Showing papers in "Epilepsy Currents in 2011"

Revisiting AMPA Receptors as an Antiepileptic Drug Target

Abstract: In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As drugs became available that selectively target AMPA receptors, it was possible to demonstrate that AMPA receptor antagonists have powerful antiseizure activity in in vitro and in vivo models. A decade later, promising clinical studies with AMPA receptor antagonists, including the potent noncompetitive antagon...

Anxiety disorders in epilepsy: The forgotten psychiatric comorbidity

Abstract: Commentary In the last decade, epileptologists have recognized the importance of identifying and treating psychiatric comorbidities in patients with epilepsy (PWE). Yet, in clinical practice and research alike, most of the attention has been focused on depressive disorders (DD), as they are the most frequent psychiatric comorbidity (1). In addition, DD yield a negative effect on the quality of life of PWE (2), increase significantly their suicidal risk, (3) worsen their tolerance to antiepileptic drugs, and have been associated with a worse response of seizures to pharmacologic and surgical treatments (4, 5). Although anxiety disorders (AD) are the second most frequent psychiatric comorbidity in PWE (1), they remain underrecognized and undertreated despite the fact that they have as negative impact on the life of these patients as DD (see below). In a Canadian population-based study, the lifetime prevalence of any AD in PWE was 22.8% (vs 11% in nonepilepsy subjects). Anxiety disorders are also relatively frequent in patients with treatment-resistant epilepsy, as shown in the study by Brandt et al., which accompanies this commentary and in which close to 20% of the 96 patients exhibited an AD. Of note, AD and DD tend to occur together with a high frequency, and, in the Canadian study, a lifetime prevalence of 34.2% was found for comorbid AD and DD in PWE (vs 19.6% in nonepilepsy subjects). The clinical significance of the comorbid occurrence of primary AD and DD led the committee developing the fifth edition of the Statistical Manual of Mental Disorders (DSM-V) to create a new diagnostic category of “mixed depression/anxiety disorders.” Patients with and without epilepsy can experience more than one AD. In a study of 188 consecutive PWE from five epilepsy centers in the United States (50% of whom had been seizure-free for the last 6 months), current AD (identified with the Mini International Neuropsychiatric Interview) were found in 49 patients (26%), with agoraphobia, generalized anxiety disorder (GAD), and social phobia being the most frequent (5). Among these 49 patients, 27 (55%) had two or more anxiety disorders while 28 (57%) were also suffering from a comorbid major depressive episode (MDE). As in the case of DD, AD has a negative effect on the life of PWE at several levels. For example, the presence of anxiety symptoms at the time of diagnosis of epilepsy was associated with a worse response to pharmacotherapy after a 12-month follow-up period (4). The effect of AD on the quality of life of PWE has been demonstrated in several studies as well. In one study, AD and MDE had a comparable negative effect on the quality of life measured with the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) while the presence of more than one AD occurring together with a MDE had the worst effect on health-related measures of quality of life (5). In a South Korean study of 154 Prevalence of Anxiety Disorders in Patients With Refractory Focal Epilepsy—A Prospective Clinic Based Survey.

Efficacy of new antiepileptic drugs.

Abstract: Regarding efficacy of new antiepileptic drugs (AEDs) for seizure control, there are three important clinical questions. How effective are new AEDs when corrected for the efficacy of placebo...

Does acquired epileptogenesis in the immature brain require neuronal death.

Abstract: Because epilepsy often occurs during development, understanding the mechanisms by which this process takes place (epileptogenesis) is important In addition, the age-specificity of seizures and epilepsies of the neonatal, infancy, and childhood periods suggests that the processes and mechanisms that culminate in epilepsy might be age specific as well Here we provide an updated review of recent and existing literature and discuss evidence that neuronal loss may occur during epileptogenesis in the developing brain, but is not required for the epileptogenic process We speculate about the mechanisms for the resilience of neurons in immature limbic structures to epileptogenic insults, and propose that the type, duration and severity of these insults influence the phenomenology of the resulting spontaneous seizures

Genetic testing in epilepsy: what should you be doing?

Abstract: With the burgeoning array of molecular tests available in the epilepsies, the clinician needs to know which tests to order for each patient. Epileptic encephalopathies are the most important clinical group for genetic testing with an increasing number of distinctive epilepsy syndromes being recognized. Identification of the causative mutation affects treatment as well as prognostic and genetic counseling.

Rapamycin for treatment of epilepsy: antiseizure, antiepileptogenic, both, or neither?

Abstract: Commentary Current medications for epilepsy are recognized to have a couple of major limitations. First, despite over a dozen existing drugs, one third of epilepsy patients continue to have seizures and can be defined as medically intractable after failure of just two or three drugs. Second, even in patients whose seizures are well-controlled on medication, it is generally accepted that most current drugs simply suppress seizures as symptomatic therapy; they do not prevent the initial development or progression of epilepsy. In other words, these drugs primarily act as anticonvulsant or antiseizure agents but do not possess actual antiepileptogenic or disease-modifying properties. To address these limitations, completely different types of drugs with novel mechanisms of action are needed. Although there are some differences in the molecular targets of available drugs, most antiseizure medications work by similar mechanisms of action: to directly suppress neuronal excitability by reducing excitatory neurophysiological mechanisms (e.g., sodium or calcium channels, glutamate receptors) or enhancing inhibitory mechanisms (e.g., potassium channels, GABA receptors). A novel mechanistic approach to address the issues of medical intractability and disease modification in epilepsy is to modulate primary cell signaling pathways that initially trigger various downstream mechanisms mediating epileptogenesis and increased neuronal excitability. The mammalian target of rapamycin (mTOR) pathway has recently received attention as a candidate signaling pathway that may be central to epileptogenesis and could be targeted therapeutically with mTOR inhibitors, such as rapamycin (1, 2). mTOR is a ubiquitous protein kinase with multiple physiological functions, including regulation of cell growth, proliferation, and survival (1, 2). In the brain, mTOR is also involved in numerous functions that can affect neuronal signaling and excitability, such as axonal and dendritic morphology, neurotransmitter receptor expression, and synaptic plasticity, under physiological conditions, and could potentially contribute to epileptogenesis under pathological conditions. In the disease, tuberous sclerosis complex (TSC), an important genetic cause of epilepsy, hyperactivation of the mTOR pathway triggered by TSC gene mutations has been strongly implicated in promoting tumor growth, as well as contributing to epilepsy and other neurological symptoms in this disease. In mouse models of TSC, early treatment with rapamycin appears to have antiepileptogenic effects in preventing the development of epilepsy and the underlying molecular and histopathological mechanisms of epileptogenesis in presymptomatic mice (3, 4). In addition, later treatment with rapamycin in symptomatic mice can suppress or reverse seizures, as well as learning deficits, in TSC mouse models (4, 5). Furthermore, in related genetic mouse models of PTEN inactivation, rapamycin also decreased seizures, behavioral deficits, and histopathological abnormalities (6, 7). Thus, mTOR inhibitors may have both antiepileptogenic and antiseizure applications in specific types of genetic epilepsy. In fact, initial clinical studies already suggest that mTOR inhibitors decrease seizures in TSC patients with established epilepsy (1, 8), although early antiepileptogenic drug treatment to prevent epilepsy has not been reported. While genetic epilepsies involving mTOR hyperactivation are relatively rare, the widespread functions of mTOR suggest Pharmacological Inhibition of the Mammalian Target of Rapamycin Pathway Suppresses Acquired Epilepsy

