Epilepsy review

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

Review Article

Epilepsy: a review of selected clinical syndromes and advances in basic science Carl E Stafstrom1,2 1

Department 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 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 numerous hereditary patterns. New and improved imaging technologies have documented subtle structural lesions and provided structure–function correlations. Experimental models have expanded our understanding of the mechanisms underlying seizures 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

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: stafstrom@neurology.wisc.edu Received 12 October 2005; accepted 14 November 2005; published online 25 January 2006

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 epilepsy 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 examples 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 (Scheffer and Berkovic, 2003), new imaging modalities (Koepp and Woermann, 2005), and novel treatment

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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 dysfunction during which synchronized neuronal firing leads to clinical changes in motor control, sensory perception, behavior, or autonomic function. Based on clinical and electroencephalographic (EEG) criteria, seizures are divided into generalized (seizure onset in both hemispheres at once) or partial (focal; seizure onset in one part of the brain). The mechanisms of partial and generalized seizures differ, which has implications for treatment and prognosis. Epilepsy is the condition of recurrent, unprovoked seizures, suggesting that the brain has become permanently altered pathophysiologically or structurally to support abnormal, hypersynchronous neuronal firing. Patients with an epilepsy syndrome have a similar seizure type, EEG pattern, age of onset, family history, treatment response, and natural history. An updated classification system of the epilepsies includes elements of the older International League Against Epilepsy classification scheme (generalized versus localization-related; idiopathic versus symptomatic) as well as the effects of epilepsy on an individual’s daily function (Engel, 2001). Epileptogenesis is the process by which the brain becomes epileptic, that is, the changes that occur at various levels (e.g., genes, membrane channels, intracellular signaling cascades, neurotransmission, synaptic connectivity) to induce a permanent state of hyperexcitability and hypersynchrony. The mechanisms of epileptogenesis are the focus of extensive current research, including possible interventions to avert the long-term physiological, behavioral and cognitive consequences of epilepsy (Cole and Dichter, 2002; Sutula, 2004).

The hallmarks of a seizure are hyperexcitability of neurons and hypersynchrony of neuronal networks.

Hypersynchrony refers to a population of neurons firing at the same time at a similar rate. While an individual neuron might fire in an ‘epileptic’ pattern, that is, produce rapid, repetitive, paroxysmal discharges, a seizure is inherently a network event, involving numerous neurons firing synchronously. Hyperexcitability refers to the concept of seizure ‘threshold’; a certain level of excitability must be exceeded for a seizure to be generated. Any brain region can potentially generate a seizure under the appropriate conditions, that is, when excitation exceeds inhibition. Each step in seizure generation, propagation, and termination is governed by the balance between excitation and inhibition; excessive excitation, reduced inhibition, or both can lead to a seizure. Understanding the contribution of the excitation/inhibition balance at each step in the Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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

However, the conceptualization of a seizure as merely an imbalance between excitation and inhibition is oversimplified. It is now appreciated that loss of inhibition is not universal in epilepsy, and gamma-amino-butyric acid (GABA)-mediated neurotransmission can even be increased in epilepsy (Cossart et al, 2005). Similarly, GABA, the most prevalent inhibitory neurotransmitter, can sometimes exert excitatory effects. Two examples of this latter phenomenon are now recognized. First, in early development, GABA acts as a depolarizing neurotransmitter (Dzhala and Staley, 2003; Sipila et al, 2005). Second, in adults with temporal lobe epilepsy (TLE), firing of neurons in the subiculum caused by depolarizing GABAergic responses could contribute to hyperexcitability and interictal discharges (Cohen et al, 2002). Finally, genes involved in some epilepsy syndromes do not encode proteins that would, a priori, be expected to affect excitability. For example, cystatin B is a cysteine protease inhibitor with no obvious role in neuronal excitability, yet mutations of the cystatin B gene are responsible for a progressive myoclonic epilepsy syndrome, Unverricht–Lundborg disease (EPM1) (Pennacchio et al, 1996; Lehesjoki, 2003).

For each of the examples of epilepsy below, it is informative to consider how excitation or inhibition are unbalanced, while acknowledging that in a biological system as complex as the brain, multiple factors surely contribute to the epileptic phenotype.

In fact, in epilepsy, numerous pathophysiological mechanisms may coexist and act simultaneously (e.g., gene mutations leading to abnormal ionic channel function, superimposed on aberrant network connectivity). Furthermore, each of the mechanisms described is subject to developmental regulation, with different seizure susceptibility or manifestations at different stages of brain maturation. While the emphasis here is on epilepsy mechanisms, it should be appreciated that the chronic effects of repeated seizures on brain function can lead to psychological, social, and intellectual impairments (Elger et al, 2004). Indeed, the psychosocial aspects of epilepsy and its treatment are often more detrimental to an individual’s daily life and function than the seizures themselves.

Examples of Epilepsy Syndromes and Mechanisms Hyperexcitability at the Level of Genes for Ionic Channels

Case history: A healthy infant was born at 38 weeks gestation following a normal pregnancy. There was no perinatal distress or need for resuscitation. In the first week of life, the infant developed episodes of tonic stiffening of all limbs, accompanied by apnea

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and arterial oxygen saturation (SaO2) declines to 80% or less; some of these episodes were accompanied by head and eye deviation to either side. The seizures lasted up to one minute and resolved spontaneously. The baby was normal between seizures, and the seizures were easily controlled with phenobarbital. Workup for infectious, metabolic, congenital, and hypoxic causes of seizures was negative. Family history revealed that the baby’s mother had similar seizures as a neonate that resolved by about 6 weeks of age. Similarly, this infant’s seizures remitted at about age 2 months, and phenobarbital was withdrawn. The child is now 7 years old. Development has proceeded normally and no further seizures have occurred.

Clinical syndrome and genetics—benign familial neonatal convulsions: Benign familial neonatal convulsions (BFNC) is a rare, autosomal dominant epilepsy that is classified as idiopathic generalized, although some affected neonates have partial onset seizures by clinical or EEG criteria (Bye, 1994; Hirsch et al, 1993). Benign familial neonatal convulsions is an age-related disorder, with seizures appearing in the first week of life and ceasing spontaneously by several months of age. The infants are normal between seizures and diagnostic evaluations do not reveal any pathology. The syndrome is considered benign because most children outgrow the seizures; however, about 10% to 15% of affected children develop epilepsy later in life.

Benign familial neonatal convulsions as a clinical entity was recognized as early as the 1960s (e.g., Bjerre and Corelius, 1968). In 1989, several families with BFNC were linked to chromosome 20q (Leppert et al, 1989). Subsequently, other families were linked to chromosome 8q. It was found that the BFNC genes on chromosomes 20q and 8q encode mutations of KCNQ, 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 familial syndrome of altered cardiac excitability, the long QT syndrome, or KCNQ1). The genes for BFNC are called KCNQ2 (on chromosome 20q) and KCNQ3 (on chromosome 8q). In situ, KCNQ subunits 2 and 3 coassemble as tetramers (Cooper et al, 2000). Mutations in the amino-acid sequences or the polypeptide tails in either KCNQ2 or 3 result in abnormal function of this channel. Figure 1A depicts numerous such mutations that have been described in families, causing the clinical syndrome (Singh et al, 2003).

Pathophysiology of benign familial neonatal convulsions: KCNQ channels encode subunits of a subclass of potassium channels known as Mchannels (for muscarine (M)-activated outward current). M-channels mediate slowly rectifying outward potassium (K + ) current that hyperpolarizes the neuronal membrane. M-channels were originally described in frog sympathetic neurons (Brown and Adams, 1980) but are now known to exist through-

A KCNQ2 / KCNQ3 - BFNC

COO-

NH3+

B Control

Na K

Ik Im

Mutant lacks Im

Na Ik K

Figure 1 Benign familial neonatal convulsions. (A) Schematic diagram of M-channel and mutations in KCNQ2 (stars, filled circles) and KCNQ3 (open circles). The circles represent missense mutations; the stars represent truncation mutations.

