epilepsy review

22
Review Article Epilepsy: a review of selected clinical syndromes and advances in basic science Carl E Stafstrom 1,2 1 Department of Neurology, University of Wisconsin, Madison, Wisconsin, USA; 2 Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, USA Epilepsy is a common neurologic disorder that manifests in diverse ways. There are numerous seizure types and numerous mechanisms by which the brain generates seizures. The two hallmarks of seizure generation are hyperexcitability of neurons and hypersynchrony of neural circuits. A large variety of mechanisms alters the balance between excitation and inhibition to predispose a local or widespread region of the brain to hyperexcitability and hypersynchrony. This review discusses five clinical syndromes that have seizures as a prominent manifestation. These five syndromes differ markedly in their etiologies and clinical features, and were selected for discussion because the seizures are generated at a different ‘level’ of neural dysfunction in each case: (1) mutation of a specific family of ion (potassium) channels in benign familial neonatal convulsions; (2) deficiency of the protein that transports glucose into the CNS in Glut-1 deficiency; (3) aberrantly formed local neural circuits in focal cortical dysplasia; (4) synaptic reorganization of limbic circuitry in temporal lobe epilepsy; and (5) abnormal thalamocortical circuit function in childhood absence epilepsy. Despite this diversity of clinical phenotype and mechanism, these syndromes are informative as to how pathophysiological processes converge to produce brain hyperexcitability and seizures. Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004. doi:10.1038/sj.jcbfm.9600265; published online 25 January 2006 Keywords: epilepsy; epileptogenesis; hyperexcitability; hypersynchrony; seizure Introduction Epilepsy affects up to 1% of the population, making it second to stroke as one of the most common serious neurologic disorders. In the past several years, our understanding of epilepsy has increased in several respects. Advances in molecular genetics have revealed new syndromes and identified nu- merous hereditary patterns. New and improved imaging technologies have documented subtle struc- tural lesions and provided structure–function corre- lations. Experimental models have expanded our understanding of the mechanisms underlying sei- zures and epilepsy. Yet, despite these advances and the availability of numerous new antiepileptic drugs (AEDs), our ability to eradicate seizures remains limited; approximately one-third of patients still has uncontrolled seizures, and an even larger percentage suffers from treatment side effects of AEDs or from the psychological and social stigmata of epilepsy. This review covers selected aspects of epilepsy using a case-based approach. In a somewhat arbitrary manner, I have chosen to discuss five examples of epilepsy syndromes or disorders that include epi- lepsy as a major manifestation. For each syndrome, a clinical case history is used to launch into a discussion of advances in our understanding of the basic science underlying each syndrome. The exam- ples were chosen to cover a variety of levels of pathophysiology, from mutation of genes coding for ionic channels to dysfunction of large-scale neuronal circuits. This is not a comprehensive survey of all epilepsy advances. Instead, it is intended to provide a glimpse into the varied clinical manifestations of epilepsy and its underlying mechanisms. Hopefully, such understanding of mechanism will lead to therapeutic advances, as a disconnection currently exists between our ability to diagnose and classify epilepsy and our ability to treat it adequately. Recent reviews have concentrated on other aspects of epilepsy such as seizure pathophysiology (Chang and Lowenstein, 2003), advances in genetics (Schef- fer and Berkovic, 2003), new imaging modalities (Koepp and Woermann, 2005), and novel treatment Received 12 October 2005; accepted 14 November 2005; published online 25 January 2006 Correspondence: Dr CE Stafstrom, Departments of Neurology and Pediatrics, University of Wisconsin, H6-528, 600 Highland Avenue H6-528, Madison, WI 53792, USA. E-mail: [email protected] Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004 & 2006 ISCBFM All rights reserved 0271-678X/06 $30.00 www.jcbfm.com

Upload: mason-gasper

Post on 10-Mar-2016

234 views

Category:

Documents


1 download

DESCRIPTION

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004. doi:10.1038/sj.jcbfm.9600265; published online 25 January 2006 Carl E Stafstrom 1,2 Received 12 October 2005; accepted 14 November 2005; published online 25 January 2006 Correspondence: Dr CE Stafstrom, Departments of Neurology and Pediatrics, University of Wisconsin, H6-528, 600 Highland Avenue H6-528, Madison, WI 53792, USA. E-mail: [email protected] www.jcbfm.com

TRANSCRIPT

Page 1: Epilepsy review

Review Article

Epilepsy: a review of selected clinical syndromesand advances in basic science

Carl E Stafstrom1,2

1Department of Neurology, University of Wisconsin, Madison, Wisconsin, USA; 2Department of Pediatrics,University of Wisconsin, Madison, Wisconsin, USA

Epilepsy is a common neurologic disorder that manifests in diverse ways. There are numerousseizure types and numerous mechanisms by which the brain generates seizures. The two hallmarksof seizure generation are hyperexcitability of neurons and hypersynchrony of neural circuits. A largevariety of mechanisms alters the balance between excitation and inhibition to predispose a local orwidespread region of the brain to hyperexcitability and hypersynchrony. This review discusses fiveclinical syndromes that have seizures as a prominent manifestation. These five syndromes differmarkedly in their etiologies and clinical features, and were selected for discussion because theseizures are generated at a different ‘level’ of neural dysfunction in each case: (1) mutation of aspecific family of ion (potassium) channels in benign familial neonatal convulsions; (2) deficiency ofthe protein that transports glucose into the CNS in Glut-1 deficiency; (3) aberrantly formed localneural circuits in focal cortical dysplasia; (4) synaptic reorganization of limbic circuitry in temporallobe epilepsy; and (5) abnormal thalamocortical circuit function in childhood absence epilepsy.Despite this diversity of clinical phenotype and mechanism, these syndromes are informative asto how pathophysiological processes converge to produce brain hyperexcitability and seizures.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004. doi:10.1038/sj.jcbfm.9600265; published online25 January 2006

Keywords: epilepsy; epileptogenesis; hyperexcitability; hypersynchrony; seizure

Introduction

Epilepsy affects up to 1% of the population, makingit second to stroke as one of the most commonserious neurologic disorders. In the past severalyears, our understanding of epilepsy has increasedin several respects. Advances in molecular geneticshave revealed new syndromes and identified nu-merous hereditary patterns. New and improvedimaging technologies have documented subtle struc-tural lesions and provided structure–function corre-lations. Experimental models have expanded ourunderstanding of the mechanisms underlying sei-zures and epilepsy. Yet, despite these advances andthe availability of numerous new antiepileptic drugs(AEDs), our ability to eradicate seizures remainslimited; approximately one-third of patients still hasuncontrolled seizures, and an even larger percentage

suffers from treatment side effects of AEDs or fromthe psychological and social stigmata of epilepsy.

This review covers selected aspects of epilepsyusing a case-based approach. In a somewhat arbitrarymanner, I have chosen to discuss five examples ofepilepsy syndromes or disorders that include epi-lepsy as a major manifestation. For each syndrome, aclinical case history is used to launch into adiscussion of advances in our understanding of thebasic science underlying each syndrome. The exam-ples were chosen to cover a variety of levels ofpathophysiology, from mutation of genes coding forionic channels to dysfunction of large-scale neuronalcircuits. This is not a comprehensive survey of allepilepsy advances. Instead, it is intended to providea glimpse into the varied clinical manifestations ofepilepsy and its underlying mechanisms. Hopefully,such understanding of mechanism will lead totherapeutic advances, as a disconnection currentlyexists between our ability to diagnose and classifyepilepsy and our ability to treat it adequately. Recentreviews have concentrated on other aspects ofepilepsy such as seizure pathophysiology (Changand Lowenstein, 2003), advances in genetics (Schef-fer and Berkovic, 2003), new imaging modalities(Koepp and Woermann, 2005), and novel treatment

Received 12 October 2005; accepted 14 November 2005; publishedonline 25 January 2006

Correspondence: Dr CE Stafstrom, Departments of Neurology andPediatrics, University of Wisconsin, H6-528, 600 HighlandAvenue H6-528, Madison, WI 53792, USA.E-mail: [email protected]

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004& 2006 ISCBFM All rights reserved 0271-678X/06 $30.00

www.jcbfm.com

Page 2: Epilepsy review

approaches (Avanzini and Franceschetti, 2003;Cascino, 2004; Sheth et al, 2005).

Hyperexcitability and Hypersynchrony:Hallmarks of a Seizure

A seizure is a single episode of neurologic dysfunc-tion during which synchronized neuronal firingleads to clinical changes in motor control, sensoryperception, behavior, or autonomic function. Basedon clinical and electroencephalographic (EEG) cri-teria, seizures are divided into generalized (seizureonset in both hemispheres at once) or partial (focal;seizure onset in one part of the brain). Themechanisms of partial and generalized seizuresdiffer, which has implications for treatment andprognosis. Epilepsy is the condition of recurrent,unprovoked seizures, suggesting that the brain hasbecome permanently altered pathophysiologicallyor structurally to support abnormal, hypersynchro-nous neuronal firing. Patients with an epilepsysyndrome have a similar seizure type, EEG pattern,age of onset, family history, treatment response, andnatural history. An updated classification system ofthe epilepsies includes elements of the olderInternational League Against Epilepsy classificationscheme (generalized versus localization-related;idiopathic versus symptomatic) as well as the effectsof epilepsy on an individual’s daily function (Engel,2001). Epileptogenesis is the process by which thebrain becomes epileptic, that is, the changes thatoccur at various levels (e.g., genes, membranechannels, intracellular signaling cascades, neuro-transmission, synaptic connectivity) to induce apermanent state of hyperexcitability and hypersyn-chrony. The mechanisms of epileptogenesis are thefocus of extensive current research, includingpossible interventions to avert the long-term phy-siological, behavioral and cognitive consequences ofepilepsy (Cole and Dichter, 2002; Sutula, 2004).

The hallmarks of a seizure are hyperexcitability ofneurons and hypersynchrony of neuronal networks.Hypersynchrony refers to a population of neuronsfiring at the same time at a similar rate. While anindividual neuron might fire in an ‘epileptic’pattern, that is, produce rapid, repetitive, paroxys-mal discharges, a seizure is inherently a networkevent, involving numerous neurons firing synchro-nously. Hyperexcitability refers to the concept ofseizure ‘threshold’; a certain level of excitabilitymust be exceeded for a seizure to be generated. Anybrain region can potentially generate a seizure underthe appropriate conditions, that is, when excitationexceeds inhibition. Each step in seizure generation,propagation, and termination is governed by thebalance between excitation and inhibition; exces-sive excitation, reduced inhibition, or both can leadto a seizure. Understanding the contribution of theexcitation/inhibition balance at each step in the

seizure cascade will facilitate the design of noveltreatments based on specific mechanisms.

However, the conceptualization of a seizure asmerely an imbalance between excitation and inhibi-tion is oversimplified. It is now appreciated that lossof inhibition is not universal in epilepsy, andgamma-amino-butyric acid (GABA)-mediated neuro-transmission can even be increased in epilepsy(Cossart et al, 2005). Similarly, GABA, the mostprevalent inhibitory neurotransmitter, can some-times exert excitatory effects. Two examples of thislatter phenomenon are now recognized. First, inearly development, GABA acts as a depolarizingneurotransmitter (Dzhala and Staley, 2003; Sipila etal, 2005). Second, in adults with temporal lobeepilepsy (TLE), firing of neurons in the subiculumcaused by depolarizing GABAergic responses couldcontribute to hyperexcitability and interictal dis-charges (Cohen et al, 2002). Finally, genes involvedin some epilepsy syndromes do not encode proteinsthat would, a priori, be expected to affect excit-ability. For example, cystatin B is a cysteine proteaseinhibitor with no obvious role in neuronal excit-ability, yet mutations of the cystatin B gene areresponsible for a progressive myoclonic epilepsysyndrome, Unverricht–Lundborg disease (EPM1)(Pennacchio et al, 1996; Lehesjoki, 2003).

For each of the examples of epilepsy below, it isinformative to consider how excitation or inhibitionare unbalanced, while acknowledging that in abiological system as complex as the brain, multiplefactors surely contribute to the epileptic phenotype.In fact, in epilepsy, numerous pathophysiologicalmechanisms may coexist and act simultaneously(e.g., gene mutations leading to abnormal ionicchannel function, superimposed on aberrant networkconnectivity). Furthermore, each of the mechanismsdescribed is subject to developmental regulation,with different seizure susceptibility or manifesta-tions at different stages of brain maturation. Whilethe emphasis here is on epilepsy mechanisms, itshould be appreciated that the chronic effects ofrepeated seizures on brain function can lead topsychological, social, and intellectual impairments(Elger et al, 2004). Indeed, the psychosocial aspectsof epilepsy and its treatment are often more detri-mental to an individual’s daily life and function thanthe seizures themselves.

Examples of Epilepsy Syndromes andMechanisms

Hyperexcitability at the Level of Genes for IonicChannels

Case history: A healthy infant was born at 38 weeksgestation following a normal pregnancy. There wasno perinatal distress or need for resuscitation. In thefirst week of life, the infant developed episodes oftonic stiffening of all limbs, accompanied by apnea

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

984

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 3: Epilepsy review

and arterial oxygen saturation (SaO2) declines to80% or less; some of these episodes were accom-panied by head and eye deviation to either side. Theseizures lasted up to one minute and resolvedspontaneously. The baby was normal betweenseizures, and the seizures were easily controlledwith phenobarbital. Workup for infectious, meta-bolic, congenital, and hypoxic causes of seizureswas negative. Family history revealed that the baby’smother had similar seizures as a neonate thatresolved by about 6 weeks of age. Similarly, thisinfant’s seizures remitted at about age 2 months, andphenobarbital was withdrawn. The child is now 7years old. Development has proceeded normally andno further seizures have occurred.

Clinical syndrome and genetics—benign familialneonatal convulsions: Benign familial neonatalconvulsions (BFNC) is a rare, autosomal dominantepilepsy that is classified as idiopathic generalized,although some affected neonates have partial onsetseizures by clinical or EEG criteria (Bye, 1994;Hirsch et al, 1993). Benign familial neonatal con-vulsions is an age-related disorder, with seizuresappearing in the first week of life and ceasingspontaneously by several months of age. The infantsare normal between seizures and diagnostic evalua-tions do not reveal any pathology. The syndrome isconsidered benign because most children outgrowthe seizures; however, about 10% to 15% of affectedchildren develop epilepsy later in life.

Benign familial neonatal convulsions as a clinicalentity was recognized as early as the 1960s (e.g.,Bjerre and Corelius, 1968). In 1989, several familieswith BFNC were linked to chromosome 20q (Leppertet al, 1989). Subsequently, other families were linkedto chromosome 8q. It was found that the BFNC geneson chromosomes 20q and 8q encode mutations ofKCNQ, a family of potassium channels (Singh et al,1998). KCNQ gets it name from K (potassium), CN(channel), Q (referring to a gene for a familialsyndrome of altered cardiac excitability, the longQT syndrome, or KCNQ1). The genes for BFNC arecalled KCNQ2 (on chromosome 20q) and KCNQ3 (onchromosome 8q). In situ, KCNQ subunits 2 and 3coassemble as tetramers (Cooper et al, 2000). Muta-tions in the amino-acid sequences or the polypeptidetails in either KCNQ2 or 3 result in abnormalfunction of this channel. Figure 1A depicts numeroussuch mutations that have been described in families,causing the clinical syndrome (Singh et al, 2003).