The fat is in the fire: ketogenic diet for refractory status epilepticus.

Abstract: Commentary Status epilepticus has a high degree of long-term functional poor outcomes, with mortality rates as high as 50% (1). Standard anticonvulsant treatments include benzodiazepines, phenytoin, and phenobarbital; newer agents include levetiracetam and valproate (2). Unfortunately, status epilepticus can remain refractory to these interventions, at times requiring anesthetics such as pentobarbital, midazolam, propofol, and ketamine to achieve burst suppression (2). Yet even these treatments can eventually fail, with patients experiencing persistent seizures when they are weaned off general anesthesia. Sadly, few other options are then available. The ketogenic diet is a high-fat, low-carbohydrate nonpharmacologic treatment for epilepsy (3). In continuous use since 1921, over the past two decades, there has been a dramatic resurgence in research and clinical interest in this therapy, typically for children with intractable epilepsy. There is a misperception that the ketogenic diet is universally comprised of bacon, eggs, and heavy whipping cream. The reality is that several all-liquid ketogenic formulas exist and can be provided by a trained dietitian, typically for infants and children with gastrostomy tubes (3). The study by Nabbout and her colleagues from five centers in France and Argentina retrospectively examined their use of the ketogenic diet for refractory status epilepticus caused by the condition FIRES, (fever-induced refractory epileptic encephalopathy) in school age children (4). In this epileptic encephalopathy, previously normal children aged 4 to11 years develop the abrupt onset of typically refractory febrile status epilepticus without a clear pathogen identified. The prognosis for epilepsy and cognitive development is quite poor. Nine children, ages 5 to 8 years were treated with the ketogenic diet after from three to six anticonvulsants used as long as 55 days had failed to control their status epilepticus. One can only imagine the ketogenic diet was perceived a last hope for survival for most of these children. The ketogenic diet was started using various formulas via nasogastric tubes, and glucose was removed from both medications and intravenous fluids. Within a mean of 2.8 days, all but one of these children developed ketonuria and, remarkably, seven of these eight children rapidly responded to the ketogenic diet. The authors add details regarding one subject, a 6-year-old boy, who became seizure-free but within hours returned to status epilepticus after the ketogenic diet was stopped by the intensivists who did not believe it was helping. He later died of his condition. All six successfully treated children did develop sporadic seizures 1 to 6 months after recovering from status epilepticus, not surprisingly. Although this study is not the first to report the successful use of the ketogenic diet for status epilepticus, it is the largest. The first case report was only 2 years prior, from Bodenant Efficacy of Ketogenic Diet in Severe Refractory Status Epilepticus Initiating Fever Induced Refractory Epileptic Encephalopathy in School Age Children (FIRES).

Explaining the Unexplained; Expecting the Unexpected: Where Are We With Sudden Unexpected Death in Epilepsy?

Abstract: Sudden death is over 20 times more frequent in people with epilepsy than the general population. The literature on clinical risk factors is now able to define individuals at the highest risk. Despite these advances in our understanding of risk, the mechanism of sudden unexpected death in epilepsy remains elusive. While it is unlikely that a single mechanism will be found to explain all deaths, there have been recent advances that identify factors that play a critical role. This review provides an update on new advances in the understanding of sudden unexpected death in epilepsy.

Epilepsy in a dish: an in vitro model of epileptogenesis.

Abstract: Commentary Animal models of epilepsy have helped to promote investigations of underlying mechanisms of epileptogenesis and to facilitate the development and screening of novel treatments. A large number and variety of animal models have been created, involving pharmacologic (e.g., pilocarpine, kainate), electrical (e.g., kindling), genetic (e.g., knock-out mice), and other injurious (e.g., trauma, hypoxia, stroke) methods or stimuli, to match the equally numerous types and causes of epilepsy in people. Of course, in vivo models of epilepsy, in which animals exhibit actual behavioral and electroencephalographic seizures, most closely mimic the clinical features of human epilepsy. However, reduced biological systems, including brain slices, cell culture, and molecular assays, may also be advantageous in offering unique mechanistic insights into epilepsy. As there is obviously no perfect animal model of epilepsy, ultimately each model system must be carefully evaluated for its specific advantages and limitations in studying different aspects of epilepsy. Given the complexity of epilepsy, there is increasing interest in developing simplified in vitro models of epilepsy that allow more detailed investigations of cellular and molecular mechanisms of epileptogenesis while still preserving the critical network phenotypic features of epilepsy, particularly the development of spontaneous seizures. Intact hippocampal preparations or acute brain slices maintain much of the needed circuitry to generate electrographic seizures (1, 2). However, these preparations are typically only viable for several hours and thus are primarily useful only for studying acutely provoked seizures, not chronic epileptogenesis. Organotypic slice cultures, which can be maintained for weeks or longer, have been used to study a number of physiological and pathological processes in the brain, including circuit development, synaptic plasticity, and axonal sprouting (3). Slice cultures also afford the opportunity to investigate epilepsy. Most previous studies of organotypic slice cultures have focused on interictal spikes and electrographic seizures acutely provoked by convulsant drugs or other pharmacologic conditions over a relatively short time course (4–6). However, some studies have examined the development of spontaneous epileptiform activity over several weeks, which more closely mimics the process of epileptogenesis that occurs with in vivo animal models and human epilepsy (7, 8). The recent study by Dyhrfjeld-Johnsen et al. provides perhaps the most detailed characterization to date of the development and evolution of epileptiform activity within a chronic, Interictal Spikes Precede Ictal Discharges in an Organotypic Hippocampal Slice Culture Model of Epileptogenesis.