KCNQ2 mutations affect both transmembrane sensors and polypeptide tail. There are many fewer KCNQ3 mutations and so 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 in response to depolarizing currents pulses. In the normal cell with intact M-current (top), only two action potentials are produced by the current pulse (spike frequency adaptation), whereas in the cell from an animal with mutation dominant negative mutation 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 (increased excitability). Reproduced with permission from Peters et al (2005). Right: Cartoons of single pyramidal neurons with inward sodium current and outward potassium currents, IK and IM. In the mutation, IM is reduced.

out the mammalian brain. M-channels are closed by muscarine; in the absence of muscarinic agonists, current through M-channels repolarizes the membrane and limits repetitive firing. M-channels are partially activated at resting potential and activate further as the neuronal membrane is depolarized. Mchannels open and close slowly (10 times slower than sodium channels), so they are activated only minimally during a single action potential. However, during repetitive neuronal firing, the Mchannel is strongly activated and its slow kinetics are well suited to oppose sustained membrane depolarization (Cooper and Jan, 2003). During Mchannel activation by muscarine or a wide variety of Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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neuropeptides, or if the KCNQ channel is mutated as in BFNC, the M-current is turned off; spike frequency adaptation is diminished and repetitive discharge of action potentials occurs (Figure 1B).

Therefore, mutation of the KCNQ gene results in dysfunction of the M-channel to allow repetitive firing and hence will facilitate the unfettered neuronal firing of a seizure (Jentsch, 2000; Cooper and Jan, 2003). In transgenic mice that conditionally express dominant-negative KCNQ2 subunits, suppression of M-current is associated with spontaneous seizures and hippocampal-dependent memory impairment (Peters et al, 2005). Therefore, M-channels are important determinants of cellular and network excitability and M-channel dysfunction has functional and cognitive consequences.

Future considerations and unanswered questions: M-channels are found in regions of brain known to participate in epilepsy, such as hippocampus (Cooper et al, 2001). Subcellular localization of the subunits may yield additional information about how this channel regulates paroxysmal firing. It is unknown why the mutation in this channelopathy is most effectively expressed in the first few weeks of life, when the seizures of BFNC occur, and why seizures only occur in this restricted age window, while the mutation remains present throughout life.

A variety of molecular mechanisms alter M-channel function (Castaldo et al, 2002; Rogawski, 2000). A new AED, retigabine, acts to keep M-channels open and prevent repetitive firing (Blackburn-Munro et al, 2005; Cooper and Jan, 2003). This AED holds promise for BFNC, though the rarity of the disorder precludes large-scale clinical trials. An intriguing possibility is that retigabine might be effective in other etiologies of neonatal seizures, such as hypoxia-ischemia and other acquired brain injuries.

Hyperexcitability at the Level of a Membrane Transport Protein

Case history: An infant presented with a first generalized tonic-clonic seizure at age 9 months and was started on phenobarbital. Over the next few months, the baby developed additional seizures involving episodes of nystagmus, staring, and head drop. The initial EEG was normal, but subsequent EEGs showed multifocal slow spike-waves on a disorganized background. The pregnancy, labor, and delivery were normal. Some early motor delays were documented; for example, the infant began to roll over at 7 months of age and sit without support at 11 months of age. Search for an etiology revealed no infectious, structural, metabolic, or hypoxic cause.

The brain MRI scan was normal. Phenobarbital and valproic acid proved ineffective for seizure control.

Because of persistent seizures, at age 16 months, the child was started on a ketogenic diet with a 4:1 ratio (by weight) of fat to carbohydrate plus protein, at which time the seizures stopped.

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In the course of the evaluation, a lumbar puncture was performed, at age 18 months. There were no red or white blood cells present in the cerebrospinal fluid (CSF), but the CSF glucose was only 36 mg/dL (simultaneous blood glucose was 74 mg/dL, giving a CSF-to-blood glucose ratio of 0.49). This decreased ratio suggested the diagnosis of glucose transporter (Glut-1) deficiency. Subsequent genetic analysis revealed a heterozygous missense mutation at R333W, with tryptophan substituting for arginine at amino-acid site 333.

Subsequent history reveals that the child is now almost 8 years old. Expressive speech was initially delayed (first words at almost 4 years of age), but now the child speaks in full sentences with minor dysarthria and the neurologic examination is remarkable only for mild hypotonia and fine motor incoordination. The child is in special education classes but is quite talkative and sociable. Otherwise, the child has been healthy and has remained on a ketogenic diet. The only seizure in several years occurred during an attempted ketogenic diet taper.

Clinical syndrome and genetics—glucose transporter type 1 deficiency: The syndrome of Glut-1 deficiency (OMIM 606777) is a treatable epileptic encephalopathy resulting from an inborn error of glucose transport into the brain (Klepper, 2004). The syndrome was defined by DeVivo et al (1991), who reported 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 (Gordon and Newton, 2003). The mean CSF glucose to blood glucose ratio in Glut-1 deficiency is 0.3770.06, whereas a value of greater than 0.6 is expected in unaffected individuals (Klepper and Voit, 2002; Wang et al, 2005).

Normally, glucose enters the brain by facilitated transport via Glut-1. Without sufficient glucose transport to provide the brain with fuel, the clinical manifestations of Glut-1 deficiency become apparent, usually in the first year of life. Neurologic deficits range from mild developmental delays to severe mental retardation, seizures that can become intractable, and abnormal movements such as ataxia or dystonia (Wang et al, 2005). The seizure semiology is quite varied. Seizure types most commonly include generalized tonic-clonic, myoclonic, atonic, and atypical absence (Boles et al, 1999); abnormal eye movements and cyanosis are frequent accompaniments. Seizures are especially prone to occur during periods of fasting, when glucose availability is low, for example, following a night’s sleep.

The gene encoding the Glut-1 protein is located on chromosome 1p35.31.3, and inheritance follows an autosomal dominant pattern. Many different mutations have been identified (Wang et al, 2005). Most patients manifest with heterozygous de novo muta-

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

Pathophysiology of glucose transporter type 1 deficiency: The Glut-1 protein is located on both luminal and abluminal surfaces capillary endothelial cells as well as on astrocytes and neurons (Duelli and Kuschinsky, 2001). Glucose transporter type 1 thus forms part of the blood–brain barrier and functions to transport glucose from the vascular space into the brain (Figure 2). Lack of Glut-1 deprives neurons and glia of glucose as a fuel source. Seizures in Glut-1 deficiency likely derive from an alteration in energy metabolism, comprising a mechanism somewhat different from the usual excitation/inhibition imbalance invoked to explain seizure pathogenesis. Glucose deprivation predisposes neurons to synchronous firing, and seizure generation is favored in conditions of low blood (and therefore low brain) glucose levels, including hypoglycemia (Schwechter et al, 2003).

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

Vascular Space

CNS

Normal Glucose Glut-1

Glut-1 Deficiency Glucose

Glut-1 Deficiency and Ketogenic Diet Ketones MCT

Figure 2 Glucose transporter type 1 deficiency. The brain normally obtains energy from glucose transport via the protein Glut-1 (Normal, top). In the case of Glut-1 deficiency, glucose cannot be transported across the blood–brain barrier (middle).

In Glut-1 deficiency plus the ketogenic diet, ketones enter the CNS via the monocarboxylate transporter (MCT) and provide the brain with metabolic fuel.

2). The high-fat, low-carbohydrate and protein ketogenic diet circumvents the brain glucose deficiency by providing energy directly in the form of fats that can be oxidized into acetyl CoA and eventually into ATP. Ketone bodies (hydroxybutyrate, acetoacetate, acetone), formed in the liver by oxidation of fatty acids, circulate to the brain vasculature and enter the brain via the monocarboxylate transporter (Pierre and Pellerin, 2005). Once circulating ketones have entered the brain, it is unknown whether they exert a primary anticonvulsant action by conventional mechanisms (e.g., alteration of ionic channels or synaptic transmission) or whether some other mechanism comes into play. Ketones are considered necessary but not sufficient for an anticonvulsant action. Available data do not support ketones as the sole (or perhaps even the primary) mechanism. In patients and animal models, the correlation between the level of ketosis and seizure control is imprecise. Application of ketones directly onto cultured hippocampal neurons or hippocampal slices failed to find an effect of the ketones on glutamate or GABA postsynaptic currents, or on electrographic seizures induced by 4-aminopyridine (Thio et al, 2000).