Pathophysiology of benign familial neonatal con-vulsions: KCNQ channels encode subunits of asubclass of potassium channels known as M-channels (for muscarine (M)-activated outwardcurrent). M-channels mediate slowly rectifying out-ward potassium (K+) current that hyperpolarizes theneuronal membrane. M-channels were originallydescribed in frog sympathetic neurons (Brown andAdams, 1980) but are now known to exist through-

out the mammalian brain. M-channels are closed bymuscarine; in the absence of muscarinic agonists,current through M-channels repolarizes the mem-brane and limits repetitive firing. M-channels arepartially activated at resting potential and activatefurther as the neuronal membrane is depolarized. M-channels open and close slowly (10 times slowerthan sodium channels), so they are activated onlyminimally during a single action potential. How-ever, during repetitive neuronal firing, the M-channel is strongly activated and its slow kineticsare well suited to oppose sustained membranedepolarization (Cooper and Jan, 2003). During M-channel activation by muscarine or a wide variety of

KIk

Im

Na

KIk

Na

COO-

Control

Mutantlacks Im

NH3+

KCNQ2 / KCNQ3 - BFNCA

B

Figure 1 Benign familial neonatal convulsions. (A) Schematicdiagram of M-channel and mutations in KCNQ2 (stars, filledcircles) and KCNQ3 (open circles). The circles representmissense mutations; the stars represent truncation mutations.KCNQ2 mutations affect both transmembrane sensors andpolypeptide tail. There are many fewer KCNQ3 mutations andso far these have been identified in the ion pore region.Reproduced with permission from Turnbull et al (2005). (B)Left: Intracellular recordings from CA1 pyramidal neurons inresponse to depolarizing currents pulses. In the normal cell withintact M-current (top), only two action potentials are producedby the current pulse (spike frequency adaptation), whereas inthe cell from an animal with mutation dominant negativemutation of KCNQ2 and abnormal M-current. In the mutation,spike frequency adaptation is diminished and the neuron fires,repetitively, in response to the current pulse (increasedexcitability). Reproduced with permission from Peters et al(2005). Right: Cartoons of single pyramidal neurons withinward sodium current and outward potassium currents, IK andIM. In the mutation, IM is reduced.

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

985

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 4: Epilepsy review

neuropeptides, or if the KCNQ channel is mutatedas in BFNC, the M-current is turned off; spikefrequency adaptation is diminished and repetitivedischarge of action potentials occurs (Figure 1B).Therefore, mutation of the KCNQ gene results indysfunction of the M-channel to allow repetitivefiring and hence will facilitate the unfetteredneuronal firing of a seizure (Jentsch, 2000; Cooperand Jan, 2003). In transgenic mice that conditionallyexpress dominant-negative KCNQ2 subunits, sup-pression of M-current is associated with sponta-neous seizures and hippocampal-dependentmemory impairment (Peters et al, 2005). Therefore,M-channels are important determinants of cellularand network excitability and M-channel dysfunc-tion has functional and cognitive consequences.

Future considerations and unanswered questions:M-channels are found in regions of brain known toparticipate in epilepsy, such as hippocampus (Coop-er et al, 2001). Subcellular localization of thesubunits may yield additional information abouthow this channel regulates paroxysmal firing. It isunknown why the mutation in this channelopathy ismost effectively expressed in the first few weeks oflife, when the seizures of BFNC occur, and whyseizures only occur in this restricted age window,while the mutation remains present throughout life.A variety of molecular mechanisms alter M-channelfunction (Castaldo et al, 2002; Rogawski, 2000). Anew AED, retigabine, acts to keep M-channels openand prevent repetitive firing (Blackburn-Munroet al, 2005; Cooper and Jan, 2003). This AED holdspromise for BFNC, though the rarity of the disorderprecludes large-scale clinical trials. An intriguingpossibility is that retigabine might be effective inother etiologies of neonatal seizures, such ashypoxia-ischemia and other acquired brain injuries.

Hyperexcitability at the Level of a MembraneTransport Protein

Case history: An infant presented with a firstgeneralized tonic-clonic seizure at age 9 monthsand was started on phenobarbital. Over the next fewmonths, the baby developed additional seizuresinvolving episodes of nystagmus, staring, and headdrop. The initial EEG was normal, but subsequentEEGs showed multifocal slow spike-waves on adisorganized background. The pregnancy, labor, anddelivery were normal. Some early motor delays weredocumented; for example, the infant began to rollover at 7 months of age and sit without support at 11months of age. Search for an etiology revealed noinfectious, structural, metabolic, or hypoxic cause.The brain MRI scan was normal. Phenobarbital andvalproic acid proved ineffective for seizure control.Because of persistent seizures, at age 16 months, thechild was started on a ketogenic diet with a 4:1 ratio(by weight) of fat to carbohydrate plus protein, atwhich time the seizures stopped.

In the course of the evaluation, a lumbar puncturewas performed, at age 18 months. There were no redor white blood cells present in the cerebrospinalfluid (CSF), but the CSF glucose was only 36 mg/dL(simultaneous blood glucose was 74 mg/dL, giving aCSF-to-blood glucose ratio of 0.49). This decreasedratio suggested the diagnosis of glucose transporter(Glut-1) deficiency. Subsequent genetic analysisrevealed a heterozygous missense mutation atR333W, with tryptophan substituting for arginineat amino-acid site 333.

Subsequent history reveals that the child is nowalmost 8 years old. Expressive speech was initiallydelayed (first words at almost 4 years of age), butnow the child speaks in full sentences with minordysarthria and the neurologic examination is remar-kable only for mild hypotonia and fine motorincoordination. The child is in special educationclasses but is quite talkative and sociable. Other-wise, the child has been healthy and has remainedon a ketogenic diet. The only seizure in several yearsoccurred during an attempted ketogenic diet taper.

Clinical syndrome and genetics—glucose transpor-ter type 1 deficiency: The syndrome of Glut-1deficiency (OMIM 606777) is a treatable epilepticencephalopathy resulting from an inborn error ofglucose transport into the brain (Klepper, 2004). Thesyndrome was defined by DeVivo et al (1991), whoreported two children with intractable epilepsy,developmental delays, and acquired microcephaly,who had low CSF glucose but normal blood glucose.The hallmark of the diagnosis is hypoglycorrhachia(low CSF glucose) without hypoglycemia (Gordonand Newton, 2003). The mean CSF glucose to bloodglucose ratio in Glut-1 deficiency is 0.3770.06,whereas a value of greater than 0.6 is expected inunaffected individuals (Klepper and Voit, 2002;Wang et al, 2005).

Normally, glucose enters the brain by facilitatedtransport via Glut-1. Without sufficient glucosetransport to provide the brain with fuel, the clinicalmanifestations of Glut-1 deficiency become appar-ent, usually in the first year of life. Neurologicdeficits range from mild developmental delays tosevere mental retardation, seizures that can becomeintractable, and abnormal movements such as ataxiaor dystonia (Wang et al, 2005). The seizure semiol-ogy is quite varied. Seizure types most commonlyinclude generalized tonic-clonic, myoclonic, atonic,and atypical absence (Boles et al, 1999); abnormaleye movements and cyanosis are frequent accom-paniments. Seizures are especially prone to occurduring periods of fasting, when glucose availabilityis low, for example, following a night’s sleep.

The gene encoding the Glut-1 protein is located onchromosome 1p35.31.3, and inheritance follows anautosomal dominant pattern. Many different muta-tions have been identified (Wang et al, 2005). Mostpatients manifest with heterozygous de novo muta-

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

986

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 5: Epilepsy review

tions of Glut-1; homozygous mutations are probablyfatal in utero.

Pathophysiology of glucose transporter type 1deficiency: The Glut-1 protein is located on bothluminal and abluminal surfaces capillary endothe-lial cells as well as on astrocytes and neurons (Duelliand Kuschinsky, 2001). Glucose transporter type 1thus forms part of the blood–brain barrier andfunctions to transport glucose from the vascularspace into the brain (Figure 2). Lack of Glut-1deprives neurons and glia of glucose as a fuelsource. Seizures in Glut-1 deficiency likely derivefrom an alteration in energy metabolism, comprisinga mechanism somewhat different from the usualexcitation/inhibition imbalance invoked to explainseizure pathogenesis. Glucose deprivation predis-poses neurons to synchronous firing, and seizuregeneration is favored in conditions of low blood(and therefore low brain) glucose levels, includinghypoglycemia (Schwechter et al, 2003).

From both theoretical and practical standpoints,the ketogenic diet is an essential component oftreatment of children with Glut-1 deficiency (Figure

2). The high-fat, low-carbohydrate and proteinketogenic diet circumvents the brain glucose defi-ciency by providing energy directly in the form offats that can be oxidized into acetyl CoA andeventually into ATP. Ketone bodies (hydroxybuty-rate, acetoacetate, acetone), formed in the liver byoxidation of fatty acids, circulate to the brainvasculature and enter the brain via the monocarbox-ylate transporter (Pierre and Pellerin, 2005). Oncecirculating ketones have entered the brain, it isunknown whether they exert a primary anticonvul-sant action by conventional mechanisms (e.g.,alteration of ionic channels or synaptic transmis-sion) or whether some other mechanism comes intoplay. Ketones are considered necessary but notsufficient for an anticonvulsant action. Availabledata do not support ketones as the sole (or perhapseven the primary) mechanism. In patients andanimal models, the correlation between the level ofketosis and seizure control is imprecise. Applicationof ketones directly onto cultured hippocampalneurons or hippocampal slices failed to find aneffect of the ketones on glutamate or GABApostsynaptic currents, or on electrographic seizuresinduced by 4-aminopyridine (Thio et al, 2000).While it is premature to conclude that ketones haveno direct membrane actions, these negative resultssuggest that other mechanisms must be considered.For example, ketones may have a direct suppressanteffect on the excitability of certain neuronal popula-tions involved in seizure modulation, such as thedentate gyrus (Bough et al, 2003). Ketones also alterbrain neurotransmitter levels, favoring increasedGABA synthesis and reduced availability of excita-tory neurotransmitters (Yudkoff et al, 2004).

Alternative hypotheses for the ketogenic dietmechanism of action include the role of lipids,which are elevated in this high-fat diet. Indeed,certain lipids reduce neuronal excitability (Cunnaneet al, 2002; Stafstrom, 2001; Voskuyl et al, 1998), andpolyunsaturated fatty acids are elevated in the CSFof children on a ketogenic diet (Fraser et al, 2003).This intriguing link between lipids and excitabilityis under investigation (Cullingford, 2004).

In addition to direct effects of ketones and lipidson excitability, accumulating evidence suggests thatan important factor in ketogenic diet action is thetotal amount of calories provided. Children on theketogenic diet are typically restricted to 75% to 90%of the recommended daily calorie allowance. Ani-mals undergoing similar calorie restriction haveincreased seizure thresholds as well, in seizures ofvarious types (Bough et al, 2003; Greene et al, 2001).Such a mechanism makes sense in terms of theshifting metabolic demands of the brain exposed tothe ketogenic diet. Ketones, unlike glucose, maysustain normal neuronal functions but not theexcessive neuronal firing that occurs during aseizure (Greene et al, 2003).

A final possibility for the ketogenic diet mechan-ism is reduction of free-radical induced membrane

VascularSpace

CNS

Normal

Glut-1Deficiency

Glut-1 Deficiency and Ketogenic Diet

Glucose

Glucose

Ketones

Glut-1

MCT

Figure 2 Glucose transporter type 1 deficiency. The brainnormally obtains energy from glucose transport via the proteinGlut-1 (Normal, top). In the case of Glut-1 deficiency, glucosecannot be transported across the blood–brain barrier (middle).In Glut-1 deficiency plus the ketogenic diet, ketones enter theCNS via the monocarboxylate transporter (MCT) and provide thebrain with metabolic fuel.

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

987

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 6: Epilepsy review

damage. Mitochondrial reactive oxygen speciesgenerated during excessive neuronal firing couldlead to further impairment of neuronal function andeven cell death. The ketogenic diet may interferewith this cascade by increasing the production ofmitochondrial uncoupling proteins, which havebeen shown to decrease the production of reactiveoxygen species (Sullivan et al, 2004). Hypoglyce-mia-induced cell death was reduced in weanlingrats fed a ketogenic diet (Yamada et al, 2005).

Although the exact mechanism of ketogenic dietaction is unknown, such knowledge is criticallyimportant in efforts to simplify and optimize itsefficacy. In the case of Glut-1 deficiency syndrome,in which a patient may need to use the ketogenicdiet lifelong, an understanding of how the dietworks on a cellular and molecular basis is urgent(Klepper et al, 2004; Stafstrom and Bough, 2003;Stafstrom and Rho, 2004).

Future considerations and unanswered questions:The patient described here developed intractableseizures in the first year of life, along with develop-mental delays. The diagnosis of Glut-1 deficiencywas made after the child was already on theketogenic diet, in contrast to the usual situation inwhich a patient is diagnosed with Glut-1 deficiencyand then started on the ketogenic diet. Nevertheless,this case stresses the importance of analyzing CSFglucose in young children with intractable seizures.Furthermore, the use of a ketogenic diet is necessaryin this syndrome, to provide adequate brain energyfor neuronal function and optimal development.Aside from increasing the awareness of cliniciansabout this novel syndrome and its specific treatmentwith the ketogenic diet, other methods to increasebrain glucose availability need to be explored. Forexample, efforts to increase CSF glucose by a high-carbohydrate diet, enhancing Glut-1 translocationfrom intracellular pools to the plasma membrane(with the antioxidant thioctic acid), enhancing Glut-1 expression or increasing glucose transport aretheoretically beneficial but have not been successfulas yet (Gordon and Newton, 2003; Wang et al, 2005).Patients with Glut-1 deficiency should avoid drugsthat interfere with glucose transport such as caffeineand phenobarbital. The widespread use of the latterdrug in infants with seizures underscores theimportance of establishing this diagnosis.