Ezogabine: a new angle on potassium gates.

Abstract: Ezogabine is a new drug for adjunctive therapy of partial-onset seizures with a novel mechanism of action. As a potassium-channel facilitator, it promotes membrane repolarization and thus opposes rapid repetitive discharges. Side effects are typical for antiepileptic drugs and the safety profile is good. Occasional instances of urinary difficulty may require surveillance.

Classification and epilepsy: the future awaits.

Abstract: By now, most are aware that changes are afoot in the concepts and terminology used for discussing and "classifying" epilepsy (1). The changes have been met with scorn and derision by some (2, 3). In balance, they seem to be appreciated, not for being a final product but for finally moving the field from out of an archaic past in which it was stuck and into the present and, may we hope, the future. As it stands, the report, and its recommendations likely elicit feelings of dissatisfaction for not being complete, final, and carved in stone. The report did not even presume to present a new classification. The authors of the report share that frustration, with the caveat that little should ever be carved in stone in a field that is moving as rapidly as the life sciences.

Carbamazepine hypersensitivity: progress toward predicting the unpredictable.

Abstract: Commentary Cutaneous adverse drug reactions are among some of the most frequent adverse events associated with a number of our commonly used aromatic ring–containing antiepileptic drugs (AEDs), including carbamazepine, phenytoin, oxcarbazepine, and lamotrigine (1–3). In its mildest form, maculopapular exanthema may occur in perhaps up to 10% of patients receiving carbamazepine. In some patients, however, more severe dermatologic hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms [DRESS]) may occur and has been associated with a mortality rate of about 10%. This hypersensitivity syndrome is associated with rash, fever, and organ dysfunction such as nephritis or hepatitis (4), and most commonly presents within the first 2 months of therapy, with flu-like symptoms such as fever and malaise. For patients receiving carbamazepine or phenytoin, the incidence of DRESS is estimated to be 1 in 5,000. Among the most severe of these reactions are StevensJohnson Syndrome (SJS) and toxic epidermal necrolysis (TEN). Treatment with commonly used AEDs such as carbamazepine, phenytoin, phenobarbital, and lamotrigine is considered to increase the risk of SJS/TEN. For carbamazepine, the risk of developing SJS/TEN in individuals of European decent is about 1 to 6 cases of 10,000 patients exposed (5, 6). SJS and TEN are considered to be variants of the same process, with the mortality rate for patients developing TEN approaching 30%. Clearly, it would be advantageous to be able to identify patients at possible risk for developing any sort of hypersensitivity reaction to these commonly used medications. Until relatively recently, dermatologic reactions were considered to be idiosyncratic events, and thus, largely unpredictable. This notion changed however following the demonstration of a relationship between these potentially life-threatening reactions and the human leukocyte antigen (HLA)-B*1502 in various Asian populations (7, 8). Indeed, HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans.

Hippocampal atrophy: another common pathogenic mechanism of depressive disorders and epilepsy?

Abstract: Commentary Since the arrival of MRI of the brain, hippocampal atrophy (HA) has been recognized as the most frequent neuroradiologic abnormality in temporal lobe epilepsy (TLE). The use of volumetric measurements of temporal lobe structures on MRI facilitated the recognition of subtle HA, not identified by visual exam, including HA contralateral to the seizure focus in patients with unilateral TLE. In psychiatry, the use of volumetric measurements has revolutionized our understanding of the pathogenic role played by temporal and frontal lobes in mood disorders. In fact, bilateral HA has become one the most frequent neuroradiologic findings in major depressive disorders (MDD), but volumetric measurements are necessary to detect the 10 to 20 percent volume loss in this condition (1). Sheline et al. were the first to report bilateral HA in a group of women with recurrent MDD (1). The magnitude of the decrease in hippocampal volumes was correlated with the duration of the depressive episode, and in particular with the duration of “untreated” depression (2). Hippocampal atrophy in MDD can be detected after recurrent MDDs (1, 3); it is a trait of this disease, as patients with a remitted depressive episode, off antidepressant medication, continue to have smaller posterior hippocampal volumes (3). In addition to measuring the volume of mesial temporal structures, investigators have examined changes in the shape of the hippocampal formation with high–dimension brain mapping. This method revealed surface deformations at the level of the subiculum (4) and in CA1-CA3 cell fields (5). As in the case of mesial temporal sclerosis in TLE, the presence of HA in MDD has been associated with memory deficits (6). Thus, it is not surprising that in the study selected for this commentary, Finegersh et al. found that depressive symptomatology was associated with bilateral HA in patients with unilateral TLE. Is it possible that the presence of bilateral HA in depressed patients with epilepsy may account for the worse response of the seizure disorder to pharmacologic, surgical therapy, or both reported in recent years (7, 8)? In one study of 780 patients with new-onset epilepsy, a history of depression preceding the onset of the seizure disorder was associated with a two-fold higher risk to develop treatment-resistant epilepsy (7). Likewise, in a study of 138 patients with new-onset epilepsy, the identification of symptoms of depression, anxiety, or both at the time of diagnosis of epilepsy was associated with a significantly lower probability of seizure-freedom at 12-month follow-up (8). In MDD, HA is also associated with a worse prognosis, as evidenced by the higher risk of recurrence of MDD in these patients (9). The HA in MDD has been attributed to high cortisol serum concentrations associated with a hyperactive hypothalamicpituitary-adrenal axis, which has been demonstrated in up to 50% of patients with the dexamethasone suppression test (DST). These high cortisol levels are a trait, as nonsuppression in the DST has been found in patients who have remitted from an MDD. In experimental studies with rats and monkeys, high concentrations of cortisol were found to be neurotoxic as they were associated with 1) damage of hippocampal neurons, particularly CA3 pyramidal neurons mediated by reduction Bilateral Hippocampal Atrophy in Temporal Lobe Epilepsy: Effect of Depressive Symptoms and Febrile Seizures.

