, dysphagia, and hoarseness of voice Affects respiration during sleep and can worsen sleep apnea Contraindications Short-wave diathermy, microwave diathermy, and therapeutic ultrasound Switch off VNS device prior to MRI Avoid machines that generate strong electric or magnetic fields Adverse events reported during VNS use include dyspnea, increased coughing, laryngismus, pharyngitis, nausea, throat pain, dysphagia, and hoarseness of voice VNS therapy also affects respiration during sleep and has been shown to worsen pre-existing obstructive sleep apnea hypopnea syndrome Short-wave diathermy, microwave diathermy, and therapeutic ultrasound are contraindicated in people with a VNS device VNS implantation is not an absolute contraindication for MRI; however, the VNS device should be switched off prior to the MRI Patients should exercise reasonable caution and avoid machines that generate strong electrical or magnetic fields Sethi The Internet J Neurol 2008 Sethi NK, et al. The Internet J Neurol. 2008;9.

Deep Brain Stimulation
SANTE study 3-month double-blind phase — 40.4% reduction in seizures in stimulated group vs 14.5% in control group; P = .002 2-year follow-up — 54% had ≥ 50% reduction in seizure rate and 14 patients were seizure-free for ≥ 6 months Approved in Europe and Canada; not FDA approved RNS System (by NeuroPace) Cranially implanted responsive neurostimulator (RNS) Significant  in seizures with RNS (n=97) vs sham (n=94) -37.9% vs -17.3%, P = .012 FDA approved for treatment of adults with partial-onset seizures not controlled with ≥2 AEDs Lega Neuro biology of Disease 2010, p355 DBS delivers controlled electrical pulses to a target brain region The SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) study by Fisher et al was a randomized, controlled, double-blind study evaluating bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy Patients (n = 110) had medically refractory partial seizures, had failed to respond to at least 3 prior AEDs, and had ≥ 6 seizures per month A Medtronic deep brain stimulator was implanted and patients continued AED therapy while on study The 3-month double-blind phase showed statistically significant reduction in seizures (40.4% in stimulated group vs 14.5% in control group; P = .002) In the 2-year follow-up, 54% of patients experienced a ≥ 50% reduction in seizure rate, and 14 patients were seizure-free for ≥ 6 months These data led to approval of DBS in Europe and Canada for patients with medically refractive epilepsy; DBS currently is not FDA approved treatment for epilepsy The RNS® System, developed by NeuroPace, is a cranially implanted responsive neurostimulator In a study of 191 adults with refractory partial epilepsy, seizures were significantly reduced in the RNS (n = 97) vs sham (n = 94) group (-37.9% vs -17.3%, respectively; P = 0.012) during the double-blind period. During the open-label period, seizure reduction was sustained in the RNS group and a significant seizure reduction was observed in the sham group upon stimulation This system was approved by the FDA in 2013 for the treatment of adults with partial-onset seizures that were not controlled with 2 or more AEDs. Fisher Epilepsia 2010, p899 Lega BC, et al. Neurobiology of Disease. 2010;38: Fisher R, et al. Epilepsia. 2010;51: Morrell M, et al. Neurology. 2011;77: Morrell Neurology 2011, p1295

Ketogenic Diet for Children With Refractory Epilepsy
High-fat, low-protein, low-carbohydrate diet effective in children with refractory epilepsy > 50% of children have a > 50% reduction in seizure frequency 10% − 15% become seizure-free In the “classic” diet, 90% of calories are derived from fat Production of ketone bodies may diminish hyperexcitability of neurons and improve seizure control The ketogenic diet is a special high-fat, low-protein, low-carbohydrate diet that is an effective treatment for children with refractory epilepsy, especially for those with Lennox-Gastaut syndrome More than 50% of children who go on the diet have at least a 50% reduction in the number of seizures they experience Some children, usually 10% − 15%, even become seizure-free Patients continue to take AEDs while on the diet but may be able to take smaller doses or fewer medications The “classic” diet consists of long-chain saturated triglycerides with a 3:1 or 4:1 [fat]:[protein + carbohydrate] ratio by weight, with 90% of calories derived from fat It is prescribed by a physician and carefully monitored by a dietitian Foods that can provide fat for the ketogenic diet include butter, heavy whipping cream, mayonnaise, and oils It is believed that production of ketone bodies may diminish hyperexcitability of neurons and improve seizure control page/Non_pharmacologic_therapies.html Accessed May 18, 2011.