Hyperexcitability at the Level of the Local NeuronalCircuit

Case history: A full-term infant was born after anuneventful pregnancy, labor, and delivery. Therewere no perinatal complications. In the first severalmonths of life, developmental delays became appar-ent, especially in motor skills. Muscle tone was lowdiffusely, and there was less spontaneous movementof the right arm and leg compared with the left. At

the age of 4 months, the infant began having episodesof right arm stiffening and jerking, accompanied byhead twitches and gaze deviation to the right side.These seizures, which lasted from seconds to min-utes, were resistant to several antiepileptic medica-tions. Magnetic resonance imaging (MRI) scan ofbrain revealed an area of dysplastic cerebral cortex inthe left frontal region (Figure 3A). Video-EEG mon-itoring revealed subclinical electrographic seizures aswell as electroclinical seizures, all arising from theleft frontocentral region (Figure 3B). At the age of 14months, the child underwent surgical resection ofthis malformed cortex. Pathology revealed focalcortical dysplasia (FCD) and reactive gliosis (Figure3C), with a lack of neuronal lamination, aberrantlyoriented neurons (e.g., apical dendrites pointingtoward the white matter), large, dysmorphic neurons,and reactive gliosis. After surgery, there were nofurther seizures and AEDs were gradually withdrawn.Now, at 2 years of age, the child has a mild righthemiparesis affecting the arm more than the leg, butcognitive skills are age-appropriate.

Clinical syndrome and genetics—focal cortical dys-plasia: Malformations of cortical development areclassified according to the stage of brain develop-ment giving rise to the phenotype, includingabnormalities of: (1) cortical neuron formation andproliferation, (2) migration, or (3) organization.Advances in neuroimaging and molecular neuro-pathology are allowing ever more precise classifica-tion of disorders of neuronal development (Palminiet al, 2004). Two broad groups are recognized at eachof the above developmental stages—those with focalabnormalities, and those with large areas of brainaffected diffusely. The etiology of cortical dysplasiasis often genetic and many gene defects are beingdiscovered (e.g., an abnormal gene such as LIS1 inlissencephaly of the Miller–Dieker type). Othercases are acquired (e.g., fetal exposure to a toxin,such as alcohol or cocaine). The cause of many casesis unknown and is presumed to be multifactorial.The timing and severity of the external insult orgenetic mutation will determine the type and extentof the cortical malformation.

Focal cortical dysplasia is a subtype of corticalmaldevelopment. Among cases of FCD, three basicpatterns have been described: (1) abnormal corticallamination with ectopic neurons in white matter,(2) anomalies of lamination plus giant neurons, and(3) abnormal lamination, giant neurons, and verylarge dysmorphic neurons (Taylor-type dysplasia)(Guerrini and Filippi, 2005; Tassi et al, 2002). Figure3D illustrates, in graphic form, how neuronalorganization is disrupted in FCD. In Figure 3D(a),cellular lamination is orderly and the neuronsare oriented appropriately. In FCD (Figure 3D(b)),lamination is disrupted, with no orderly arrange-ment or lamination, and cellular orientation ismaintained. The etiology of the FCD in the childdescribed in this case vignette is idiopathic, with

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

988

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 7: Epilepsy review

the pathology most closely classifiable as a disorderof neuronal proliferation.

Developmental abnormalities of neuronal genesisand proliferation, migration, and connection/orga-nization can all predispose to epilepsy. Generally,the more extensive the malformation, the earlier andmore severe the epilepsy. The mechanism(s) ofepilepsy in these malformations is likely to bemultifactorial, involving aberrant intrinsic excitabil-ity, circuits, receptors, or ionic channels (Jacobset al, 1999b; Schwartzkroin and Walsh, 2000).Abnormal circuits, either locally or over a widecortical area, lead to hyperexcitability and enableneurons to fire hypersynchronously. Numerousstudies have verified the epileptogenicity of focaldysplastic cortex (Avoli et al, 1999; Mathern et al,2000; Palmini et al, 1995). The clinical manifesta-tions of FCD are quite varied, related to the specificfeatures of aberrant neural circuitry. Patients withFCD often have cognitive and motor abnormalitiesas well as seizures, depending on the location andextent of the dysplasia. If the malformed region isamenable to surgical resection, as in this case,excellent seizure control is often achieved. If thedysplasia is more widespread, the outcome is lessoptimistic. While MRI techniques can identify

tissue that is macroscopically abnormal, the epilep-togenic region may encompass a broader area thanthat suggested by imaging (Cohen-Gadol et al, 2004).

Pathophysiology of focal cortical dysplasia: In thelaboratory, models of cortical malformation havepermitted the investigation of some of the mechan-isms by which seizures can arise. Three models havebeen particularly informative—the neonatal externalfreeze lesion, prenatal exposure to the DNA alkylat-ing toxin methylazoxymethanol (MAM), and cranialgamma-irradiation at certain developmental stages.Each of these techniques kills proliferating, dividingcells. The mechanisms underlying the hyperexcit-ability in each model are being explored, andalthough none exactly reproduces a human disorder,useful insights into possible mechanisms can beobtained (Chevassus-au-Louis et al, 1999; Najm etal, 2004; Schwartzkroin et al, 2004; Schwartzkroinand Walsh, 2000). The cortex directly adjacent toeither the freeze lesion microgyrus or irradiatedzone tends to be hyperexcitable, rather than thelesioned area itself. For example, in cortex adjacentto a freeze lesion, a weak stimulus evokes an all-or-none paroxysmal burst of action potentials (Figure3E). Spontaneous seizures have only rarely been

Figure 3 Focal cortical dysplasia. (A) Coronal MRI section showing area of dysplasia in left frontal cortex (arrows). (B) EEG frompatient in (A), showing ictal discharges over the left frontal-central region (arrows). There were no clinical changes during thiselectrographic seizure. (C) Pathological specimen of FCD showing abnormally oriented neurons and gliosis. Examples of abnormallyoriented neurons are encircled. A large, dysmorphic neuron is indicated by the arrow. (D) Cartoons of normal and dysplastic cortex,showing normal lamination pattern (D(a)) and focal cortical dysplasia with disoriented neurons and abnormal lamination (D(b)). Inexperimental dysplasia induced by a cortical freeze lesion induced by brief application of a cold rod (D(c)), dyslamination and corticaldisorganization is seen in the vicinity of the freezing probe. (E) Intracellular recordings from a layer II/III pyramidal neuron from cortexadjacent to an experimental freeze lesion, showing all-or-none paroxysmal action potentials elicited by a weak stimulus in deepercortical layers. Reproduced with permission from Swann and Hablitz (2000).

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

989

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 8: Epilepsy review

recorded in animals with any of these lesions(Kellinghaus et al, 2004; Peters et al, 2004), but thepresence of frequent interictal discharges andincreased seizure susceptibility (decreased seizurethreshold) in each model suggests that the brain ishyperexcitable. In addition to induced malfor-mations, genetic mutants with cortical dysplasiaalso exhibit hyperexcitability. For example, thetish (telencephalic internal structure heterotopia)mutant rat has a double cortex (band heterotopia),and the p53 knockout mouse has an invertedcortical lamination pattern; in both models, sponta-neous seizures have been documented (Lee et al,1997; Wenzel et al, 2001).

Of the three inducible dysplasia models, theneonatal freeze lesion most closely mimicsthe FCD syndrome of the patient described above(Luhmann, 2006). The freeze lesion is induced inneonatal rats by brief application of a cold rod to theskull (Figure 3D(c)); this produces an area ofabnormal four-layered cortex (resembling humanmicrogyria) due to death of neurons in corticallayers IV and V (rather than to abnormalities ofneuron proliferation as in human FCD). Neuronsgenerated at later time points can migrate throughthe injured region, forming a grossly observablemicrogyrus with abnormal cortical lamination andorganization in the adjacent cortex (Dvorak et al,1978; Jacobs et al, 1999a). The cortex adjacent to themicrogyrus is hyperexcitable due to a variety offactors, both synaptic and intrinsic to the mem-brane. There appears to be reorganization of thecortical network bordering the malformed region,creating a region of hyperexcitability adjacent to themicrogyrus (Chevassus-au-Louis et al, 1999; Jacobset al, 1999a). The tissue adjacent to the microgyrushas increased glutamatergic inputs onto inhibitoryinterneurons, possibly due to loss of target neuronsfor thalamocortical afferents (Luhmann et al, 1998).This local circuit is hyperexcitable in part becauseof enhanced N-methyl-D-aspartate (NMDA)-mediated neurotransmission. Dysplastic neuronsadjacent to the lesion have altered expression ofNMDA subunits (increased expression of NR2B),favoring excessive NMDA currents and reduced Mg2+

-sensitivity of NMDA receptors (Defazio andHablitz, 2000). By whole-cell patch clamp techni-ques, the frequency of both spontaneous and minia-ture excitatory postsynaptic currents is greater inneurons in the paramicrogyral region (Jacobs andPrince, 2005). Inhibitory GABAergic function isalso altered in the freeze lesion model, due to bothalterations in GABAergic interneuron number andGABA receptor function (Defazio and Hablitz, 1999;Redecker et al, 2000; Rosen et al, 1998). Impairedlong-term potentiation in the region adjacent to thefreeze-lesion-induced microgyrus has been docu-mented, associated with diminished GABAA-recep-tor subunit g2 (Peters et al, 2004). In addition toabnormal neuronal structure and connectivity, glialcells also contribute to epileptogenicity adjacent to

the freeze lesion microgyrus; astrocytes in thehyperexcitable cortex bordering the microgyrusshow a loss of inwardly rectifying potassiumcurrents and reduced gap junction coupling, sug-gesting compromised potassium buffering, a situa-tion that would favor hyperexcitability and seizures(Bordey et al, 2001).

Animals with freeze lesions induced on postnatalday 1 that were subjected to hyperthermia-inducedseizures on postnatal day 10 (mimicking a febrileseizure) had lower thresholds and latencies togeneralized seizures than controls that did not havea prior freeze lesion (Scantlebury et al, 2005). Thisresult is an example of a ‘second hit’, wherebyanimals that have incurred a lesion or brain insult ata younger developmental age have a greater predis-position to seizures later in life compared withnoninjured animals. The second hit phenomenonwas also seen after MAM-induced dysplasia(Germano et al, 1996) and after kainic-acid-inducedstatus epilepticus (Koh et al, 1999).

Intrauterine exposure to MAM disrupts neocorti-cal and hippocampal neuron proliferation andproduces diffuse cortical dysplasia, microcephaly,dyslamination, and heterotopic neurons with abnor-mal intrinsic membrane properties, synaptic con-nectivity, and receptor stoichiometry. These factorsproduce hyperexcitability as assessed by reducedseizure threshold (Baraban and Schwartzkroin,1996) and cognitive dysfunction (Gourevitch et al,2004). Altered balance of excitation and inhibitionin the MAM model is due to a number of factorsincluding enhanced NMDA-mediated neurotrans-mission (Calcagnotto and Baraban, 2005) and dys-functional potassium Kv4.2 channels (Castro et al,2001). Prenatal gamma irradiation causes corticalthinning, cell death, and dysplasia, as well asheightened cortical excitability and clinically ob-servable spontaneous seizures (Kondo et al, 2001;Roper et al, 1997). The local circuits have deficientGABA function (Zhu and Roper, 2000).

Recordings from dysplastic tissue removed fromhumans during epilepsy surgery holds the promiseof providing more direct information on mechan-isms of epileptogenicity (Tasker et al, 1996). Suchstudies have long been vexed by sampling anddifficulties determining appropriate control tissue(i.e., what tissue is normal versus abnormal). Recentefforts have circumvented some of these difficultiesand a picture is now emerging that certain dys-morphic cells (especially balloon and cytomegaliccells) have abnormal membrane properties andvoltage-gated sodium and calcium currents (Cepedaet al, 2005), as well as abnormal NMDA receptorsubunit composition and Mg2 + sensitivity (Andre etal, 2004), as also seen in the experimental modelsdescribed above. In addition to intrinsic membraneproperties, the proportion of excitatory and inhibi-tory connections is altered in human FCD, but not ina readily predictable manner (Alonso-Nanclareset al, 2005).

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

990

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 9: Epilepsy review

Future considerations and unanswered questions: Inall of the models of cortical dysplasia, as well as inhuman dysplastic tissue, abnormalities appear to bepresent in both the neurons and the neural network,that is, both in the epileptic neuron and in theepileptic circuit (Schwartzkroin et al, 2004). Thecorrelation between seizure predisposition (seizurethreshold) and the type and degree of dysplasia isimprecise. The manner in which the dysplasticregion interacts with the rest of the brain needs to beunderstood in greater detail. Also, it is unknownwhy certain types of malformation are more prone toepilepsy and how seizures emerge as a function ofage. Studies using resected human tissue to studythe excitability of cortical dysplasia are informativebut have the inherent disadvantage of tissue sam-pling compared with appropriate control material.

Hyperexcitability at the Level of a Large NeuralSystem (Limbic System)

Case history: A 16-year-old patient presents withseveral complex partial seizures per day, beginningabout 3 years ago. The seizures consist of staring,fumbling movements of the left hand and headturning to the left, followed at times by tonic-clonicconvulsions involving all limbs. Seizure duration isabout 1 to 2 mins, followed by sleep. The child wasthe product of a normal pregnancy, labor, anddelivery, and was healthy until a prolonged febrileseizure (estimated at 40 mins) occurred at 2 years ofage. Subsequently, there were no further seizuresuntil age 13 years. Mild developmental delays arepresent and the patient attends special educationclasses, but motor function is normal. The seizuresare currently incompletely controlled on two antic-onvulsants (carbamazepine and lamotrigine), andpreviously failed to respond to several other AEDs.Medication compliance is erratic, despite concertedefforts by the family. Video-EEG monitoring failed toreveal a consistent epileptic focus from which theseizures originate. Magnetic resonance imaging andPET scans show bilateral hippocampal sclerosis andinterictal hypometabolism, respectively. Because ofthe bilateral temporal lobe interictal spikes, withoutictal localization, the patient is not considered to bea candidate for resective surgery at this time.

Clinical syndrome and genetics—temporal lobeepilepsy: Temporal lobe epilepsy is the mostcommon partial epilepsy affecting adolescents andadults. Seizures originate in one or both temporallobes. The hallmark pathological lesion, sclerosis orgliosis of one or both mesial temporal lobes(especially hippocampus) provides a presumedanatomic basis for the seizures, although, as dis-cussed below, there are controversies about theactual substrate for seizure origination. The hippo-campus is a very seizure-prone structure, due to itsinherent circuitry and physiology. However, not all

patients with chronic TLE have evidence of hippo-campal neuronal loss (Thom et al, 2005). On amicroscopic level, mesial temporal sclerosis con-sists death or injury to cells of the dentate hilus andhippocampal pyramidal cell layer, as well as recentevidence that cell death also occurs in extra-hippocampal limbic areas such as the subiculum,entorhinal cortex, and amygdala (Bernasconi et al,2003; Schwarcz et al, 2002). In some cases, theetiology of TLE can be attributed to a neuronalinjury early in life (e.g., prolonged febrile seizure,encephalitis, traumatic brain injury). The early lifeinjury probably sets up a complex cascade ofmolecular, physiological, and structural changes inthe brain, eventually resulting in the classic hippo-campal sclerosis. During this several year ‘latentperiod’, brain function is progressively altered(epileptogenesis), but no seizures are apparent.Eventually, in the teen years or older, clinicalseizures emerge.