Is It Safe to Use a Diuretic to Treat Seizures Early in Development

Abstract: There has been considerable interest in using bumetanide, a diuretic chloride importer NKCC1 antagonist, to reduce intracellular chloride ([Cl−]i) in epileptic neurons, thereby shifting the polarity of GABA from excitatory to inhibitory and ameliorating the actions of GABA-acting antiepileptic drugs. However, a recent study raises the important issue of potential deleterious actions of bumetanide on immature neurons, because reduction of (Cl−)i also alleviates a major source of excitation in developing neurons, upon which GABA exerts a trophic action. This review considers the importance of separating intrauterine from postnatal effects of bumetanide in normal versus pathologic neurons.

Distinct mechanisms mediate interictal and pre-ictal discharges in human temporal lobe epilepsy.

Abstract: Commentary The mechanisms governing the transition of neural firing from the interictal state to the ictal state (ictogenesis) are largely unknown. However, mechanistic information about this transition is critical for several reasons. First, such details would enhance the accurate prediction of seizure occurrence from clinical and EEG data. Second, this information would help to identify factors that enhance or limit the generation of seizures. Third, knowledge about the interictal-to-ictal transition could aid the development of directed therapies. Interictal spikes are brief paroxysmal discharges that arise from synchronous neuronal firing. In addition to denoting neuronal hyperexcitability, interictal discharges cause transient cognitive impairment (1) and comprise the electrical substrate for chronic epilepsy (2, 3). Interictal spikes are considered to be a predictor of the site of ictal onset, though scalp-recorded EEG in humans does not always localize the seizure-onset zone (4). Therefore, reduced systems can be used experimentally to study the role of interictal neuronal activity. In both animal models and organotypic cultures of epilepsy, interictal spikes develop prior to the onset of the first seizure and are considered to be a marker for epileptogenesis (5–7). However, the frequency of interictal spikes does not necessarily correlate with imminent seizure occurrence. That is, interictal spikes may indicate chronic excitability and epileptogenesis, but not the impending occurrence of an actual seizure. What, then, would be the usefulness of documenting the location and frequency of interictal spikes? Or, is there another electrophysiological marker that accurately presages ictal occurrence? Huberfeld and colleagues approach these questions with a complex yet elegant series of studies using brain slices of resected hippocampal/limbic tissue from patients undergoing temporal lobectomy for refractory epilepsy. Brain slices containing hippocampus, presubiculum, subiculum, and entorhinal cortex were subjected to a convulsant stimulus (high potassium, increased HCO3 − to alkalinize the perfusate, or low magnesium, or a combination of these agents). Each of these experimental conditions produced region-specific interictal discharges (IIDs) and ictal-like discharges; in addition, a third type of discharge was identified, which they named “pre-ictal discharges” (PIDs). PIDs represent a novel form of neuronal firing that directly precedes an electrographic seizure, thus representing a possible key to the interictal-to-ictal transition. The primary finding of this article is that prior to the ictus, two distinct patterns of neuronal firing are discernible in extracellular recordings: IIDs and PIDs. These two firing patterns are best illustrated by a figure from the paper (Figure 1). IIDs and PIDs could be differentiated by their electrographic characteristics, onset site within the slice, and pharmacologic responsiveness, leading the investigators to postulate that different mechanisms underlie interictal versus pre-ictal activity. The physiological underpinnings of the two patterns were explored in this system using intracellular recordings and blockers of various aspects of excitatory and inhibitory neurotransmission. Furthermore, presurgical intracranial EEG studies Glutamatergic Pre-ictal Discharges Emerge at the Transition to Seizure in Human Epilepsy.

Neonatal seizures due to hypoxic-ischemic encephalopathy: should we care?

Abstract: Commentary Most child neurologists approach the hospital neonatal intensive care unit (NICU) with fear and trepidation. The most frequent consultation, which leads to this sense of unease, is a newborn term infant with hypoxic-ischemic encephalopathy (HIE) who has now just started to develop seizures. Unlike seizures in older children, to some extent, for whom some evidence-based guidelines do exist, neonatal seizures are often beyond our comfort zone. Why? For one, seizures are common with HIE and can be extremely subtle to the extent of being not clinically observable in nearly half of neonates (1, 2). Additionally, the relatively new technology of amplitude-integrated EEG (aEEG) has emerged in the NICU as standard-of-care, in which long epochs of information derived from limited electrode channels, is typically interpreted by neonatologists (3). The true value and benefit of this technology is unclear. Last, as shown both by the authors of this paper in a previous article (4) and by a recent Cochrane group analysis (5), commonly used anticonvulsants for neonates such as phenobarbital and phenytoin, are unproven at best and harmful at worst. Certainly it is difficult for a neonatologist, nurse, parent, or neurologist to stand at the incubator and watch a neonate convulse. However, if our treatments do not work, and the seizures are not having any true impact on the child’s long-term outcomes, then perhaps watching is the appropriate intervention. We know from the infantile spasms literature that the underlying etiology trumps the success of treatment in regard to long-term development (6). In many cases of epilepsy, the seizures are mostly a symptom of an abnormal brain structure or genetic etiology, as opposed to a true epileptic encephalopathy. Neonates who are in the intensive care unit with HIE are under close, intense, respiratory and hemodynamic supervision and protection; a brief seizure will likely have minimal systemic impact. It is into the fray of this exceptional equipoise that this research by Kwon and colleagues from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network is now available. Just 4 years ago in this same journal (Journal of Child Neurology), the same first two authors evaluated 146 infants with seizures, by a phone survey, and determined that phenobarbital prophylaxis did not improve neurologic outcomes after up to 12 years (4). They continue to question the status quo by addressing in this current study whether clinical (not solely electrographic) seizures in neonates with HIE have a true independent direct effect on development, as measured by the Bayley Mental Development Index (MDI) at 18 months of age. Data from the Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data From the Neonatal Research Network Hypothermia Trial.

Treatment of childhood absence epilepsy-an evidence-based answer at last!