While it is premature to conclude that ketones have no direct membrane actions, these negative results suggest that other mechanisms must be considered.

For example, ketones may have a direct suppressant effect on the excitability of certain neuronal populations involved in seizure modulation, such as the dentate gyrus (Bough et al, 2003). Ketones also alter brain neurotransmitter levels, favoring increased GABA synthesis and reduced availability of excitatory neurotransmitters (Yudkoff et al, 2004).

Alternative hypotheses for the ketogenic diet mechanism of action include the role of lipids, which are elevated in this high-fat diet. Indeed, certain lipids reduce neuronal excitability (Cunnane et al, 2002; Stafstrom, 2001; Voskuyl et al, 1998), and polyunsaturated fatty acids are elevated in the CSF of children on a ketogenic diet (Fraser et al, 2003).

This intriguing link between lipids and excitability is under investigation (Cullingford, 2004).

In addition to direct effects of ketones and lipids on excitability, accumulating evidence suggests that an important factor in ketogenic diet action is the total amount of calories provided. Children on the ketogenic diet are typically restricted to 75% to 90% of the recommended daily calorie allowance. Animals undergoing similar calorie restriction have increased seizure thresholds as well, in seizures of various types (Bough et al, 2003; Greene et al, 2001).

Such a mechanism makes sense in terms of the shifting metabolic demands of the brain exposed to the ketogenic diet. Ketones, unlike glucose, may sustain normal neuronal functions but not the excessive neuronal firing that occurs during a seizure (Greene et al, 2003).

A final possibility for the ketogenic diet mechanism is reduction of free-radical induced membrane Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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damage. Mitochondrial reactive oxygen species generated during excessive neuronal firing could lead to further impairment of neuronal function and even cell death. The ketogenic diet may interfere with this cascade by increasing the production of mitochondrial uncoupling proteins, which have been shown to decrease the production of reactive oxygen species (Sullivan et al, 2004). Hypoglycemia-induced cell death was reduced in weanling rats fed a ketogenic diet (Yamada et al, 2005).

Although the exact mechanism of ketogenic diet action is unknown, such knowledge is critically important in efforts to simplify and optimize its efficacy. In the case of Glut-1 deficiency syndrome, in which a patient may need to use the ketogenic diet lifelong, an understanding of how the diet works 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 intractable seizures in the first year of life, along with developmental delays. The diagnosis of Glut-1 deficiency was made after the child was already on the ketogenic diet, in contrast to the usual situation in which a patient is diagnosed with Glut-1 deficiency and then started on the ketogenic diet. Nevertheless, this case stresses the importance of analyzing CSF glucose in young children with intractable seizures.

Furthermore, the use of a ketogenic diet is necessary in this syndrome, to provide adequate brain energy for neuronal function and optimal development.

Aside from increasing the awareness of clinicians about this novel syndrome and its specific treatment with the ketogenic diet, other methods to increase brain glucose availability need to be explored. For example, efforts to increase CSF glucose by a highcarbohydrate diet, enhancing Glut-1 translocation from intracellular pools to the plasma membrane (with the antioxidant thioctic acid), enhancing Glut1 expression or increasing glucose transport are theoretically beneficial but have not been successful as yet (Gordon and Newton, 2003; Wang et al, 2005).

Patients with Glut-1 deficiency should avoid drugs that interfere with glucose transport such as caffeine and phenobarbital. The widespread use of the latter drug in infants with seizures underscores the importance of establishing this diagnosis.

Hyperexcitability at the Level of the Local Neuronal Circuit

Case history: A full-term infant was born after an uneventful pregnancy, labor, and delivery. There were no perinatal complications. In the first several months of life, developmental delays became apparent, especially in motor skills. Muscle tone was low diffusely, and there was less spontaneous movement of the right arm and leg compared with the left. At Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

the age of 4 months, the infant began having episodes of right arm stiffening and jerking, accompanied by head twitches and gaze deviation to the right side.

These seizures, which lasted from seconds to minutes, were resistant to several antiepileptic medications. Magnetic resonance imaging (MRI) scan of brain revealed an area of dysplastic cerebral cortex in the left frontal region (Figure 3A). Video-EEG monitoring revealed subclinical electrographic seizures as well as electroclinical seizures, all arising from the left frontocentral region (Figure 3B). At the age of 14 months, the child underwent surgical resection of this malformed cortex. Pathology revealed focal cortical dysplasia (FCD) and reactive gliosis (Figure 3C), with a lack of neuronal lamination, aberrantly oriented neurons (e.g., apical dendrites pointing toward the white matter), large, dysmorphic neurons, and reactive gliosis. After surgery, there were no further seizures and AEDs were gradually withdrawn.

Now, at 2 years of age, the child has a mild right hemiparesis affecting the arm more than the leg, but cognitive skills are age-appropriate.

Clinical syndrome and genetics—focal cortical dysplasia: Malformations of cortical development are classified according to the stage of brain development giving rise to the phenotype, including abnormalities of: (1) cortical neuron formation and proliferation, (2) migration, or (3) organization.

Advances in neuroimaging and molecular neuropathology are allowing ever more precise classification of disorders of neuronal development (Palmini et al, 2004). Two broad groups are recognized at each of the above developmental stages—those with focal abnormalities, and those with large areas of brain affected diffusely. The etiology of cortical dysplasias is often genetic and many gene defects are being discovered (e.g., an abnormal gene such as LIS1 in lissencephaly of the Miller–Dieker type). Other cases are acquired (e.g., fetal exposure to a toxin, such as alcohol or cocaine). The cause of many cases is unknown and is presumed to be multifactorial.

The timing and severity of the external insult or genetic mutation will determine the type and extent of the cortical malformation.

Focal cortical dysplasia is a subtype of cortical maldevelopment. Among cases of FCD, three basic patterns have been described: (1) abnormal cortical lamination with ectopic neurons in white matter, (2) anomalies of lamination plus giant neurons, and (3) abnormal lamination, giant neurons, and very large dysmorphic neurons (Taylor-type dysplasia) (Guerrini and Filippi, 2005; Tassi et al, 2002). Figure 3D illustrates, in graphic form, how neuronal organization is disrupted in FCD. In Figure 3D(a), cellular lamination is orderly and the neurons are oriented appropriately. In FCD (Figure 3D(b)), lamination is disrupted, with no orderly arrangement or lamination, and cellular orientation is maintained. The etiology of the FCD in the child described in this case vignette is idiopathic, with

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Figure 3 Focal cortical dysplasia. (A) Coronal MRI section showing area of dysplasia in left frontal cortex (arrows). (B) EEG from patient in (A), showing ictal discharges over the left frontal-central region (arrows). There were no clinical changes during this electrographic seizure. (C) Pathological specimen of FCD showing abnormally oriented neurons and gliosis. Examples of abnormally oriented 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)). In experimental dysplasia induced by a cortical freeze lesion induced by brief application of a cold rod (D(c)), dyslamination and cortical disorganization is seen in the vicinity of the freezing probe. (E) Intracellular recordings from a layer II/III pyramidal neuron from cortex adjacent to an experimental freeze lesion, showing all-or-none paroxysmal action potentials elicited by a weak stimulus in deeper cortical layers. Reproduced with permission from Swann and Hablitz (2000).

the pathology most closely classifiable as a disorder of neuronal proliferation.

Developmental abnormalities of neuronal genesis and proliferation, migration, and connection/organization can all predispose to epilepsy. Generally, the more extensive the malformation, the earlier and more severe the epilepsy. The mechanism(s) of epilepsy in these malformations is likely to be multifactorial, involving aberrant intrinsic excitability, circuits, receptors, or ionic channels (Jacobs et al, 1999b; Schwartzkroin and Walsh, 2000).