However, in many cases of TLE, an etiology is notapparent. As an acquired epilepsy, genetics does notplay a primary role in TLE, yet information isaccumulating about familial predisposition to acqui-red partial seizures as well as to the genetic basisof AED resistance in some families with TLE(Gutierrez-Delicado and Serratosa, 2004; Kobayashiet al, 2003). The syndrome of idiopathic partialepilepsy with auditory features is one example of aTLE syndrome with a hereditary basis (Bisulli et al,2004). Mutations in a gene called epitempin or LCI1(leucine-rich glioma-inactivated 1), originally iden-tified in gliomas, have been implicated in lateraltemporal lobe seizures (Ottman et al, 2004). Thenormal function of this gene, its predilection for thelateral temporal lobe, and how it alters the excita-tion/inhibition balance to cause epilepsy are beinginvestigated.

Although the seizures in TLE may respond toAEDs, seizures tend to become refractory. Forappropriately chosen patients, surgical resection(such as anterior temporal lobectomy) may becurative (Cascino, 2004). There is a large body ofclinical research into optimal surgical strategies andoutcomes of surgery with respect to seizure control,quality of life, and cognitive sequelae.

Pathophysiology of temporal lobe epilepsy: Tempor-al lobe epilepsy has been investigated extensively atmany levels. Due to space limitations, only a fewrecent advances can be discussed here. For each ofthese topics, an attempt is made to correlate newclinical information with basic science advances: (1)TLE as a progressive disease, in the context ofepileptogenesis; (2) TLE as a disease involvingneuronal regions outside the hippocampus, and (3)seizure prediction.

Epileptogenesis and temporal lobe epilepsy asa progressive disease: Prospective longitudinalimaging studies using volumetric MRI have shown

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

991

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 10: Epilepsy review

that there is progressive decrease in hippocampalvolume over time (years) as a function of seizurenumber (Briellmann et al, 2002; Fuerst et al, 2003;Liu et al, 2003). These studies suggest that even inpatients with no precipitating injury, progressivebrain damage can occur as a consequence ofrepeated seizures. Similarly, in long-term cross-sectional neuropsychological studies spanning obser-vational periods as long as 30 years, cumulativecognitive impairments have been documented thatincrease as a function of TLE duration (Helmstaed-ter, 2002; Hermann et al, 2002; Jokeit and Ebner,2002). In a large study of almost 100 TLE patients,comprehensive neuropsychological testing showedthat, compared with controls, TLE patients per-formed worse on tests of memory function as well ason measures of intelligence, language, and executivefunction, suggesting that cognitive dysfunction isnot limited to limbic-related tasks (Oyegbile et al,2004). The degree of impairment correlated with theduration of epilepsy. Longitudinal studies alsodemonstrate progressive cognitive declines whenseizures are poorly controlled. A prospective neu-ropsychological study has revealed progressivecognitive declines in intractable TLE patients,particularly when seizures are poorly controlledafter temporal lobectomy (Helmstaedter et al, 2003).Therefore, a subset of TLE patients appears to be atrisk for progressive cognitive and structural braindamage as a function of repeated seizures, support-ing the contention that TLE can be a progressivedisorder (Pitkanen and Sutula, 2002; Sutula, 2004).

The idea that TLE is a progressive disease is alsosupported by experimental data (Buckmaster, 2004).Numerous studies in animals (e.g., using the kind-ling model) demonstrate that brief repeated seizuresinduce neuronal death and cumulative damage(Bengzon et al, 1997; Cavazos et al, 1994; Kotloskiet al, 2002). Kindling is an experimental model ofrepeated brief seizures in which the progressivenature of epileptogenesis can be characterized.Kindling is considered an example of repeatednetwork synchronization and seizure-induced plas-ticity, whereby a sequence of activity-dependentprocesses causes increasing neurologic deficits asthe number of seizures increases. The experimentercontrols the number of seizures, allowing study ofthe precise cellular and molecular alterations indu-ced by a specific number of ictal events. Suchstudies have yielded a predictable sequence ofcellular and molecular changes elicited by therepeated network synchronization of kindled sei-zures. Initially, kindling-induced alterations insynaptic transmission cause morphological reorga-nization of neurons and neural circuits, especiallyin the hippocampus, that leads to functional deficitsand enhanced seizure susceptibility. Along withprogressive neuronal loss, which resembles hippo-campal sclerosis, animals with kindled seizuresbecome more susceptible to seizure generation byseveral methods, develop hippocampal-dependent

memory and learning deficits, and eventuallydevelop spontaneous recurrent seizures, the defin-ing milestone of epilepsy (Stafstrom and Sutula,2005). The pattern of progressive cell damage andneuronal death, particularly in the dentate hilus,CA1 and CA3 subfields, resembles the distributionof hippocampal sclerosis in patients with TLE.

In addition to neuronal loss, the long-term effectsof repeated brief seizures also include a sequence ofactivity-dependent processes that alter neurons andneural circuits from gene expression to systems-level function and behavior. An initial seizureacutely increases excitatory synaptic transmission,which potentiates NMDA-receptor-dependent in-ward synaptic currents, enhancing excitability andelevating the intracellular Ca2 + concentration (Sayinet al, 1999). As a consequence of network synchro-nization, increases in intracellular Ca2 + and activa-tion of other signal transduction pathways inducetranscription of early immediate genes (Hughes et al,1998), and eventually, protein-encoding genes thatcontribute to long-term alterations associated withchronic epilepsy (Sutula et al, 1996), such as thesubunit composition of neurotransmitter receptors(Brooks-Kayal et al, 1998; Mathern et al, 1999).

At the cellular level, seizure-induced repeatednetwork synchronization also induces neurogenesis,gliosis, and axon sprouting, which reorganizethe synaptic connectivity in hippocampal circuits(Sutula, 2004). In adult rats, kindled seizures areassociated with the proliferation of progenitor cellsin the dentate gyrus (neurogenesis) (Bengzon et al,1997; Parent et al, 1998). These newly born cells arepredominantly neurons that integrate into localnetworks and become activated during seizures(Scharfman et al, 2002).

Mossy fiber sprouting refers to axonal reorganiza-tion in the dentate gyrus as a consequence ofseizures, whereby axons of dentate granule cellsreinnervate their own dendrites in the inner mole-cular layer (where such connections are not nor-mally found). This synaptic reorganization sets up ahyperexcitable circuit in the hippocampus (Buck-master et al, 2002; Koyama et al, 2004; Santhakumaret al, 2005; Scharfman et al, 2003). Mossy fibersprouting develops after only a few kindled sei-zures, progresses with seizure number, and repre-sents a permanent synaptic alteration (Sutula et al,1988). Mossy fiber sprouting has been verified inmany epilepsy models (Okazaki et al, 1995) as wellas in humans with hippocampal resections (Sutulaet al, 1989). The recurrent excitatory circuits formedby sprouted mossy fibers contribute to the chronichyperexcitability that marks the epileptic state(Buckmaster et al, 2002). Neurotrophins such asbrain-derived neurotrophic factor (BDNF) may playa crucial role in epileptogenesis (Scharfman, 2005),an effect that is dependent on the tyrosine kinaseTrkB receptor (Binder et al, 1999; He et al, 2004).BDNF facilitates epileptogenesis by enhancingexcitatory neurotransmission (Zhu and Roper,

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

992

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 11: Epilepsy review

2001) and accumulates in dendrites after seizures(Tongiorgi et al, 2004).

The emergence of spontaneous seizures definesepilepsy. Spontaneous seizures are seen in a varietyof epilepsy models, including kainic acid andpilocarpine (Cavalheiro et al, 1982; Dudek et al,2002; Stafstrom et al, 1992). However, in thekindling model, spontaneous seizures occur onlyafter about 90 class V evoked kindled seizures (Sayinet al, 2003), suggesting that the molecular andcellular alterations induced by repeated episodesof neural synchronization during kindled seizuresare accompanied by progressive functional altera-tions in neural circuits. The relationship betweenneuronal loss and spontaneous seizure occurrenceneeds to be clarified; some data failed to find acorrelation between spontaneous seizures and hip-pocampal neuronal damage (Brandt et al, 2004).

The occurrence of spontaneous seizures in thekindling model correlates with alterations in inhi-bitory circuitry. The apoptosis and cumulativeneuronal loss induced by repeated brief seizureseventually involve subclasses of GABAergic inter-neurons labeled by cholecystokinin (CCK) and theneuronal GABA transporter (GAT-1). These inhibi-tory axo-somatic and axo-axonic inputs regulate thepropagation of activity into axons. The loss of theseinterneuron subclasses is associated with reductionof the amplitude and duration of evoked inhibitorypostsynaptic currents and emphasizes the impor-tance of inhibition in preventing spontaneousseizures (Sayin et al, 2003). GABAergic pathwayscan function in multiple ways in normal andepileptic networks, permitting dynamic regulationof neuronal function (Cossart et al, 2005).

In summary, a defined temporal sequence con-sisting of a series of critical steps occurs in thedevelopment of the epileptic brain, with epilepto-genesis, seizure-induced plasticity, and finally, afully reorganized hippocampus underlying intract-able epilepsy, similar to the chronic epilepticcondition of human TLE (Figure 4A). A singlekindled seizure induces apoptosis and neurogen-esis. Five kindled seizures are sufficient for thedevelopment of mossy fiber sprouting, while hippo-campal sclerosis and cognitive and behavioralimpairments are seen after about 30 kindled sei-zures. By 90 to 100 kindled seizures, spontaneousseizures occur, possibly as a consequence of reducedsynaptic inhibition. Detailed knowledge of thesecellular and molecular intricacies is critical fordesigning appropriate interventions for neuropro-tection (Stafstrom and Sutula, 2005).

Involvement of extrahippocampal regions in tem-poral lobe epilepsy: The involvement of neuralstructures in TLE beyond the hippocampus issupported by numerous imaging and pathologystudies (Stafstrom, 2005). Clinical, pathological,and physiological studies of focal epilepsy oftemporal lobe origin have historically emphasized

± Initiating brain injury

Epilepsy

Latent period - “epileptogenesis”

Spontaneousseizures

Furtherepilepticdamage

Cognitive deficits, increased seizure susceptibility

A

B

C 1

2

Figure 4 Temporal lobe epilepsy. (A) Sequence of epilepsy andepileptogenesis. In TLE, an initial precipitating injury is some-times, but not always, identified. During the latent period,epileptogenesis occurs, causing permanent structural and/orfunctional alterations that imbue the brain with hyperexcitabilityand hypersynchrony. Once spontaneous seizures occur, thebrain is considered epileptic. Further seizures may causecognitive impairment and an enhanced predisposition tosubsequent seizures. (B) Coronal T1-weighted MRI sectionfrom a patient with right (R) temporal lobe epilepsy, normalhippocampal volume, and atrophy of the right entorhinal cortex(arrow). Reproduced with permission from Bernasconi et al(2001). (C) Fast ripples. Top (1): Interictal high frequencyepileptiform oscillations in the seizure onset zone (dashed line,G2-3 and G3-4) of a patient with neocortical seizures.Reproduced with permission from Worrell et al (2004). Bottom(2): Examples of extracelullarly recorded fast ripples occurringsimultaneously in dentate gyrus (top) and entorhinal cortex(bottom) in a rat with chronic kainate-induced epilepsy.Reproduced with permission from Bragin et al (2002).

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

993

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 12: Epilepsy review

the role of the hippocampus, giving rise to a‘hippocampocentric’ perspective (Sloviter, 2005).Certainly, damage in the hippocampus proper(dentate gyrus, dentate hilus, and cornu ammonis(CA)) is central to TLE, with cell loss and gliosis ofCA1 and CA3 subfields and the dentate hilusrepresenting the pathological hallmarks of thesyndrome. However, emerging pathophysiologicaland imaging evidence strongly implicates a criticalrole for distant structures in TLE as well (Figure 4B)(Avoli et al, 2002; Bernasconi et al, 2003; GoncalvesPereira et al, 2005; Stafstrom, 2005). For example,the subiculum, located between the hippocampusproper and the parahippocampal region, representsan anatomic transition zone between the CA andentorhinal cortex. The subiculum is the majoroutput of the hippocampus and the first brain regionencountered by neural activity emanating from thehippocampus. With this privileged location, thesubiculum is exquisitely poised to modulate normaland abnormal neuronal firing as it propagates fromthe hippocampus to other cortical and subcorticalregions.

Numerous investigations of hippocampal tissueresected from patients with TLE have revealed littlespontaneous firing that could be considered apathophysiological marker of epilepsy. In suchtissue, hyperexcitability is mainly observed whenthe system is manipulated pharmacologically, forexample, by blocking GABA receptors. A possiblereason for the lack of observable spontaneousepileptiform activity is that excessive hippocampalcell death prevents synchronization of neuronalfiring in hippocampus proper. In fact, astrocytes,in their functions of water homeostasis, potassiumbuffering, and mediation of inflammation, may playa larger role in excitability in TLE than has beenappreciated to date (DeLanerolle and Lee, 2005).

Yet, seizures of hippocampal origin do occur inTLE, so the question arises as to exactly whereinterictal and ictal discharges originate. There isrelatively little cell loss in the subiculum of patientswith TLE (Dawodu and Thom, 2005; Fisher et al,1998). This observation, in conjunction with theclose physical proximity of the subiculum to CA1and the presence of intrinsic bursting cells in thesubiculum, raises the possibility that the subiculummight participate in abnormal epileptic firing inTLE. To evaluate the hypothesis that subicularneurons could serve as an origin of epileptiformactivity, tissue from patients with mesial temporalsclerosis and refractory temporal lobe seizures wasstudied in vitro (Cohen et al, 2002). Multielectroderecordings identified spontaneous rhythmic spikesand epileptiform field potentials in subiculum butnot in the hippocampus proper. The epilepticactivity originated in the subiculum and thenpropagated to the hippocampus. Subicular inter-neurons fired before and during interictal spikes onEEGs, suggesting a mechanism to synchronize theactivity of pyramidal neurons. The population of

subicular neurons that gave rise to this abnormalactivity varied over time, implying that there is nospecific set of ‘epileptic neurons’, but rather, thatdifferent neuron groups take on this role at differenttimes.

A distinct subpopulation of subicular pyramidalneurons (22% of the total) responded to GABAergicinterneuron input with depolarizing responses,rather than with expected hyperpolarizing res-ponses. It was speculated that these depolarizingGABAergic responses endowed those pyramidalneurons with properties that favored epileptic firing(Cohen et al, 2002). The explanation for thedepolarizing GABA responses was presumed to besimilar to the developmentally regulated GABAexcitatory phenomenon seen early in ontogeny, thatis, an abnormal chloride gradient causing thechloride reversal potential to reside at a depolarizedlevel relative to resting potential (Ben-Ari, 2002;Cohen et al, 2003; Dzhala and Staley, 2003). It isunknown whether this phenomenon is widespread,whether it is mediated by specific GABA receptorsubtypes, and whether it is due to neuronal injury.Clearly, however, our understanding of GABAmechanisms in normal and abnormal neuronalfunction is expanding beyond a simple inhibitoryrole (Cossart et al, 2005). It is also clear that thesubiculum exhibits increased excitability and exces-sive synchrony in human TLE.