Abstract: Commentary The significance of the recent study by Glauser et al. from the Childhood Absence Epilepsy Study Group (1) can best be appreciated in its historical context. “Absence” as a term to describe seizures was introduced by Poupart in 1705 and was subsequently followed by the terms “petit mal” in 1838 and “pyknolepsy” in 1916 (2). Adie (1924) is credited with introducing the latter term into the English literature (3). This was not a trivial issue, because the word derived from the Greek denotes something that is “densely packed”. Thus, the definition of pyknolepsy epilepsy extends beyond the discrete seizure type (absence) and directly implies frequency of the events. The description provided by Adie (with appropriate attribution to previous authors) contains the elements of what would become the syndrome of Childhood Absence Epilepsy (CAE). The semiology of the events is described as “an inhibition of the higher psychical processes lasting from 5–10 seconds.... The child sits or stands with limbs relaxed staring vacantly before him, the eyeballs may roll upwards, the lids may flicker, but there are no convulsive movements, and consciousness is never entirely lost. After the attack the child is well at once, and continues his interrupted game or task as if nothing had happened.”(3) Key features described include: age of presentation between 4 and 10 years, frequency of 6 to 100 seizures per day, refractory to treatments available at the time and complete resolution with normal cognition in the setting of a previously normal child. The next major advance came in 1935 with the pioneering work of Gibbs et al., who reported that the semiology of pyknolepsy was correlated with a 3-Hz, generalized spike-wave pattern on the recently developed electroencephalogram (4). Thus, the constellation of features for CAE was defined and included semiology, seizure frequency, age of onset, prognosis and EEG correlate. Despite the perceived benign nature of the syndrome, the need to provide children with symptomatic relief during the active phase of their epilepsy and the reality that not all children spontaneously stopped having seizures led to the use of available antiepileptic drugs (AEDs). The burgeoning field of medicinal chemistry identified a number of heterocyclic compounds Treatment of Childhood Absence Epilepsy— An Evidence-Based Answer at Last!

Generalized Postictal EEG Background Suppression: A Marker of SUDEP Risk.

Abstract: Commentary Although epilepsy-related mortality and sudden unexplained death in epilepsy (SUDEP) have been recognized for centuries, our understanding of the pathophysiology remains limited. For patients with epilepsy, an increased standardized mortality of two to three times has been reported, with multiple factors accounting for this risk, including accidental death and deaths secondary to the underlying etiology for seizures (e.g., stroke, tumor) (1). The incidence of SUDEP varies between studies and patient populations but ranges from 0.09 and 0.35 per 1,000 person years in the general epilepsy population to between 6.3 and 9.3 per 1,000 person years in treatment resistant epilepsy (TRE) who have failed epilepsy surgery (2). Efforts to understand SUDEP are limited by both its relatively infrequent occurrence and the limited number of direct observations during or preceding the patient’s death. Although a number of studies have, largely retrospectively, identified risk factors associated with SUDEP, methodologic issues limit comparisons between studies and the generalizability to broader populations with epilepsy (e.g., definition of SUDEP and choice of control population) (2). A review of ten case-controlled studies utilizing living patients with epilepsy as controls identified several common risk factors, including poor seizure control, longer duration of epilepsy, and younger age at onset of seizures (2). Effects of antiepileptic drug (AED) therapy varied between studies. Polytherapy was associated with an increased risk of SUDEP in four studies, two studies identified carbamazepine as an independent risk, and one study identified absence of treatment with AEDs as a significant SUDEP risk (2–4). Although these data provide a potential method for identifying higher risk populations, they provide only limited insights into the underlying pathophysiology. Most theories on SUDEP focus on either cardiac or pulmonary mechanisms, although specific physiologic biomarkers of susceptibility to SUDEP remain elusive. In two cases undergoing scalp EEG monitoring, SUDEP was preceded by profound postictal generalized EEG suppression (PGES) (5, 6). Lhatoo et al. investigated the risk of SUDEP relative to the duration of PGES, studying ten definite SUDEP patients (from 1997–2009) with at least one prior seizure in the video EEG monitoring unit along with 30 consecutive patients who had undergone monitoring prior to March 2009. All patients had TRE. EEG and clinical data were reviewed by two blinded teams. PGES was defined as a generalized absence of background activity above 10 μV beginning within 30 seconds An Electroclinical Case-Control Study of Sudden Unexpected Death in Epilepsy.

The sound of noninvasive seizure control.

Abstract: Commentary The failure of small-molecule antiepileptic drugs (AEDs) to effectively treat the symptoms of epilepsy in about one-third of patients with epilepsy has spawned the development of alternative treatment modalities. Among them, invasive surgical strategies are now routinely used in clinical practice. These include surgical resection of an epileptogenic focus (1) and electrical stimulation of either the vagus nerve or of deep brain structures using implanted electrodes (2). Although such invasive approaches have demonstrated benefits in a subset of patients; based on their nature, invasive strategies are necessarily associated with irreversible manipulations and bear inherent risks. For example, intracranial electrode implantation is associated with significant risks for brain hemorrhage and infection (5% risk, each) (3). Promising alternative strategies might in the future make use of unconventional noninvasive procedures, which remain understudied to date. Repetitive transcranial magnetic stimulation (rTMS), direct current stimulation (tDCS) (4), and focal cooling (5) have received the most attention so far in preclinical and in a limited number of clinical studies. rTMS can be delivered via a handheld magnet and seems to be more effective in neocortical compared with mesial temporal foci, suggesting that penetration of the stimulus into deeper brain areas might be a limiting factor. tDCS is based on application of low current to the scalp via electrodes and, as in studies performed with rTMS, mixed results have been obtained (4). Focal cooling can be achieved by applying thermoelectric devices to the surface of the skull. This strategy is conceptually based on findings that hyperthermia (e.g., fever) promotes seizures, whereas hypothermia is known to protect the brain. Experimental data in animals are promising, but translation into a clinical setting remains a challenge (5). In a new method paper, Min et al. describe a novel noninvasive strategy to reduce seizure activity by focused ultrasound sonication (FUS). The authors of this study used an air-backed, spherical ultrasound transducer operating at a frequency of 690 kHz to administer a low-intensity FUS (~130 mW/cm) to a specified focal brain area. The high frequency used is far beyond the audible range in rodents (up to 70 to 90 kHz) or humans (up to 20 kHz), thereby avoiding interference with the auditory centers in the brain stem. Of importance, the transcranial delivery of acoustic energy according to the above specifications was able to penetrate into deep brain areas (i.e., the thalamus) but did not affect brain temperature. In a feasibility study, designed to test the therapeutic potential of the ultrasound device, acute seizures were Focused Ultrasound-Mediated Suppression of Chemically-Induced Acute Epileptic EEG Activity.

To test our guess that breast is best: anticonvulsants and breastfeeding.

