· PDF fileFigure 5.1 NICE Epilepsy Care Algorithm Figure 6.1 Recently Proposed Model for SUDEP ... Febrile Seizures Table 3.2 Genes Involved in Dravet Syndrome

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EpilepsyE p i l e p s y

•••Amanda Steele and Jane Mijovic Kondejewski

Pocket Guide

Epilepsy...

Amanda SteeleJane Mijovic Kondejewski

Although the information about medication given in this book hasbeen carefully checked, the author and publisher accept no liability forthe accuracy of this information. In every individual case the user must check such information by consultingthe relevant literature.This work is subject to copyright. All rights are reserved, whether thewhole or part of the material is concerned, specifically the rights oftranslation, reprinting, reuse of illustrations, recitation, broadcasting,reproduction on microfilm or in any other way, and storage in data banks.

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Pocket Guide

Epilepsy...

Amanda SteeleJane Mijovic Kondejewski

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Epilepsy // Pocket Guide

BiographyAmanda Steele is a medical science writer and editor residing in Denver,Colorado. She has published several peer-reviewed manuscripts, andwritten and edited medical and scientific material on an ever expandingrange of topics. Dr. Steele obtained her Bachelors of Science degreewith honors from Trinity University in San Antonio, Texas in 2003. Shethen went on to obtain her doctorate in Microbiology from theUniversity of Texas Southwestern Medical Center in Dallas, Texas in2009. Her doctoral research assessed a novel immunotherapeutic forrestoring the immune system of non-human primates infected with anHIV-like virus. She then went on to a postdoctoral position at theUniversity of Colorado Anschutz Medical Campus in Aurora, Colorado.Her work there focused on understanding how HIV infection impactshuman health during normal aging and the ways that infection leads tothe death of cells in the immune system. Through her research, Dr.Steele developed a strong foundation in immunology, infectious disease,inflammation, aging, cell death pathways and mechanisms, andclinical/translational research studies. She has since pursued her interestin scientific communication and education. Dr. Steele is committed tohelping scientists broadly disseminate their work and to increasingscientific literacy in the general population.

Jane Mijovic Kondejewski is a medical writer residing in Canada.She has published peer-reviewed manuscripts, reviews, book chaptersand books, and presented her own research at prestigious scientificconferences. She obtained her Bachelor of Science (Honours) degreefrom The University of Bristol in the United Kingdom, and wasawarded her PhD in Physiology from The University of Alberta. DrMijovic Kondejewski is committed to disseminating knowledge aboutadvances in medical and scientific research and to translatingdiscoveries made through medical and scientific research into practice.

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Table of ContentsTable of FiguresTable of TablesList of Abbreviations

Chapter 1 IntroductionEpilepsy Prevalence and EpidemiologyEpilepsy Versus SeizuresTypes of EpilepsyCauses of Epilepsy

Environmental TriggersBrain InjuryTumorsTuberous SclerosisFeverNeurocysticercosisBrain MalformationFocal Cortical DysplasiaHemimegalencephalyClassical LissencephalyPolymicrogyriaGenetic

Conclusions

Chapter 2 Physiology and PathophysiologyIntroductionThe BrainBasic Anatomy of the Cerebral CortexNeurons and Their FunctionNeuronal Excitability: the Action PotentialPathophysiologic MechanismsAlteration of Inhibition and ExcitationEpileptogenesis

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Epilepsy Co-morbiditiesAutismPsychiatric, Cognitive and Social Comorbidities

Conclusion

Chapter 3 Genetics and EpigeneticsIntroductionGenetics of Epilepsy DisordersGeneralized and Idiopathic EpilepsyDravet Syndrome and Other Syndromic EpilepsiesEpilepsy with Encephalopathy and Mental RetardationProgressive Myoclonic EpilepsyEpigenetics

DNA MethylationChromatinRole of MicroRNA

Conclusion

Chapter 4 Diagnosis and GuidelinesIntroductionGuidelines

The International League Against Epilepsy (ILAE)The American Epilepsy Society (AES)

Diagnosis of EpilepsyDiagnostic Tests

Conclusion

Chapter 5 Treatment and ManagementIntroductionTreatment of New Onset Epilepsy Treatment of Refractory EpilepsyTreatment of Febrile SeizuresImaging Guidelines for Epilepsy StudiesConclusion

Chapter 6 Recent AdvancesIntroductionEpidemiology Advances

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Sudden Unexplained Death in Epilepsy (SUDEP)Future Directions

Diagnosis and TreatmentNovel BiomarkersNovel TreatmentsNovel Surgical Techniques

Conclusion

Chapter 7 References

Chapter 8 List of Relevant Websites

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Figure 2.1 Left Lateral View of the Major Brain AreasFigure 2.2 Anatomy of the HippocampusFigure 2.3 Basic Structure of a NeuronFigure 2.4 Functional Classification of NeuronsFigure 2.5 Neurodevelopmental Changes in Pediatric Epilepsy Figure 2.6 Mediators of Neurobehavioral Comorbidities of

EpilepsyFigure 3.1 Relationship Between Genetics and Epigenetics in

Cognitive Phenotypes of Epilepsy Figure 3.2 Diagrams of Domain Organization of EMP2A and

NHLRC1 (EMP2B) GenesFigure 3.3 REST Protein Induction in Experimental Epilepsy

in Dentate Granule NeuronsFigure 3.4 miRNAs Implicated in Different Stages of Cerebral

Cortex DevelopmentFigure 4.1 10/20 System for EEG Electrode Positioning Figure 4.2 Patient Set Up in fMRIFigure 5.1 NICE Epilepsy Care AlgorithmFigure 6.1 Recently Proposed Model for SUDEPFigure 6.2 Model for High-throughput Studies of Epilepsy

Table of Figures

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Table 1.1 Psychosocial Impacts of Epilepsy Around theWorld

Table 1.2 Types of Epileptic SeizuresTable 1.3 Partial List of Epileptic SyndromesTable 1.4 Partial List of Childhood Epileptic SyndromesTable 1.5 Mitochondrial Disorders Associated with

EpilepsyTable 3.1 Genes Involved in Generalized Epilepsy and

Febrile Seizures Table 3.2 Genes Involved in Dravet Syndrome Table 3.3 Genes Identified in Syndromic Epilepsy Table 3.4 Genes Associated with Epilepsies Occurring

with Encephalopathies Table 3.5 Partial List of Epilepsy Types with Mental

RetardationTable 3.6 MicroRNAs and Their Potential Role in

EpilepsyTable 4.1 Guidelines for Etiologic Classification of

EpilepsyTable 4.2 Ten Golden Rules for TDM in AED Therapy Table 4.3 Differences Between PNES and Epileptic

SeizuresTable 4.4 Clinical Uses for Genetic Testing in Epilepsy Table 5.1 Summary of Adverse Events Associated with

New AEDsTable 5.2 Summary of AAN Guidelines for Treating

Newly Diagnosed EpilepsyTable 5.3 Summary of the Efficacy of AEDs for Use as

Initial MonotherapyTable 5.4 AAN Recommendations for Treating

Refractory Epilepsy Using AEDs

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Table 5.5 Evidence Supporting the Use of DBS andVNS to Treat Drug Resistant Epilepsy

Table 5.6 ILAE Essential Elements for High QualityImaging Studies

Table 5.7 Pediatric Imaging GuidelinesTable 6.1 Electrophysiology and Imaging Biomarkers

of EpilepsyTable 6.2 Body Fluid and Tissue Biomarkers of

EpilepsyTable 6.3 Anticonvulsant Profile of Experimental

AEDs in Mouse ModelsTable 6.4. Partial Anticonvulsant Profile of

Experimental AEDs in Rat ModelsTable 6.5 Localization of Different Types of Voltage-

gated Sodium Channels in Epilepsy (partiallist)

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List of AbbreviationsAbbreviation Definition5-HT 5-hydroxytriptamine AAN American Academy of NeurologyAED Anti-epileptic drugAES American Epilepsy SocietyAET Antiepileptic TreatmentARX aristaless-related homeobox Ca2+ Calcium IonsCACNA1A Calcium channel, voltage dependent, alpha 1A CGH Comparative Genomic HybridizationCLIA Clinical Laboratory Improvement Act CSF Cerebrospinal FluidCSN Central Nervous SystemCSTB Cystatin BCT Computed tomographyDBS Deep brain stimulationDTI Diffusion Tensor ImagingEcoG ElectrocorticographyEEG ElectroencephalogramER Endplasmic ReticulumFCD Focal cortical dysplasiaFLAIR Fluid-Attenuated Inversion Recovery FLE Frontal Lobe EpilepsyfMRI Functional Magnetic Resonance ImagingGABA Gamma-amino-butyric acid GABAAR Gamma-aminobutyric acid type A receptorGABRA1 Gamma-aminobutyric acid A receptor, alpha 1GABRG2 Gamma-aminobutyric acid A receptor, gamma21GRIA3 Glutamate receptor, ionotropic, AMPA3

GRIN2A Glutamate receptor, ionotropic, N-methyl D-aspartate 2AHMG HemimegalencephalyIL-1ra Interleukin 1 Receptor AntagonistIL-1b Interleukin 1 betaILAE International League Against EpilepsyIPE Idiopathic Partial EpilepsyKNMA1 Potassium Large Conductance Calcium-Activated

Channel, Subfamily M, Aplha member 1LGL1 Leucine-Rich, Glioma Activated 1LIS LissencephalyMDR1 Multidrug Resistance Protein 1MECP2 Methyl CpG Binding Protein 2MEG MagnetoencephalographyMEG/MSI Magnetoencephalogram/Magnetic Source ImagingMeHg MethylmercuryMELAS Mitochondrial encephalopathy, lactacidosis and stroke-

like episodes MERRF Myclonic epilepsy with ragged-red fibers MRgFUS Magnetic Resonance-guided Focused Ultrasound MRgLITT MRI-guided Laser Interstitial Thermal TherapyMRI Magnetic Resonance ImagingMRP2 Multidrug Resistance Protein 2 MRS Magnetic Resonance SpectroscopyMT-ND5 NADH-ubiquinone oxidoreductase subunit 5MT-TH Mitochondrially Encoded tRNA histidineMT-TK Mitochondrially Encoded tRNA lysineMT-TL1 Mitochondrially Encoded tRNA leucine 1MT-TV Mitochondrially Encoded tRNA valinemTOR mammailan target of rapamycinNADH Nicotinamide Adenine DinucleotideNGS Next-Generation SequencingPAK3 p21 Protein (Cdc42/Rac)-Activated Kinase 3PCDH19 Protocadherin 19PET Positron Emission TomographyPGE Primary Generalized EpilepsyPME Progressive Myclonic EpilepsyPMG PolymicrogyriaPNES Psychogenic Nonepileptic Seizures

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RAB39B Member RAS Oncogene FamilyRF RadiofrequencySCN1A Sodium Channel, Voltage-Gated, type 1, Alpha SubunitSCN1B Sodium Channel, Voltage-Gated, type 1, Beta SubunitSCNA Sodium Channel, Voltage-Gated, type 2, Alpha SubunitSEEG StereoelectroencephalographySGE Symptomatic Generalized EpilepsySNC8A Sodium Channel, Voltage-Gated, type 8, Alpha SubunitSPECT Single Photon Emission Computed TomographySRS Stereotactic RadiosurgerySTXBP1 syntaxin binding protein 1SUDEP Sudden Unexplained Death in EpilepsyTBI Traumatic Brain InjuryTDM Therapeutic Drug MonitoringTLDA TaqMan® low-density arrayTLE Temporal Lobe EpilepsyTNS Trigeminal Nerve StimulationtRNA transfer RNAVGSC Voltage-Gated Sodium Channels VNS Vagal Nerve StimulationWHO World Health Organization

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Chapter 1 Introduction

Epilepsy Prevalence and Epidemiology

Epilepsy is a chronic neurological disorder that is characterized bysudden recurrent episodes of sensory disturbance. It can lead to lossof consciousness and/or convulsions. The term “epilepsy”encompasses a wide variety of seizure disorders. According to theEpilepsy Foundation, it is one of the most common neurologicaldisorders, affecting 65 million people worldwide and over 2 millionpeople in the United States (Epilepsy Foundation; www.epilepsy.com).The prevalence of epilepsy is higher in the developing world, affectingalmost twice the number of people in low- and middle-incomecountries than in the developed world. The estimated incidence ofepilepsy (adults and children) in high-income countries isapproximately 50.4 out of 100,000 persons/year, while the incidencein low income countries is approximately 81.7 out of 100,000persons/year (Ngugi et al., 2011).

Epilepsy in most forms is considered a treatable disease. However,according to the World Health Organization (WHO), up to threequarters of people with epilepsy who need treatment in the developingworld do not receive that treatment (WHO 2012). Commonly citedreasons for this disparity include the high cost of drugs and drugavailability. Financial hardship is also cited as a reason for treatmentnon-compliance in North American populations (United States andCanada) (Burneo et al., 2009). Additional factors that lead to non-compliance are difficulty interacting with the care providers andnon-private insurance (United States) (Burneo et al., 2009). In thedeveloped world, minorities have reduced access to medical care for

epilepsy, but there is insufficient data to determine whether this disparityis a function of race/ethnicity or other closely related factors such associoeconomic status and education level (Bureno et al., 2009).

People who suffer from epilepsy face numerous social stigmas and canbe targets of prejudice. Even in high income countries, people withepilepsy have reduced access to medical and life insurance and can beprevented from pursuing certain occupations (WHO 2012). Some of thepsychosocial impacts associated with epilepsy are shown in Table 1.1.

Table 1.1 Psychosocial Impacts of Epilepsy Around the World(WHO 2012)

Country Psychosocial Impacts of EpilepsyCanada Lower annual income and quality of life compared to

patients with other chronic illnessesChina Difficulties finding a spouse, familial shameEcuador Social exclusion, altered relationships with

spouses/parents, housing difficulties, employment problems

Ethiopia Treated as outcastsKenya Difficulties finding marriage partnersNetherlands Children have lower school attendance and

performance

In North America, lack of education and socioeconomic status wereassociated with negative attitudes toward epilepsy, which manifestedas concerns about children having friends with epilepsy, that epilepsymight be contagious, and that people with epilepsy should not haveusual jobs (Burneo et al. 2009). However, overall, the number ofpeople expressing concerns has gone down over time, and educationspecifically related to epilepsy is beneficial (Burneo et al. 2009).

The WHO, the International League against Epilepsy, and theInternational Bureau for Epilepsy initiated the Out of the Shadowscampaign in 1997 (WHO Report Out of the Shadows, 2001) to helpreverse the stigma associated with epilepsy. The program had five goalswhen it was developed:

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• To reduce the burden of epilepsy by improving treatment• To improve the understanding of epilepsy• To promote epilepsy prevention• To improve epilepsy care• To reduce the limitations experienced by people with epilepsy and

their families.

As of 2003, the latest available annual report, pilot programs had beenestablished in 16 countries to benefit epilepsy patients including:Argentina, China, Senegal, Zimbabwe, Brazil, and Pakistan. Additionalpilot programs were being developed in Kenya, Afghanistan, Djibouti,Sudan, Somalia, Yemen, Georgia, India, Korea, Myanmar, andIndonesia (WHO report Out of the Shadows, 2003).

Epilepsy Versus Seizures

Epilepsy is a disorder of the central nervous system in which adisturbance of regular neuronal activity occurs, generating intermittentseizures (Fisher et al., 2005). Epilepsy is considered a chronic disorderin itself, and may require long term treatment (Bromfield et al., 2006).In contrast, seizures are brief episodes of involuntary shaking that canalso lead to loss of consciousness and loss of bowel or bladder control.They are a consequence of abnormal electrical activity of the neuronsin the cerebral cortex (Fisher et al, 2005). Seizures can be partial,affecting only a part of the body, or generalized, where the whole bodyis affected. The area of the brain affected by epileptic seizures canvary (WHO 2012). The different types of seizures that can happen inepilepsy are described in Table 1.2.