Seizure prediction: Finally, brief mention is made ofprogress in the emerging field of seizure prediction.An ability to predict the onset of a seizure wouldsignificantly expand the range of treatment modal-ities for epilepsy (Litt and Echauz, 2002). Forexample, if sufficient time were available, a varietyof electrical stimulation or drug delivery methodscould be employed to abort the seizure. Seizureprediction methods use a wide array of sophisti-cated mathematical techniques, especially nonlinearanalysis of EEG signals (Iasemidis et al, 1994). Usingthese techniques, the notion that seizures ‘begin’long before the onset of clinical signs and symptoms(mins to h) is receiving increasing support (Litt et al,2001). Technical, definitional, and logistical chal-lenges still abound in this field, but fruitfulcollaborations are yielding promising data (Lehnertzand Litt, 2005).

At the same time, experimental models haveestablished that very fast EEG oscillations( > 200 Hz, well beyond the frequencies usuallymeasured on standard EEGs in patients) existinterictally and build up before localized seizureonset (Figure 4C) (Bragin et al, 2002). These so-called ‘fast ripples’ are seen only in the region of thelocalized seizure (Staba et al, 2002). Furthermore,they have been demonstrated in both humans andanimal models (e.g., chronic epilepsy induced byintraventricular kainate) (Bragin et al, 2002; Stabaet al, 2002). The physiological basis of fast ripplesis uncertain; there is some evidence that they are

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

994

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 13: Epilepsy review

mediated by electrical transmission via gap junc-tions, with diminished inhibition as a contributingfactor as well (Traub et al, 2001; Traub, 2003). Togenerate fast ripples, it appears that neurons in localneuronal ensembles must fire action potential burstssynchronously, which is dependent on recurrentglutamatergic excitatory synaptic transmission(Dzhala and Staley, 2004). Hopefully, the analysisof the EEG in humans and experimental models willconverge to provide a way to sense, predict, andabort seizures (Worrell et al, 2004). Such techniquesmight be beneficial in cases in which the site of ictalonset is ambiguous, as the patient with bilateral TLEdescribed here. Additional correlation with func-tional neuroimaging would add even more clinicalpower to these techniques (Federico et al, 2005).

Future considerations and unanswered questions:There are numerous unanswered questions aboutTLE, its pathophysiology, and its treatment. It seemsmost urgent to understand the process of epilepto-genesis, and further, to devise beneficial interven-tions once epilepsy is already established in thebrain. The molecular changes occurring during thelatent period need to be elucidated to designstrategies to prevent the development of the patho-logical effects of epilepsy. From a developmentalperspective, it is unknown why the young brain ismore susceptible to limbic seizures yet moreresistant to the pathological and behavioral abnorm-alities seen when seizures occur at older ages(Stafstrom, 2002). Seizure prediction, seizure sup-pression, and remediation of the long-term beha-vioral and cognitive effects of epilepsy are all topicsof pressing concern.

Hyperexcitability at the Level of the Thalamo-CorticalCircuits

Case history: A healthy, normally developing 10-year-old child presents with multiple daily staringspells. Several times a day, teachers notice daily‘spacing out’ spells for about 10 secs, with failure torespond to verbal commands. Occasionally, thesestaring episodes are accompanied by repetitive headnods and eye blinks. Afterwards, there is immediatereturn to baseline mental status. The EEG shows anormal background; with hyperventilation, a typicalepisode of staring with lack of responsivenessoccurred, accompanied by 3-Hz generalized spike-wave discharges. The brain MRI scan and neurologicexamination are normal. The seizures are initiallycontrolled by ethosuximide, but 3 months later,breakthrough seizures occur and the medication isswitched to valproic acid with improved control.There is no family history of epilepsy.

Clinical Syndrome and Genetics—Childhood Ab-sence Epilepsy: This case history is typical for CAE,an idiopathic generalized epilepsy that begins in

childhood and often remits (approximately 75% ofcases) during adolescence. The typical absenceattack consists of a sudden arrest of ongoing activitywith staring and unresponsiveness. In addition,some motor activity may occur, such as head nods,facial clonus, or blinking. The duration of a staringspell is usually less than 20 secs, and there is noaura or postictal state. The main differential diag-nosis is between nonepileptic staring as often seenin disorders of attention, and other epilepsies thathave staring as a prominent component, such asjuvenile absence epilepsy, juvenile myoclonic epi-lepsy, atypical absence seizures, and complexpartial seizures.

The diagnosis of CAE is usually straightforward,especially if the typical EEG features are seen. TheEEG background is normal, with intermittent burstsof 3-Hz generalized spike-waves. These dischargescan often be evoked by hyperventilation, whichdecreases cerebral blood flow via hypocapnia-induced vasoconstriction (Wirrell et al, 1996) andresults in mild alkalosis. The seizures in CAEfrequently respond to ethosuximide; valproic acidis also effective, especially if there are also general-ized tonic-clonic seizures or the absence seizures areaccompanied by significant motor activity (Coppolaet al, 2004). Alternatively, lamotrigine has someefficacy against absence seizures and can be triedwhen ethosuximide and valproate are ineffective(Posner et al, 2005). Risk factors for a poor prognosis(e.g., persistent seizures) in CAE include lack ofresponse to the typical AEDs, prior neurological ordevelopmental impairment, absence seizures ex-ceeding 30 secs, and the coexistence of other seizuretypes, especially tonic or atonic (Arzimanoglou et al,2004).

As a primary generalized epilepsy, CAE isassumed to have a genetic basis, though a specificgene has not yet been identified. Some of the genesimplicated in CAE have been linked in somefamilies to mutations in calcium channel subunits,and may relate to the underlying pathophysiologicalmechanism. Specifically, mutations of genes codingfor subunits of the calcium channel a1H subunit(CACNA1H) have been identified in families withCAE (Chen et al, 2003; Heron et al, 2004). This geneencodes the Cav3.2 T-type calcium channel that isinvolved in thalamocortical synchronization (seebelow) and may function to enhance epilepsysusceptibility (Khosravani et al, 2005). However,there is probably genetic heterogeneity in CAE, asother calcium channel mutations have been identi-fied in absence epilepsies with similar epilepsyphenotypes to CAE (e.g., CACNA1A in absenceepilepsy with episodic ataxia (Imbrici et al, 2004)).

Pathophysiology of Childhood Absence Epilepsy:Childhood absence epilepsy is considered to resultfrom dysfunction of thalamocortical pathways, butthe exact pathophysiology remains incompletelyunderstood. Multiple levels of physiological regula-

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

995

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 14: Epilepsy review

tion, each assumed to be under genetic control,underlie this epilepsy. Thus, the genetic defect(s) inCAE produce widespread dysfunction of thalamo-cortical circuits affecting both hemispheres.

Absence seizures and their underlying spike-wavedischarges have long been considered to result fromabnormal neuronal oscillations between cortical andthalamic neurons. Over the past several decades thedetails of this interaction—for example, which firesfirst, the cortex or the thalamus—have evolved, asdiscussed in a comprehensive historical review(Meeren et al, 2005). The centrencephalic theory ofJasper and Penfield held that thalamic dischargesrecruited widespread cortical areas into spike-wavedischarges (Jasper and Fortuyn, 1947). Subse-quently, the involvement of cortex was shown inexperiments in which convulsants applied to thecortical surface also produced 3-Hz discharges.Gloor’s corticoreticular theory held that the diffuselyincreased excitability of the cortex allowed thethalamus and cortex to drive each other (Gloor etal, 1990). Recent experimental work in a geneticstrain of rats with spontaneous absence seizures(WAG/Rij), using signal processing techniques thatallowed fine dissection of the timing of dischargesin different parts of the brain, showed that a corticalfocus (in this case, in the perioral region ofsomatosensory cortex) always leads thalamic dis-charges by a few hundred milliseconds (Meerenet al, 2002). Therefore, despite the appearance of‘generalized’ spike-wave discharges on EEG, it maybe that discharges actually begin in discrete cortical

foci and propagate rapidly across the cortex. Ionicand cellular network mechanisms by which burstfiring in one brain region leads to synchronizationof other regions, ultimately leading to seizure gene-ration, is the subject of ongoing investigation(Blumenfeld and McCormick, 2000). This transitionlikely involves alterations of neurotransmitters andtheir receptors, ionic channels, intracellular signal-ing cascades, and other factors that influence theexcitation/inhibition balance. The possibility mustalso be considered that generalized seizures are lesssynchronized than previously believed (GarciaDominguez et al, 2005; Netoff and Schiff, 2002).

Generalized spike-wave discharges seen inabsence seizures reflect widespread oscillationsbetween excitation (i.e., spike) and inhibition (i.e.,slow wave) in mutually connected thalamocorticalnetworks (McCormick and Contreras, 2001). Threegroups of neurons are primarily involved: corticalpyramidal neurons, thalamic relay (TR) neurons,and thalamic reticular nucleus neurons (Figure 5A).Neocortical layer VI neurons are excitatory (gluta-matergic) and project onto TR neurons, which arealso excitatory (glutamatergic); this interaction bet-ween neocortical pyramidal cells and TR neuronswould create a positive feedback situation, butincessant excitation is prevented by the interposedinhibitory (GABAergic) neurons comprising thethalamic reticular nucleus (NRT). Cortical pyrami-dal cells project onto the NRT neurons, which thenrelease GABA onto TR neurons, which have bothGABAA and GABAB receptors. This reciprocal

Figure 5 Childhood absence epilepsy. (A) Simplified diagram of thalamocortical circuitry underlying spike-wave discharges in theabsence epilepsy (see text). Excitatory connections (glutamatergic) are indicated with solid lines and ( + ) signs. Inhibitory connection(GABAergic) is indicated by dashed line and (�) sign. (B(a)) Diagram of intracellularly recorded spike-wave discharge in thalamicrelay neuron, showing sequence of ionic currents. 1: Ih activation, 2: IT activation, 3: IT inactivation, 4: Ih deactivation, 5: removal of ITinactivation. (B(b)) Intracellular responses to prolonged intracellular current injection, illustrating the effects of Ih. The darker trace inresponse to a hyperpolarizing current pulse shows depolarizing sag reflecting Ih activation. The darker trace in response to thedepolarizing current pulse shows a hyperpolarizing sag reflecting Ih activation (arrowhead). When Ih is blocked pharmacologically(lighter traces), the membrane potential reaches a steady state plateau. Therefore, Ih tends to stabilize membrane potential towardresting potential (dashed line) against both depolarizing and hyperpolarizing inputs. Reproduced with permission from Poolos(2004). (B(c)) EEG tracing showing classic 3-Hz generalized spike-wave discharges during an absence seizure. During the seizure,the patient was unresponsive to verbal commands but returned to normal responsiveness as soon as the discharges stopped. Ih, IT,and thalamocortical circuitry combine to alter the excitation/inhibition balance so as to favor the hyperexcitability that underliesthe 3-Hz generalized discharges.

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

996

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 15: Epilepsy review

thalamocortical relay loop is a critical substrate forthe generation of cortical rhythms and this circuitryis largely responsible for normal EEG oscillationsduring wake and sleep states (e.g., 14-Hz sleepspindles in stage II sleep). In CAE, due to geneticalteration of one or more ion channel involved inrhythm generation, the circuit could become hyper-excitable and produce rhythmic spike-wave dis-charges (in the case of CAE, at a frequency of 3-Hzduring wakefulness).

Multiple ionic conductances interact to generatespike-wave discharges, but two ionic channels arebelieved to play an especially key role in regulatingthalamocortical rhythmicity. The first is a subtype ofvoltage-gated calcium channel known as the ‘low-threshold’ or T-type calcium channel, so-namedbecause it can be activated by small depolarizationsof the neuronal membrane. Calcium influx throughthese channels triggers low-threshold spikes,which in turn activate a burst of action potentials(McCormick and Contreras, 2001; Perez-Reyes,2003). Such an excitatory burst is believed tounderlie the ‘spike’ portion of a generalized spike-wave oscillation. T-type calcium channels exist inthree functional states—open, inactivated, andclosed. When the neuronal membrane is depola-rized, Ca2 + enters the neuron and produces actionpotentials in bursts. However, immediately uponCa2 + entry, the channels inactivate, that is, cannotpass further current until they are ‘de-inactivated’by hyperpolarization. This hyperpolarization isprovided by NRT neurons, which release GABAtonically. The GABA binds to GABAB receptors onTR cells. At this point, the T-channels are closed andcannot conduct current again until the membrane isdepolarized. This cycle of depolarization/hyperpo-larization is the critical substrate of TR neuronrhythm generation and drives the thalamocorticaloscillation (Figure 5B(a)). Anticonvulsants known tobe clinically effective against absence seizures (e.g.,ethosuximide and valproic acid) can block T-typecalcium currents (Coulter et al, 1989).

Several experimental models reinforce the impor-tance of T-type calcium currents in the pathophy-siology of absence epilepsy. Mice with spontaneouscalcium channel mutations or knockout of certaincalcium channel subunits have absence seizures andspike-waves on EEG (Kim et al, 2001; Zhang et al,2002). Strasbourg rats with genetic absence epilepsy(GAERs) have upregulated T-calcium currents inthalamic reticular neurons (Danober et al, 1998;Tsakiridou et al, 1995).

Another important ion channel involved in theregulation of thalamocortical rhythmicity is thehyperpolarization-activated cation channel (HCNchannel), responsible for the so-called H-current(Ih). Hyperpolarization-activated cation channels areactivated by hyperpolarization and produce adepolarizing current carried by an inward flux ofNa+ and K+ (Robinson and Siegelbaum, 2003). InTR neurons, this depolarization helps to bring the

resting membrane potential toward threshold foractivation of T-type calcium channels, which in turnproduces a calcium spike and a burst of actionpotentials (Figure 5B(a)).

A unique physiological property of H-currentsamong voltage-gated conductances is that they areboth inhibitory and excitatory, and mediate negativefeedback: hyperpolarization activates HCN chan-nels, leading to depolarization, which then deacti-vates the HCN channels (Figure 5B(b)). The neteffect of HCN channel activation is to stabilize themembrane against either excitatory or inhibitoryinputs (Poolos, 2005; Santoro and Baram, 2003).hyperpolarization-activated cation channel chan-nels are expressed maximally on TR neuron apicaldendrites, near excitatory inputs, allowing H-cur-rents to suppress prolonged excitation as occurs in aseizure. H-currents tend to reestablish restingpotential whether the input is hyperpolarizing ordepolarizing. In a mouse model in which the HCN2isoform is knocked out, animals develop sponta-neous absence seizures and spike-wave discharges(Ludwig et al, 2003). In the WAG/Rij rat model ofabsence epilepsy, defective Ih augments excitatorypostsynaptic potentials and leads to height-ened neocortical excitability (Strauss et al, 2004).Together, these channels enable the thalamocorticalcircuit to produce the classic 3-Hz generalizedspike-wave discharges of an absence seizure (Figure5B(c)).