Abnormal circuits, either locally or over a wide cortical area, lead to hyperexcitability and enable neurons to fire hypersynchronously. Numerous studies have verified the epileptogenicity of focal dysplastic cortex (Avoli et al, 1999; Mathern et al, 2000; Palmini et al, 1995). The clinical manifestations of FCD are quite varied, related to the specific features of aberrant neural circuitry. Patients with FCD often have cognitive and motor abnormalities as well as seizures, depending on the location and extent of the dysplasia. If the malformed region is amenable to surgical resection, as in this case, excellent seizure control is often achieved. If the dysplasia is more widespread, the outcome is less optimistic. While MRI techniques can identify

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

Pathophysiology of focal cortical dysplasia: In the laboratory, models of cortical malformation have permitted the investigation of some of the mechanisms by which seizures can arise. Three models have been particularly informative—the neonatal external freeze lesion, prenatal exposure to the DNA alkylating toxin methylazoxymethanol (MAM), and cranial gamma-irradiation at certain developmental stages.

Each of these techniques kills proliferating, dividing cells. The mechanisms underlying the hyperexcitability in each model are being explored, and although none exactly reproduces a human disorder, useful insights into possible mechanisms can be obtained (Chevassus-au-Louis et al, 1999; Najm et al, 2004; Schwartzkroin et al, 2004; Schwartzkroin and Walsh, 2000). The cortex directly adjacent to either the freeze lesion microgyrus or irradiated zone tends to be hyperexcitable, rather than the lesioned area itself. For example, in cortex adjacent to a freeze lesion, a weak stimulus evokes an all-ornone paroxysmal burst of action potentials (Figure 3E). Spontaneous seizures have only rarely been Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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recorded in animals with any of these lesions (Kellinghaus et al, 2004; Peters et al, 2004), but the presence of frequent interictal discharges and increased seizure susceptibility (decreased seizure threshold) in each model suggests that the brain is hyperexcitable. In addition to induced malformations, genetic mutants with cortical dysplasia also exhibit hyperexcitability. For example, the tish (telencephalic internal structure heterotopia) mutant rat has a double cortex (band heterotopia), and the p53 knockout mouse has an inverted cortical lamination pattern; in both models, spontaneous seizures have been documented (Lee et al, 1997; Wenzel et al, 2001).

Of the three inducible dysplasia models, the neonatal freeze lesion most closely mimics the FCD syndrome of the patient described above (Luhmann, 2006). The freeze lesion is induced in neonatal rats by brief application of a cold rod to the skull (Figure 3D(c)); this produces an area of abnormal four-layered cortex (resembling human microgyria) due to death of neurons in cortical layers IV and V (rather than to abnormalities of neuron proliferation as in human FCD). Neurons generated at later time points can migrate through the injured region, forming a grossly observable microgyrus with abnormal cortical lamination and organization in the adjacent cortex (Dvorak et al, 1978; Jacobs et al, 1999a). The cortex adjacent to the microgyrus is hyperexcitable due to a variety of factors, both synaptic and intrinsic to the membrane. There appears to be reorganization of the cortical network bordering the malformed region, creating a region of hyperexcitability adjacent to the microgyrus (Chevassus-au-Louis et al, 1999; Jacobs et al, 1999a). The tissue adjacent to the microgyrus has increased glutamatergic inputs onto inhibitory interneurons, possibly due to loss of target neurons for thalamocortical afferents (Luhmann et al, 1998).

This local circuit is hyperexcitable in part because (NMDA)of enhanced N-methyl-D-aspartate mediated neurotransmission. Dysplastic neurons adjacent to the lesion have altered expression of NMDA subunits (increased expression of NR2B), favoring excessive NMDA currents and reduced Mg2 + -sensitivity of NMDA receptors (Defazio and Hablitz, 2000). By whole-cell patch clamp techniques, the frequency of both spontaneous and miniature excitatory postsynaptic currents is greater in neurons in the paramicrogyral region (Jacobs and Prince, 2005). Inhibitory GABAergic function is also altered in the freeze lesion model, due to both alterations in GABAergic interneuron number and GABA receptor function (Defazio and Hablitz, 1999; Redecker et al, 2000; Rosen et al, 1998). Impaired long-term potentiation in the region adjacent to the freeze-lesion-induced microgyrus has been documented, associated with diminished GABAA-receptor subunit g2 (Peters et al, 2004). In addition to abnormal neuronal structure and connectivity, glial cells also contribute to epileptogenicity adjacent to Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

the freeze lesion microgyrus; astrocytes in the hyperexcitable cortex bordering the microgyrus show a loss of inwardly rectifying potassium currents and reduced gap junction coupling, suggesting compromised potassium buffering, a situation that would favor hyperexcitability and seizures (Bordey et al, 2001).

Animals with freeze lesions induced on postnatal day 1 that were subjected to hyperthermia-induced seizures on postnatal day 10 (mimicking a febrile seizure) had lower thresholds and latencies to generalized seizures than controls that did not have a prior freeze lesion (Scantlebury et al, 2005). This result is an example of a ‘second hit’, whereby animals that have incurred a lesion or brain insult at a younger developmental age have a greater predisposition to seizures later in life compared with noninjured animals. The second hit phenomenon was also seen after MAM-induced dysplasia (Germano et al, 1996) and after kainic-acid-induced status epilepticus (Koh et al, 1999).

Intrauterine exposure to MAM disrupts neocortical and hippocampal neuron proliferation and produces diffuse cortical dysplasia, microcephaly, dyslamination, and heterotopic neurons with abnormal intrinsic membrane properties, synaptic connectivity, and receptor stoichiometry. These factors produce hyperexcitability as assessed by reduced seizure threshold (Baraban and Schwartzkroin, 1996) and cognitive dysfunction (Gourevitch et al, 2004). Altered balance of excitation and inhibition in the MAM model is due to a number of factors including enhanced NMDA-mediated neurotransmission (Calcagnotto and Baraban, 2005) and dysfunctional potassium Kv4.2 channels (Castro et al, 2001). Prenatal gamma irradiation causes cortical thinning, cell death, and dysplasia, as well as heightened cortical excitability and clinically observable spontaneous seizures (Kondo et al, 2001; Roper et al, 1997). The local circuits have deficient GABA function (Zhu and Roper, 2000).

Recordings from dysplastic tissue removed from humans during epilepsy surgery holds the promise of providing more direct information on mechanisms of epileptogenicity (Tasker et al, 1996). Such studies have long been vexed by sampling and difficulties determining appropriate control tissue (i.e., what tissue is normal versus abnormal). Recent efforts have circumvented some of these difficulties and a picture is now emerging that certain dysmorphic cells (especially balloon and cytomegalic cells) have abnormal membrane properties and voltage-gated sodium and calcium currents (Cepeda et al, 2005), as well as abnormal NMDA receptor subunit composition and Mg2 + sensitivity (Andre et al, 2004), as also seen in the experimental models described above. In addition to intrinsic membrane properties, the proportion of excitatory and inhibitory connections is altered in human FCD, but not in a readily predictable manner (Alonso-Nanclares et al, 2005).

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Future considerations and unanswered questions: In all of the models of cortical dysplasia, as well as in human dysplastic tissue, abnormalities appear to be present in both the neurons and the neural network, that is, both in the epileptic neuron and in the epileptic circuit (Schwartzkroin et al, 2004). The correlation between seizure predisposition (seizure threshold) and the type and degree of dysplasia is imprecise. The manner in which the dysplastic region interacts with the rest of the brain needs to be understood in greater detail. Also, it is unknown why certain types of malformation are more prone to epilepsy and how seizures emerge as a function of age. Studies using resected human tissue to study the excitability of cortical dysplasia are informative but have the inherent disadvantage of tissue sampling compared with appropriate control material.