Table 1.2 Types of Epileptic Seizures

Types of Seizure Brief Description

Complex partial seizure Seizures last for 1-2 minutes. They usually beginin the frontal lobe or temporal lobe, but quicklyspread to other areas of the brain. Theysometimes have warning signs that patients candetect. The patient is not aware during the seizurebut will engage in automatic behaviors likemoving their mouths.

Simple partial seizure

Clonic Seizure

Tonic Seizure

Tonic-clonic seizure(also called grand malseizures)

Seizures last for a few seconds to 1 minute andare rare. Repetitive jerking movements.

Seizures usually last less than 20 seconds. Themuscles stiffen and patients usually remainconscious. Usually occur during sleep and involvethe whole brain.

Seizures usually last 1-3 minutes, more than 5minutes is considered a medical emergency. Thestereotypical convulsive seizure. The patient isunconscious as their muscles stiffen (tonic) andthen begin to jerk (clonic). Seizures that last morethan 10 minutes or more than 3 seizures that areabnormally close together may indicate thepatient is experiencing convulsive statusepilepticus (emergency situation).

Myclonic seizures Seizures last for seconds and are brief shock-likejerks of muscles or muscle groups. Can benormal occurrences (e.g., as a person is fallingasleep) or indicative of a more serious condition.

Absence seizures Sudden cessation of movement, staring, andblinking. May be accompanied by loss of bodytone causing the body to tilt slightly forward orbackward. Occur without warning.a

Seizures last for less than 2 minutes and thepatient is usually aware that they are having aseizure. These seizures can be motor, sensory,autonomic or psychic seizures. The classificationis based on the part of the brain affected. Motorseizures affect muscle activity and may lead tojerking or weakness. Sensory seizures affect anyof the five senses and may cause the patient toexperience sensations or sounds that are not real.Autonomic seizures affect bodily functions andcan lead to changes in heart rate, breathing, orsweating. Psychic seizures affect how patientsthink, feel, or experience things. Patients mayexperience trouble communicating, feel suddenemotions, or experience out of body feelings.

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Atonic seizures Sudden loss of muscle tone that can lead tofalling, drooping eyelids or head, and droppingthings.

Secondary generalizedseizures

Seizures last from 1-3 minutes. Consideredsecondary when a partial seizure begins in onepart of the brain and spreads to include the wholebrain. The seizures are usually sudden anddramatic. The patient loses consciousness and theseizure often looks similar to a primary tonic-clonic seizure.

Sources: Epilepsy Foundation http://www.epilepsy.com unless otherwise noted. a-Comprehensive Epilepsy Center NYU Langone Medical Center (http://epilepsy.med.nyu.edu/)

Types of Epilepsy

There are many different syndromes that can be grouped under theterm “epilepsy”. They have unique symptoms, affect distinct areas ofthe brain, have different ages of onset, and different etiologies. A briefdescription of some of these syndromes is provided for adults (Table1.3) and children (Table 1.4).

Table 1.3 Partial List of Epileptic Syndromes

Type of Epilepsy Brief Description

Temporal lobeepilepsy (TLE)

Patients experience overwhelming emotion (pleasure,fear or unreality), odd physical sensations, and performrepetitive automatic movements. Seizures affect thetemporal lobe which controls memory and emotion.

Frontal lobeepilepsy (FLE)

The symptoms patients experience depends on thearea of the frontal lobe involved in the seizure. Thefrontal lobe is involved in many different functionsincluding motor function and language.

Parietal lobeepilepsy

Patients can experience somatosensory seizures, somaticillusions (feelings that the body is in distorted positions),vertigo, visual illusions and hallucinations, and languagedisturbances. Seizures affect the parietal lobe whichprocesses and integrates sensory and visual perception.

Occipital lobeepilepsy

Patients experience an array of visual symptoms that aresimilar to migraine symptoms including hallucinations(flickering or colored lights), blinking, and other visualsymptoms. Seizures affect the major visual center of thebrain, the occipital lobe.

Reflex epilepsy Patients experience seizures in response to specific stimulisuch as flickering lights. Stimuli can include non-visualstimuli such as thinking about a specific subject or aperson’s voice. The area of the brain affected depends onthe triggering stimuli. Seizures are generally absence,myoclonic, or tonic-clonic.

Primarygeneralizedepilepsy (PGE)

PGE is an umbrella term for several different epilepticsyndromes that have unknown origins, but are oftengenetically based. Patients experience different symptomsdepending on the specific syndrome. In some casesseizures can affect the entire brain.

Source: Comprehensive Epilepsy Center NYU Langone Medical Center

Idiopathicpartial epilepsy(IPE)

IPE is an umbrella term for several different partialepilepsy syndromes that have unknown origins, but areoften genetic. Symptoms depend of the specificsyndrome. The brain regions affected vary.

Symptomaticgeneralizedepilepsy (SGE)

SGE refers to syndromes that have both generalized andpartial seizures. Generalized seizures are usuallymyoclonic, tonic, atonic, atypical absence, or tonic-clonicseizures. The types of partial seizures that can occurdepends on the underlying brain injury. SGE is usuallycaused by a known severe brain injury or disorder.

Progressivemyoclonicepilepsy (PME)

This type of epilepsy is rare and frequently caused byinherited metabolic disorders. Patients experiencemuscular symptoms (unsteadiness, rigidity) and cognitivedegeneration. The disease becomes more severe overtime and less responsive to treatment.

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Table 1.4 Partial List of Childhood Epileptic Syndromes

Type of ChildhoodEpilepsy

Brief Description

Febrile seizures Febrile seizures are associated with fevers inchildren 6 months to 5-6 years of age. Patients aregenerally healthy children who develop feversfollowing a viral infection and experience tonic-clonic seizures that can last from a few seconds toseveral minutes.

Benign Rolandicepilepsy

Patients often experience partial motor seizures(twitching) or a sensory seizure (tingling,numbness) that affects the face, and can havetonic-clonic seizures in their sleep. The seizuresgenerally begin between 2-13 years of age and areoutgrown by 15. Seizures are infrequent and areoften hereditary.

Juvenile myoclonicepilepsy

Type of PGE where patients will often experiencejerking movements and occasionally more intenseseizures. An electroencephalogram (EEG) tomonitor the brain’s electrical activity often showsintermittent spikes, which can be detected evenwhen the patient is not experiencing a seizure.Onset occurs around puberty.

Infantile spasms Also called West’s Syndrome. This is a rare formof epilepsy that begins in infants between 3-12months of age. Seizures can be subtle movementslimited to specific body parts or more generalizedsuch as “jackknife seizures” where the arms areflung out and the body bends forward. In 60% ofthese cases a brain disorder or trauma accounts forthe seizures, etiology is unknown in the remainder.Approximately 20% of patients develop Lennox-Gastaut Syndrome.

Type of SGE characterized by three traits:generalized seizures that are resistant tomedication, mental handicap, and slowspike/wave patterns on an EEG. Patients aretypically 1-6 years of age at onset.

Lennox-GastautSyndrome

Type of PGE where patients experience absenceseizures that have a characteristic 3-Hzgeneralized spike and wave complex. Patients aretypically school aged children between 5 and 9years of age.

Childhood absenceepilepsy

Patients experience seizures that often includesymptoms such as visual hallucination (brightlycolored shapes), loss of vision, vomiting, andheadaches. Some patients also experience jerkingmovements on one side of their body. Onset isbetween 5-7 years of age.

Benign occipitalepilepsy

Also called acquired epileptic aphasia, Causeschildren to lose previously acquired languageabilities, particularly verbal abilities bothunderstanding and speaking. Typical age of onsetis 3-7 years of age and the disease progressivelyworsens. The primary feature is the language loss,seizures are rare and usually occur during sleep.Abnormal electrical activity is triggered by sleepand EEG recordings during sleep are key todiagnosis.

Landau-Kleffnersyndrome

Patients are typically diagnosed between 14months and 14 years of age. Rasmussensyndrome is a progressive disorder that is rarelyfatal but has serious long-term consequencessuch as hemiparesis and mental handicap.Seizures are usually the first symptom to appear.Most seizures are partial motor seizures but in20% of patients the first seizure can be a partialor tonic-clonic epilepticus.

Rasmussensyndrome

Tumors that affect the hypothalamus can lead toseizures, symptoms of early puberty, irritability,and aggression. The seizures are generally simpleor complex partial seizures or secondarygeneralized tonic-clonic seizures.

Hypothalamichamartoma andepilepsy

Source: Comprehensive Epilepsy Center NYU Langone Medical Center

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Causes of Epilepsy

The most common form of epilepsy is called idiopathic epilepsy,which occurs in 60% of cases and has no identifiable cause.Symptomatic, or secondary epilepsy has an identifiable cause (WHO2012), some of which are discussed below.

Environmental TriggersEnvironmental factors such as alcohol and drugs are thought to playa role in developing epilepsy. Exposure to chemical pollutants, suchas ozone, lead, manganese, and organophosphates, has been linked toan increased risk of developing epilepsy. Methylmercury, which iscommonly found in fish, can also contribute to the onset of epilepsyfollowing acute or chronic exposure to the toxin (Yuan, 2012).

Brain InjuryThere are several types of brain injury that can lead to the onset ofepilepsy including oxygen deprivation during birth, low birth weight,stroke, and trauma. The trauma related to explosive blast exposure isparticularly relevant because of its prevalence as a combat casualtyduring the Global War on Terror, including the operations in Iraq andAfghanistan. During these operations, approximately 290,000 servicepersonnel (United States) suffered traumatic brain injuries (TBI). Ofthese, an estimated 10-25% of patients with closed head TBI andnearly 50% of patients with penetrating TBI are expected to developpost-traumatic epilepsy. As many as 62% of patients with post-traumatic epilepsy develop temporal lobe epilepsy. In blast related TBI,the pressure from the blast wave is thought to damage the brain leadingto lesions and altered blood flow (Kovacs et al., 2014).

TumorsBrain tumors have long been known to cause epilepsy. In fact 30-50%of patients with a brain tumor present with seizures as an earlysymptom. Seizures are more common in slow growing brain tumorsthat are thought to have less effect on the underlying electricalarchitecture of the brain than highly infiltrative fast growing tumors.The location of the tumor also determines how epileptogenic it is.Tumors that are near the limbic system, the frontal lobe, or temporal

lobe are more likely to cause epilepsy. Tumors can also lead todisruption of the blood brain barrier and gap junctions, which canlead to miscommunication between neurons and result in epilepsy.Tumor cells themselves are also thought to initiate some actionpotentials, the electrical activity that allows neurons to communicate,making those tumor cells epileptogenic. Finally, the tumormicroenvironment is radically different than the normal brainenvironment and that can lead to epilepsy due to morphologicalchanges, hypoxia and metabolic changes, changes in the ion balance,changes in the levels of neurotransmitters, and inflammation orimmunological changes (You et al., 2012).

Tuberous SclerosisTuberous sclerosis is a specific type of inherited disease that leadsto tumors in many different tissues including the skin, heart, lung,kidney, and brain. It is estimated to affect 1:6,000 to 1:10,000individuals. The genetic mutations that cause tuberous sclerosis leadto hyperactivation of the mammalian target of rapamycin (mTOR)pathway, which is linked to uncontrolled cell growth and tumorformation. Tuberous sclerosis often presents as infantile spasms, butis refractory to treatment with conventional anti-epilepsy drugs.Many patients with tuberous sclerosis also have other neurologicalsymptoms such as mental retardation, cognitive delays, autistic traits,and hydrocephalus. Tuberous sclerosis is thought to require a“second hit” to occur in patients with the inherited genetic mutationsbefore the disease emerges. The timing and location of the secondhit helps to determine the severity of the disease and the resultinglesions (Feliciano et al., 2013).

FeverFebrile seizures occur in 3-7% of children up to 7 years of age, theenvironmental trigger for a febrile seizure is fever (defined as atemperature greater than 38°C) that is likely associated with anunderlying viral infection. However, the seizure can occur well beforethe underlying illness becomes apparent. Children that present withfebrile seizures have a 2.4% chance of developing epilepsy later, whichis slightly higher than the 1.4% chance in the general population. Thereis some evidence from rodent model that there is a genetic component

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to susceptibility to febrile seizures. However, in some patients, febrileseizures indicate febrile infection-related epilepsy syndrome. In thiscase, seizures occur in clusters or become continuous and are resistantto standard anti-epilepsy drugs; immunosuppressive therapies havenot been shown to help. Prognosis for these patients is often poorand many of the children that survive have poor neurocognitiverecovery. Mortality with febrile infection-related epilepsy syndromecan reach 30% (Cross, 2012).

NeurocysticercosisCysticercosis is caused by the larvae of the tapeworm Taenia solium.It accounts for approximately 29% of epilepsy cases in regions of theworld where T. solium is endemic and is a major cause of acquiredadult onset epilepsy. Neurocysticercosis is the invasion of the centralnervous system by the larvae, which normally reside in the gut. In2011, an estimated 1.7-3 million people were affected by epilepsyrelated to neurocysticercosis. The tapeworms are ingested asoncospheres, in which larvae are contained in an external embryonicenvelope with six hooks. Oncospheres move with the blood streamand lodge in small blood vessels in the brain and other organs, wherethey form cysts. The host ingests multiple oncospheres, so it is notuncommon to find multiple cysts in the brain at different stages ofdevelopment. The symptoms of neurocysticercosis depend on thenumber of cysts, their location, growth, stage of degeneration,inflammation, host factors, and parasite genetics. The pathophysiologyof neurocysticercosis is associated with the host inflammatoryresponse to the parasite cysts (Nash and Garcia, 2011).

Brain MalformationMost cases of epilepsy are associated with malformation of corticaldevelopment. These malformations are the result of abnormal braindevelopment and affect cells that would form part of the cerebralcortex (Leventer et al., 2008). Some types of malformations are morelikely than others to cause epilepsy. Examples of epileptogenicmalformations are discussed.

Focal Cortical DysplasiaFocal cortical dysplasia (FCD) is the cause of epilepsy in 5-25% of allepilepsy surgeries. The seizures caused by FCD do not typically

respond to medication and require surgery for symptom relief. Interms of anatomical changes, FCD can manifest in many differentways including neuronal heterotopia (neurons that are incorrectlypositioned), undulations of cortical layering, and architecturalabnormalities such as delamination or abnormal cells in thecortex (Leventer et al., 2008). Interestingly, the FCD tissue isinherently epileptogenic.

HemimegalencephalyAs the name implies, hemimegalencephaly (HMG) is when onecerebral hemisphere is abnormally enlarged. The other hemisphere isoften compressed or distorted in response, but otherwise appearsnormal. HMG can affect either the right or the left hemispheres anddoes not appear to be more common in one or the other. ClinicallyHMG is characterized by intractable partial seizures that begin duringinfancy, hemiparesis, and developmental delays (Leventer et al., 2008).

Classical LissencephalyLissencephaly (LIS) is the absence of normal gyration (convolutionson the surface of the brain) in the brain. Most cases of LIS combineagyria, the absence of gyration, and pachygyria, simplified gyration.Patients with LIS also tend to have smaller brains, although still withinthe normal range. The cortex of the brain is poorly organized and hasfour layers instead of the normal six layers. One hypothesis is thatneurons migrating toward the surface of the brain stop prematurelyin LIS patients so that the deep layers of the brain are much thickerthan normal. The clinical manifestation of LIS depends on the severityof the malformation, the brain abnormalities associated with themalformation, and whether other organ systems are affected (Leventeret al., 2008).

PolymicrogyriaIn contrast to LIS, polymicrogyria (PMG) is excessive gyration at themicroscopic level, which often appears as an irregular cortical surface.PMG is one of the most common malformations. PMG can takemany forms, including unilateral, bilateral symmetric, and bilateralasymmetric. PMG is also associated with many differentmalformations including ventriculomegaly and abnormalities in the

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corpus callosum, brain stem, and cerebellum. All of the manifestationsof PMG are characterized by abnormal lamination and excessivefolding and fusion of adjacent gyri. The clinical presentations of PMGare highly variable and depend on the part of the brain affected andthe severity (Leventer et al., 2008).