The clinical relevance of HCN channels in thepathogenesis of absence seizures is supported by thedemonstration that lamotrigine, which has anti-absence activity, enhances activation of dendriticH-currents in hippocampal pyramidal neurons(Poolos et al, 2002). Interestingly, H-currents havealso been implicated in the pathogenesis of hyper-thermia-induced seizures in rat pups, which mimicfebrile seizures in children. In that model, ahyperthermic seizure early in life leads to apersistent increase in both GABAergic currentsand H-currents in CA1 hippocampal pyramidalneurons (Chen et al, 2001). This combination ofpersistent changes in neuronal excitability waslinked to lowered seizure threshold later in life.Although no human HCN channelopathy has beenidentified, these studies attest to the importance ofH-currents in the control of neuronal excitabilityand seizure predisposition (Santoro and Baram,2003).

In addition to the involvement of T-type calciumchannels and HCN-channels, other neurotransmitterreceptors have also been implicated in thalamocor-tical rhythmicity and absence seizures. Antagonistsof GABAB receptors and dopaminergic agonists alsointerrupt abnormal thalamocortical discharges inexperimental absence epilepsy models (Snead,1995). GABAB receptors are involved in mediatinglong-lasting thalamic inhibitory postsynaptic poten-tials involved in the generation of normal thalamo-cortical rhythms, while brainstem monoaminergic

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

997

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 16: Epilepsy review

projections disrupt these rhythms. Of note, someGABAergic drugs can exacerbate absence seizures(Cocito and Primavera, 1998; Knake et al, 1999;Panayiotopoulos, 1999).

Future considerations and unanswered questions:The gene(s) for absence epilepsy is not yet char-acterized and the pathophysiology is complex. It isuncertain whether application of advanced signalanalysis methods such as nonlinear associationanalysis will enhance our understanding of thisphysiologically complex syndrome, converting itfrom a generalized epilepsy to a partial onset one.The existence of absence seizures in a multitude ofepilepsy syndromes with different prognoses raisesthe possibility that several pathophysiological me-chanisms coexist.

Summary and Conclusions

Advances in clinical and basic science are increas-ing our understanding of epilepsy mechanisms. Inparticular, new information from molecular genet-ics, imaging techniques, and cellular physiology arecreating conditions whereby these advances willtranslate into therapeutic advances. This review hasdiscussed five selected examples of epilepsies,summarized in Table 1. By focusing on multiplelevels of nervous system function, it can be seen thatepilepsy manifestations and consequences are wide-spread, involving many aspects of brain functionbeyond the seizure itself. The mechanisms des-cribed here are by no means restricted to the level ofthe nervous system affected primarily. Indeed,abnormal ionic channel function can affect synapticand network function, and both in turn caninfluence behavior and cognition. Our challenge isto find the links between the different levels ofpathophysiology in epilepsy, and translate theseinto beneficial therapies.

References

Alonso-Nanclares L, Garbelli R, Sola RG, Pastor J, Tassi L,Spreafico R, DeFelipe J (2005) Microanatomy of thedysplastic neocortex from epileptic patients. Brain128:158–73

Andre VM, Flores-Hernandez J, Cepeda C, Starling AJ,Nguyen S, Lobo MK, Vinters HV, Levine MS, MathernGW (2004) NMDA receptor alterations in neurons frompediatric cortical dysplasia tissue. Cereb Cortex14:634–46

Arzimanoglou A, Guerrini R, Aicardi J (2004) Epilepsieswith typical absence seizures. In: Aicardi’s epilepsy inchildren (Arzimanoglou A, Guerrini R, Aicardi J, eds),3rd ed. Philadelphia: Lippincott Williams & Wilkins,88–104

Avanzini G, Franceschetti S (2003) Prospects for novelantiepileptic drugs. Curr Opin Invest Drugs 4:805–14

Avoli M, Bernasconi A, Mattia D, Olivier A, Hwa GG(1999) Epileptiform discharges in the human dysplasticneocortex: in vitro physiology and pharmacology. AnnNeurol 46:816–26

Avoli M, D’Antuono M, Louvel J, Kohling R, Biagini G,Pumain R, D’Arcangelo G, Tancredi V (2002) Networkand pharmacological mechanisms leading to epilepti-form synchronization in the limbic system in vitro. ProgNeurobiol 68:167–207

Baraban SC, Schwartzkroin PA (1996) Flurothyl seizuresusceptibility in rats following methylazoxymethanoltreatment. Epilepsy Res 23:189–94

Ben-Ari Y (2002) Excitatory actions of GABA duringdevelopment: the nature of the nurture. Nat RevNeurosci 3:728–39

Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M,Lindvall O (1997) Apoptosis and proliferation ofdentate gyrus neurons after single and intermittentlimbic seizures. Proc Natl Acad Sci USA 94:10432–7

Bernasconi N, Bernasconi A, Caramanos Z, Antel SB,Andermann F, Arnold DL (2003) Mesial temporaldamage in temporal lobe epilepsy: a volumetric MRIstudy of the hippocampus, amygdala, and parahippo-campal region. Brain 126:462–9

Bernasconi N, Bernasconi A, Caramanos Z, Dubeau F,Richardson J, Andermann F, Arnold DL (2001) Ento-rhinal cortex atrophy in epilepsy patients exhibitingnormal hippocampal volumes. Neurology 56:1335–9

Table 1 Selected examples of epilepsies and underlying mechanisms

Case Level of abnormalexcitability

Mechanism of abnormalexcitabilitya

Clinical syndrome Epilepsy syndromeclassification

Prognosis

1 Ionic channels Decreased M-channelfunction

BFNC Generalizedsymptomatic

Good

2 Glucose transportprotein

Decreased brain glucoseavailability

Glut-1 deficiencysyndrome

Generalizedsymptomatic

Variable; better withketogenic diet

3 Small-scale (local)neuronal circuit

Abnormal circuitformation and synapticconnectivity

Focal cortical dysplasia Localization-relatedsymptomatic

Variable; often goodwith resection

4 Large-scale (limbic)neuronal circuit

Hippocampal sclerosis,axonal sprouting

Temporal lobe epilepsy Localization-relatedsymptomatic

Variable; often goodwith resection

5 Thalamo-corticalcircuits

Abnormal T-typecalcium channel andHCN channel

Childhood absenceepilepsy

Primary generalized(idiopathic)

Good

aSeveral other mechanisms may also be involved.

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

998

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 17: Epilepsy review

Binder DK, Routbort MJ, Ryan TE, Yancopoulos GD,McNamara JO (1999) Selective inhibition of kindlingdevelopment by intraventricular administration ofTrkB receptor body. J Neurosci 19:1424–36

Bisulli F, Tinuper P, Avoni P, Striano P, Striano S, d’Orsi G,Vignatelli L, Bagattin A, Scudellaro E, Florindo I,Nobile C, Tassinari CA, Baruzzi A, Michelucci R(2004) Idiopathic partial epilepsy with auditory fea-tures (IPEAF): a clinical and genetic study of 53sporadic cases. Brain 127:1343–52

Bjerre I, Corelius E (1968) Benign familial neonatalconvulsions. Acta Paediatr Scand 57:557–61

Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkel-sen JD, Blackburn-Munro RE (2005) Retigabine: chemi-cal synthesis to clinical application. CNS Drug Rev11:1–20

Blumenfeld H, McCormick DA (2000) Corticothalamicinputs control the pattern of activity generated inthalamocortical networks. J Neurosci 20:5153–62

Boles RG, Seashore MR, Mitchell WG, Kollros PR, MofidiS, Novotny EJ (1999) Glucose transporter type 1deficiency: a study of two cases with video-EEG. Eur JPediatr 158:978–83

Bordey A, Lyons SA, Hablitz JJ, Sontheimer H (2001)Electrophysiological characteristics of reactive astro-cytes in experimental cortical dysplasia. J Neurophysiol85:1719–31

Bough KJ, Schwartzkroin PA, Rho JM (2003) Calorierestriction and ketogenic diet diminish neuronal excit-ability in rat dentate gyrus in vivo. Epilepsia 44:752–60

Bragin A, Mody I, Wilson CL, Engel J Jr (2002) Localgeneration of fast ripples in epileptic brain. J Neurosci22:2012–21

Brandt C, Ebert U, Loscher W (2004) Epilepsy induced byextended amygdala-kindling in rats: lack of clearassociation between development of spontaneous sei-zures and neuronal damage. Epilepsy Res 62:135–56

Briellmann RS, Berkovic SF, Syngeniotis A, King MA,Jackson GD (2002) Seizure-associated hippocampalvolume loss: a longitudinal magnetic resonance studyof temporal lobe epilepsy. Ann Neurol 51:641–4

Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, CoulterDA (1998) Selective changes in single cell GABA-Areceptor subunit expression and function in temporallobe epilepsy. Nat Med 4:1166–72

Brown DA, Adams PR (1980) Muscarinic suppression of anovel voltage-sensitive K+ current in a vertebrateneuron. Nature 283:673–6

Buckmaster PS (2004) Laboratory animal models oftemporal lobe epilepsy. Comp Med 54:473–85

Buckmaster PS, Zhang GF, Yamawaki R (2002) Axonsprouting in a model of temporal lobe epilepsy creates apredominantly excitatory feedback circuit. J Neurosci22:6650–8

Bye AME (1994) Neonate with benign familial neonatalconvulsions: recorded generalized and partial seizures.Pediatr Neurol 10:164–5

Calcagnotto ME, Baraban SC (2005) Prolonged NMDA-mediated responses, altered ifenprodil sensitivity, andepileptiform-like events in the malformed hippocam-pus of methylazoxymethanol exposed rats. J Neuro-physiol 94:153–62

Cascino GD (2004) Surgical treatment for epilepsy.Epilepsy Res 60:179–86

Castaldo P, Miraglia Del Giudice E, Coppola G, Pascotto A,Annunziato L, Taglialatela M (2002) Benign familialneonatal convulsions caused by altered gating of

KCNQ2/KCNQ3 potassium channels. J Neurosci22:RC199

Castro PA, Cooper EC, Lowenstein DH, Baraban SC (2001)Hippocampal heterotopia lack functional Kv4.2 potas-sium channels in the methylazoxymethanol model orcortical malformations and epilepsy. J Neurosci21:6626–34

Cavalheiro EA, Riche DA, Le Gal La Salle G (1982) Long-term effects of intrahippocampal kainic acid injectionin rats: a method for inducing spontaneous recurrentseizures. Electroencephalogr Clin Neurophysiol53:581–9

Cavazos JE, Das I, Sutula TP (1994) Neuronal loss inducedin limbic pathways by kindling: evidence for inductionof hippocampal sclerosis by repeated brief seizures.J Neurosci 14:3106–21

Cepeda C, Andre VM, Vinters HV, Levine MS, MathernGW (2005) Are cytomegalic neurons and balloon cellsgenerators of epileptic activity in pediatric corticaldysplasia? Epilepsia 46(Suppl. 5):82–8

Chang BS, Lowenstein DH (2003) Epilepsy. N Engl J Med349:1257–66

Chen K, Aradi I, Thon N, Egbahl-Ahmadi M, Baram TZ,Soltesz I (2001) Persistently modified h-channels aftercomplex febrile seizures convert the seizure-inducedenhancement of inhibition to hyperexcitability. NatMed 7:331–6

Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y,Bao X, Yao Z, Ding K, Lo WH, Qiang B, Chan P, Shen Y,Wu X (2003) Association between genetic variation ofCACNA1H and childhood absence epilepsy. AnnNeurol 54:239–43

Chevassus-au-Louis N, Baraban SC, Gaiarsa J-L, Ben-Ari Y(1999) Cortical malformations and epilepsy: newinsights from animal models. Epilepsia 40:811–21

Cocito L, Primavera A (1998) Vigabatrin aggravatesabsences and absence status. Neurology 51:1519–20

Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R(2002) On the origin of interictal activity inhuman temporal lobe epilepsy in vitro. Science 298:1418–21

Cohen I, Navarro V, LeDuigou C, Miles R (2003) Mesialtemporal lobe epilepsy: a pathological replay of devel-opmental mechanisms? Biol Cell 95:329–33

Cohen-Gadol AA, Ozduman K, Bronen RA, Kim JH,Spencer DD (2004) outcome after epilepsy surgery forfocal cortical dysplasia. J Neurosurg 101:55–65

Cole AJ, Dichter M (2002) Neuroprotection and antiepi-leptogenesis: overview, definitions, and context. Neu-rology 59(Suppl 5):S1–2

Cooper EC, Aldape KD, Abosch A, Barbaro NM, BergerMS, Peacock WS, Jan YN, Jan LY (2000) Colocalizationand coassembly of two human brain M-type potassiumchannel subunits that are mutated in epilepsy. Proc NatAcad Sci USA 97:4914–9

Cooper EC, Harrington E, Jan YN, Jan LY (2001) M channelKCNQ subunits are localized to key sites for control ofneuronal network oscillations and synchronization inmouse brain. J Neurosci 21:9529–40

Cooper EC, Jan LY (2003) M-channels: neurologicaldiseases, neuromodulation, and drug development.Arch Neurol 60:496–500

Coppola G, Auricchio G, Federico R, Carotenuto M,Pascotto A (2004) Lamotrigine versus valproic acid asfirst-line monotherapy in newly diagnosed typicalabsence seizures: an open-label, randomized, parallel-group study. Epilepsia 45:1049–53

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

999

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 18: Epilepsy review

Cossart R, Bernard C, Ben-Ari Y (2005) Multiple facets ofGABAergic neurons and synapses: multiple fates ofGABA signalling in epilepsies. Trends Neurosci28:108–15

Coulter DA, Huguenard JR, Prince DA (1989) Specific petitmal anticonvulsants reduce calcium currents in thala-mic neurons. Neurosci Lett 98:74–8

Cullingford TE (2004) The ketogenic diet; fatty acids, fattyacid-activated receptors and neurological disorders.Prostagl Leukot Essent Fatty Acids 70:253–64

Cunnane SC, Musa K, Ryan MA, Whiting S, Fraser DD(2002) Potential role of polyunsaturates in seizureprotection achieved with the ketogenic diet. ProstaglLeukot Essent Fatty Acids 67:131–5

Danober L, Deransart C, Depaulis A, Vergnes M, Mares-caux C (1998) Pathophysiological mechanisms ofgenetic absence epilepsy in the rat. Prog Neurobiol55:27–57