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

Case history: A 16-year-old patient presents with several complex partial seizures per day, beginning about 3 years ago. The seizures consist of staring, fumbling movements of the left hand and head turning to the left, followed at times by tonic-clonic convulsions involving all limbs. Seizure duration is about 1 to 2 mins, followed by sleep. The child was the product of a normal pregnancy, labor, and delivery, and was healthy until a prolonged febrile seizure (estimated at 40 mins) occurred at 2 years of age. Subsequently, there were no further seizures until age 13 years. Mild developmental delays are present and the patient attends special education classes, but motor function is normal. The seizures are currently incompletely controlled on two anticonvulsants (carbamazepine and lamotrigine), and previously failed to respond to several other AEDs. Medication compliance is erratic, despite concerted efforts by the family. Video-EEG monitoring failed to reveal a consistent epileptic focus from which the seizures originate. Magnetic resonance imaging and PET scans show bilateral hippocampal sclerosis and interictal hypometabolism, respectively. Because of the bilateral temporal lobe interictal spikes, without ictal localization, the patient is not considered to be a candidate for resective surgery at this time.

Clinical syndrome and genetics—temporal lobe epilepsy: Temporal lobe epilepsy is the most common partial epilepsy affecting adolescents and adults. Seizures originate in one or both temporal lobes. The hallmark pathological lesion, sclerosis or gliosis of one or both mesial temporal lobes (especially hippocampus) provides a presumed anatomic basis for the seizures, although, as discussed below, there are controversies about the actual substrate for seizure origination. The hippocampus is a very seizure-prone structure, due to its inherent circuitry and physiology. However, not all

patients with chronic TLE have evidence of hippocampal neuronal loss (Thom et al, 2005). On a microscopic level, mesial temporal sclerosis consists death or injury to cells of the dentate hilus and hippocampal pyramidal cell layer, as well as recent evidence that cell death also occurs in extrahippocampal limbic areas such as the subiculum, entorhinal cortex, and amygdala (Bernasconi et al, 2003; Schwarcz et al, 2002). In some cases, the etiology of TLE can be attributed to a neuronal injury early in life (e.g., prolonged febrile seizure, encephalitis, traumatic brain injury). The early life injury probably sets up a complex cascade of molecular, physiological, and structural changes in the brain, eventually resulting in the classic hippocampal sclerosis. During this several year ‘latent period’, brain function is progressively altered (epileptogenesis), but no seizures are apparent.

Eventually, in the teen years or older, clinical seizures emerge.

However, in many cases of TLE, an etiology is not apparent. As an acquired epilepsy, genetics does not play a primary role in TLE, yet information is accumulating about familial predisposition to acquired partial seizures as well as to the genetic basis of AED resistance in some families with TLE (Gutierrez-Delicado and Serratosa, 2004; Kobayashi et al, 2003). The syndrome of idiopathic partial epilepsy with auditory features is one example of a TLE syndrome with a hereditary basis (Bisulli et al, 2004). Mutations in a gene called epitempin or LCI1 (leucine-rich glioma-inactivated 1), originally identified in gliomas, have been implicated in lateral temporal lobe seizures (Ottman et al, 2004). The normal function of this gene, its predilection for the lateral temporal lobe, and how it alters the excitation/inhibition balance to cause epilepsy are being investigated.

Although the seizures in TLE may respond to AEDs, seizures tend to become refractory. For appropriately chosen patients, surgical resection (such as anterior temporal lobectomy) may be curative (Cascino, 2004). There is a large body of clinical research into optimal surgical strategies and outcomes of surgery with respect to seizure control, quality of life, and cognitive sequelae.

Pathophysiology of temporal lobe epilepsy: Temporal lobe epilepsy has been investigated extensively at many levels. Due to space limitations, only a few recent advances can be discussed here. For each of these topics, an attempt is made to correlate new clinical information with basic science advances: (1) TLE as a progressive disease, in the context of epileptogenesis; (2) TLE as a disease involving neuronal regions outside the hippocampus, and (3) seizure prediction.

Epileptogenesis and temporal lobe epilepsy as a progressive disease: Prospective longitudinal imaging studies using volumetric MRI have shown Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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that there is progressive decrease in hippocampal volume over time (years) as a function of seizure number (Briellmann et al, 2002; Fuerst et al, 2003; Liu et al, 2003). These studies suggest that even in patients with no precipitating injury, progressive brain damage can occur as a consequence of repeated seizures. Similarly, in long-term crosssectional neuropsychological studies spanning observational periods as long as 30 years, cumulative cognitive impairments have been documented that increase as a function of TLE duration (Helmstaedter, 2002; Hermann et al, 2002; Jokeit and Ebner, 2002). In a large study of almost 100 TLE patients, comprehensive neuropsychological testing showed that, compared with controls, TLE patients performed worse on tests of memory function as well as on measures of intelligence, language, and executive function, suggesting that cognitive dysfunction is not limited to limbic-related tasks (Oyegbile et al, 2004). The degree of impairment correlated with the duration of epilepsy. Longitudinal studies also demonstrate progressive cognitive declines when seizures are poorly controlled. A prospective neuropsychological study has revealed progressive cognitive declines in intractable TLE patients, particularly when seizures are poorly controlled after temporal lobectomy (Helmstaedter et al, 2003).

Therefore, a subset of TLE patients appears to be at risk for progressive cognitive and structural brain damage as a function of repeated seizures, supporting the contention that TLE can be a progressive disorder (Pitkanen and Sutula, 2002; Sutula, 2004).

The idea that TLE is a progressive disease is also supported by experimental data (Buckmaster, 2004).

Numerous studies in animals (e.g., using the kindling model) demonstrate that brief repeated seizures induce neuronal death and cumulative damage (Bengzon et al, 1997; Cavazos et al, 1994; Kotloski et al, 2002). Kindling is an experimental model of repeated brief seizures in which the progressive nature of epileptogenesis can be characterized.

Kindling is considered an example of repeated network synchronization and seizure-induced plasticity, whereby a sequence of activity-dependent processes causes increasing neurologic deficits as the number of seizures increases. The experimenter controls the number of seizures, allowing study of the precise cellular and molecular alterations induced by a specific number of ictal events. Such studies have yielded a predictable sequence of cellular and molecular changes elicited by the repeated network synchronization of kindled seizures. Initially, kindling-induced alterations in synaptic transmission cause morphological reorganization of neurons and neural circuits, especially in the hippocampus, that leads to functional deficits and enhanced seizure susceptibility. Along with progressive neuronal loss, which resembles hippocampal sclerosis, animals with kindled seizures become more susceptible to seizure generation by several methods, develop hippocampal-dependent Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

memory and learning deficits, and eventually develop spontaneous recurrent seizures, the defining milestone of epilepsy (Stafstrom and Sutula, 2005). The pattern of progressive cell damage and neuronal death, particularly in the dentate hilus, CA1 and CA3 subfields, resembles the distribution of hippocampal sclerosis in patients with TLE. In addition to neuronal loss, the long-term effects of repeated brief seizures also include a sequence of activity-dependent processes that alter neurons and neural circuits from gene expression to systemslevel function and behavior. An initial seizure acutely increases excitatory synaptic transmission, which potentiates NMDA-receptor-dependent inward synaptic currents, enhancing excitability and elevating the intracellular Ca2 + concentration (Sayin et al, 1999). As a consequence of network synchronization, increases in intracellular Ca2 + and activation of other signal transduction pathways induce transcription of early immediate genes (Hughes et al, 1998), and eventually, protein-encoding genes that contribute to long-term alterations associated with chronic epilepsy (Sutula et al, 1996), such as the subunit composition of neurotransmitter receptors (Brooks-Kayal et al, 1998; Mathern et al, 1999).

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

Mossy fiber sprouting refers to axonal reorganization in the dentate gyrus as a consequence of seizures, whereby axons of dentate granule cells reinnervate their own dendrites in the inner molecular layer (where such connections are not normally found). This synaptic reorganization sets up a hyperexcitable circuit in the hippocampus (Buckmaster et al, 2002; Koyama et al, 2004; Santhakumar et al, 2005; Scharfman et al, 2003). Mossy fiber sprouting develops after only a few kindled seizures, progresses with seizure number, and represents a permanent synaptic alteration (Sutula et al, 1988). Mossy fiber sprouting has been verified in many epilepsy models (Okazaki et al, 1995) as well as in humans with hippocampal resections (Sutula et al, 1989). The recurrent excitatory circuits formed by sprouted mossy fibers contribute to the chronic hyperexcitability that marks the epileptic state (Buckmaster et al, 2002). Neurotrophins such as brain-derived neurotrophic factor (BDNF) may play a crucial role in epileptogenesis (Scharfman, 2005), an effect that is dependent on the tyrosine kinase TrkB receptor (Binder et al, 1999; He et al, 2004).