GeneticThere is often a genetic predisposition for many forms of epilepsy.For example, early infantile epileptic encephalopathy (OhtaharaSyndrome) is known to be associated with mutations to the aristaless-related homeobox (ARX) and syntaxin binding protein 1 (STXBP1)genes that can lead to brain malformation and interfere withGABAergic neurons, a specific type of neuron that produces theneurotransmitter γ-aminobutyric acid (GABA), which reducesneuronal excitability in the brain (Parisi et al., 2011). Genetic links havebeen identified for many of the other childhood epileptic syndromes,including: benign familial neonatal seizures, benign infantile seizures,benign neonatal-infantile seizures, West syndrome, Dravet syndrome,and early onset absence epilepsy (Parisi et al., 2011).

Mitochondrial disorders are inherited through the maternal line andhave been linked to a many epilepsy syndromes. The syndromes arecategorized based on the frequency of the resulting seizures. Thefrequency of epilepsy in mitochondrial disorders has not been wellcharacterized to date, but epilepsy is the dominant presentation forseveral mitochondrial diseases.

Table 1.5 Mitochondrial Disorders Associated with Epilepsy(Finsterer et al., 2012)

Disorders with Frequent Seizures Disorders with Rare Seizures

Alpers-Huttenlocher Syndrome

Ataxia Neuropathy Spectrum

Leigh Syndrome

Infantile-onset spinocerebellar ataxia

Kearns-Sayre Syndrome

Leucencephalopathy with brainstem and spinal cord involvementand lactacidosis

Myclonic Epilepsy, myopathy andsensory ataxia (previously known asspinocerebellar ataxia with epilepsy)

Leber’s hereditary optic neuropathy

Mitochondrial encephalopathy,lactacidosis and stroke-like episodes(MELAS)

Neuropathy, ataxia, and retinitispigmentosa

Myclonic epilepsy with ragged-redfibers (MERRF)

Non-syndromic mitochondrialdisorders

Conclusions

The term epilepsy includes a broad array of disorders that affect thebrain and lead to seizures. It is a chronic condition that requires carefulmanagement. There is a stigma associated with epilepsy worldwidethat can make it difficult for patients to live normal lives. There aremany different causes of epilepsy including environmental toxins,trauma, and infection, but there is often an underlying genetic causeas well. The interactions between environmental, genetic, and otherfactors leading to epilepsy are still poorly understood.

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Chapter 2 Physiology andPathophysiology

Introduction

This chapter will address the physiological basis for epilepsy and thepathophysiology that accompanies the disease. The anatomy of thebrain, in particular, the structure and function of the cerebral cortexwill be discussed, followed by the relationship between epilepsy andseizures. Finally, the chapter will address co-morbidities of epilepsysuch as behavioral and emotional changes, and the association betweenepilepsy and pre-existing conditions (Jacobs et al., 2009).

The Brain

The brain is the main component of the central nervous system (CNS)and the largest and most complex organ of the human body. It weighsapproximately three pounds and is considered the body’scommunication center. It is divided into four major parts: thecerebrum, the diencephalon, the brain stem, and the cerebellum. Thecerebrum is the largest of the four and located in the upper part ofthe brain; it comprises a cortex of grey matter (cerebral cortex), whichis the area most often affected by epilepsy (Figure 2.1). It is thoughtthat epilepsy and seizures can occur anywhere within the cerebralcortex, affecting the frontal, occipital, or temporal lobes (Figure 2.1).

Figure 2.1 Left Lateral View of the Major Brain Areas (Marieb, 2010)

Precentralgyrus

Frontal lobe

Central sulcusPostcentral gyrus

Parietal lobe

Parieto-occipitalsulcus (deep)

Lateral sulcusOccipital lobe

Temporal lobe

Cerebellum

Spinalcord

GyrusSulcus

Cerebral white matter

Fissure (a deep sulcus)

Cerebral cortex(gray matter)

Basic Anatomy of the Cerebral Cortex

The cerebral cortex is the largest part of the brain and located in theupper part of the brain. It is associated with functions such as speech,logic, emotional responses, and voluntary movement. Epileptic eventsoccur most frequently in the hippocampus, located in the medialtemporal lobe. The type of epilepsy that occurs in this organ is knownas temporal lobe epilepsy (TLE), and is the most common form seenin adults (Ang et al., 2006; Kandratavicius et al., 2014). Thehippocampus, from the Greek hippokampus (“hippo” meaning horseand “kampus” meaning “sea monster”) is a seahorse shaped-structurethat controls memory formation and organization and is composedof three major regions: the subiculum, Ammon's horn, and the dentategyrus (Figure 2.2). Within the cerebrum the occipital lobe controls

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vision, while the frontal lobe controls the primary motor area. Epilepsycan occur in both areas, but these types only account for 5% of allepileptic disorders.

Figure 2.2 Anatomy of the Hippocampus (Bromfield, 2006)

Optic Tract Caudate nucleus

Inferior homlateral ventricle

Dentate gyrus

Entorhinal cortex

Subiculum

Fimbria

CA3

CA2

CA1

Neurons and Their Function

Neurons (nerve cells) are specialized cells of the nervous systemresponsible for transmitting messages, known as nerve impulses, fromone part of the body to another. Neurons are made of a cell body andfibers, also known as processes. The fibers responsible for incomingnerve impulses to the cell body are known as dendrites, while the onesthat conduct impulses away are called axons. Each neuron hashundreds of dendrites, but only one axon that ends to form hundredsto thousands of axon terminals (Figure 2.3).

Figure 2.3 Basic Structure of a Neuron (Marieb, 2010)

In terms of function, afferent (sensory) neurons conduct impulsesfrom sensory receptors (e.g. in the skin or muscles) to the CNS, whileefferent (motor) neurons conduct impulses from the CNS toperipheral parts of the body. Interneurons (approximately 20%) arecells that link communication between afferent and efferent neurons(Bromfield et al., 2006) (Figure 2.4).

Dendrite

Mitochondrion

Cell body

Neurofibrils

Axon hillock

Nissl substance

Axon

Nucleus

One Schwann cell

Node of Ranvier

Schwann cells,forming themyelin sheathon axon

Axonal terminal

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Figure 2.4 Functional Classification of Neurons (Marieb, 2010)

Axon terminals are composed of microscopic vesicles containingneurotransmitters, chemicals that propagate signals across tiny gaps(synapses) and bind to receptors on the membranes of the nextneuron (Marieb, 2012). Two of the major neurotransmitters in thebrain are glutamate and GABA. Glutamate acts via two classes ofreceptors, ligand gated ion channels, which open and allow ions(charged molecules) to pass through the membrane when they bindto glutamate, and G-protein coupled receptors, which start a proteinsignal transduction pathway inside the cell. Activation of thesereceptors transmits an action potential from one neuron to the nextand is thought to be the molecular mechanism underlying learning andmemory. GABA is the major inhibitory neurotransmitter in the brain,rather than initiating a new action potential (excitatory) in aneighboring neuron, GABA prevents action potentials. It acts throughtwo receptors GABAAR and GABABR; their activation induceshyperpolarization of the neuron at the end of an action potential(described in detail in the next section). Dysfunction inneurotransmitter receptors likely contributes to CNS disorders suchas epilepsy, and hence could be therapeutic targets.

Peripheralprocess(axon)

Afferenttransmission

Efferenttransmission

Peripheral nervous system

Ganglion Cell body Spinal cord(central nervoussystem)Central

process(axon)

Associationneuron(interneuron)

Motor neuron

Neuronal Excitability: the Action Potential

Different stimuli (e.g., light for eye receptors) are capable of excitingneurons to activate and generate a nerve impulse. Nerve impulses arethe basis of the electrical signals in the brain. The electrical activitycan be “seen” through an EEG where electrodes are attached to theskull. The basis of neuronal excitability is the action potential. Theaction potential is an all-or-nothing-response that involves the entireaxon and leads to the release of neurotransmitters (Marieb, 2010). Inthe resting state, a neuron is highly polarized across its cellularmembrane and carries a negative charge (-70mV). The extracellularconcentration of Na+ is much higher than the intracellularconcentration, and the intracellular K+ concentration is much higherthan the extracellular concentration of K+. When the neuron isstimulated Na+ channels open in the cell membrane, this allows Na+from outside the cell to enter the cell and completely reverses itspolarity, so the electrical charge switches from -70mV to +100mV.This is known as depolarization and initiates an action potential.Depolarization opens additional voltage gated Na+ channels furtherdown the axon as the intracellular concentration of Na+ increasescausing the action potential to propagate along the neuronalmembrane. When the membrane potential is reversed (+100mV) theNa+ channels close. At the same time, voltage gated ion channels thatare specific for K+ open and allow K+ to exit the cell, causing theneuron to become hyperpolarized (more negative voltage than in theresting state). Hyperpolarization prevents the action potential fromtraveling backward up the axon until the neuron can reset.

Pathophysiologic Mechanisms

Although the mechanisms underlying epilepsy are still being elucidated,it has been shown that abnormally repeated action potentials triggeredinitially by depolarization in abnormal neurons can induce a seizure.The electrical activity of a large number of neurons becoming linkedtogether creates a cascade effect, generating a series of actionpotentials, which may eventually spread to other areas of the brain.

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Alteration of Inhibition and Excitation

Overall, seizures that generally characterize all types of epilepsy resultfrom an imbalance between normal excitatory and inhibitory processesin the brain. Electrical discharges that initiate a seizure are triggeredin a specific region of the cerebral cortex and subsequently spread tonearby regions. The start of a seizure features continuous actionpotentials, and hypersynchronization of a specific neuronal population(e.g. neurons within the hippocampus,). These events are usuallysuccessfully recorded by an EEG. Within single neurons, epilepsy isthe result of continuous depolarization events inducing bursts ofaction potentials and the loss of GABA-mediated inhibitoryinterneurons, which can increase the hyperexcitability leading torecurrent seizures. This dramatic sequence of events is called theparoxysmal depolarizing shift. Studies have demonstrated how T-typeCa2+ channels regulate excitability of neurons in both normal andpathological brain function in a number of processes, including sleeprhythms, pain mechanisms, and epilepsy (Cheong and Shin, 2013).

Epileptogenesis

Epileptogenesis is the onset of epilepsy. It is a process involvingmolecular and cellular changes in the cerebral cortex, which increaseneuronal excitability, and eventually lead to recurrent spontaneousseizures (Gonzalez, 2013). Epileptogenesis involves a slow and gradualtransformation of neural networks over time. Changes occurringduring this time, called the latent or silent period, are critical and mayinvolve a plethora of molecular, biochemical, and physiologicaltransformations within the neuronal networks. The most common andbest characterized type of epilepsy is TLE, where epileptogenesis ischaracterized by exaggerated neuronal excitability, followed by deathof interneurons within the hippocampus (Bromfield et al., 2006).Granule cells of the dentate gyrus can also be damaged in this process.One of the molecular events that is thought to contribute toepileptogenesis in TLE is reduced expression of GABAAR at theplasma membrane, which may contribute to increased neuronexcitability (González, 2013). One hypothesis is that decreasedexpression of the synaptic protein gephyrin might interfere with the

recycling of GABAAR, thereby reducing the stability of the receptorwithin the plasma membrane and leading to reduced receptorexpression. Interestingly, animal models of epilepsy have shown thatfollowing repeated seizures the expression of neurotransmittersreceptors in the brain becomes reminiscent of the immature brain withunderexpressed inhibitory receptors (e.g. GABA receptors) andoverexpressed excitatory receptors (e.g. glutamate receptors)(Fernandez et al., 2014).

Epilepsy Co-morbidities

People affected by epilepsy are at high risk for comorbidities that maylead to difficulties in disease management and cause early mortality.Both psychiatric and non-psychiatric diseases have been found tocoexist and complicate epilepsy. Adults with epilepsy have an increasedprevalence of anxiety, depression, and bipolar disorder but alsodiabetes, high blood pressure, asthma, and pain associated conditionssuch as migraines and fibromyalgia (Ottman et al., 2011). Specific co-morbidities are discussed below.

AutismSeveral studies have reported the possible association of epilepsy withautism, speculating the two may share some common pathophysiologicmechanisms, although exact mechanisms are still poorly understood(Berg et al., 2012). Some of the hypotheses include the possible sharingof an underlying encephalopathy characterized by abnormalneurological activity. Interestingly, in absence of mental retardation orcerebral palsy in autistic patients, the risk of epilepsy decreasesdramatically. Different theories have been proposed to explain therelationship between the two conditions, including occurrence of bothearly in development or being two different forms of the same brainpathology (Levisohn, 2007).

Psychiatric, Cognitive and Social ComorbiditiesThe relationship between epilepsy and psychiatric, cognitive and socialdisorders has been well-established (Lin et al., 2012). In children, theassociation with psychiatric disorders such as anxiety and deficithyperactive disorder has been well documented, particularly in epilepsy

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with a brain lesion. Epilepsy affects the brain physically in several waysin children. Figure 2.5A shows how gray matter pruning occurs duringnormal brain development, with red areas indicating thicker and blueareas denoting thinner cortical regions. Children with generalizedepilepsy exhibit thinning in several regions of the cerebral cortex andreduction in gray matter pruning (red regions) and white matterexpansion (blue regions), compared with their healthy peers (Figure2.5B). The epileptic brain also shows accumulation of tau protein38in the temporal pole (Figure 2.5C1) and hippocampus (Figure2.5C2), and inflammatory changes (Figure 2.5C3-4) in thehippocampus of patients with TLE. The cognitive changes and brainatrophy are more pronounced in epilepsy patients than healthycontrols (Figure 2.5D).

Learning disabilities and academic achievement problems were alsofound to be more prevalent in children with epilepsy when comparedwith other children in community-based studies. Children with epilepsyalso exhibited a diminished capacity of social interactions, impactingpeer interactions, independence, and employment later in life. Similarpatterns were described in adults, with dramatic consequences onmemory, visual perception, employment, and lifestyle quality (poornutrition, obesity, and smoking). Figure 2.6 shows the framework forunderstanding mediators in psychiatric, cognitive, and socialcomorbidities of epilepsy (Lin et al., 2012).

Figure 2.5 Neurodevelopmental Changes in Pediatric Epilepsy(Lin et al., 2012)

Altered Neurodevelopmental Trajectory in Pediatric Epilepsy

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Figure 2.6 Mediators of Neurobehavioral Comorbidities ofEpilepsy (Lin et al., 2012)

Conclusion

Epilepsy is a complex disorder affecting the basic physiology of thecerebral cortex, characterized by recurrent seizures with or withoutpreexisting brain lesions. Mechanisms of disease development arepartially understood, but further studies are needed to elucidate thepathophysiology, especially in terms of different epilepsy syndromesin different areas of the brain and comorbidities. Future findings willprovide more solid evidence for developing antiepileptic treatmentsin both children and adults.

EpilepsySyndromes

UnderlyingBrain

Disorders

BrainDevelopmentand Aging

NeurobehavioralComorbiditiesCognitivePsychiatricSocial

CoreEpilepsy

Characteristics

Genotypic, psychological andsociocultural influences

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Chapter 3 Genetics and Epigenetics

Introduction

Epilepsies are a complex, multifaceted group of disorders that are theresult of an intricate relationship between acquired, environmental, andhereditary factors. Figure 3.1 shows the approach that has been usedmost often to understand the interplay between genetics and epilepsyphenotypes. Historically, the relationship between genes and epilepsyhas been examined by comparing DNA isolated from peripheral bloodsamples to epileptic endophenotypes. Endophenotypes are stablemeasurable phenotypes, like brain blood flow or protein expression,that link genetic information and behavioral phenotypes, such asprocessing speed or attention. More recently, new technologies haveallowed studies that focus on characterizing the epigenetic, proteomic,and transcriptomic profiles in the brains of epileptic patients andhow they relate to endophenotypes and cognitive processes inepilepsy (Busch et al., 2014).