Ketogenic Diet for Adults With Refractory Epilepsy
Very limited studies in adults Data from small prospective studies (9 − 12 patients each) demonstrate that 22% − 33% have > 50% reduction in seizure frequency Larger, randomized studies needed to further support potential efficacy in adults with refractory epilepsy Despite its success in children, there have been very limited studies of the ketogenic diet in adults The main reason appears to be the untested assumption that adults would not comply with the unpalatable diet In a prospective pilot study by Sirven et al, 11 adult patients with refractory epilepsy were treated for 8 months with an adjunctive 4:1 ratio ketogenic diet Three patients had > 90%, 3 had 50% − 89%, and 1 had < 50% reduction in seizure frequency Four patients stopped the diet prematurely: 2 because of lack of efficacy, and 2 because of noncompliance In another prospective pilot study by Mosek et al, 9 adults with refractory epilepsy were treated with the ketogenic diet for 12 weeks Only 2 patients completed the study, both of whom had a > 50% reduction in seizure frequency The remaining patients dropped out because of side effects or lack of efficacy In a more recent prospective, open-label, pilot-study published by Klein et al in 2010, 12 patients were treated for up to 26 months with the ketogenic diet Four patients had > 85% and 6 patients had > 50% reduction in seizure frequency Seven patients were fully compliant, 4 were partially compliant, and 1 was noncompliant Additional larger, randomized studies are needed to further support the potential efficacy of the ketogenic diet in adults with refractory epilepsy Klein Epilepsy Behav 2010, p575 Klein P, et al. Epilepsy Behav. 2010;19:

Modified Atkins Diet for Refractory Epilepsy
Modified version of ketogenic diet “Modified Atkins”: allows less carbohydrates than traditional Atkins with higher fat intake Initial studies in children and adults showed 50% seizure reduction after 6 months in about two-thirds of patients Many patients able to reduce medications Potential side effects: weight loss, increased cholesterol level, and kidney stones Blood and urine monitoring every 3 months Urine ketones tested once or twice weekly The modified Atkins diet is a modified version of the traditional ketogenic diet Foods in both the Atkins and ketogenic diet are similar; however, there are several differences, including 1) no fluid or calorie limitations with the Atkins diet; 2) no restrictions on protein; 3) foods are not weighed and measured, although patients/parents have to monitor carbohydrate counts; 4) no fasting; and 5) foods can be eaten more freely in restaurants and outside of the home. The diet is referred to as “modified Atkins” because it allows for less carbohydrates than traditional Atkins (10-20 g/day) and more strongly encourages fat intake In early studies conducted in children and adults to date, two-thirds of patients have had a 50% reduction in seizures after 6 months. Many patients were able to reduce medications Potential side effects can include weight loss, increases in cholesterol level, feeling ill and not wanting to drink (due to change in diet and resultant ketosis), and kidney stones. The modified Atkins diet should not be followed without physician supervision Blood and urine monitoring every 3 months and urine ketone monitoring once or twice weekly is recommended Accessed June 8, 2011.

Summary and Conclusions
This section provides a summary and conclusions

Summary and Conclusions
Affects 7.5 − 10 million people worldwide Approximately one-third of patients have uncontrolled seizures Several treatment strategies Pharmacologic: AEDs Nonpharmacologic: surgery, electrical stimulation, herbal treatment, ketogenic diet Increased understanding of epileptogenesis should improve diagnosis and treatment so more patients can be seizure-free Refractory complex partial seizures affect at least 7.5 million and up to as many as 10 million people worldwide Despite advances in the diagnosis and management of epilepsy, about one-third of patients continue to have uncontrolled seizures There are several strategies for treating patients with refractory epilepsy, including pharmacologic intervention with AEDs and nonpharmacologic options such as surgery, electrical stimulation, herbal treatment, and ketogenic diet Increased understanding of epileptogenesis should further improve diagnosis and treatment strategies so that more patients with refractory disease can be seizure-free Treiman Neuropsych Dis & Treat 2010, p306 Treiman DM. Neuropsych Dis and Treat. 2010;6:

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