Abstract: Commentary Breastfeeding exists at a complex cultural crossroads in American society. The widespread use of infant formula for many decades left breastfeeding sorely underutilized and even eroded the very skill set itself, leaving subsequent generations of American women with inadequate resources to attempt it, even when motivated to do so. That motivation came from the steady stream of research articles establishing numerous health benefits from breastfeeding accruing to both child and mother, resulting in an aggressive push by both health authorities and grassroots advocates to increase breastfeeding rates. This, in turn, has spawned an occasional backlash, in part from harried mothers, unable or unwilling, who felt criticized for failing to meet this new maternal standard (1), and in part from prudish bystanders and managers of public spaces (2). Mixing drugs with the milk produces additional crosscurrents. Many educated mothers who would typically be interested in a “natural” or “healthy” lifestyle might be expected to be very favorably inclined to breastfeed. But if the mother in question has epilepsy, she is very likely under treatment with an antiepileptic drug (AED), and exposing one’s baby to drugs is emphatically not “natural.” Given the forced choice between exposing a newborn to an artificial food source or a CNS-active drug, breastfeeding is generally considered “elective” in the epilepsy population, and conservative obstetricians, pediatricians, and neurologists may counsel against it. Up to this point, the extant literature has been of little help in resolving this dilemma; the 2009 joint American Academy of Neurology/American Epilepsy Society (AAN/AES) practice parameter (3) noted only that the older AEDs (with the notable exception of primidone) may penetrate into breast milk less than many of the newer AEDs, but the clinical utility of this observation is mitigated by evidence that circulating levels in the newborn may be much lower than those in ingested breast milk (4), and by the fact that there is no clear standard for what AED level in a newborn can be considered “significant.” This practitioner has generally taken the opposite tack, encouraging breastfeeding on the (admittedly speculative) reasoning that any harms from modest AED exposure are likely outweighed by the manifold established benefits of breastfeeding. But a test is a better than a guess, so we can be grateful for the efforts of the NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) study investigators for shining some light Effects of Breastfeeding in Children of Women Taking Antiepileptic Drugs.

Stopping seizures with carbon dioxide.

Abstract: Commentary Although it has been known for more than 80 years that inhalation of an increased concentration of CO2 may suppress seizures (1, 2), this phenomenon has not been exploited as a clinical treatment. Nonetheless, there is extensive experimental and clinical literature documenting that CO2 concentrations of 10% and above can block or terminate a variety of seizures in animals and humans (3, 4), including electroshock seizures in psychiatric patients (5). The purpose of the current study by Tolner and colleagues is not only to revive attention for this neglected area of investigation but also to demonstrate the efficacy of 5% CO2, a clinically appropriate concentration, and to carry out a preliminary study of this intervention to treat acute seizures in the epilepsy monitoring unit. For the experimental animals in this study, hypercapnia was induced by pumping 5% CO2 in air into a chamber holding the rats, or, in the macaques, by hypoventilation with artificial ventilation to adjust the pCO2 to the level that would be expected from breathing 5% CO2. Spontaneous seizures were not studied in animals. Rather, these interventions were shown to shorten afterdischarges induced by electrical cortical stimulation in both the rats and monkeys and reduce the amplitude and frequency of spikes induced by application of bicuculline to motor cortex. Acetazolamide produced a similar, but smaller, shortening of afterdischarges in the rats. The human trial was done in patients with medically intractable localization-related epilepsy. Four patients were monitored with scalp electrodes, and three with subdural electrode arrays. As soon as possible after the electrographic seizure discharge spread bilaterally, a mixture of 5% CO2 and 95% O2 was applied by mask and then stopped when the seizure terminated. While 13 seizures were treated, 7 seizures from 5 of these patients were chosen as control events because they had semiology similar to the treated seizures. Application of the gas occurred at a mean of 40 seconds after the beginning of the electrographic seizures, and seizure duration was reduced by an average of 30% compared with the seven selected untreated seizures. No monitoring of pCO2 or pO2 is described. It appears that hypercapnia suppresses and terminates seizures by altering pH, rather than by affecting cerebral blood flow. The antiepileptic effects of acetazolamide may also be due to lowering of brain pH (6). Moreover, respiratory alkalosis may be responsible for the activating effects of hyperventilation on epileptiform activity, and for fever-induced seizures (7). These facts indicate the need for clinicians to avoid respiratory alkalosis when ventilating patients with status epilepticus and other acute severe seizures. In vivo studies demonstrate strong inhibition of neuronal activity with acidosis (8). This may be mediated by direct acFive Percent CO2 Is a Potent, Fast-Acting Inhalation Anticonvulsant.

Galanin receptors modulate seizures.

Abstract: Commentary Galanin is a 29 amino acid peptide (30 in humans), which is widely distributed in the brain. Galanin has been implicated in multiple physiological actions such as appetite, mood, anxiety, and learning. Galanin is also believed to play a role in diseases including epilepsy (1). Much of the knowledge about galanin’s role in epilepsy comes from studies of status epilepticus involving the hippocampus. The hippocampus and, particularly, the dentate gyrus receive a rich innervation of galanin-containing fibers. Cholinergic fibers from septum contain galanin in addition to acetylcholine. Noradrenergic fibers from locus caeruleus innervating the hippocampus also contain the neuropeptide. Galanin appears to be secreted Galanin Receptor 1 Deletion Exacerbates Hippocampal Neuronal Loss After Systemic Kainate Administration in Mice.

Brand spanking? The presumptive risks of generic antiepileptic drugs.

Abstract: Commentary In a room full of epilepsy physicians—or their patients—the one topic most likely to cause the proverbial excrement to strike the rotating blades is that of generic antiepileptic drugs (AEDs). Passions run high, with those at one end of the worry spectrum convinced that the widespread use of generics poses a primordial threat to the well-being of patients with seizures, while those at the other end seem equally convinced that the former group, as one clinical pharmacologist said to me not long ago, “must believe in some vital force outside of pharmacokinetics.” The first group probably outnumbers the second by at least 2:1. Yet a very important stakeholder remaining firmly in the latter camp is the U.S. Food and Drug Administration (FDA), which has insisted, despite all protestations, that there is no convincing evidence that generic AEDs pose any danger, and thus no reason to consider altering the FDA’s typical standards for generic preparations for this category. Those standards are often misunderstood, in that physicians hear something about “80%” and “125%” and think that patients may have their levels go up and down by a quarter; in reality those numbers refer to 90% confidence intervals, and the most a given generic preparation could vary from the brand, while still remaining within those limits, is about 5 to 8% (1). This has been inadequate to assuage the fears of many physicians, who aver that their practices are full of previously well epilepsy patients who “fell off the seizure-free wagon” (or the side-effect wagon) with no identifiable cause except that recent switch at the pharmacy. The only evidentiary basis to support these concerns has been a couple of studies showing increased healthcare utilization among users of generic lamotrigine and topiramate relative to the branded preparations (2, 3). Labiner and colleagues have now entered this fray with a study that is similar in concept to the aforementioned, but considerably larger and involving five different AEDs instead of just one. The drugs chosen—phenytoin (PHT), carbamazepine, primidone, gabapentin, and zonisamide—were those for which over 100 users of brand and generic preparations for Generic Antiepileptic Drugs and Associated Medical Resource Utilization in the United States

Anterior temporal lobectomy - how safe is it?