Genetics of Epilepsy Disorders

Technical advances in molecular genetics have improved our ability toidentify genetic mutations that are involved in the development ofepilepsy over the last fifteen years. Two of the key advances areOligonucleotide Arrays Comparative Genomic Hybridization (Array-CGH) and Next-Generation Sequencing (NGS) (Garofalo et al., 2012).Array-CGH is a molecular technique based on the co-hybridizationof sample and control genomic DNA, and allows the identificationof the subtlest chromosomal abnormalities associated with epilepsy.NGS is an attractive sequencing technique in the field of epilepsy,because it increases the amount of sequencing data, while reducingthe cost per nucleotide. Due to the heterogeneous nature of epilepsy,

Processing speed

AttentionWorkingmemory

Visuospatial skills

Language

Executive functionEpisodic memory

Figure 3.1 Relationship Between Genetics and Epigenetics inCognitive Phenotypes of Epilepsy (Busch et al., 2014)

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a selection of genes, mutations, and pathways identified in associationwith the most prominent disease groups will be discussed. Distinctgenes appear to be connected to different epilepsy disorders, althoughsome are involved in more than one type (e.g. SCN1A).

Generalized and Idiopathic Epilepsy

Generalized epilepsy is a type of disorder that cannot be attributed toany specific cause. Partial idiopathic epilepsy comprises different partialepilepsy syndromes of unknown origin, but is often genetic in nature.Both are associated with typical absence and primary generalized tonic–clonic seizures and will be discussed together. Table 3.1 reports genesidentified via array-CGH and NGS in generalized and idiopathicepilepsies and febrile seizures, as these conditions share some commongenetic loci. Most of these are genes associated with eitherchannelopathies, which are disorders that affect ion channel subunits(e.g., CACNA1A, KNMA1, and SCN1A), or genes that directly affectthe activity of excitatory or inhibitory neurotransmitters in the nervoussystem (e.g., GABRA1 and GRIN2A). Mouse models of febrileseizures have shown that K+ channels and T-type Ca2+ channels playimportant roles in the generation of seizures, and suppression of theirfunction in knock-out mice can antagonize epileptogenesis (Lerche etal., 2013).

noitpircseDdnaemaNeneGlobmySeneG

1Arebmem,ylimaf7esanegordyhededyhedlA1A7HDLA

2gniniatnocniamodomorB2DRB

tinubusA1ahpla,epytQ/P,tnedneped-egatlov,lennahcmuiclaCA1ANCAC

tinubusH1ahpla,epytT,tnedneped-egatlov,lennahcmuiclaCH1ANCAC

tinubus4ateb,tnedneped-egatlov,lennahcmuiclaC4BNCAC

rotpecergnisnes-muiclaCRSAC

)lanoruen(2ahpla,cinitocin,rotpecercigrenilohC2ANRHC

4ahpla,cinitocin,rotpecercigrenilohC4ANRHC

)lanoruen(2ateb,cinitocin,rotpecercigrenilohC2BNRHC

2lennahcedirolhC2NCLC

)Bnfiets(BnitatsyCBTSC

1gniniatnoc)lanimret-C(niamoddnah-FE1CHFE

)nirofal(esaesidarofaL,A2epytsunolcoymevissergorp,yspelipEA2MPE

1ahpla,rotpecerA)ABAG(dicacirytubonima-ammaG1ARBAG

3ateb,rotpecerA)ABAG(dicacirytubonima-ammaG3BRBAG

atled,rotpecerA)ABAG(dicacirytubonima-ammaGDRBAG

2ammag,rotpecerA)ABAG(dicacirytubonima-ammaG2GRBAG

89rotpecerdelpuoc-nietorpG89RPG

A2etatrapsa-Dlyhtem-N,ciportonoi,rotpeceretamatulGA2NIRG

B2etatrapsa-Dlyhtem-N,ciportonoi,rotpeceretamatulGB2NIRG

1rebmemahpla,Mylimafbus

,lennahcdetavitca-muiclacecnatcudnocegralmuissatoP1AMNCK

2rebmem,ylimafbusekil-TQK,lennahcdetag-egatlovmuissatoP2QNCK

3rebmem,ylimafbusekil-TQK,lennahcdetag-egatlovmuissatoP3QNCK

7gniniatnocniamodnoitasiremartetlennahcmuissatoP7DTCK

5nietorpniamodgnidnib-GpC-lyhteM5DBM

lairdnohcotim,tnedneped-)+(DAN,2emyznecilaM2EM

1gniniatnoctaeperLHN1CRLHN

91nirehdacotorP91HDCP

)alihposorD(1golomohelkcirP1ELKCIRP

)alihposorD(2golomohelkcirP2ELKCIRP

2rebmem,BssalcrotpecerregnevacS2BRACS

tinubusahpla,Iepyt,detag-egatlov,lennahcmuidoSA1NCS

tinubusateb,Iepyt,detag-egatlov,lennahcmuidoSB1NCS

tinubusahpla,IIepyt,detag-egatlov,lennahcmuidoSA2NCS

tinubusahpla,XIepyt,detag-egatlov,lennahcmuidoSA9NCS

1rebmem,)retropsnartesoculgdetatilicaf(2ylimafreirracetuloS1A2CLS

42rebmem,ylimafniamod1CBT42D1CBT

Table 3.1 Genes Involved in Generalized Epilepsy and FebrileSeizures (Garofalo et al., 2012)

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Dravet Syndrome and Other SyndromicEpilepsies

Dravet syndrome (DS), also known as Juvenile Myoclonic Epilepsy(JME), is another common form of epilepsy, accounting for about 7%of all epilepsy cases. This disorder is often inherited and genesassociated with developing DS are located on chromosomes 6, 8, or15. The genetic mutations that are known to be involved in DS aresummarized in Table 3.2. Like idiopathic epilepsy, DS is considered achannelopathy and mutations in the SCN1A gene, encoding thevoltage-gated sodium channel, type I, alpha subunit, are encounteredin 85% of all patients (Akiyama et al., 2012). Other genes that havebeen linked to DS include PCDH19, which encodes protocadherin 19,and produces a milder form of DS when mutated, and GABRG2encoding for GABAA receptor, type II, gamma subunit.

Table 3.2 Genes Involved in Dravet Syndrome (Akiyama et al., 2012)

1 (2q24)

19 (X q22)

2 (5q34)

1 (19q13)

2 (2q24)

9 (2q24)

4 (2q22-q23)

Voltage-gatedsodium channel α1subunit

Around 85% Typical andborderlineDravetsyndrome

Claes et al.Depienne et al.

Protocadherin 19 Around 5% Mild type ofDravetsyndrome

Depienne et al.

GABAA receptor γ2subunit

Rare Not yetestablished

Harkin et al.

Voltage-gatedsodium channel β1subunit


Patino et al.



Shi et al.


Unknown Modi!er Singh et al.

Voltage-dependentcalcium channel β4subunit

Unknown Modi!er Ohmori et al.

Gene (location) ProductProportion of

cases in Dravetsyndrome

Contribution References

Table 3.3 Genes Identified in Syndromic Epilepsy (Garofalo et al., 2012)

emordnySnoitpircseDdnaemaNeneGlobmySeneG

aipotoretehralucirtnevireP2FEGrotcafnoitalysobir-PDA2FEGFRAyspelipehtiwaixelpkerepyH9FEG24cdC9FEGHRA

Ataxin 2-binding protein 1(RNA binding protein fox-1 homolog 1)

emordnysnavanaCesalycaotrapsAAPSAeniargimcigelpimehlailimaF

editpepylop2ahpla,gnitropsnartK/aN,esaPTA2A1PTA

emordnysetihW-reiraD2hctiwtwols,elcsumcaidrac

,gnitropsnartaC,esaPTA2A2PTA

noitadraterlatnemdnayspelipehtiwaxalsituC

2atinubus0Vlamososyl,gnitropsnart+H,esaPTA2A0V6PTA

Calcium channel, voltage-dependent,P/Q type, alpha 1A subunit

mulucitrevidlaidemhtiwsulahpecordyHC88gniniatnocniamodlioc-delioCC88CDCC

emordnysrettraBaKlennahcedirolhCAKNCLCemordnysrettraBbKlennahcedirolhCBKNCLC

Cohen syndrome protein 1—vacuolarprotein sorting 13 homolog B

noitadraterlatnemhtiwyspelipeevissergorP

2nietorpdetaicossa-golomoh)alihposorD(egral,scsiD2PAGLD

esaesidrednaxelAnietorpcidicayrallirbfilailGPAFGemordnysllah-retsillaP3regnficnizylimafILG3ILG

aixelpkerepyH1ahpla,rotpecerenicylG1ARLGaixelpkerepyHateb,rotpecerenicylGBRLGaixelpkerepyHniryhpeGNHPGaixatacidosipE

detaler-rekahs,lennahcdetag-egatlovmuissatoP1ANCK

Potassium inwardly rectifying channel,subfamily J, member 1Potassium inwardly rectifying channel,subfamily J, member 10

neztnirphS-grebdloGnietorpgnidnib1rebmemylimafniseniK9721AAIKycneicfiednisoreM2ahpla,ninimaL2AMAL

emordnysteuH-regleProtpecerBnimaLRBL

yspelipeebollaropmetlaretaltnanimodlamosotuA1detavitcaniamoilg,hcir-enicueL1IGL

A2BP1

CACNA1A

COH1

KCNJ1

KCNJ10

M

Bartter syndrome

Seizures, deafness, ataxia,mental retardation

Mental retardation and epilepsy

Cohen syndrome

Familial hemiplegic migraine

Several other syndromic epilepsies also have a genetic basis. Thecommon gene mutations associated with the syndromes aredescribed in Table 3.3. Of note is the discovery of a mutation inthe LGL1 gene, encoding for leucine rich, glioma inactivated 1protein, as it is implicated in the well-established autosomaldominant lateral–temporal lobe epilepsy (TLE), one of the mostcommon forms in adults (Rees, 2010).

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Megalencephalic leukoencephalopathywith subcortical cysts 1

emordnysikubaK2aimekuelegaenil-deximrodiohpmyl/dioleyM2LLM

sisotamorbfiorueN1nimorbfiorueN1FNemordnysegnaLedailenroC)alihposorD(golomohB-deppiNLBPIN

noitalumuccanoriniarbhtiwnoitarenegedorueN2esaniketanehtotnaP2KNAP

Serpin peptidase inhibitor, clade I(neuroserpin), member 1

noitadraterlatnemhtiwaisatahpsohprepyH

Vssalc,sisehtnysoibrohcnanacylglotisonilyditahpsohPVGIP

Phospholipase A2, group VI(cytosolic, calcium independent)

MLC1

PI12

PLA2G6

Megalencephalicleukoencephalopathy with cysts

Encephalopathy withneuroserpin inclusion bodies

Infantile neuroaxonal dystrophy

M

Epilepsy with Encephalopathy and MentalRetardation

Epileptic encephalopathies are characterized by the development ofseizures at a very early age. The electric discharge of these aggressiveand continuous seizures interferes with the normal function of thedeveloping brain possibly causing cognitive and neuro-psychologicaldeterioration later in life. The genes involved in thisneurodevelopmental epilepsy group are numerous and varied in nature.Examples are gene mutations causing early infantile epilepticencephalopathy, including SCN1A, SCN1B, SCN2A, and SNC8A,which encode sodium channel protein subunits (Garofalo et al., 2012;O’Brien et al., 2013), and GRIN2A and GRIN2B, which encodeglutamate receptor subunits (Table 3.4). Of note is the mutation orabsence of the X-linked methyl-CpG-binding protein 2 gene (MECP2)in Rett syndrome, as this protein plays a major role in the normalfunction of mature neurons by maintaining synaptic contacts. MECP2also plays a major role in gene expression mechanisms by modifyingchromatin, the molecule complex that organizes and packages DNAinto chromosomes. The MECP2 gene was discovered in 2004 andfound to be duplicated in hypotonic male infants with milddysmorphic features (Ramocki et al., 2010).

Table 3.4 Genes Associated with Epilepsies Occurring withEncephalopathies (Garofalo et al., 2012)

sesaesiDnoitpircseDdnaemaNeneGlobmySeneG

ARHGEF9 Cdc42 guanine nucleotideexchange factor (GEF) 9

Early infantile epilepticencephalopathy

yhtapolahpecnecitpelipeelitnafniylraExoboemohdetalersselatsirAXRA

yhtapolahpecnecitpelipeelitnafniylraE

5ekil-esaniktnedneped-nilcyC5LKDC

emordnyssnikpoHttiP2ekil-nietorp

detaicossanitcatnoC2PANTNC

emordnystteR1GxobdaehkroF1GXOFGABRG2 Gamma-aminobutyric acid (GABA)

A receptor, gamma 2Early infantile epilepticencephalopathy

GRIN2A Glutamate receptor, ionotropic,N-methyl D-aspartate 2A


GRIN2B Glutamate receptor, ionotropic,N-methyl D-aspartate 2B


emordnystuatsaGxonneL01esaniknietorpdetavitca-negotiM01KPAMemordnystteR2nietorpgnidnibGpClyhteM2PCEM

emordnySsnikpoHttiP1nixerueN1NXRN

yhtapolahpecnecitpelipeelitnafniylraE91nirehdacotorP91HDCP

yhtapolahpecnecitpelipeelitnafniylraEesatahpsohp-’3esanikeditoelcunyloPPKNP

emordnyssereituoG-idraciAAtinubus,2HesaelcunobiRA2HESANR

emordnyssereituoG-idraciABtinubus,2HesaelcunobiRB2HESANR

emordnyssereituoG-idraciACtinubus,2HesaelcunobiRC2HESANR

emordnyssereituoG-idraciA1niamodDHdnaniamodMAS1DHMAS

SCN1A Sodium channel, voltage-gated,type I, alpha subunit


SCN1B Sodium channel, voltage-gated,type I, beta subunit

Early Infantile epilepticencephalopathy

SCN2A Sodium channel, voltage-gated,type II, alpha subunit

Early infantile epilepticEncephalopathy

SCN9A Sodium channel, voltage-gated,type IX, alpha subunit


SLC2A1 Solute carrier family 2 (facilitatedglucose transporter), member 1

GLUT1 deficiencysyndrome

SLC25A22 Solute carrier family 25 (mitochondrialcarrier: glutamate), member 22


SLC9A6 Solute carrier family 9 (sodium/hydro-gen exchanger), member 6

Angelman syndrome

Spectrin, alpha, non-erythrocytic 1(alpha-fodrin)

SPTAN1 Early infantile epilepticencephalopathy


1nietorpgnidnibnixatnyS1PBXTS

emordnyssnikpoHttiP4rotcafnoitpircsnarT4FCT

emordnyssereituoG-idraciA1esaelcunoxeriaperemirpeerhT1XERT

emordnysnamlegnAA3EesagilnietorpnitiuqibUA3EBU

emordnysnosliW-tawoM2xoboemohgnidnibxob-EregnficniZ2BEZ

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Additional genes are reported in concomitance with mental retardation(Table 3.5). Examples are genes encoding a heterogeneous group ofproteins identified in epilepsy with X-linked mental retardation,encompassing neurotransmitter receptors (e.g. GRIA3), oncogeneproteins (e.g. RAB39B), and kinases (e.g. PAK3) (Garofalo et al., 2012).