Dawodu S, Thom M (2005) Quantitative neuropathologyof the entorhinal cortex region in patients withhippocampal sclerosis and temporal lobe epilepsy.Epilepsia 46:23–30

Defazio RA, Hablitz JJ (1999) Reduction of zolpidemsensitivity in a freeze lesion model of neocorticaldysgenesis. J Neurophysiol 81:404–7

Defazio RA, Hablitz JJ (2000) Alterations in NMDAreceptors in a rat model of cortical dysplasia. JNeurophysiol 83:315–21

DeLanerolle NC, Lee T-S (2005) New facets of theneuropathology and molecular profile of human tem-poral lobe epilepsy. Epilepsy Behav 7:190–203

DeVivo DC, Trifiletti RR, Jacobson RI, Ronen GM,Behmand RA, Harik SI (1991) Defective glucosetransport across the blood–brain barrier as a cause ofpersistent hypoglycorrhachia, seizures, and develop-mental delay. N Engl J Med 325:703–9

Dudek FE, Hellier JL, Williams PA, Ferraro DJ, Staley KJ(2002) The course of cellular alterations associatedwith the development of spontaneous seizures afterstatus epilepticus. Prog Brain Res 135:53–65

Duelli R, Kuschinsky W (2001) Brain glucose transporters:relationship to local energy demand. News Physiol Sci16:71–6

Dvorak K, Feit J, Jurankova Z (1978) Experimentallyinduced focal microgyria and status verucosus defor-mis in rats: pathogenesis and interrelation. Histologicaland autoradiographical study. Acta Neuropathol (Berl)44:121–9

Dzhala VI, Staley KJ (2003) Excitatory actions of endogen-ously released GABA contribute to initiation of ictalepileptiform activity in the developing hippocampus.J Neurosci 23:1840–6

Dzhala VI, Staley KJ (2004) Mechanisms of fast ripples inthe hippocampus. J Neurophysiol 24:8896–906

Elger CE, Helmstaedter C, Kurthen M (2004) Chronicepilepsy and cognition. Lancet Neurol 3:663–72

Engel J (2001) A proposed diagnostic scheme for peoplewith epileptic seizures and epilepsy: report of the ILAEtask force on classification and terminology. Epilepsia42:796–803

Federico P, Abbott DF, Briellmann RS, Harvey AS, JacksonGD (2005) Functional MRI of the pre-ictal state. Brain128:1811–7

Fisher PD, Sperber EF, Moshe SL (1998) Hippocampalsclerosis revisited. Brain Dev 20:563–73

Fraser DD, Whiting S, Andrew RD, Macdonald EA, Musa-Veloso K, Cunnane SC (2003) Elevated polyunsaturated

fatty acids in blood serum obtained from children onthe ketogenic diet. Neurology 60:1026–9

Fuerst D, Shah J, Shah A, Watson C (2003) Hippocampalsclerosis is a progressive disorder: a longitudinalvolumetric MRI study. Ann Neurol 53:413–6

Garcia Dominguez L, Wennberg RA, Gaetz W, Cheyne D,Snead OC, Perez Velazquez JL (2005) Enhancedsynchrony in epileptiform activity? Local versus dis-tant phase synchronization in generalized seizures.J Neurosci 25:8077–84

Germano IM, Zhang YF, Sperber EF, Moshe SL (1996)Neuronal migration disorders increase seizure suscept-ibility to febrile seizures. Epilepsia 37:902–10

Gloor P, Avoli M, Kostopoulos G (1990) Thalamocorticalrelationships in generalized epilepsy with bilaterallysynchronous spike-and-wave discharge. In: General-ized epilepsy: neurobiological approaches (Avoli M,Gloor P, Kostopoulos G, Naquet R, eds), Boston:Birkhauser, 190–212

Goncalves Pereira PM, Insaustid R, Artacho-Perulad E,Salmenperae T, Kalviainene R, Pitkanen A (2005) MRvolumetric analysis of the piriform cortex and corticalamygdala in drug-refractory temporal lobe epilepsy.Am J Neuroradiol 26:319–32

Gordon N, Newton RW (2003) Glucose transporter type 1(GLUT-1) deficiency. Brain Dev 27:477–80

Gourevitch R, Rocher C, Pen GL, Krebs MO, Jay TM (2004)Working memory deficits in adult rats after prenataldisruption of neurogenesis. Behav Pharmacol 15:287–292

Greene AE, Todorova MT, McGowan R, Seyfried TN (2001)Caloric restriction inhibits seizure susceptibility inepileptic EL mice by reducing blood glucose. Epilepsia42:1371–8

Greene AE, Todorova MT, Seyfried TN (2003) Perspectiveson the metabolic management of epilepsy throughdietary reduction of glucose and elevation of ketonebodies. J Neurochem 86:529–37

Guerrini R, Filippi T (2005) Neuronal migration disorders,genetics, and epileptogenesis. J Child Neurol 20:287–99

Gutierrez-Delicado E, Serratosa JM (2004) Genetics of theepilepsies. Curr Opin Neurol 17:147–53

He XP, Kotloski R, Nef S, Luikart BW, Parada LF,McNamara JO (2004) Conditional deletion of TrkB butnot BDNF prevents epileptogenesis in the kindlingmodel. Neuron 43:31–42

Helmstaedter C (2002) Effects of chronic epilepsyon declarative memory systems. Prog Brain Res 135:439–53

Helmstaedter C, Kurthen M, Lux S, Reuber M, Elger CE(2003) Chronic epilepsy and cognition: a longitudinalstudy in temporal lobe epilepsy. Ann Neurol 54:425–32

Hermann B, Seidenberg M, Bell B (2002) The neurodeve-lopmental impact of childhood onset temporal lobeepilepsy on brain structure and function and the riskof progressive cognitive effects. Prog Brain Res 135:429–38

Heron SE, Phillips HA, Mulley JC, Mazarib A, NeufieldMY, Berkovic SF, Scheffer IE (2004) Genetic variation ofCACNA1H in idiopathic generalized epilepsy. AnnNeurol 55:595–6

Hirsch E, Velez A, Sellal F, Maton B, Grinspan A,Malafosse A, Marescaux C (1993) Electroclinical signsof benign familial neonatal convulsions. Ann Neurol34:835–41

Hughes PE, Young D, Preston KM, Yan Q, Dragunow M(1998) Differential regulation by MK801 of immediate-

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

1000

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 19: Epilepsy review

early genes, brain-derived neurotrophic factor and trkreceptor mRNA induced by a kindling afterdischarge.Mol Brain Res 53:138–51

Iasemidis LD, Olson LD, Savit RS, Sackellares JC(1994) Time dependencies in the occurrences ofepileptic seizures: a nonlinear approach. Epilepsy Res17:81–94

Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C,Robertson R, Kullmann DM, Hanna MG (2004) Dys-function of the brain calcium channel Cav2.1 in absenceepilepsy and episodic ataxia. Brain 127:2682–92

Jacobs KM, Hwang BJ, Prince DA (1999a) Focal epilepto-genesis in a rat model of polymicrogyria. J Neurophy-siol 81:159–73

Jacobs KM, Kharazia VN, Prince DA (1999b) Mechanismsunderlying epileptogenesis in cortical malformations.Epilepsy Res 36:165–88

Jacobs KM, Prince DA (2005) Excitatory and inhibitorypostsynaptic currents in a rat model of epileptogenicmicrogyria. J Neurophysiol 93:687–96

Jasper HH, Fortuyn JD (1947) Experimental studies on thefunctional anatomy of petit mal epilepsy. Res PublAssoc Res Nerv Ment Dis 26:272–98

Jentsch TJ (2000) Neuronal KCNQ potassium channels:physiology and role in disease. Nat Rev Neurosci 1:21–30

Jokeit H, Ebner A (2002) Effects of chronic epilepsy onintellectual functions. Prog Brain Res 135:455–63

Kellinghaus C, Kunieda T, Ying Z, Pan A, Luders HO,Najm IM (2004) Severity of histopathologic abnormal-ities and in vivo epileptogenicity in the in uteroradiation model of rats is dose dependent. Epilepsia45:583–91

Khosravani H, Bladen C, Parker DB, Snutch TP, McRoryJE, Zamponi GW (2005) Effects of Cav3.2 channelmutations linked to idiopathic generalized epilepsy.Ann Neurol 57:745–9

Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEneryMW, Shin HS (2001) Lack of the burst firingof thalamocortical relay neurons and resistance toabsence seizures in mice lacking a1G T-type Ca2+

channels. Neuron 31:35–45Klepper J (2004) Impaired glucose transport into the

brain: the expanding spectrum of glucose transportertype 1 deficiency syndrome. Curr Opin Neurol 17:193–196

Klepper J, Diefenbach S, Kohlschutter A, Voit T (2004)Effects of the ketogenic diet in the glucose transporter 1deficiency syndrome. Prostagl Leukot Essent FattyAcids 70:321–7

Klepper J, Voit T (2002) Facilitated glucose transporterprotein type 1 (GLUT1) deficiency syndrome: impairedglucose transport into the brain—a review. Eur J Pediatr161:295–304

Knake S, Hamer HM, Schomburg U, Oertel WH, RosenowF (1999) Tiagabine-induced absence status in idio-pathic generalized epilepsy. Seizure 8:314–7

Kobayashi E, D’Agostino M, Lopes-Cendes I, AndermannE, Dubeau F, Guerreiro C, Schenka A, Queiroz L,Olivier A, Cendes F, Andermann F (2003) Outcome ofsurgical treatment in familial mesial temporal lobeepilepsy. Epilepsia 44:1080–4

Koepp MJ, Woermann FG (2005) Imaging structure andfunction in refractory focal epilepsy. Lancet Neurol4:42–53

Koh S, Storey T, Santos T, Mian A, Cole A (1999) Early-lifeseizures in rats increase susceptibility to seizure-

induced brain injury in adulthood. Neurology 53:915–921

Kondo S, Najm I, Kunieda T, Perryman S, Yacubova K,Luders HO (2001) Electroencephalographic character-ization of an adult rat model of radiation-inducedcortical dysplasia. Epilepsia 42:1221–7

Kotloski R, Lynch M, Lauersdorf S, Sutula T (2002)Repeated brief seizures induce progressive hippocam-pal neuron loss and memory deficits. Prog Brain Res135:95–110

Koyama R, Yamada MK, Fujisawa S, Katoh-Semba R,Matsuki N, Ikegaya Y (2004) Brain-derived neuro-trophic factor induces hyperexcitable reentrant circuitsin the dentate gyrus. J Neurosci 24:9215–24

Lee KS, Schottler F, Collins JL, Lanzino G, Couture D, RaoA, Hiramatsu K, Goto Y, Hong SC, Caner H, YamamotoH, Chen ZF, Bertram E, Berr S, Omary R, Scrable H,Jackson T, Goble J, Eisenman L (1997) A genetic animalmodel of human neocortical heterotopia associatedwith seizures. J Neurosci 17:6236–42

Lehesjoki AE (2003) Molecular background of progressivemyoclonus epilepsy. EMBO J 22:3473–8

Lehnertz K, Litt B (2005) The first international collabora-tive workshop on seizure prediction: summary anddata description. Clin Neurophysiol 116:493–505

Leppert M, Anderson VE, Quattlebaum T, Stauffer D,O’Connell P, Nakamura Y, Lalouel JM, White R (1989)Benign familial neonatal convulsions linked to geneticmarkers on chromosome 20. Nature 337:647–8

Litt B, Echauz J (2002) Prediction of epileptic seizures.Lancet Neurol 1:22–30

Litt B, Esteller R, Echauz J, D’Alessandro M, Shor R, HenryT, Pennell P, Epstein C, Bakay R, Dichter M (2001)Epileptic seizures may begin hours in advance ofclinical onset: a report of five patients. Neuron 30:51–64

Liu RS, Lemieux L, Bell GS, Hammers A, Sisodiya SM,Bartlett PA, Shorvon SD, Sander JW, Duncan JS (2003)Progressive neocortical damage in epilepsy. AnnNeurol 53:312–24

Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C,Holthoff K, Langebartels A, Wotjak C, Munsch T, ZongX, Feil S, Feil R, Lancel M, Chien KR, Konnerth A, PapeH-C, Biel M, Hofmann F (2003) Absence epilepsy andsinus dysrhythmia in mice lacking the pacemakerchannel HCN2. EMBO J 22:216–24

Luhmann HJ (2006) The cortical freeze lesion model. In:Models of seizures and epilepsy (Pitkanen A,Schwartzkroin PA, Moshe SL, eds), Amsterdam: Else-vier, 295–303

Luhmann HJ, Karpuk N, Qu M, Zilles K (1998) Character-ization of neuronal migration disorders in neocorticalstructures: II. Intracellular in vitro recordings. J Neuro-physiol 80:92–102

Mathern GW, Cepeda C, Hurst RS, Flores-Hernandez J,Mendoza D, Levine MS (2000) Neurons recorded frompediatric epilepsy surgery patients with cortical dys-plasia. Epilepsia 41:S162–7

Mathern GW, Pretorius JK, Mendoza D, Leite JP, ChimelliL, Born DE, Fried I, Assirati JA, Ojemann GA,Adelson PD, Cahan LD, Kornblum HI (1999) Hippo-campal N-methyl-D-aspartate receptor subunit mRNAlevels in temporal lobe epilepsy patients. Ann Neurol46:343–58

McCormick DA, Contreras D (2001) On the cellular andnetwork bases of epileptic seizures. Annu Rev Physiol63:815–46

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

1001

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 20: Epilepsy review

Meeren H, Van Luijtelaar EL, Lopes da Silva FH, Coenen A(2005) Evolving concepts on the pathophysiology ofabsence seizures. Arch Neurol 62:371–6

Meeren HK, Pijn JP, Van Luijtelaar EL, Coenen AM, Lopesda Silva FH (2002) Cortical focus drives widespreadcorticothalamic networks during spontaneous absenceseizures in rats. J Neurosci 22:1480–95

Najm I, Ying Z, Babb T, Crino PB, Macdonald R, MathernGW, Spreafico R (2004) Mechanisms of epileptogenicityin cortical dysplasias. Neurology 62:S9–13

Netoff TI, Schiff SJ (2002) Decreased neuronal synchroni-zation during experimental seizures. J Neurosci 22:7297–307

Okazaki M, Evenson D, Nadler J (1995) Hippocampalmossy fiber sprouting and synapse formation afterstatus epilepticus in rats: visualization after retrogradetransport of biocytin. J Comp Neurol 352:515–34

Ottman R, Winawer MR, Kalachikov S, Barker-CummingsC, Gilliam TC, Pedley TA, Hauser WA (2004) LGI1mutations in autosomal dominant partial epilepsy withauditory features. Neurology 62:1120–6

Oyegbile TO, Dow C, Jones J, Bell B, Rutecki P, Sheth R,Seidenberg M, Hermann BP (2004) The nature andcourse of neuropsychological morbidity in chronictemporal lobe epilepsy. Neurology 62:1736–42