Abstract: Commentary The increasing call for epilepsy surgery is driven by an understanding that in certain cases it can halt the epileptic process and greatly reduce the associated risks that include: 1) disease risk (sudden unexplained death in epilepsy [SUDEP], injury, suicide, comorbidities), 2) iatrogenic risk (medication reactions, injury during medication change), and 3) compliance risk (poor medication compliance, ignoring seizure precautions, drug and alcohol use). Determining the point at which the risk/benefit balance for surgery actually tilts in favor of the patient is more complex than generally understood. Unfortunately, strong medical evidence is missing in most areas of epilepsy surgery (1). Even in situations where one is armed with efficacy and morbidity outcomes, it is useful to remember that the medical evidence mental construct for risk assessment is an idealized “statistical” patient, cared for by the medical team that performed the study; not necessarily a patient in your own hospital, cultural, and social setting. McClelland and colleagues investigated the surgical risk of anterior temporal lobectomy (ATL) using an interesting informatics resource (2). There is now a family of nationwide patient-care databases (i.e., the Nationwide Inpatient Sample [NIS]) or healthcare cost and utilization project (HCUPnet) that offers a variety of search features. McClelland and colleagues searched the NIS hospital discharge database (overview available at http://www.hcup-us.ahrq.gov/nisoverview. jsp) for the time span of 1988 through 2003 to identify patients 18 years or older who had a diagnostic code of 345.41 (intractable partial epilepsy with impairment of consciousness) or 345.51 (intractable partial epilepsy without impairment of consciousness), and a primary procedure code of 01.53 (brain lobectomy). Their search covered approximately 20% of all inpatient admissions to non-federal hospitals in the United States. In contrast to most retrospective studies, the NIS database allowed the authors to quickly search a remarkable number of hospital admissions. However, it also imposed limitations: 1) information included in HCUP’s nationwide databases only reveals what occurred during a single hospital stay; 2) it is not possible to track patients after discharge or analyze their readmissions or postdischarge morbidity and mortality; 3) it cannot be used to determine whether morbidity is transient Population-Based Analysis of Morbidity and Mortality Following Surgery for Intractable Temporal Lobe Epilepsy in the United States.

Infantile spasms: the devil is in the details, but do we see the forest for the trees?

Abstract: Commentary It is generally acknowledged that infantile spasms (IS) are a devastating disease with a poor prognosis. Hormonal preparations in the form of ACTH or oral corticosteroids, as well as vigabatrin, are well-established treatments (1–4). The cessation of spasms is achieved in 30 to 93 percent of patients and does not necessarily indicate a good developmental outcome (3–4). Several small and large prospective trials were conducted (3–4). Practice guidelines from 2004 concluded that ACTH is probably effective, but the evidence is too inconclusive to make recommendations about one treatment method over another. In the interim, a large prospective controlled trial, the United Kingdom Infantile Spasms Study (UKISS), demonstrated the superiority of steroids in spasm cessation but showed no difference in seizure or cognitive outcome at 1 year (1). This particular trial excluded children with tuberous sclerosis (TS). There is general agreement that tuberous sclerosis appears selectively responsive to vigabatrin (3). Cryptogenic spasms without proven etiology have a better prognosis than symptomatic spasms. The study by Mohamed et al. retrospectively reviews treatment of IS in a single center. It confirms that cryptogenic IS have a more favorable prognosis, and that oral steroids lead to a more rapid cessation of spasms than vigabatrin. However, overall responder rate and long-term outcome are similar regardless of treatment. Children whose spasms responded to treatment tended to have a better prognosis. They could not reproduce that treatment delay (>28 days after the onset of spasms) was associated with a worse prognosis (5). Although many aspects of the study are confirmatory, retrospective studies of this type serve an important function. First, the study includes all comers and reflects more general neuropediatric practice. Prospective clinical trials enroll very selective populations. The study is useful to counsel parents about the prognosis and provides some guidelines for treatment. The investigators also examined second-line treatment, which is studied less frequently. Combination therapy did not have a synergistic effect. Second, such studies give us the opportunity to reflect upon our clinical practice and subsequent treatment decisions. Controlled prospective trials influence what we do, as demonstrated in this study. UKISS had a significant influence on the treatment patterns of the investigators. However, only a few questions in neurology are truly settled by prospective studies, and we have to resort to the art of medicine, where the devil lies in the detail, such as preparations, dosages and subpopulation of patients. Mohamed et al. treated patients with oral prednisolone at higher doses. Other important trials used highor low-dose Seizure Outcome in Infantile Spasms—A Retrospective Study.

Cognitive Activation of "Hyperexcitable Cortex" in JME: Can It Trigger Seizures?

Abstract: Commentary Juvenile Myoclonic Epilepsy (JME) is classified as an idiopathic generalized epilepsy syndrome with “generalized polyspike and slow waves” on EEG. A number of clinical and electrophysiological studies in patients with JME, however, demonstrate alterations in specific cortical systems involving bilateral cortical and subcortical regions, including frontal lobe and anterior cingulate areas (1), motor cortex and supplementary motor areas (SMA) (2, 3), and thalamocortical pathways (4). JME has been associated with abnormalities in white matter pathways in the anterior internal capsule, especially in the anterior thalamic radiation fibers connecting the anterior thalamus with prefrontal cortical areas (4). Overall, these structural and functional studies support an emerging view that JME is a bilateral thalamocortical disorder with widespread cortical hyperexcitability, maximally involving the frontal lobe (1). JME, however, also appears to be a heterogeneous disorder with only mild abnormalities in tasks dependent on frontal lobe executive regions and variable PET/MRS and MRI abnormalities (5–7). One of the most striking abnormalities in cortical function in patients with JME has been increased cortical sensitivity to transcranial magnetic stimulation (TMS), particularly in anterior brain regions, following sleep deprivation (8) and during the morning hours (9). This increased sensitivity to transcranial evoked responses suggests abnormalities in intracortical inhibitory networks (10) and corresponds to the effectiveness of antiepileptic drugs (AEDs), which modulate GABA-mediated neurotransmission in treating JME (11). Consistent with these findings, patients with JME often report that seizures are associated with stress (83% of patients) or sleep deprivation (77%), factors which can decrease intracortical inhibition (12). A smaller proportion of patients report that seizures may be associated with “thoughts and concentration” (23%) or hand activities (20%) (12). In a new study, Vollmar et al. used fMRI to explore how praxis (“the ideation or execution of complicated movements”) activates cortical pathways in patients with JME and determined whether these pathways correspond to motor systems activated during myoclonic seizures (3). During performance of a visuospatial working memory task, patients with JME and Motor System Hyperconnectivity in Juvenile Myoclonic Epilepsy: A Cognitive Functional Magnetic Resonance Imaging Study.