BDNF facilitates epileptogenesis by enhancing excitatory neurotransmission (Zhu and Roper,

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

The emergence of spontaneous seizures defines epilepsy. Spontaneous seizures are seen in a variety of epilepsy models, including kainic acid and pilocarpine (Cavalheiro et al, 1982; Dudek et al, 2002; Stafstrom et al, 1992). However, in the kindling model, spontaneous seizures occur only after about 90 class V evoked kindled seizures (Sayin et al, 2003), suggesting that the molecular and cellular alterations induced by repeated episodes of neural synchronization during kindled seizures are accompanied by progressive functional alterations in neural circuits. The relationship between neuronal loss and spontaneous seizure occurrence needs to be clarified; some data failed to find a correlation between spontaneous seizures and hippocampal neuronal damage (Brandt et al, 2004).

The occurrence of spontaneous seizures in the kindling model correlates with alterations in inhibitory circuitry. The apoptosis and cumulative neuronal loss induced by repeated brief seizures eventually involve subclasses of GABAergic interneurons labeled by cholecystokinin (CCK) and the neuronal GABA transporter (GAT-1). These inhibitory axo-somatic and axo-axonic inputs regulate the propagation of activity into axons. The loss of these interneuron subclasses is associated with reduction of the amplitude and duration of evoked inhibitory postsynaptic currents and emphasizes the importance of inhibition in preventing spontaneous seizures (Sayin et al, 2003). GABAergic pathways can function in multiple ways in normal and epileptic networks, permitting dynamic regulation of neuronal function (Cossart et al, 2005).

In summary, a defined temporal sequence consisting of a series of critical steps occurs in the development of the epileptic brain, with epileptogenesis, seizure-induced plasticity, and finally, a fully reorganized hippocampus underlying intractable epilepsy, similar to the chronic epileptic condition of human TLE (Figure 4A). A single kindled seizure induces apoptosis and neurogenesis. Five kindled seizures are sufficient for the development of mossy fiber sprouting, while hippocampal sclerosis and cognitive and behavioral impairments are seen after about 30 kindled seizures. By 90 to 100 kindled seizures, spontaneous seizures occur, possibly as a consequence of reduced synaptic inhibition. Detailed knowledge of these cellular and molecular intricacies is critical for designing appropriate interventions for neuroprotection (Stafstrom and Sutula, 2005).

Involvement of extrahippocampal regions in temporal lobe epilepsy: The involvement of neural structures in TLE beyond the hippocampus is supported by numerous imaging and pathology studies (Stafstrom, 2005). Clinical, pathological, and physiological studies of focal epilepsy of temporal lobe origin have historically emphasized

A

Latent period “epileptogenesis”

± Initiating brain injury

Epilepsy

Further epileptic damage

Spontaneous seizures Cognitive deficits, increased seizure susceptibility

B

C 1

2

Figure 4 Temporal lobe epilepsy. (A) Sequence of epilepsy and epileptogenesis. In TLE, an initial precipitating injury is sometimes, but not always, identified. During the latent period, epileptogenesis occurs, causing permanent structural and/or functional alterations that imbue the brain with hyperexcitability and hypersynchrony. Once spontaneous seizures occur, the brain is considered epileptic. Further seizures may cause cognitive impairment and an enhanced predisposition to subsequent seizures. (B) Coronal T1-weighted MRI section from a patient with right (R) temporal lobe epilepsy, normal hippocampal volume, and atrophy of the right entorhinal cortex (arrow). Reproduced with permission from Bernasconi et al (2001). (C) Fast ripples. Top (1): Interictal high frequency epileptiform 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 occurring simultaneously in dentate gyrus (top) and entorhinal cortex (bottom) in a rat with chronic kainate-induced epilepsy.

Reproduced with permission from Bragin et al (2002).

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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 of CA1 and CA3 subfields and the dentate hilus representing the pathological hallmarks of the syndrome. However, emerging pathophysiological and imaging evidence strongly implicates a critical role for distant structures in TLE as well (Figure 4B) (Avoli et al, 2002; Bernasconi et al, 2003; Goncalves Pereira et al, 2005; Stafstrom, 2005). For example, the subiculum, located between the hippocampus proper and the parahippocampal region, represents an anatomic transition zone between the CA and entorhinal cortex. The subiculum is the major output of the hippocampus and the first brain region encountered by neural activity emanating from the hippocampus. With this privileged location, the subiculum is exquisitely poised to modulate normal and abnormal neuronal firing as it propagates from the hippocampus to other cortical and subcortical regions.

Numerous investigations of hippocampal tissue resected from patients with TLE have revealed little spontaneous firing that could be considered a pathophysiological marker of epilepsy. In such tissue, hyperexcitability is mainly observed when the system is manipulated pharmacologically, for example, by blocking GABA receptors. A possible reason for the lack of observable spontaneous epileptiform activity is that excessive hippocampal cell death prevents synchronization of neuronal firing in hippocampus proper. In fact, astrocytes, in their functions of water homeostasis, potassium buffering, and mediation of inflammation, may play a larger role in excitability in TLE than has been appreciated to date (DeLanerolle and Lee, 2005).

Yet, seizures of hippocampal origin do occur in TLE, so the question arises as to exactly where interictal and ictal discharges originate. There is relatively little cell loss in the subiculum of patients with TLE (Dawodu and Thom, 2005; Fisher et al, 1998). This observation, in conjunction with the close physical proximity of the subiculum to CA1 and the presence of intrinsic bursting cells in the subiculum, raises the possibility that the subiculum might participate in abnormal epileptic firing in TLE. To evaluate the hypothesis that subicular neurons could serve as an origin of epileptiform activity, tissue from patients with mesial temporal sclerosis and refractory temporal lobe seizures was studied in vitro (Cohen et al, 2002). Multielectrode recordings identified spontaneous rhythmic spikes and epileptiform field potentials in subiculum but not in the hippocampus proper. The epileptic activity originated in the subiculum and then propagated to the hippocampus. Subicular interneurons fired before and during interictal spikes on EEGs, suggesting a mechanism to synchronize the activity of pyramidal neurons. The population of Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

subicular neurons that gave rise to this abnormal activity varied over time, implying that there is no specific set of ‘epileptic neurons’, but rather, that different neuron groups take on this role at different times.

A distinct subpopulation of subicular pyramidal neurons (22% of the total) responded to GABAergic interneuron input with depolarizing responses, rather than with expected hyperpolarizing responses. It was speculated that these depolarizing GABAergic responses endowed those pyramidal neurons with properties that favored epileptic firing (Cohen et al, 2002). The explanation for the depolarizing GABA responses was presumed to be similar to the developmentally regulated GABA excitatory phenomenon seen early in ontogeny, that is, an abnormal chloride gradient causing the chloride reversal potential to reside at a depolarized level relative to resting potential (Ben-Ari, 2002; Cohen et al, 2003; Dzhala and Staley, 2003). It is unknown whether this phenomenon is widespread, whether it is mediated by specific GABA receptor subtypes, and whether it is due to neuronal injury.

Clearly, however, our understanding of GABA mechanisms in normal and abnormal neuronal function is expanding beyond a simple inhibitory role (Cossart et al, 2005). It is also clear that the subiculum exhibits increased excitability and excessive synchrony in human TLE. Seizure prediction: Finally, brief mention is made of progress in the emerging field of seizure prediction.

An ability to predict the onset of a seizure would significantly expand the range of treatment modalities for epilepsy (Litt and Echauz, 2002). For example, if sufficient time were available, a variety of electrical stimulation or drug delivery methods could be employed to abort the seizure. Seizure prediction methods use a wide array of sophisticated mathematical techniques, especially nonlinear analysis of EEG signals (Iasemidis et al, 1994). Using these 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 challenges still abound in this field, but fruitful collaborations are yielding promising data (Lehnertz and Litt, 2005).