Table 3.5 Partial List of Epilepsy Types with Mental Retardation(Garofalo et al., 2012)

esaesiDemaNlobmySeneG

(a) Mental Retardation (25 Genes)

yhtapolahpecnecitpelipeelitnafniylraE

9)FEG(rotcafegnahcxeeditoelcuneninaug24cdC9FEGHRA

yhtapolahpecnecitpelipeelitnafniylraExoboemohdetalersselatsirAXRA

ATP6AP2 ATPase, H+ transporting,lysosomal accessory protein 2

Epilepsy with XLMR*

ATRX

CASK Calcium/calmodulin-dependentserine protein kinase(MAGUK family)

Mental retardationand microcephaly

yhtapolahpecnecitpelipeelitnafniylraE5ekil-esaniktnedneped-nilcyC5LKDC

R*MLXhtiwyspelipEB4nilluCB4LUC

emordnyslemheB-ibaloG-nospmiS1emordnyslatigid-laicaf-larO5FROXC

ylahpecnessiLnitrocelbuoDXCD

emordnysttocS-goksraA1gniniatnoc

niamodHPdnaFEGohR,EVYF1DGF

emordnyslemheB-ibaloG-nospmiS3nacipylG3CPG

R*MLXhtiwyspelipE3APMA

,cihportonoi,rotpeceretamatulG3AIRG

R*MLXhtiwyspelipE01esanegordyhed

)ateb-71(dioretsyxordyH01B71DSH

R*MLXhtiwyspelipEC5esalyhtemedcfiiceps-)K(enisyLC1DIRAJ

R*MLXhtiwyspelipE1ninerhpogilO1NHPO

R*MLXhtiwyspelipE3esanikdetavitca

-)caR/24cdC(nietorp12P3KAP

emordnysnnamheLnnamssroFnosejroB6nietorpregnfiDHP6FHP

esaesidrehcabzreM-sueazileP1nietorpdipiloetorP1PLP

R*MLXhtiwyspelipE1nietorpgnidnibenimatulgyloP1PBQP

R*MLXhtiwyspelipEylimafenegocno

SARrebmem,B93BARB93BAR

Epilepsy with XLMR*Alpha thalassemia/mentalretardation syndrome X-linked

Progressive Myoclonic Epilepsy

Progressive myoclonic epilepsies (PME), characterized by severemyoclonic and tonic-clonic seizures, are among the rarest epilepsy typesand often arise from hereditary metabolic disorders. Mitochondrialdisorders are included under the umbrella of PME and inherited throughthe maternal line as a consequence of abnormalities in DNA or specificgenes within mitochondria, the energy factories of our body. Mutationsto the mitochondrial DNA are linked to a number of epileptic syndromesdiscussed below.

Unverricht-Lundborg disease is an autosomal recessive inherited disorderresulting from a mutation of the EPM1 (CSTB) gene, encoding epithelialmembrane protein 1; the specific gene mutation is a 12-base pair repeatin the cystatin B gene located on chromosome 21. Although the role ofcystatin B is still not completely understood, it may participate inpreventing cathepsins (protein-degrading enzymes) from leaking out oflysosomes, cell vesicles that help digest foreign material. Levels of cystatinB in individuals affected by Unverricht-Lundborg disease are dramaticallydecreased due to the mutation described above, and as a consequencecathepsin levels are significantly increased. This process is thought tocause signs and symptoms of Unverricht-Lundborg, but the exactmechanism is still unknown.

Lafora progressive myoclonus epilepsy is caused in up to 90% of all casesby mutations in either EPM2A or NHLRC1 (EPM2B) genes, encodingfor proteins known as laforin and malin, respectively (Figure 3.2).

SLC9A6 Solute carrier family9 (sodium/hydrogenexchanger), member 6

Angelman-Like syndrome

emordnysegnaLeDailenroCA1semosomorhc

foecnanetniamlarutcurtSA1CMS

R*MLXhtiwyspelipEesahtnysenimrepSSMS

yspelipecidnaloR2deknil-X

,nietorpgniniatnoctaeper-ihsuS2XPRS

R*MLXhtiwyspelipEnisyhpotpanySPYS

*XLMR: X-linked mentaretardation

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Figure 3.2 Diagrams of Domain Organization of EMP2A andNHLRC1 (EMP2B) Genes (Spuch et al., 2012)

Laforin and malin are known to co-localize in the endoplasmicreticulum (ER), the cell organelle responsible for protein transport,and work together to regulate the production of glycogen and preventits buildup in the body. Cells from patients with Lafora progressivemyoclonus epilepsy present with clumps called Lafora bodies, anabnormal accumulation of glycogen in nerve cells that ultimatelycauses nerve damage. Both EPM2A and NHLRC1 are involved in theproduction of Lafora bodies, although the exact contributions are stillunclear (Spuch et al., 2012).

Mitochondrial encephalopathy, lactacidosis, and stroke-like episodes(MELAS) is a mitochondrial disorder that induces stroke-like episodesbefore 40 years of age. The transfer RNA (tRNA) gene, MT-TL1(mitochondrially encoded tRNA leucine 1) is responsible for morethan 80 percent of all cases of MELAS. Mutation of MT-TL1 reducestRNA aminoacylation and modifies its anti-codon wobble position,leading to defective mitochondrial protein synthesis and reducedactivities of respiratory chain complexes (Karicheva et al., 2011).Mutations from other genes, including MT-TH, encoding a tRNA

histidine, MT-TV, encoding a tRNA valine and MT-ND5, whichencodes the NADH-ubiquinone oxidoreductase subunit 5 havealso been described.

Another mitochondrial disorder with epileptic seizures similar toMELAS is myoclonic epilepsy with ragged red muscle fibers(MERRF). MERRF syndrome is characterized by myoclonic andgeneralized tonic-clonic seizures. About 80% of individuals affectedby MERRF carry the 8344A>G mutation in the lysine tRNA gene(MT-TK) (Spuch et al., 2012). This mutation affects the translation ofmitochondrial DNA encoded proteins, disrupting the assembly of theelectron transport chain complexes, ultimately decreasingmitochondrial respiratory function (De la Mata et al., 2012). Additionalmutations involved in MERFF have been found in other tRNA genes(MT-TL1, MT-TH) or in the MT-ND5 gene as in the case of MELAS.

Epigenetics

Epilepsy can induce permanent pathophysiologic changes in thenervous system that ultimately impact gene expression patterns. Aclear understanding of the epigenetic and epigenomic factors thataffect the natural history and progression of complex epileptic diseasestates could ultimately lead to more effective treatment and preventionstrategies. The role of DNA methylation and other epigeneticprocesses is to regulate gene transcription, maintain genomic integrity,and modulate gene expression of cells and tissues duringdevelopmental stages and throughout life. In the CNS, DNAmethylation abnormalities are associated with epilepsy.

DNA MethylationDNA methylation is a gene regulation mechanism involving themodification of a DNA strand after its replication. In this process, amethyl group is added to a cytosine on the DNA helix, causingsuppression of the gene involved. DNA methylation factors play anessential role in the pathogenesis of epileptic disorders. For example,Rett syndrome, caused by mutations in the MECP2 gene, is the result

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of abnormal expression and function of the methyl-CpG-bindingdomain protein involved in gene regulation at methylated genomic loci(Qureshi and Mehler, 2010). MECP2 interacts with transcriptionalrepressors such as Nuclear Receptor Corepressor (NCoR). MECP2 isalso implicated in the formation of large chromatin loops and involvedin the regulation of RNA splicing (Qureshi and Mehler, 2010). DNAmethylation also impacts TLE by regulating the expression of Reelin(RELN), an extracellular matrix protein essential for the migration ofhippocampal granule cells during brain development, and importantfor the maintenance of the dentate gyrus integrity later in life. RELNpromoter methylation was found to be greater in temporal lobeepilepsy specimens when compared to healthy controls. Theupregulation of RELN correlated with granule cell dispersion (GCD),a physiopathologic feature of TLE in which the tight organizationof the dentate gyrus granule cells is lost, and axons need to stretchlonger to reach neighboring granule cells for communication(Qureshi and Mehler, 2010).

ChromatinChromatin is a macromolecule involved in packaging DNA within thecell nucleus, and it plays a role in controlling gene expression and DNAreplication. Similar to DNA methylation, regulation of chromatin inneural cells mediates several aspects of nervous system development,and mutations in its structure are associated with neurologic disorders.One of the features of epilepsy, particularly the type associated withmental retardation (e.g., mutations in alpha thalassemia/mentalretardation syndrome X-linked (ATRX) gene), is biotin deficiency.Biotin is a key coenzyme in the metabolism of fatty acids, amino acids,and glucose. Chromatin is regulated in part by the addition of biotinmolecules, a process called biotinylation. ATRX is a chromatinremodeling enzyme that interacts with several epigenetic factors,including MECP2, and mediates transcriptional regulation,heterochromatin formation, DNA repair, and chromosomesegregation. Other major proteins involved in chromatin regulationand gene expression are KDM5C, a histone demethylase enzyme, andREST (Repressor Element 1-Silencing Transcription factor), atranscriptional repressor that recruits histone deacetylases,demethylases, and methyltransferases to cause epigenetic remodeling

of chromatin architecture. REST was induced in hippocampal anddentate granule neurons in experimental animal models of epilepsy(Figure 3.3). REST also regulates the expression of various factorsimplicated in epileptogenesis such as growth factors, ion channels, andneurotransmitter receptors, as we all genes involved in neuronalexcitability (Roopra et al., 2012).

Figure 3.3 REST Protein Induction in Experimental Epilepsy inDentate Granule Neurons (Qureshi and Mehler, 2010)

Control Pilo, 5 hr

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Role of MicroRNAA microRNA (miRNA) is a 22-nucleotide non coding RNA sequencethat is implicated in post-transcriptional regulation of gene expression.Brain tissue obtained from patients with temporal lobe epilepsyshowed significant reduction of miRNA expression followingTaqMan® low-density array (TLDA) analysis, a technique used forhigh throughput screening by simultaneously detecting mRNAexpression of multiple genes (Dogini et al., 2013). Examples ofmiRNAs involved in epilepsy-associated inflammatory pathwaysinclude miR-146a, which has a role in the regulation of astrocyte-mediated inflammatory responses, and miR-155, which plays a criticalrole in inflammation of the blood brain barrier and is upregulated inthe hippocampus of children affected by TLE (Dogini et al., 2013).

Several miRNAs are associated with cerebral cortex development(Figure 3.4). In the first stage, stem cells undergo proliferation(regulated by miR-9, miR-124, miR-137, miR-184, and let-7b) andgenerate progenitors that differentiate into neurons, astrocytes, andoligodendrocytes (regulated by let-7b, miR-34a, miR-153, miR-324,and miR- 181a). In the second phase of development, neurons migratetoward the more external areas of the cortex (regulated by miR-9, miR-134, and miR-137), and finally in the third stage, the organization ofcortical layers is regulated by miR-137 and miR-125b (Figure 3.4).

Figure 3.4 miRNAs Implicated in Different Stages of CerebralCortex Development (Dogini et al., 2013)

I

II

III

IV

V

VI

Stem Cells

Progenitors

Neuron

Astrocyte

Oligodentrocyte

Proliferation

miRNAs

Stage:(weeks)

miR-9, miR-124, miR-137,

miR-184, let-7b

5th - 20th 6th - 24th 16th - 40th

miR-34a, miR-153, miR-324, miR-181a

miR-9, miR-134, miR-137

miR-125b, miR-137

Differentiation Neuronalmigration

Neuronal organization

The consequences of the dysregulation of the miRNAs that areassociated with these processes are summarized in Table 3.6. Bothanimal and human studies have implicated in the development ofcortical malformations, which are associated with epileptogenesis.

MicroRNA Human Studies/

Experimental Models

yspelipEnieloRlaitnetoP

Human; immature rat

Human; mousekainic acid

V

Human (in vitro experiments);mouse kainic acid

Suppresses evoked seizures;regulates cell migration

J

Human; rat

Human; mouse; rat

miR-324,miR-181a

Human; mousekainic acid

K

seruziesfoecnerruccoehthtiwdetaicossAHuman

Y

Rat pilocarpine

following status epilepticus

RHuman; rat pilocarpine;mouse kainic acid

Involved in seizure-inducedneuronal death; critical for

neural differentiation

A

Potential role in mesialtemporal lobe epilepsy;control cell proliferation

Regulates cell proliferation;critical for neural differentiationRegulation of astrocyte-mediated inflammatory response; neuralinflammation

Regulates cell proliferation;neuroprotective effect

Possible associated withincreased neuronal loss

R

Associated to neuronalactivatioand synaptic plasticity

miR-132

miR-134

miR-137

miR-184

miR-196b

miR-21

miR-34a

miR-124

miR-146

miR-153, Human; rat Critical role in neuraldifferentiation

Table 3.6 MicroRNAs and Their Potential Role in Epilepsy(Dogini et al., 2013)

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Human (in vitro experiments)

accelerates neuraldifferentiation

K Human; rat kainic acid

K

Regulates cell proliferation;promotes cell migration;

miR-9

let-7b Regulates cell proliferation

m

Conclusion

Epilepsies are a varied group of diseases whose causes are oftenunknown. In some instances, epilepsy disorders can be induced byenvironmental triggers, infection, tumors, genetics, or acombination of those factors. Many genes regulate the onset anddevelopment of epilepsy. Epigenetic mechanisms controllingepilepsy-associated genes are mediated via DNA methylation,chromatin, and miRNA expression.

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Chapter 4 Diagnosis and Guidelines

Introduction

Guidelines in medicine are designed to offer information and supportthe decision-making processes in patient care, based on a systematicreview of clinical research evidence and practice parameters.Professional, international, and national guidelines are in place to aidthe diagnosis, management, and treatment of epilepsy and a select listwill be discussed here. The development of biomarkers and techniquesfor the identification of seizure foci and diagnosis of epileptic disordersis essential for making decisions about treatment (drugs vs. surgery)and implement control strategies. The clinical diagnostic process isdiscussed below, highlighting some of the most novel technologies.

Guidelines

The International League Against Epilepsy (ILAE)The International League Against Epilepsy (ILAE) is the majorinternational association for epilepsy and disseminates the latestresearch and breakthroughs in the field. Its guidelines provideinformation on major aspects of epilepsy, including etiology, definitionsand classification, diagnostic tools, treatment, epidemiology andsurveillance, and pediatric disorders. The current etiologic classificationof epilepsy divides it into the well-known categories, idiopathic,symptomatic, provoked, and cryptogenic (Table 4.1). Suggestions foralternative definitions reflecting the diversity of epileptic disorders arecurrently being discussed.

ExamplesaSubcategoryMain category

Pure epilepsies dueto singlegene disorders

Benign familial neonatal convulsions;autosomal dominant nocturnalfrontal lobe epilepsy; generalizedepilepsy with febrile seizures plus;severe myoclonic epilepsyof childhood; benign adult familialmyoclonic epilepsy

Pure epilepsieswith complexinheritance

Idiopathic generalized epilepsy(and its subtypes); benign partialepilepsies of childhood

Symptomatic epilepsyPredominately geneticor developmentalcausation

Childhood epilepsysyndromes Progressivemyoclonic epilepsies

Neurocutaneous syndromesOther neurologic single gene disorders organic acidurias and peroxisomal

disorders; prophyria; pyridoxine-dependent epilepsy; Rett syndrome;Urea cycle disorders; Wilsondisease; disorders of cobalaminand folate metabolism

chromosome 15; ring chromosome 20

Developmentalanomaliesof cerebralstructure

Hemimegalencephaly;focal corticaldysplasia; agyria-pachygyria-bandspectrum; agenesis of corpuscallosum; polymicrogyria;schizencephaly; periventricularnodular heterotopia; microcephaly;arachnoid cyst

Predominatelacquired causation

Hippocampal sclerosis Hippocampal sclerosisPerinatal and infantilecauses

Neonatal seizures; postneonatalseizures; cerebral palsy; vaccinationand immunization

Open head injury; closed head injury; neurosurgery; epilepsy afterepilepsy surgery; nonaccidental head injury in infants

Cerebral trauma

Idiopathic epileps

West syndrome; Lennox-Gastaut syndrome Unverricht-Lundborg disease; Dentato-rubro-pallido-luysian atrophy;Lafora body disease;mitochondrial cytopathy;sialidosis; neuronalceroid lipofuscinosis;myoclonus renal failure syndrome

Tuberous sclerosis; neurofibromatosis;Sturge-Weber syndromeAngelman syndrome; lysosomaldisorders; neuroacanthocytosis;

Disorders ofchromosomefunction

Down syndrome;Fragile X syndrome;4p-syndrome; isodicentric

Table 4.1 Guidelines for Etiologic Classification of Epilepsy(Shorvon, 2011)

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Glioma; ganglioglioma and hamartoma; DNET; hypothalamichamartoma; meningioma; secondary tumors

Cerebral tumor

Viral meningitis and encephalitis; bacterial meningitis and abscess;malaria; neurocysticercosis, tuberculosis; HIV

Cerebral infection

Cerebrovasculardisorders

Cerebral hemorrhage; cerebral infarction; degenerative vasculardisease; arteriovenous malformation; cavernous hemangioma

Cerebralimmunologicdisorders

Rasmussen encephalitis; SLE and collagen vascular disorders; in�ammatory and immunologic disorders

Degenerativeand otherneurologic conditions

Alzheimer disease and other dementing disorders; multiple sclerosisand demyelinating disorders; hydrocephalus and porencephalyFever; menstrual cycle and catamenial epilepsy; sleep-wake cycle;metabolic and endocrine-induced seizures; drug-induced seizures;alcohol and toxin-induced seizuresalcohol and toxin-induced seizures

Provoking factors

Provoked epilepsy

Photosensitive epilepsies; startle-induced epilepsies;reading epilepsy; auditory-induced epilepsy; eating epilepsy; hot-water epilepsy

Re�ex epilepsies

DNET, dysembryoplastic neuroepithelial tumor.aThese examples are not comprehensive, and in every category there are other causes.bBy de�nition, the causes of the cryptogenic epilepsies are ‘‘unknown.’’ However, these are an important category, accounting for at least 40% of epilepsies encountered in adult practice and a lesser proportion in pediatric practice.This list is derived from the book Causes of Epilepsy (Shorvon et al., 2011).