Chloride's Exciting Role in Neonatal Seizures Suggests Novel Therapeutic Approach.

Abstract: Commentary Inhibition in the central nervous system is dependent on chloride conductance through GABAA receptor-associated channels. When chloride channels open, the membrane potential is driven toward chloride’s reversal potential, and because chloride’s reversal potential is negative to the neuron’s threshold for firing action potentials, it normally has an inhibitory effect. GABAA receptors have binding sites for both barbiturates and benzodiazepines, allowing them to enhance the inhibitory effect of GABA at this receptor; it is this mechanism of action that is responsible for the anticonvulsant activity of these agents. Prolonged seizure activity reduces the efficacy of GABAergic antiepileptic drugs (AEDs) such as benzodiazepines and barbiturates. If postsynaptic GABAA receptor responsiveness was reduced, one would expect GABAergic agents to lose efficacy as well. Indeed, a gradual suppression of GABAA receptor responses occurs during in vitro kindling (1) and GABA receptor internalization during ongoing seizures and status epilepticus has been documented (2), accounting for pharmacoresistance to GABAergic agents in these settings. One might also expect reduced inhibitory efficacy to result from intracellular buildup of chloride: prolonged neuronal activity results in elevated extracellular potassium concentrations, and this potassium is cleared in part by neuronal transporters that bring potassium back into the cells. NKCC1 is one such transporter, and when this transporter brings potassium back into the cells, it imports chloride with it. The resultant elevation of intracellular chloride will reduce efficacy of GABAA receptor-mediated synaptic inhibition by making the chloride reversal potential less negative. However, in the mature nervous system, the KCC2 transporter will do its best to counteract this chloride buildup by extruding chloride and restoring normal homeostasis. In the immature nervous system, however, the KCC2 transporter is not fully expressed. This makes the neonate more vulnerable to intracellular chloride buildup mediated by the NKCC1 transporter. Indeed, immature neurons have elevated baseline concentrations of intracellular chloride; as a result, neonatal GABAA receptor responses are not only less inhibitory, they may actually be excitatory (3, 4). The excitatory action of GABA-mediated chloride conductance is believed to contribute to the increased incidence of seizures in human neonates (5). There is a progressive developmental increase in expression of the chloride-extruding transporter KCC2 in the brain that eventually allows for the full expression of hyperpolarizing GABAA receptor responses; in the rat hippocampus, this occurs by the end of the second postnatal week (6). Numerous experiments have been done examining the efficacy of barbiturates in neonatal seizure models in vitro and in vivo, with conflicting results (7, 8). The current paper by Dzhala and colleagues attempts to make sense of this controversial area of investigation. The authors propose that the differences in response to GABAergic AEDs may correlate with Progressive NKCC1-Dependent Neuronal Chloride Accumulation During Neonatal Seizures.

Classifying Seizures and Epilepsies: Limits of Science and Semantics

Abstract: "If I wished to show a student the difficulties of getting at truth from medical experience, I would give him the history of epilepsy to read." Oliver Wendell Holmes (1)If the medical experience of epilepsy is obscured by uncertainties, then its classification is mired in the mud of expert opinion. The newly revised terms and concepts for "organizing" (also known as "classifying") seizures and epilepsy provide a humble and modern perspective, with many superb suggestions (2). The central points are well articulated and valid: 1) divorcing classification from "expert opinion" and marrying it to science; 2) acknowledging what is unknown; and 3) simplifying and clarifying terminology. Yet, the revision lacks the crisp clarity needed to educate students, patients, and colleagues. And some recommendations lack a clear scientific or semantic basis.

Carts, Horses, and Push-Pull Regulation of EGABA in Neonatal Seizures.

Abstract: Commentary In this interesting study, Ben-Ari and colleagues continue their study of synaptic GABA signaling in the developing brain. This group pioneered the idea that excitatory actions of GABA in the immature brain could contribute to physiological synchronization of neuronal activity in normal brain slices (1). This study examines whether excitatory actions of GABA contribute to anticonvulsant failure in the treatment of neonatal seizures. GABAA receptors operate an anion-permeable channel in the cytoplasmic membrane that is permeable to chloride and bicarbonate ions. Because chloride is five times more permeable and the extracellular concentration is four times the concentration of bicarbonate (2), the concentration of chloride inside the neuron is the principal determinant of the direction of ion flow through open GABAA channels: inward (inhibitory) or outward (excitatory). The concentration of chloride is considered to be regulated by two transporters: a sodium-potassium-chloride transporter called NKCC1 and a potassium chloride cotransporter, KCC2 (3). NKCC1 is expressed early in development, and at typical ion concentrations is a net importer of chloride. KCC2 is expressed later in development, and at typical ion concentrations is a net exporter of chloride. Because high intracellular chloride concentrations can reverse the flow of ions through the GABA receptor, the chloride importer NKCC1 can reduce the efficacy of GABA-mediated inhibition. This effect may be critical in neonatal seizures, which respond poorly to anticonvulsants that enhance the effects of GABA, such as barbiturates and benzodiazepines (4, 5). Bumetanide, a lipid-soluble inhibitor of NKCC1, which has been safely used as a diuretic in neonates for decades, is currently being tested as an adjunct to barbiturate treatment of neonatal seizures in clinical trials in the United States (6) and Europe (7). Neuronal Chloride Accumulation and Excitatory GABA Underlie Aggravation of Neonatal Epileptiform Activities by Phenobarbital.