Palmini A, Gambardella A, Andermann F, Dubeau F,da Costa JC, Olivier A, Tampieri D, Gloor P,Quesney F, Andermann E, Paglioli E, Paglioli-Neto E,Coutinho L, Leblanc R, Kim H-I (1995) Intrinsicepileptogenicity of human dysplastic cortex as sug-gested by corticography and surgical results. AnnNeurol 37:476–87

Palmini A, Najm I, Avanzini G, Babb T, Guerrini R,Foldvary-Schaefer N, Jackson G, Luders HO, Prayson R,Spreafico R, Vinters HV (2004) Terminology and classi-fication of the cortical dysplasias. Neurology 62:S2–8

Panayiotopoulos CP (1999) Typical absence seizures andtheir treatment. Arch Dis Child 81:351–5

Parent JM, Janumpalli S, McNamara JO, Lowenstein DH(1998) Increased dentate granule cell neurogenesisfollowing amygdala kindling in the adult rat. NeurosciLett 247:9–12

Pennacchio LA, Lehesjoki AE, Stone AE, Willour VL,Virtaneva K, Miao J, D’Amato E, Ramirez L, Faham M,Koskiniemi M, Warrington JA, Norio R, de la ChapelleA, Cox DR, Myers RM (1996) Mutations in the geneencoding cystatin B in progressive myoclonus epilepsy(EPM1). Science 271:1731–4

Perez-Reyes E (2003) Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 83:117–161

Peters HC, Hu H, Pongs O, Storm JF, Isbrandt D (2005)Conditional transgenic suppression of M channels inmouse brain reveals functions in neuronal excitability,resonance and behavior. Nat Neurosci 8:51–60

Peters O, Redecker C, Hagemann G, Bruehl C, LuhmannHJ, Witte OW (2004) Impaired synaptic plasticity in thesurround of perinatally acquired dysplasia in ratcerebral cortex. Cereb Cortex 14:1081–7

Pierre K, Pellerin L (2005) Monocarboxylate transportersin the central nervous system: distribution, regulationand function. J Neurochem 94:1–14

Pitkanen A, Sutula TP (2002) Is epilepsy a progressivedisorder? Prospects for new therapeutic approaches intemporal lobe epilepsy. Lancet Neurol 1:173–81

Poolos NP (2004) The yin and yang of the H-channel andits role in epilepsy. Epilepsy Curr 4:3–6

Poolos NP (2005) The h-channel: a potential channelo-pathy in epilepsy? Epilepsy Behav 7:51–6

Poolos NP, Migliore M, Johnston D (2002) Pharmacologicalupregulation of h-channels reduces the excitability ofpyramidal neuron dendrites. Nat Neurosci 5:767–74

Posner EB, Mohamed K, Marson AG (2005) A systematicreview of treatment of typical absence seizures inchildren and adolescents with ethosuximide, sodiumvalproate, or lamotrigine. Seizure 14:117–22

Redecker C, Luhmann HJ, Hagemann G, Fritschy JM, WitteOW (2000) Differential downregulation of GABA-Areceptor subunits in widespread brain regions in thefreeze-lesion model of focal cortical malformations.J Neurosci 20:5045–53

Robinson RB, Siegelbaum SA (2003) Hyperpolarization-activated cation currents: from molecules to physio-logical function. Annu Rev Physiol 65:453–80

Rogawski MA (2000) K+ channels and the molecularpathogenesis of epilepsy: implications for therapy.Trends Neurosci 23:393–8

Roper SN, King MA, Abraham LA, Boillot MA (1997)Disinhibited in vitro neocortical slices containingexperimentally induced cortical dysplasia demons-trate hyperexcitability. Epilepsy Res 26:443–9

Rosen GD, Jacobs KM, Prince DA (1998) Effects of neonatalfreeze lesions on expression of parvalbumin in ratneocortex. Cereb Cortex 8:753–61

Santhakumar V, Aradi I, Soltesz I (2005) Role of mossyfiber sprouting and mossy cell loss in hyperexcitability:network model of the dentate gyrus incorporating celltypes and axonal topography. J Neurophysiol 93:437–53

Santoro B, Baram TZ (2003) The multiple personalities ofh-channels. Trends Neurosci 26:550–4

Sayin U, Osting S, Hagen J, Rutecki P, Sutula T (2003)Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizuresin kindled rats. J Neurosci 23:2759–68

Sayin U, Rutecki P, Sutula T (1999) NMDA-dependentcurrents in granule cells of the dentate gyrus contributeto induction but not permanence of kindling.J Neurophysiol 81:564–74

Scantlebury MH, Gibbs SA, Foadjo B, Lema P, Psarropou-lou C, Carmant L (2005) Febrile seizures in thepredisposed brain: a new model of temporal lobeepilepsy. Ann Neurol 58:41–9

Scharfman HE (2005) Brain-derived neurotrophic factorand epilepsy—a missing link? Epilepsy Curr 5:83–8

Scharfman HE, Sollas AL, Berger RE, Goodman JH (2003)Electrophysiological evidence of monosynaptic excita-tory transmission between granule cells after seizure-induced mossy fiber sprouting. J Neurophysiol 90:2536–47

Scharfman HE, Sollas AL, Goodman JH (2002) Sponta-neous recurrent seizures after pilocarpine-inducedstatus epilepticus activate calbindin-immunoreactivehilar cells of the rat dentate gyrus. Neuroscience111:71–81

Scheffer IE, Berkovic SF (2003) The genetics of humanepilepsy. Trends Pharmacol Sci 24:428–33

Schwarcz R, Scharfman HE, Bertram EH (2002) Temporallobe epilepsy: renewed emphasis on extrahippocampalareas. In: Neuropsychopharmacology: the fifth genera-tion of progress (Davis KL, Charney D, Coyle JT,Nemeroff C, eds), Philadelphia: Lippincott Williams &Wilkins, 1843–55

Schwartzkroin PA, Roper SN, Wenzel HJ (2004) Corticaldysplasia and epilepsy: animal models. In: Recent

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

1002

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 21: Epilepsy review

advances in epilepsy research (Binder DK, ScharfmanHE, eds), New York: Kluwer Academic/Plenum Pub-lishers, 145–74

Schwartzkroin PA, Walsh CA (2000) Cortical malforma-tions and epilepsy. Ment Retard Dev Disabil Res Rev6:268–80

Schwechter EM, Veliskova J, Velisek L (2003) Correlationbetween extracellular glucose and seizure susceptibil-ity in adult rats. Ann Neurol 53:91–101

Sheth RD, Stafstrom CE, Hsu D (2005) Non-pharmacolo-gical treatment options for epilepsy. Semin PediatrNeurol 12:106–13

Singh N, Charlier C, Stauffer D, DuPont B, Leach R, MelisR, Ronen G, Bjerre I, Quattlebaum T, Murphy J, McHargM, Gagnon D, Rosales T, Peiffer A, Anderson V, LeppertM (1998) A novel potassium channel gene, KCNQ2, ismutated in an inherited epilepsy of newborns. Nat Gen18:25–9

Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J,Dillon J, Consortium TBP, Anderson VE, SanguinettiMC, Leppert MF (2003) KCNQ2 and KCNQ3 potassiumchannel genes in benign familial neonatal convulsions:expansion of the functional and mutation spectrum.Brain 126:2726–37

Sipila ST, Huttu K, Soltesz I, Voipio J, Kaila K (2005)Depolarizing GABA acts on intrinsically burstingpyramidal neurons to drive giant depolarizing poten-tials in the immature hippocampus. J Neurosci25:5280–9

Sloviter RS (2005) The neurobiology of temporal lobeepilepsy: too much information, not enough knowl-edge. C R Biologies 328:143–53

Snead OC (1995) Basic mechanisms of generalizedabsence seizures. Ann Neurol 37:146–57

Staba RJ, Wilson CL, Bragin A, Fried IJ, Engel J Jr (2002)Quantitative analysis of high-frequency oscilla-tions (80–500 Hz) recorded in human epileptic hippo-campus and entorhinal cortex. J Neurophysiol 88:1743–1752

Stafstrom CE (2001) Effects of fatty acids and ketones onneuronal excitability: implications for epilepsy and itstreatment. In: Fatty acids—physiological and behavior-al functions (Mostofsky DI, Yehuda S, Salem N, eds),Totowa, NJ: Humana Press, 273–90

Stafstrom CE (2002) Assessing the behavioral and cogni-tive effects of seizures on the developing brain. ProgBrain Res 135:377–90

Stafstrom CE (2005) The role of the subiculum in epilepsyand epileptogenesis. Epilepsy Curr 5:121–9

Stafstrom CE, Bough KJ (2003) The ketogenic diet for thetreatment of epilepsy: a challenge for nutritionalneuroscientists. Nutr Neurosci 6:67–79

Stafstrom CE, Rho JM (eds) (2004) Epilepsy and theketogenic diet. Totowa, NJ: Humana Press

Stafstrom CE, Sutula TP (2005) Models of epilepsy in thedeveloping and adult brain: implications for neuropro-tection. Epilepsy Behav 7(Suppl 3):S18–24

Stafstrom CE, Thompson JL, Holmes GL (1992) Kainic acidseizures in the developing brain: status epilepticus andspontaneous recurrent seizures. Dev Brain Res 65:227–236

Strauss U, Kole MHP, Brauer AU, Pahnke J, Bajorat R,Rolfs A, Nitsch R, Deisz RA (2004) An impairedneocortical Ih is associated with enhanced excitabilityand absence epilepsy. Eur J Neurosci 19:3048–58

Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC,Agarwal AK, Rho JM (2004) The ketogenic diet

increases mitochondrial uncoupling protein levelsand activity. Ann Neurol 55:576–80

Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L (1989)Mossy fiber synaptic reorganization in the epileptichuman temporal lobe. Ann Neurol 26:321–30

Sutula T, Koch J, Golarai G, Watanabe Y, McNamara JO(1996) NMDA receptor dependence of kindling andmossy fiber sprouting: evidence thatthe NMDA recep-tor regulates patterning of hippocampal circuits in theadult brain. J Neurosci 16:7398–406

Sutula TP (2004) Mechanisms of epilepsy progression:current theories and perspectives from neuroplasti-city in adulthood and development. Epilepsy Res 60:161–71

Sutula TP, He XX, Cavazos J, Scott G (1988) Synapticreorganization in the hippocampus induced by abnor-mal functional activity. Science 239:1147–50

Swann JW, Hablitz JJ (2000) Cellular abnormalities andsynaptic plasticity in seizure disorders of the immaturenervous system. Ment Retard Dev Disabil Res Rev6:258–67

Tasker JG, Hoffman NW, Kim YI, Fisher RS, Peacock WJ,Dudek FE (1996) Electrical properties of neocorticalneurons in slices from children with intractableepilepsy. J Neurophysiol 75:931–9

Tassi L, Colombo N, Garbelli R, Francione S, Russo GL,Mai R, Cardinale F, Cossu M, Ferrario A, Galli C,Bramerio M, Citterio A, Spreafico R (2002) Focalcortical dysplasia: neuropathological subtypes, EEG,neuroimaging and surgical outcome. Brain 125:1719–1732

Thio L, Wong M, Yamada K (2000) Ketone bodies do notdirectly alter excitatory or inhibitory hippocampaltransmission. Neurology 54:325–31

Thom M, Zhou J, Martinian L, Sisodiya S (2005)Quantitative post-mortem study of the hippocampusin chronic epilepsy: seizures do not invariably causeneuronal loss. Brain 128:1344–57

Tongiorgi E, Armellin M, Giulianini PG, Bregola G,Zucchini S, Paradiso B, Steward O, Cattaneo A,Simonato M (2004) Brain-derived neurotrophic factormRNA and protein are targeted to discrete dendriticlaminas by events that trigger epileptogenesis.J Neurosci 24:6842–52

Traub RD (2003) Fast oscillations and epilepsy. EpilepsyCurr 3:77–9

Traub RD, Whittington MA, Buhl EH, LeBeau FE, BibbigA, Boyd S, Cross H, Baldeweg T (2001) A possible rolefor gap junctions in generation of very fast EEGoscillations preceding the onset of, and perhapsinitiating, seizures. Epilepsia 42:153–70

Tsakiridou E, Bertollini L, de Curtis M, Avanzini G, PapeHC (1995) Selective increase in T-type calcium con-ductance of reticular thalamic neurons in a rat model ofabsence epilepsy. J Neurosci 15:3110–7

Turnbull J, Lohi H, Kearney JA, Rouleau GA, Delgado-Escueta AV, Meisler MH, Cossette P, Minassian BA(2005) Sacred disease secrets revealed: the genetics ofhuman epilepsy. Hum Mol Gen 14:2491–500

Voskuyl RA, Vreugdenhil M, Kang JX, Leaf A (1998)Anticonvulsant effect of polyunsaturated fatty acids inrats, using the cortical stimulation model. Eur JPharmacol 341:145–52

Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, SunRP, DeVivo DC (2005) Glut-1 deficiency syndrome:clinical, genetic, and therapeutic aspects. Ann Neurol57:111–8

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

1003

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

Page 22: Epilepsy review

Wenzel HJ, Robbins CA, Tsai LH, Schwartzkroin PA (2001)Abnormal morphological and functional organizationof the hippocampus in a p35 mutant model of corticaldysplasia associated with spontaneous seizures.J Neurosci 21:983–98

Wirrell EC, Camfield PR, Gordon KE, Camfield CS, DooleyJM, Hanna BD (1996) Will a critical level of hyperven-tilation-induced hypocapnia always induce an absenceseizure? Epilepsia 37:459–62

Worrell GA, Parish L, Cranstoun SD, Jonas R, Baltuch G,Litt B (2004) High-frequency oscillations and seizuregeneration in neocortical epilepsy. Brain 127:1496–506

Yamada KA, Rensing N, Thio LL (2005) Ketogenic dietreduces hypoglycemia-induced neuronal death inyoung rats. Neurosci Lett 385:210–4

Yudkoff M, Daikhin Y, Nissim I, Nissim I (2004) Theketogenic diet: interactions with brain aminoacid handling. In: Epilepsy and the ketogenic diet(Stafstrom CE, Rho JM, eds), Totowa, NJ: Humana Press,185–99

Zhang Y, Mori M, Burgess DL, Noebels JL (2002) Muta-tions in high-voltage-activated calcium channel genesstimulate low-voltage-activated currents in mousethalamic relay neurons. J Neurosci 22:6362–71

Zhu WJ, Roper SN (2000) Reduced inhibition in an animalmodel of cortical dysplasia. J Neurosci 20:8925–31

Zhu WJ, Roper SN (2001) Brain-derived neurotro-phic factor enhances fast excitatory synaptic transmis-sion in human epileptic dentate gyrus. Ann Neurol50:188–94

Review of selected epilepsy syndromes and mechanismsCE Stafstrom

1004

Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004