Cryptogenic epilepsiesb

Although there are several reports from ILAE that offer informationon different drugs and their efficacy and effectiveness, best practiceshave been proposed for therapeutic drug monitoring (TDM), basedon serum concentration measurements following the administrationof old and new generation antiepileptic drugs (AEDs) (Patsalos et al.,2008). TDM can have a key role in guiding disease treatment andmanagement, and is based on specific recommendations for its optimalapplication (Table 4.2).

The ILAE guidelines also contain a comprehensive section dedicated topediatric epilepsy, including diagnostic tools through surgical options fortreatment.

The American Epilepsy Society (AES)Nationally, the American Epilepsy Society (AES) offers a series ofevidence-based guidelines and practice parameters to health careprofessional professionals to provide quality care to patients affected byepileptic disorders. Several practice parameters are in place for themanagement of epilepsy in pregnancy. Recommendations for pregnant

Table 4.2Ten Golden Rules for TDM in AED Therapy (Patsalos et al., 2008)

1. The application of TDM requires adequate knowledge of the specificpharmacokinetic and pharmacodynamic properties of the AED to bemonitored.

2. Ensure that the laboratory has adequate measures for quality control.3. Request the measurement of serum AED concentrations only when there

is a clear clinical question.4. Except for situations requiring immediate action (e.g., suspected toxicity,

or drug overdose), serum AED concentrations should be determinedat steady state.

5. Sampling time should be standardized, particularly with AEDs havingshort half-lives (≤12 h). Under most circumstances, a sample takenimmediately before the next dose will be adequate.

6. Interpretation of serum AED concentrations must take into account theinterval since the last dose intake and the expected pharmacokineticprofile of the AED being monitored.

7. Be aware that reference ranges of AED concentrations have solely aprobabilistic value, and that many patients may require concentrationsbelow or above these ranges. Make sure that the patient is informed aboutthe limitations of reference ranges.

8. When interpreting serum AED concentrations, consider situations whichmay alter the relationship between serum AED concentration and clinicalresponse (e.g., old age, type, and severity of epilepsy, clinical conditionsresulting in altered serum protein binding, presence of pharmacologicallyactive metabolites, possibility of pharmacodynamic interactions withconcurrently administered drugs).

9. Consider the possibility of applying the individual therapeuticconcentration concept (see text).

10.Treat the patient and not the serum concentration! Never make clinicaldecisions on the basis of drug concentrations alone. Take into accountinformation on patient history, clinical signs and symptoms, and anyrelevant additional laboratory information.

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Figure 4.1 10/20 System for EEG Electrode Positioning(Bromfield et al., 2006)

LeftSide

Front

RightSide

Back

A2A1

FP2F

F8F4FZF3F7

T3

PT5

O O1 2

3 P PZ

F

T64

4T

Z

PZ

CZ

3

F7

A1

T5 O1

FP1P3

C3

10%

10%

20%

Nasion

InionEar

Pg1

Vertex20%

20%

20%

T3

FP1

ZC

4CC3

women with epilepsy include supplementing with 0.4 mg folic acid beforebecoming pregnant and avoidance of valproic acid (VPA) and AEDpolytherapy to prevent possible fetal abnormalities (Harden et al., 2009).

Diagnosis of Epilepsy

The challenge of diagnosing epilepsy begins with correctly identifying aseizure, as patients rarely experience one during a medical visit. For thisreason, the diagnostic process should begin with obtaining a detailedmedical history and a thorough physical examination. As part of thephysical examination, clinicians are recommended to begin by examiningthe patient for head scars, head size, or any notable birth defects, followedby a skin examination for fibrous plaques or light brown patches, toexclude tuberous epilepsy. The patient should also receive a completeauditory test and be examined for vision defects including eye movementanomalies and retina function analysis. A generalized examination ofother body systems should also be conducted, including blood pressuretesting.

Diagnostic TestsEEG and SEEGThe use of electrophysiology is an essential tool for diagnosing epilepsy,particularly for distinguishing between generalized and focal seizures. Themost traditional and widely used test is the electroencephalogram (EEG),which records abnormal electrical discharges from a patient’s cerebralcortex, through electrodes positioned on the scalp (Figure 4.1).

Table 4.3 Differences Between PNES and Epileptic Seizures(Gedzelman and LaRoche, 2014)

PNES Epileptic Seizure

TimingDirectly induced by stress or confrontation

++ +

Waxes and wanes ++ -Occurs in physician office ++ -Worsens with witnesses in the room

++ -

SemiologyCrying + -Whispering + -Stuttering + -Opisthotonic posture + -Full body shaking with preserved awareness

++ -

Ictal cry - ++ (before GTC seizure)Post-ictal buzz saw snore - ++ (after GTC seizure)Eyes closed ++ -Head/body/eye version - ++ (focal seizure)Fencer’s posture - ++ (focal seizure)Side-to-side head movement + -

The electrode positioning is based on the 10/20 system, in which thelocation of an electrode on the scalp corresponds to an underlyingarea of cerebral cortex. Each letter identifies a specific lobe, frontal(F), temporal (T), central (C), parietal (P), and occipital (O). Evennumbers (2, 4, 6, 8) refer to the right brain hemisphere and oddnumbers (1, 3, 5, 7) to the left hemisphere. The Z refers to electrodeslocated on the midline (Figure 4.1). Patients may be required to carryan EEG monitor for several days or weeks before abnormal brainactivity is detected. EEG is also used to identify seizure zones beforesurgery. Recent advances include the use of video EEG todifferentiate between psychogenic nonepileptic seizures (PNES), thephysical manifestations of a psychological disturbance, and epilepsy(Table 4.3) (Gedzelman and LaRoche, 2014).

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Pelvic thrusting + +Cyanosis - + (during GTC seizure)Severe injury or trauma (burns and fractures)

- + (during GTC seizure)

When an EEG is not able to conclusively establish the nature of theepileptic disorder, the more invasive surgical test known asstereoelectroencephalography (SEEG) is used to define the areas ofthe brain where seizures originate.

During SEEG, surgeons place electrodes inside targeted areas of thebrain to precisely locate the source of the seizure. The SEEGtrajectory is planned using a robotic assistant device (ROSA®,Medtech®, Montpellier, France) native planning software . Registrationis then conducted using a face recognition method. The operatingroom is set up with the patient under general anesthesia and the robotis appropriately situated before the procedure begins. Pinholes arecreated in the dura using 2-mm-diameter handheld drill, with roboticguidance. Finally, the patient is ready for SEEG recordings.

NeuroimagingThe use of MRI has become an essential tool for evaluating anddiagnosing epilepsy patients, and identifying surgical candidates. MRIprovides anatomic and pathological information about the brain,especially when combined with other techniques, such as fluid-attenuated inversion recovery (FLAIR), which improves imagingcontrast. High Resolution MRI can detect even subtle changes such ascortical dysplasia. Real-time functional MRI (fMRI) is a technique thatmaps the physiological consequences of abnormal electrical activity inthe brain and can be conducted without the use of radiation (Kesavadasand Thomas 2008). An fMRI scan allows patients to respond to anumber of visual/auditory stimuli using a response box (Figure 4.2).

A recent case report highlighted how magnetic resonance spectroscopy(MRS), which aids MRI by determining chemical metabolites in the brain(e.g. lactate and choline), allows the differential diagnosis ofneurocysticercosis (Shetty et al., 2014).

Positron Emission Tomography (PET scan) and ictal single photonemission computed tomography (ictal SPECT) are functional neuro-imaging technique traditionally used to determine areas of epileptogenesis.Newer techniques such as magnetoencepha-logram/magnetic sourceimaging (MEG/MSI) and diffusion tensor imaging (DTI), which allowmore accurate assessments of cellular and molecular profiles, have recentlybeen used to localize seizure loci and in particular, to perform functionalmapping to evaluate surgery candidates (Haneef and Chen, 2014).

Genetic TestingThe presence of genetic mutations may help diagnose epilepsy. The majorclinical uses of genetic testing for diagnosing epilepsy are presented inTable 4.4. For example, what is referred to as “diagnostic testing” isconducted in people known or suspected to have epilepsy, while“predictive testing” can determine those patients at risk of developingepilepsy because of family history (Ottman 2010). The moleculartechniques used for genetic testing include sequencing whole and partialgenes and microarrays to analyze multiple loci simultaneously.

Figure 4.2 Patient Set Up in fMRI (Kesavadas and Thomas, 2008)

Mirror

Earphone

Screen

Responsebox

Projector

Computer for presentation

Magnet


Table 4.4 Clinical Uses for Genetic Testing in Epilepsy (Ottman 2010)

Clinical Context DefinitionDiagnostic testing Testing used to confirm or exclude

a known or suspected geneticdisorder in an affected individual

Predictive testing Testing used to predict developmentof a disorder in an unaffectedindividual at risk of developing thedisorder because of a family history

Prenatal diagnosis A special type of predictive testingused to confirm or exclude adisorder in a fetus at risk for thedisorder

Carrier testing Testing used to identify usuallyasymptomatic individuals who havea gene mutation for an autosomalrecessive or X-linked disorder

(also called carrier detection)

In the past, only clinicians could prescribe genetic testing, but recentlydirect to consumer tests have been developed that allow patients ordertests for diagnostic purposes. ILAE recommends that the benefits/harmsthat can result from genetic testing should be carefully weighed beforeundertaking any form of testing. Genetic testing should never beundertaken without the informed consent of the patient. The ILAErecommends that a clinical laboratory, certified by the Clinical LaboratoryImprovement Act (CLIA), conducts the tests and provides the results toordering physician and/or patients. ILAE also recommends that pre- andpost- testing counseling should be available to help patients understandtheir genetic test results. The advantages of a positive diagnostic testinginclude clarifying a diagnosis, providing insights about prognosis andtreatment, avoidance of more costly invasive tests, and guidancepertaining to reproductive decisions. In terms of predictive testing, anegative test result can relieve stress and anxiety and reduce the need forfurther expensive testing and seizure monitoring. However, genetic testingcan also raise anxiety and lead to labeling that adversely affects access tohealth and life insurance or stigmatizes the patient (Ottman, 2010). Atthis time, relatively few genes have been validated for clinical use,somewhat limiting the utility of these diagnostic tests.

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The Wada TestDeveloped by a Japanese scientist, the Wada test, officially known asthe intracarotid sodium amobarbital test, is based on a cerebralangiogram and analyzes brain functions by putting one cerebralhemisphere to sleep with the short-acting anesthetic amobarbital, andobserving memory and language functions of the other hemisphere.Once this is done, the procedure is repeated on the opposite side.

Conclusion

Nationally and internationally recognized guidelines provide informationfor the diagnosis, etiology, classification, assessment of disease severity,control, and treatment of epilepsy. Guidelines can be distinct forchildren and adults particularly regarding diagnostic neuroimaging. Sincethere are several types of epileptic disorders and many are associatedwith co-morbidities, diagnosis is often complex. Advances in the fieldsof electrophysiology, imaging, and genetic testing are being used todifferentiate between disease foci and provide the foundation forprevention, and options for management and treatment.

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Introduction

Treatment guidelines for epilepsy have been issued by the InternationalLeague Against Epilepsy (ILAE), the American Academy ofNeurology (AAN), and the American Epilepsy Society (AES) amongothers. This chapter reviews those guidelines associated with new onsetepilepsy, drug refractory epilepsy, febrile seizures, infantile spasms, andimaging studies. Additional guidelines are available and can beconsulted as needed.

Treatment of New Onset Epilepsy (French et al., 2004a; AAN and AES)

Figure 5.1 shows the care algorithm suggested for patients presentingwith a suspected seizure by the National Institutes for Health and CareExcellence (UK; www. nice.org.uk). The care algorithm is meant to aidprimary care givers in establishing whether a patient is epileptic, andwhen a patient requires specialized care.

Chapter 5 Treatment andManagement

Figure 5.1 NICE Epilepsy Care Algorithm (NICE guidelines, 2012)

Investigation and classi�cation byseizure type and epilepsy syndrome

by specialist

Suspected seizure

A&E(protocols in place for assessment)

Initial screeening by pysician

Primary care

Diagnostic doubt

Referral to epilepsy specialist

or other specialist(e.g. cardiologist)

Referral to specialist as soon aspossible (The GDG recommended

within 2 weeks)

Diagnosis by specialistwith investigations as necessary

Uncertain

Further investigation,including assessment of

othet physical causes(e.g. cardiac) or

Referral to tertiary care

Woman with epilepsy

Special groups• People with learning

disabilities• Black and ethnic minority

groups• Older people

Prolonged or repeatedseizures

Status epilepticus

Referral totertiary careTreatment

Epilepsy Non-epileptic attack disorder

Referral to psychological or psychiatric service

Treatment withAEDs only inexceptional

circumstances

Suspected epilepticseizure

Information obtained about the eventPhysical examination

Regular structured review for all

Key: As necessary

App

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info

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ion

prov

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at a

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ages

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Once patients have been diagnosed as epileptic, or the cliniciandetermines that treatment is warranted, there are several differentpharmacological options available. The AEDs that were in use before1990 (phenytoin, carbamazepine, phenobarbital, primidone, valproicacid, and ethosuximide) were considered inadequate in many patientsdue to continued seizures, side effects, and drug-drug interactions(French et al., 2004a). However, these AEDs remain in use becausetheir efficacy profiles are known, they are widely covered by third-partypayers, and clinicians have experience with them. The second-generation AEDs that have been approved by the FDA includefelbamate, gabapentin, lamotrigine, topiramate, tiagabine,oxcarbazepine, levetiracetam, and zonisamide. These drugs are moreexpensive than the older compounds, but they have fewer druginteractions (French et al., 2004a). The adverse events associated withthe second-generation AEDs are summarized in Table 5.1. The AANand AES guidelines (French et al., 2004a) recommend starting newlydiagnosed patients on older AEDs such as carbamazepine, phenytoin,valproic acid, and phenobarbital, or on the second-generation AEDslamotrigine, gabapentin, oxcarbazepine, and topiramate. However, onlylamotrigine is effective in children newly diagnosed with absenceseizures. The AAN guidelines for the use of the second-generationAEDs are summarized in Table 5.2.

Nearly two-thirds of newly diagnosed patients respond to treatmentwith AEDs, and often respond at some level to treatment with all ofthe AEDs. Therefore, according to the AAN, the treating clinicianshould choose the drug that is most tolerable for the patient, with theleast potential for harm, and the lowest likelihood of negativelyaffecting patient quality of life. This requires tailoring treatmentstrategies to the individual patient.