At the same time, experimental models have established that very fast EEG oscillations ( > 200 Hz, well beyond the frequencies usually measured on standard EEGs in patients) exist interictally and build up before localized seizure onset (Figure 4C) (Bragin et al, 2002). These socalled ‘fast ripples’ are seen only in the region of the localized seizure (Staba et al, 2002). Furthermore, they have been demonstrated in both humans and animal models (e.g., chronic epilepsy induced by intraventricular kainate) (Bragin et al, 2002; Staba et al, 2002). The physiological basis of fast ripples is uncertain; there is some evidence that they are

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mediated by electrical transmission via gap junctions, with diminished inhibition as a contributing factor as well (Traub et al, 2001; Traub, 2003). To generate fast ripples, it appears that neurons in local neuronal ensembles must fire action potential bursts synchronously, which is dependent on recurrent glutamatergic excitatory synaptic transmission (Dzhala and Staley, 2004). Hopefully, the analysis of the EEG in humans and experimental models will converge to provide a way to sense, predict, and abort seizures (Worrell et al, 2004). Such techniques might be beneficial in cases in which the site of ictal onset is ambiguous, as the patient with bilateral TLE described here. Additional correlation with functional neuroimaging would add even more clinical power to these techniques (Federico et al, 2005).

Future considerations and unanswered questions: There are numerous unanswered questions about TLE, its pathophysiology, and its treatment. It seems most urgent to understand the process of epileptogenesis, and further, to devise beneficial interventions once epilepsy is already established in the brain. The molecular changes occurring during the latent period need to be elucidated to design strategies to prevent the development of the pathological effects of epilepsy. From a developmental perspective, it is unknown why the young brain is more susceptible to limbic seizures yet more resistant to the pathological and behavioral abnormalities seen when seizures occur at older ages (Stafstrom, 2002). Seizure prediction, seizure suppression, and remediation of the long-term behavioral and cognitive effects of epilepsy are all topics of pressing concern.

Hyperexcitability at the Level of the Thalamo-Cortical Circuits

Case history: A healthy, normally developing 10year-old child presents with multiple daily staring spells. Several times a day, teachers notice daily ‘spacing out’ spells for about 10 secs, with failure to respond to verbal commands. Occasionally, these staring episodes are accompanied by repetitive head nods and eye blinks. Afterwards, there is immediate return to baseline mental status. The EEG shows a normal background; with hyperventilation, a typical episode of staring with lack of responsiveness occurred, accompanied by 3-Hz generalized spikewave discharges. The brain MRI scan and neurologic examination are normal. The seizures are initially controlled by ethosuximide, but 3 months later, breakthrough seizures occur and the medication is switched to valproic acid with improved control.

There is no family history of epilepsy.

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

childhood and often remits (approximately 75% of cases) during adolescence. The typical absence attack consists of a sudden arrest of ongoing activity with staring and unresponsiveness. In addition, some motor activity may occur, such as head nods, facial clonus, or blinking. The duration of a staring spell is usually less than 20 secs, and there is no aura or postictal state. The main differential diagnosis is between nonepileptic staring as often seen in disorders of attention, and other epilepsies that have staring as a prominent component, such as juvenile absence epilepsy, juvenile myoclonic epilepsy, atypical absence seizures, and complex partial seizures.

The diagnosis of CAE is usually straightforward, especially if the typical EEG features are seen. The EEG background is normal, with intermittent bursts of 3-Hz generalized spike-waves. These discharges can often be evoked by hyperventilation, which decreases cerebral blood flow via hypocapniainduced vasoconstriction (Wirrell et al, 1996) and results in mild alkalosis. The seizures in CAE frequently respond to ethosuximide; valproic acid is also effective, especially if there are also generalized tonic-clonic seizures or the absence seizures are accompanied by significant motor activity (Coppola et al, 2004). Alternatively, lamotrigine has some efficacy against absence seizures and can be tried when ethosuximide and valproate are ineffective (Posner et al, 2005). Risk factors for a poor prognosis (e.g., persistent seizures) in CAE include lack of response to the typical AEDs, prior neurological or developmental impairment, absence seizures exceeding 30 secs, and the coexistence of other seizure types, especially tonic or atonic (Arzimanoglou et al, 2004).

As a primary generalized epilepsy, CAE is assumed to have a genetic basis, though a specific gene has not yet been identified. Some of the genes implicated in CAE have been linked in some families to mutations in calcium channel subunits, and may relate to the underlying pathophysiological mechanism. Specifically, mutations of genes coding for subunits of the calcium channel a1H subunit (CACNA1H) have been identified in families with CAE (Chen et al, 2003; Heron et al, 2004). This gene encodes the Cav3.2 T-type calcium channel that is involved in thalamocortical synchronization (see below) and may function to enhance epilepsy susceptibility (Khosravani et al, 2005). However, there is probably genetic heterogeneity in CAE, as other calcium channel mutations have been identified in absence epilepsies with similar epilepsy phenotypes to CAE (e.g., CACNA1A in absence epilepsy with episodic ataxia (Imbrici et al, 2004)).

Pathophysiology of Childhood Absence Epilepsy: Childhood absence epilepsy is considered to result from dysfunction of thalamocortical pathways, but the exact pathophysiology remains incompletely understood. Multiple levels of physiological regulaJournal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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tion, each assumed to be under genetic control, underlie this epilepsy. Thus, the genetic defect(s) in CAE produce widespread dysfunction of thalamocortical circuits affecting both hemispheres.

Absence seizures and their underlying spike-wave discharges have long been considered to result from abnormal neuronal oscillations between cortical and thalamic neurons. Over the past several decades the details of this interaction—for example, which fires first, the cortex or the thalamus—have evolved, as discussed in a comprehensive historical review (Meeren et al, 2005). The centrencephalic theory of Jasper and Penfield held that thalamic discharges recruited widespread cortical areas into spike-wave discharges (Jasper and Fortuyn, 1947). Subsequently, the involvement of cortex was shown in experiments in which convulsants applied to the cortical surface also produced 3-Hz discharges.

Gloor’s corticoreticular theory held that the diffusely increased excitability of the cortex allowed the thalamus and cortex to drive each other (Gloor et al, 1990). Recent experimental work in a genetic strain of rats with spontaneous absence seizures (WAG/Rij), using signal processing techniques that allowed fine dissection of the timing of discharges in different parts of the brain, showed that a cortical focus (in this case, in the perioral region of somatosensory cortex) always leads thalamic discharges by a few hundred milliseconds (Meeren et al, 2002). Therefore, despite the appearance of ‘generalized’ spike-wave discharges on EEG, it may be that discharges actually begin in discrete cortical

foci and propagate rapidly across the cortex. Ionic and cellular network mechanisms by which burst firing in one brain region leads to synchronization of other regions, ultimately leading to seizure generation, is the subject of ongoing investigation (Blumenfeld and McCormick, 2000). This transition likely involves alterations of neurotransmitters and their receptors, ionic channels, intracellular signaling cascades, and other factors that influence the excitation/inhibition balance. The possibility must also be considered that generalized seizures are less synchronized than previously believed (Garcia Dominguez et al, 2005; Netoff and Schiff, 2002).

Generalized spike-wave discharges seen in absence seizures reflect widespread oscillations between excitation (i.e., spike) and inhibition (i.e., slow wave) in mutually connected thalamocortical networks (McCormick and Contreras, 2001). Three groups of neurons are primarily involved: cortical pyramidal neurons, thalamic relay (TR) neurons, and thalamic reticular nucleus neurons (Figure 5A).