Table 5.1 Summary of Adverse Events Associated with New AEDs(French et al., 2004a)

This is not meant to be a comprehensive list but represents the most common adverseevents, based on consensus of panel. Psychosis and depression are associated with epilepsyand occur in open label studies with all new AEDs. Although these side effects may appearmore commonly with some drugs than with others, it is difficult to ascertain whether theserelationships are causal. Consequently, these side effects have been omitted from the table.

* Predominantly children.

AED=antiepileptic drug; DIC=disseminated intravascular coagulation.

Gabapentin

AED

Lamotrigine

None

Serious adverse events Nonserious adverse events

Rash, including StevensJohnson and toxic epidermalnecrolysis (increased risk forchildren, also more commonwith concomitant valproateuse and reduced with slowtitration); hypersensitivityreactions, including risk ofhepatic and renal failure,DIC, and arthritis

Weight gain, peripheral edema, behavioral changes*

Tics* and insomnia

Levetiracetam None Irritability/behaviorchange

Oxcarbazepine Hyponatremia (more common in elderly), rash

None

Tiagabine Stupor or spike wave stupor Weakness

Topiramate Nephrolithiasis, open angleglaucoma, hypohidrosis*

Metabolic acidosis,weight loss, languagedysfunction

Zonisamide Rash, renal calculi,hypohidrosis*

Irritability,photosensitivity,weight loss

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Table 5.2 Summary of AAN Guidelines for Treating NewlyDiagnosed Epilepsy (French et al., 2004a)

The ILAE released an updated assessment of the evidence supportingthe use of AEDs in newly diagnosed epilepsy in 2013 that included allof the available AEDs and ranked their efficacy for treating seizures orepilepsy syndromes (Table 5.3; Glauser et al., 2013). The ILAE efficacyrankings were based on the level of evidence supporting the use of eachdrug, which was based on the type of studies conducted using each drug.Four levels of evidence were presented: A= AED is established asefficacious or effective as a monotherapy based on more than 1 class Istudy or meta-analysis, or more than 2 class II studies; B= AED isprobably efficacious or effective based on 1 class II study or meta-analysis or more than 2 class III double-blind or open label studies; C=AED is possibly efficacious or effective as initial monotherapy based onmore than 2 class III double-blind or open label studies; and D= AEDis potentially efficacious or effective for use as initial monotherapy basedon 1 class III double-blind or open label study. Class I studies wereconsidered the most rigorous studies and were limited to randomizedcontrolled trials that met specific design criteria regarding the length oftreatment, blinding, and statistical analysis. Class II studies were blindedstudies considered less rigorous based on study design, or were shorterin duration than class I studies. Class III studies were randomizedcontrolled trials that did not meet the criteria for class I or II (e.g., openlabel instead of blinded) and were considered the least rigorous of therandomized trials in terms of design.

Drug Newly diagnosedmonotherapy Newly diagnosedpartial/mixed absence

Gabapentin Yes* NoLamotrigine Yes* Yes*Topiramate Yes* NoTiagabine No NoOxcarbazepine Yes NoLevetiracetam No NoZonisamide No No

* Not Food and Drug Administration–approved for this indication.

Table 5.3 Summary of the Efficacy of AEDs for Use as InitialMonotherapy (Glauser et al., 2013)

CBZ- carbamazepine; CLB- clobazam; CZP-clonazepam; ESM- ethosuximide; GBP-gabapentin; LEV- levetiracetam; LTG- lamotrigine; OXC-oxcarbazepine; PB-phenobarbital; PGB- pregabalin; PHT- phenytoin; PRM- primidone; STM- sulthiame;TPM- topiramate; VGB- vigabatrin; VPA- valproic acid; ZNS- zonisamide;

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Treatment of Refractory Epilepsy

Although most epilepsy patients (70-80%) are responsive to treatment,20-30% of patients develop refractory epilepsy and have uncontrolledseizures, or have significant medication related adverse events. Patientsare generally considered refractory when they have failed three or moredifferent AEDs. The AAN and AES guidelines address the use of thesecond-generation AEDs (gabapentin, lamotrgine, topiramate,tiagabine, oxcarbazepine, levetiracetam, and zonisamide) to treatpatients with refractory partial seizure disorders, primary generalizedepilepsy, and Lennox-Gastaut syndrome (French et al., 2004b). AANand AES focused on the second-generation AEDs in part becausethey were developed using randomized controlled trials and aretherefore better suited to evidence-based guidelines than the olderAEDs that were characterized using primarily case reports and caseseries (French et al., 2004b).

It is important to note that all of the AEDs demonstrate some levelof efficacy when added to the primary treatment regimen in refractorypatients. However, for the majority of the AEDs, as the doseincreased, efficacy and side effects increased as well. The AANrecommends beginning treatment at a low dose and slowly escalatingto the maximum tolerated dose (the dose just before side effectsappear) for an individual patient. Only oxcarbazepine and topiramatehave strong evidence for use as a monotherapy in refractory patients,and there is some evidence that lamotrigine can be used alone. Frenchet al. considered the evidence insufficient based on the design of theclinical trials to recommend using the other AEDs as monotherapies.The AAN recommendations for use of the second-generation AEDsare shown in Table 5.4.

Table 5.4 AAN Recommendations for Treating Refractory EpilepsyUsing AEDs (French et al., 2004b)

Gabapentin Yes No No No YesLamotrigine Yes Yes No Yes YesTopiramate Yes Yes† Yes (only Yes Yes

generalizedtonic-clonic)

Tiagabine Yes No No No NoOxcarbazepine Yes Yes No No YesLevetiracetam Yes No No No NoZonisamide Yes No No No No

Drug PartialAdjunctive

Adult

PartialMono-therapy

PrimaryGene-ralized

Sympto-matic

Genera-lized

Pedia-tric

Partial

* NB: In a previous parameter, felbamate was recommended forintractable partial seizures in patients over age 18 and patients over4 with the Lennox-Gastaut syndrome. Felbamate is associated withsignificant and specific risks, and risk-benefit ratio must beconsidered.

† Not Food and Drug Administration approved for this indication.

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In addition to pharmaceutical options for treating drug refractoryepilepsy, surgical options such as deep brain stimulation (DBS) andvagus nerve stimulation (VNS) are available. Both DBS and VNSinvolve implanting a neurostimulator, a small disk that contains abattery and impulse generator, in the clavicle and attaching theneurostimulator to an electrical lead that is implanted in the brain atthe site of stimulation (Chambers et al., 2013). While both DBS andVNS have been shown to reduce the frequency of seizures in adultsand children by more than 50%, the evidence supporting their use isstill incomplete and based on a small number of studies (Chambers etal., 2013). The treatment related adverse events associated with DBShave been primarily device related and include numbness of tingling,pain at the site of implantation, and infection at the implant site. VNShas been linked to throat pain, coughing, and vocal changes (Chamberset al., 2013). The evidence supporting the use of DBS and VNS basedon a meta-analysis conducted by Health Quality Ontario issummarized in Table 5.5 (Chambers et al., 2013).

Table 5.5 Evidence Supporting the Use of DBS and VNS to TreatDrug Resistant Epilepsy (Chambers et al., 2013)

Procedure, Population

Outcome Result GRADE

DBS, adults

Seizure frequency Significant reduction in seizure outcomes in “on ” group versus “off “

Low

Hospitalizations, ED visits

No studies –

DBS, children

Seizure frequency No studies –

Hospitalizations, ED visits No studies

–

VNS, adults

Seizure frequency Significant reduction in seizure outcomes in high versus low stimulation

Low toModerate

Hospitalizations, ED visits Hospitalizations and ED visits significantly reduced post-VNS

Low

VNS, children

Seizure frequency No significant differences between high versus low stimulation

Moderate

Hospitalizations, ED visits Hospitalizations and ED visits significantly reduced post-VNS

Low

group

Abbreviations: DBS, deep brain stimulation; ED, emergency department;GRADE, Grading of Recommendations Assessment, Development andEvaluation; VNS, vagus nerve stimulation.

According to the National Institute for Health and Care Excellence(UK) patients should be referred to specialized care if any of thefollowing conditions are met: 1) epilepsy is not controlled withmedication within 2 years; 2) epilepsy cannot be managed with twodrugs; 3) the patient is less than 2 years of age; 4) medication causesunacceptable side effects; 5) there is a unilateral structural lesion; 6) apsychological or psychiatric co-morbidity is present; 7) the diagnosisis in doubt (NICE guidelines 2012).

Treatment of Febrile Seizures (Capovilla et al., 2009; ILAE)

Febrile seizures are the most common seizure disorder in children. Forpurposes of the treatment guidelines, simple febrile seizures aredefined as a generalized seizure lasting less than 15 minutes, notrecurring within 24 hours, occurring during a febrile episode but notcaused by a nervous system disorder, in a child 6 months to 5 years ofage, with no neurological deficits. Complex febrile seizures are definedas: a focal or generalized seizure, lasting more than 15 minutes,recurring within 24 hours, and/or associated with a postictal (post-seizure) palsy or with previous neurological deficits. Hospitalization isrecommended for patients under 18 months of age at the firstoccurrence of a simple febrile seizure; so long as children over 18months of age are stable, hospitalization is not required. Likewise,patients that have already been diagnosed with simple febrile seizuresdo not require further hospitalization. Patients presenting withcomplex febrile seizures should be admitted to the hospital. In mostcases, simple febrile seizures are self-limited ending within 2-3 minutesand do not require additional treatment.

Prophylaxis is not recommended to prevent simple febrile seizures dueto possible side effects of the AEDs like phenobarbital and valproicacid and the relatively benign nature of the seizures. However, patientsthat experience frequent seizures (3+ within 6 months or 4+ withinone year) or who have seizures that last longer than 15 minutes arecandidates for intermittent therapy. Diazepam can be administered at

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the onset of the fever and may be administered up to 3 times within24 hours. Treatment beyond 24 hours is not warranted as 98% ofsimple febrile seizures occur within the first 24 hours. In the event theonset of the fever is missed, treatment with phenobarbital or valproicacid is appropriate. The guidelines recommend administering valproicacid, as it is associated with fewer side effects than phenobarbital.Family education is also key to controlling and managing febrileseizures.

Imaging Guidelines for Epilepsy Studies

Given that brain imaging techniques are critical for adequatelydiagnosing and treating epilepsy, the ILAE and AAN/AES haveestablished guidelines and practice parameters for use in adults andchildren regarding the use of imaging techniques. Under theseguidelines, imaging studies include CT, MRI, and neurophysiologicalstudies like EEG and magnetoencephalography (MEG). However,there are several challenges to developing evidence-based guidelinesfor use in imaging studies that include: 1) rapid pace of technologicaldevelopment- imaging modalities are outdated very quickly, oftenfaster than a large cohort of eligible patients can be recruited; 2) lackof an appropriate control population; 3) multi-site studies areprohibitively expensive and relevant expertise may be too localized;4) very little prospective data (Gaillard 2011). The elements that theILAE consider essential for a high quality imaging study arepresented in Table 5.6.

In adults presenting with an apparent unprovoked first seizure, AANand AES concluded that EEG is likely helpful and finds abnormalitiesin about 29% of cases that predict the recurrence of seizures(Krumholz et al., 2007). Routine EEG should be considered in allcases. More specialized brain imaging studies like CT or MRI yieldabnormal results in about 10% of cases. CT and MRI can be used todiagnosis conditions such as brain tumors, stroke, cysticercosis, andother structural lesions.

Table 5.6 ILAE Essential Elements for High Quality ImagingStudies (Gaillard et al., 2011)

No. Item1 Clear study question and clearly stated study design2 Clearly defined study population, and where relevant note

study base, based on agreed diagnostic categories3 Clearly defined control population4 Prospective data collection; where possible following

standardized protocols5 Test applied to all patients uniformly (unless randomized design)6 Clearly defined experimental measure and

comparison/outcome measure7 Data analysis clearly defined, preferably objective measures;

if not, skilled visual raters, better if measure of replicability provided

7 Assessments blinded to patient identity from the rater and from caring physicians

8 Assessment of population size and homogeneity/heterogeneity and study power

9 For surgical series, pathologic confirmation10 For outcome, follow up > 1 year ascertained by person

without a vested interest in outcomes11 State how data were (not) considered in decision making process12 Provide data in tabular form for external assessment13 Data analysis with appropriate statistical test (validity,

sensitivity, specificity): comparison with other method14 State practicalities and limitations, including sources

of selection bias, (e.g. known incomplete resection) or insurmountable factors modifying above statistical measures

15 For surgical outcome, list seizure freedom and degree of seizure reduction in those not seizure free

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In children, the ILAE concluded that imaging studies are indicatedfor the following reasons: 1) identifying a non-specific abnormality;2) identifying static remote lesions; 3) finding a focal lesionresponsible for seizures that does not require an immediateintervention but may be amenable to surgery later; 4) finding asubacute process or chronic process with implications for therapy; or5) identifying an acute process requiring immediate intervention. Thesituations in which imaging is warranted and in which it is notwarranted are summarized in Table 5.7 (Gaillard et al., 2009). ILAErecommends determining whether imaging is warranted based on thepatient history and EEG results.

Table 5.7 Pediatric Imaging Guidelines (Gaillard et al., 2009)

In children, MRI is preferable to CT because it provides superioranatomic resolution and characterization of pathological processes.However, CT scans are less expensive, more widely available, and lesslikely to require sedation. Children less than 2 years of age requirespecialized imaging sequences to account for the immature myelinationpattern in the brain. Changing myelination patterns can cause lesionsto appear and disappear. If the MRI imaging is normal, the scan canbe repeated every 6 months and after 24-30 months of age whenmature myelination patterns can be used to identify cortical dysplasia(Gaillard et al., 2009).

Imaging indicatedLocalization related seizuresa

Focal history, abnormal exam,focal EEG abnormalitiesa

Developmental regression<2years oldSymptomatic generalized epilepsysyndromeIncreased intracranial pressureHistory of status epilepticusAtypical course for BECTS/IGEaExcept for BECTS.

Imaging not indicatedChildhood absence epilepsyJuvenile absence epilepsy

Juvenile myoclonic epilepsyBECTS

Conclusion

Due to the complex nature of the epileptic syndromes there are manydifferent treatment guidelines and practice parameters available. Ingeneral, pharmacological treatment is preferred, and more invasivetherapies are considered only as a last resort. Imaging is a newer areawhere practice parameters are being actively developed to guide theclinician, but few clear recommendations have emerged. As ofOctober 2014, the AAN was actively revising its guidelines for epilepsytreatment and may issue updated guidelines.

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Introduction

Advances in epilepsy have focused on public health and epidemiology,the search for novel biomarkers in diagnostics, and innovativestrategies for treatment. Currently, there is no cure that restores brainfunction lost to epilepsy, but seizures can be controlled with AEDs,surgical interventions, and dietary instructions.

Epidemiology Advances

Epidemiology is the research component of public health. It hashelped establish the natural history of epilepsy and identify diseasepatterns and possible causes of epilepsy disorders. Traditionallyepilepsy epidemiology focused on the reporting incidence andprevalence of subjects presenting with seizures. However, it is nowwidely recognized that epilepsy is a disease related to brain function,caused by a complex interplay between developmental, cognitive, andbehavioral factors, that can often lead to dysfunctions in other bodysystems, such as the respiratory tract and the cardiovascular system(Linehan et al., 2011). Future directions in epidemiology will beaddressed below, including remarks on terminology, progress on theuse neuroimaging to determine history of disease, and the need formore population-based studies.

Sudden Unexplained Death in Epilepsy (SUDEP)Because patients affected by epilepsy are often at increased risk ofmortality, one aspect of epilepsy epidemiology that has been receiving

Chapter 6 Recent Advances

global attention is “sudden unexplained death in epilepsy,” commonlyreferred to as SUDEP. SUDEP causes around 2,000 deaths per yearin the USA alone, although this may be an underestimate because it isnot always recognized. A meta-analysis from the Centers for DiseaseControl and Prevention calculated the risk of SUDEP to be as highas 35% for patients affected by refractory epilepsy (Massey et al., 2014).Although SUDEP often occurs in younger patients, only 33% ofpediatricians are familiar with the condition (Massey et al., 2014). Oneplausible cause of SUDEP are abnormal breathing patterns anddysfunctional cardiac events, due to lack of oxygenation duringseizures. A role for 5-hydroxytriptamine (5-HT), a CNSneurotransmitter controlling respiration and arousal, has beenhypothesized. Studies have shown that defects in neuronal 5-HT genecan predispose patients to SUDEP, similar to sudden infant deathsyndrome (SIDS). A model for SUDEP has been developed, as shownin Figure 6.1.