Neocortical layer VI neurons are excitatory (glutamatergic) and project onto TR neurons, which are also excitatory (glutamatergic); this interaction between neocortical pyramidal cells and TR neurons would create a positive feedback situation, but incessant excitation is prevented by the interposed inhibitory (GABAergic) neurons comprising the thalamic reticular nucleus (NRT). Cortical pyramidal cells project onto the NRT neurons, which then release GABA onto TR neurons, which have both GABAA and GABAB receptors. This reciprocal

Figure 5 Childhood absence epilepsy. (A) Simplified diagram of thalamocortical circuitry underlying spike-wave discharges in the absence 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 thalamic relay neuron, showing sequence of ionic currents. 1: Ih activation, 2: IT activation, 3: IT inactivation, 4: Ih deactivation, 5: removal of IT inactivation. (B(b)) Intracellular responses to prolonged intracellular current injection, illustrating the effects of Ih. The darker trace in response to a hyperpolarizing current pulse shows depolarizing sag reflecting Ih activation. The darker trace in response to the depolarizing 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 toward resting 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 underlies the 3-Hz generalized discharges.

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thalamocortical relay loop is a critical substrate for the generation of cortical rhythms and this circuitry is largely responsible for normal EEG oscillations during wake and sleep states (e.g., 14-Hz sleep spindles in stage II sleep). In CAE, due to genetic alteration of one or more ion channel involved in rhythm generation, the circuit could become hyperexcitable and produce rhythmic spike-wave discharges (in the case of CAE, at a frequency of 3-Hz during wakefulness).

Multiple ionic conductances interact to generate spike-wave discharges, but two ionic channels are believed to play an especially key role in regulating thalamocortical rhythmicity. The first is a subtype of voltage-gated calcium channel known as the ‘lowthreshold’ or T-type calcium channel, so-named because it can be activated by small depolarizations of the neuronal membrane. Calcium influx through these 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 to underlie the ‘spike’ portion of a generalized spikewave oscillation. T-type calcium channels exist in three functional states—open, inactivated, and closed. When the neuronal membrane is depolarized, Ca2 + enters the neuron and produces action potentials in bursts. However, immediately upon Ca2 + entry, the channels inactivate, that is, cannot pass further current until they are ‘de-inactivated’ by hyperpolarization. This hyperpolarization is provided by NRT neurons, which release GABA tonically. The GABA binds to GABAB receptors on TR cells. At this point, the T-channels are closed and cannot conduct current again until the membrane is depolarized. This cycle of depolarization/hyperpolarization is the critical substrate of TR neuron rhythm generation and drives the thalamocortical oscillation (Figure 5B(a)). Anticonvulsants known to be clinically effective against absence seizures (e.g., ethosuximide and valproic acid) can block T-type calcium currents (Coulter et al, 1989).

Several experimental models reinforce the importance of T-type calcium currents in the pathophysiology of absence epilepsy. Mice with spontaneous calcium channel mutations or knockout of certain calcium channel subunits have absence seizures and spike-waves on EEG (Kim et al, 2001; Zhang et al, 2002). Strasbourg rats with genetic absence epilepsy (GAERs) have upregulated T-calcium currents in thalamic reticular neurons (Danober et al, 1998; Tsakiridou et al, 1995).

Another important ion channel involved in the regulation of thalamocortical rhythmicity is the hyperpolarization-activated cation channel (HCN channel), responsible for the so-called H-current (Ih). Hyperpolarization-activated cation channels are activated by hyperpolarization and produce a depolarizing current carried by an inward flux of Na + and K + (Robinson and Siegelbaum, 2003). In TR neurons, this depolarization helps to bring the

resting membrane potential toward threshold for activation of T-type calcium channels, which in turn produces a calcium spike and a burst of action potentials (Figure 5B(a)).

A unique physiological property of H-currents among voltage-gated conductances is that they are both inhibitory and excitatory, and mediate negative feedback: hyperpolarization activates HCN channels, leading to depolarization, which then deactivates the HCN channels (Figure 5B(b)). The net effect of HCN channel activation is to stabilize the membrane against either excitatory or inhibitory inputs (Poolos, 2005; Santoro and Baram, 2003). hyperpolarization-activated cation channel channels are expressed maximally on TR neuron apical dendrites, near excitatory inputs, allowing H-currents to suppress prolonged excitation as occurs in a seizure. H-currents tend to reestablish resting potential whether the input is hyperpolarizing or depolarizing. In a mouse model in which the HCN2 isoform is knocked out, animals develop spontaneous absence seizures and spike-wave discharges (Ludwig et al, 2003). In the WAG/Rij rat model of absence epilepsy, defective Ih augments excitatory postsynaptic potentials and leads to heightened neocortical excitability (Strauss et al, 2004).

Together, these channels enable the thalamocortical circuit to produce the classic 3-Hz generalized spike-wave discharges of an absence seizure (Figure 5B(c)).

The clinical relevance of HCN channels in the pathogenesis of absence seizures is supported by the demonstration that lamotrigine, which has antiabsence activity, enhances activation of dendritic H-currents in hippocampal pyramidal neurons (Poolos et al, 2002). Interestingly, H-currents have also been implicated in the pathogenesis of hyperthermia-induced seizures in rat pups, which mimic febrile seizures in children. In that model, a hyperthermic seizure early in life leads to a persistent increase in both GABAergic currents and H-currents in CA1 hippocampal pyramidal neurons (Chen et al, 2001). This combination of persistent changes in neuronal excitability was linked to lowered seizure threshold later in life.

Although no human HCN channelopathy has been identified, these studies attest to the importance of H-currents in the control of neuronal excitability and seizure predisposition (Santoro and Baram, 2003).

In addition to the involvement of T-type calcium channels and HCN-channels, other neurotransmitter receptors have also been implicated in thalamocortical rhythmicity and absence seizures. Antagonists of GABAB receptors and dopaminergic agonists also interrupt abnormal thalamocortical discharges in experimental absence epilepsy models (Snead, 1995). GABAB receptors are involved in mediating long-lasting thalamic inhibitory postsynaptic potentials involved in the generation of normal thalamocortical rhythms, while brainstem monoaminergic Journal of Cerebral Blood Flow & Metabolism (2006) 26, 983–1004

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Table 1 Selected examples of epilepsies and underlying mechanisms Case Level of abnormal excitability

Mechanism of abnormal Clinical syndrome excitabilitya

Epilepsy syndrome classification

Prognosis

1

Ionic channels Glucose transport protein Small-scale (local) neuronal circuit

Generalized symptomatic Generalized symptomatic Localization-related symptomatic

Good

2

Decreased M-channel function Decreased brain glucose availability Abnormal circuit formation and synaptic connectivity Hippocampal sclerosis, axonal sprouting Abnormal T-type calcium channel and HCN channel

Localization-related symptomatic Primary generalized (idiopathic)

Variable; often good with resection Good

3 4 5

a

Large-scale (limbic) neuronal circuit Thalamo-cortical circuits

BFNC Glut-1 deficiency syndrome Focal cortical dysplasia Temporal lobe epilepsy Childhood absence epilepsy

Variable; better with ketogenic diet Variable; often good with resection

Several other mechanisms may also be involved.

projections disrupt these rhythms. Of note, some GABAergic 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 characterized and the pathophysiology is complex. It is uncertain whether application of advanced signal analysis methods such as nonlinear association analysis will enhance our understanding of this physiologically complex syndrome, converting it from a generalized epilepsy to a partial onset one.

The existence of absence seizures in a multitude of epilepsy syndromes with different prognoses raises the possibility that several pathophysiological mechanisms coexist.

Summary and Conclusions Advances in clinical and basic science are increasing our understanding of epilepsy mechanisms. In particular, new information from molecular genetics, imaging techniques, and cellular physiology are creating conditions whereby these advances will translate into therapeutic advances. This review has discussed five selected examples of epilepsies, summarized in Table 1. By focusing on multiple levels of nervous system function, it can be seen that epilepsy manifestations and consequences are widespread, involving many aspects of brain function beyond the seizure itself. The mechanisms described here are by no means restricted to the level of the nervous system affected primarily. Indeed, abnormal ionic channel function can affect synaptic and network function, and both in turn can influence behavior and cognition. Our challenge is to find the links between the different levels of pathophysiology in epilepsy, and translate these into beneficial therapies.

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