Figure 6.1 Recently Proposed Model for SUDEP (Massey et al., 2014)

Patient with epilepsy

Dysfunction of ascending arousalsystem including 5-HT neurons

Face in pillowor blankets

Failure toarouse

PGES

Spread to medullaSpread to upper brainstem

Dysfunction of descending arousalsystem including 5-HT neurons

Seizure

Increased extracellularadenosine

Respiratory nucleidysfunction/inhibition

Autonomic andcardiovascular control

ArrhythmiasHypoventilation/apnoea

Severe hypercapnia/hypoxia

SUDEP/death

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Seizures spread to the brainstem causing abnormalities of theascending arousal system, including 5 HT neurons, and will ultimatelylead to arousal failure, which combined with the patient’s face in thepillow during sleep can induce hypoventilation and apnea. Seizures canalso spread into the medulla causing disruption of the descendingarousal system, elevating extracellular adenosine levels, and causing adysfunction of respiratory nuclei and arrhythmias. This cascade ofevents eventually leads to severe hypercapnia, hypoxia, and death(Figure 6.1; Massey et al., 2014).

Future DirectionsOur notion of epilepsy has dramatically changed in recent years, dueto new discoveries in disease features, diagnostics, and treatment.Changes are being considered in terminology, by replacing theoutdated terms to describe epilepsy (“idiopathic”, “symptomatic, etc.)with terms that more specifically align with recent developments indiagnostics. The proposed changes in epidemiological terminology arealso likely to reflect the many genetic mutations implicated in severalepilepsy syndromes; for instance, the catchall adjective “symptomaticgeneralized” may no longer fit genetically diverse epilepsy syndromes(Linehan et al., 2011).

Increasingly, neuroimaging studies have been conducted to identifyand characterize the brain lesions that can occur in epilepsy. Forexample, the use of MRI has given us perspective on the appearanceand frequency of epilepsy beginning in childhood, leading to improveddecision-making in treatment options such as brain resection.Additional imaging studies are needed to better understand the impactat the population level.

Moving forward, reports of diverse populations affected by epilepsyaccording to age and disorder onset may have to be expanded. Forexample, there are currently no epidemiologic estimates of adultpatients with childhood-onset epilepsy that could now be receivingbetter treatment, if their condition had been properly diagnosed in theearly years (Linehan et al., 2011).

Diagnosis and Treatment

Although there is currently no cure for epilepsy, the quality of life foraffected patients can be improved using a range of available treatmentsthat vary depending on the disorder type, age of the patient, and co-morbidity. Epilepsy biomarkers, experimental drugs, novel drugtargets, and surgical techniques are active and promising research areasfor epilepsy and a select list is discussed here.

Novel BiomarkersA biomarker, or biological marker, is a measurable indicator of anormal or pathological biological state. The search for biomarkers forepileptogenesis is crucial to predict an epilepsy disorder or a state ofictogenesis- the predisposition to generate spontaneous seizures- andwill aid the development of pharmaceutical agents to treat or preventthe development of epilepsy. Biomarkers are also important tools todevelop appropriate animal models of disease and to reduce clinicaltrial costs, by identifying patients at high risk for developing epilepsy(Engel et al., 2013). Table 6.1 summarizes the biomarkers that haverecently been explored for epilepsy.

Electrophysiology ImagingIctal Pattern and Interictal Spikes MRI (Magnetic Resonance Imaging)

Frequencies Duration Morphology Routine MRI Measures Enhancement (BBB)Field Size Source Localization Functional (FMRI) Spectroscopy (MRS)

Diffusion Tensor (DTI) Susceptibility (SWI)

High Frequency Oscillations (HFOs)

Provocative Maneuvers

PET (Positron Emission Tomography)

Photic Stimulation Hyperventilation FDG (Deoxyglucose) FMZ (Flumazanil)Sleep Deprivation Drug Induction AMT (alphamethyltryptophane) PK (Inflammation)

Excitability SPECT (Single Photon Emission

Computed Tomography)TMS (Transcranial Magnetic

Stimulation)

Direct Electrical Stimulation

(Part of Surgical Workup)

Table 6.1 Electrophysiology and Imaging Biomarkers of Epilepsy(Engel et al., 2013)

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Electrophysiological biomarkers are routinely used to characterizeepilepsy in patients, especially during evaluation for surgery.Traditionally, scalp EEG has been performed although this method isbeing increasingly replaced by the more sensitive electrocorticography(EcoG), which directly measures cerebral cortex activity in the exposedbrain by means of depth electrodes (Engel et al., 2013). High-frequency oscillations (HFOs) between 80 and 500 Hertz (Hz), whichcan be recorded with EEG, are novel attractive markers ofepileptogenesis based on microelectrode recordings that can revealelectrical discharges in small neuronal clusters (Jacobs et al., 2012).Current research is focusing on non-invasive electrophysiologicalmethods, including magnetoencephalography (MEG) that measuresthe magnetic fields generated by neuronal activity of the brain (Engelet al., 2013).

Neuroimaging biomarkers are another promising category to diagnoselesions associated with epilepsy. MRI measures of structure have beentraditionally used, although functional imaging techniques such aspositron emission tomography (PET), including alpha-methyl-tryptophan (AMT) PET, single-photonemission computedtomography (SPECT), and functional MRI (fMRI) are being evaluated(Engel et al., 2013).

Genomics and proteomics are useful tools that enable us to analyzeexploratory biomarkers associated with epilepsy in patients’ blood,cerebrospinal fluid (CSF) and other tissue samples. Methodologiesinclude processing of samples for RNA extraction and histologicaland immunohistochemical analysis of tissues, using specific stains andantibodies for molecule detection. Examples of exploratorybiomarkers are reported in Table 6.2.

Table 6.2 Body Fluid and Tissue Biomarkers of Epilepsy (Hedgeand Lowenstein, 2014)

Molecule Modality Notes

Bcl-2 Serum

HSP70 Serum Signi�cantly increased serum levels in TLE patients versus controls; HSP level correlated inversely with memory scores and hippocampal volume

NCAM-1 CSF Signi�cantly lower levels in epilepsy pa-tients versus controls; pharmacore-sistant patients also had signi�cantly lower NCAM-1 levels than treatment responsive group

Superoxide dismutase 1

CSF Signi�cantly lower levels in epilepsy pa-tients versus controls; pharmacore-sistant patients also had signi�cantly lower SOD-1 levels than treatment responsive group

CD-133-enrichedmembrane particles

CSF Signi�cantly elevated in CSF of epilepsy patients versus controls; signi�cantly elevated in TLE patients versus extratemporal epilepsy patients

Gelsolin CSF An actin-binding protein assisting in cytoskeletal rearrangements; signi�-cantly reduced levels in 70 epilepsy pa-tients versus 60 controls; gelsolin expression was also decreased in resected temporal neocortical tissue from TLE patients, assessed by immu-nohistochemistry and western blot

IL-17 Resected FCD tissue

IL-17, IL-17 receptor and downstream modulators NF-κB activator 1 and p65 were all signi�cantly elevated com-pared with control cortex; IL-17 and IL-17R levels correlate with seizurefrequency

Increased serum levels in children with TLE versus controls; serum levels corre-lated with epilepsy duration, severity, seizure frequency and were negatively correlated with IQ

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Nrf-2 mRNA Resected human TLE tissue; rat hippocampal tissue(pilocarpine model)

This transcription factor triggers expression of a host of antiin�amma-tory genes; Nrf-2 mRNA signi�cantly increased in resected hippocampal tissue from humans with TLE; expres-sion also found to peak shortly after SE in rats treated with pilocarpine

miR-146a Ganglioglioma and FCDresected tissue

Signi�cantly increased expression in lesions compared with control tissue; negative feedback regulator of in�am-matory processes in human glial cell cultures. Increased levels during latent period following SE in piloca pine model.Unclear if miR-146a is detectable pe-ripherally

miR-134 TLE resected tissue

Increased in CA1 and CA3 hippocampal sub�elds of mice using kainate epilepsy model; miR-134 inhibition reduces acute and chronic seizures in this model. Increased expression in resected tissue from humans with TLE . Unclear if miR-134 is detectableperipherally

miR-155 and TNF-α

TLE resected tissue

Signi�cantly higher TNF-α and miR-155 expression in resected hippocampal tissue from children with TLE versus controls.Unclear if miR-155 is detectable periph-erally

A novel area of research is the evaluation of treatment-related biomarkers,able to predict effectiveness of treatment, pharmacoresistance patterns,and side effects of antiepileptic drugs. Multidrug resistance protein 1(MDR1) and multidrug resistance protein 2 (MRP2) were once thoughtto be in part responsible for up to 40% of treatment failures inepilepsy, but subsequent studies gave mixed results (Hedge andLowenstein, 2014). This further highlights the need for markers oftreatment and drug resistance.

Novel TreatmentsEpilepsy treatment presents a major challenge in terms of controllingseizures that are often drug resistant, and interrupting the course of diseaseand its co-morbidities. There are two major groups of drugs for thetreatment of epilepsy, 1) drugs that rely on treating the frequency andseverity of individual seizures (anti-seizure treatments), and improve signsand symptoms related to co-morbidities (e.g. neurocognitive disorders), and2) disease modifying-treatments, including anti-epileptogenesis drugs, whichaim to prevent seizure development once epilepsy has been diagnosed.Overall, these treatments are referred to as anti-epileptic treatments (AET),and they are validated in a multi-step process that involves testing inappropriate pre-clinical models (Galanopoulou et al., 2012).

Experimental drugsSeveral experimental AEDs were discussed at “The Eleventh EilatConference on New Antiepileptic Drugs.” Examples of the majorexperimental AEDs currently being tested in pre-clinical and clinical studiesinclude brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin,NAX 801-2, perampanel and other AMPA receptor antagonists, andtonabersat (Bialer et al., 2013). Their mode of action, route ofinoculation, and median effective doses (therapeutic and toxic) arereported below (Table 6.3 and Table 6.4).

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Table 6.3 Anticonvulsant Profile of Experimental AEDs in MouseModels (Bialer et al., 2013)

Table 6.4. Partial Anticonvulsant Profile of Experimental AEDs inRat Models (Bialer et al., 2013)

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Novel Drug TargetsMechanisms of epileptogenesis in humans are still not completely,because data on experimental AEDs is based mostly on animal models.Systems biology approaches, based on high-throughput technologiesto simultaneously detect a large number of molecules, are beingconducted in human epileptic brain tissues and are showing promisein the search for new therapeutic targets (Loeb, 2011). In a recentlydeveloped systems biology model, data about genetic differences, geneexpression (mRNA) profiles, protein expression, and small moleculeexpression (e.g. neurotransmitters) can be integrated from specific cells(e.g., neurons) to characterize epileptic foci (Figure 6.2). This type ofsystematic approach will likely lead to the identification of drug targetsthat directly influence disease.

Figure 6.2Model for High-throughput Studies of Epilepsy (Loeb, 2011)

As the abnormal expression of voltage-gated sodium channels (VGSC)has been associated with epilepsy, several of them have been proposedas attractive candidates for novel drug development. Further evidencefor the role of VGSCs in epileptogenesis also derives from theidentification of genes implicated in the disease process. Promising drugcandidates are sodium channel blockers, although the major challenge istheir penetration of the blood brain barrier (BBB) to reach targetsincluding sodium channel alpha-subunits NaV1.1, NaV1.2, and NaV1.3that are localized in brain (Table 6.5).

Table 6.5 Localization of Different Types of Voltage-gated SodiumChannels in Epilepsy (partial list) (Waszkielewicz et al., 2013)

Examples of sodium channel blockers that act through inhibition ofsodium are phenytoin and carbamazepine, effective for tonic-clonicseizures, but not against absence seizures. Valproic acid reducedsodium currents in neocortical rat neurons and human NaV1.2channels (Waszkielewicz et al. 2013).

Because inflammation plays a role in epileptogenetic processes, anti-inflammatory drugs may be successful, especially for treatingepilepsy co-morbidities, such as depression. Administration of aninterleukin-1 receptor antagonist (IL-1ra) in epileptic rodentsabolished epilepsy-associated depression. Excessive activation ofthe IL-1b-mediated signaling pathway has been previouslyassociated with depression states in epileptic subjects, whichexplains the effect of IL-1ra and also makes IL-1b blockerspromising drug targets (Dedeurwaerdere et al., 2012).

Novel Surgical TechniquesUp to 40% of patients affected by epilepsy are refractory to medicaltreatment, often making surgery a necessary step. The mostcommon surgical procedure performed for epilepsy is temporal loberesection, as this is the area where most seizures are generated andpropagated. Neuroimaging preoperative assessments such as MRIand PET scanning ensure that removal of the area causing seizures

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will not disrupt critical functions of the temporal lobe, includingmemory and language function. Nevertheless, this option still hasinherent risks such as memory impairment, hence less invasivetechniques are being evaluated.

Radiofrequency (RF) thermocoagulation uses electric currents to controlseizure generation. Although it is generally considered safe and does notrequire the use of general anesthesia, some patients will still experienceseizures after undergoing the procedure (Nowell et al., 2014).

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) isbased on the delivery of high doses of transcranial ultrasound energy tospecific areas of the brain. Outcome of the treatment can be monitoredpostoperatively via MRI. The treatment does not involve any skinincisions and does not pose the risk of developing secondary tumors, asin the case of radiosurgery. The major risk is the possible heating of theskull base and critical structures such as cranial nerves during theprocedure. MRI-guided laser interstitial thermal therapy (MRgLITT)involves the use of a laser and hence does not pose the risk of heatingthe skull observed with the ultrasound method (Nowell et al., 2014).

Stereotactic radiosurgery (SRS) focuses on the use of ionizing radiationto target deep-seated lesions, while minimizing damage to surroundingtissue. Disadvantages include potential tissue injury and secondarymalignancies due to the use of radiation (Nowell et al., 2014).

Palliative treatments for patients who cannot undergo open surgery,include VNS, and trigeminal nerve stimulation (TNS). Both are based onstimulation of brain cell nuclei from an afferent cranial nerve. VNSinvolves the implantation of a surgical device, a 6 centimeter wide disc,which intermittently sends small electrical signals, via the vagus nerve intothe brain. TNS stimulation is achieved by the application of electrodesto the forehead to stimulate the supra-orbital nerves, eliminating the needof surgical implantations and the risks associated with it.

Conclusion

Recent advances in epilepsy include new strategies to elucidate patternsand natural history of disease, identification of new biomarkers,experimental AETs and innovative drug targets, and an array ofpromising surgical procedures. A combination of all these excitingadvances will hopefully lead toward improved disease treatment andmanagement for patients with epilepsy.

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Chapter 8: List of Relevant WebsitesWorld Health Organizationhttp://www.who.int/topics/epilepsy/en/

The Epilepsy Foundation www.epilepsy.com

BMJ Best Practice www.bestpractice.bmj.com (subscriptionrequired)

UpToDate www.uptodate.com (subscription required)

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6243a2.htm

http://epilepsy.med.nyu.edu/epilepsy/what-epilepsy#sthash.dWRKd0TV.dpbs

International League Against Epilepsy www.ilae.org

American Epilepsy Society www.aesnet.irg

Cleveland Clinichttp://my.clevelandclinic.org/services/neurological_institute/epilepsy/diagnostics-testing

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· PDF fileFigure 5.1 NICE Epilepsy Care Algorithm Figure 6.1 Recently Proposed Model for SUDEP ... Febrile Seizures Table 3.2 Genes Involved in Dravet Syndrome