Purpose: To examine the impact of diverse syndromes of focal and generalized epilepsy on language function in children with new and recent onset epilepsy. Of special interest was the degree of shared language abnormality across epilepsy syndromes and the unique effects associated with specific epilepsy syndromes. Methods: Participants were 136 youth with new or recent-onset (diagnosis within past 12 months) epilepsy and 107 healthy first-degree cousin controls. The participants with epilepsy included 20 with Temporal Lobe Epilepsy (TLE; M age = 12.99 years, SD = 3.11), 41 with Benign Epilepsy with Centrotemporal Spikes (BECTS; M age = 10.32, SD = 1.67), 42 with Juvenile Myoclonic Epilepsy (JME; M age = 14.85, SD = 2.75) and 33 with absence epilepsy (M age = 10.55, SD = 2.76). All children were administered a comprehensive test battery which included multiple measures of language and language-dependent abilities (i.e., verbal intelligence, vocabulary, verbal reasoning, object naming, reception word recognition, word reading, spelling, lexical and semantic fluency, verbal list learning and delayed verbal memory). Test scores were adjusted for age and gender and analyzed via MANCOVA. Results: Language abnormalities were found in all epilepsy patient groups. The most broadly affected children were those with TLE and absence epilepsy, whose performance differed significantly from controls on 8 of 11 and 9 of 11 tests respectively. Although children with JME and BECTS were less affected, significant differences from controls were found on 4 of 11 tests each. While each group had a unique profile of language deficits, commonalities were apparent across both idiopathic generalized and localization-related diagnostic categories. Discussion: The localization related and generalized idiopathic childhood epilepsies examined here were associated with impact on diverse language abilities early in the course of the disorder.

Commentary It is now well established that GABA receptors can mediate either excitation or inhibition, depending on the GABA reversal potential (EGABA) of the neuron, which in turn is set by the transmembrane chloride (Cl) gradient. In mature neurons, the Cl concentration outside the cell (Clo) is higher than that inside the cell, so when GABA binds to its postsynaptic type-A receptor and opens chloride channels, Cl flows down its electrochemical gradient into the cell, leading to hyperpolarization. In neonatal neurons, however, the intracellular Cl concentration (Cli) is high enough such that GABA binding-induced chloride channel opening leads to Cl efflux from the neuron, leading to membrane depolarization. Depolarizing GABA action early in development is considered to be important for neuronal plasticity and circuit maturation (1) and has also been used to explain the enhanced susceptibility of the neonatal brain to seizures (2, 3). Phenobarbital (PHB), a GABA receptor agonist, has limited effectiveness as an anticonvulsant in neonatal seizures, an effect that has been attributed to this reversed Cl gradient. In accordance with this mechanism, PHB not only fails to stop neonatal seizures but can even exacerbate them. Beyond the neonatal period, GABA depolarizing actions may have wider ramifications in epilepsy. For example, GABA induces depolarization in amygdala neurons in temporal lobe epilepsy (4). Two chloride cation cotransporters (CCCs) act in concert to govern a neuron’s Cl concentration gradient. The sodiumpotassium-chloride cotransporter 1 (NKCC1), predominates in the neonatal period and imports Cl into neurons. Later, expression of the potassium-chloride cotransporter 2 (KCC2) increases, with Cl transported out of the neuron. Thus, over development, KCC2 expression increases and NKCC1 expression decreases, such that when KCC2 predominates, the extracellular concentration of Cl is higher than its intracellular concentration. Until now, the explanation for the reversed chloride gradient and GABA-mediated depolarization early in development has implicated a developmental switch in the predominance of CCCs (3). Is the action of the CCCs sufficient to explain the relative differences in intraand extracellular Cl concentrations? The present paper by Glykys et al. proposes that CCC actions, while conceptually attractive, fail to account fully for Cli and the observed GABA equilibrium potential, EGABA. Evidence is presented that Cli sets EGABA but that CCC expression does not fully explain Cli and EGABA. If not CCC, what else could determine Cl concentration and thus the polarity of GABA action? Glykys et al. hypothesize that impermeant anions on both sides of the neuronal membrane contribute to Cl homeostasis. Intracellularly, impermeant anions consist of nucleotides with negatively charged phosphate groups and proteins with negatively charged amino and carboxyl groups. In the extracellular matrix, negatively charged sulfates on proteoglycans comprise the bulk of impermeant anions. Glykys et al. base their experiments on the assumption that the sum of intracellular anions and Cl must equal the sum of extracellular anions and Cl (Ai + Cli = Ao + Clo). There is a reciprocal relationship between Ai and Cli so that their sum must be constant—any increase in Cli must be balanced by a decrease in Ai, such that Cli is “constrained” by Ai. Similarly, in the extracellular matrix, Clo is constrained by Ao. To maintain Donnan equilibrium, an increase in either anion species within the intracellular or extracellular domain must balance. This reLocal Impermeant Anions Establish the Neuronal Chloride Concentration.

Dietary and metabolic therapies have been attempted in a wide variety of neurological diseases, including epilepsy, headache, neurotrauma, Alzheimer disease, Parkinson disease, sleep disorders, brain cancer, autism, pain, and multiple sclerosis. The impetus for using various diets to treat – or at least ameliorate symptoms of – these disorders stems from both a lack of effectiveness of pharmacological therapies, and also the intrinsic appeal of implementing a more “natural” treatment. The enormous spectrum of pathophysiological mechanisms underlying the aforementioned diseases would suggest a degree of complexity that cannot be impacted universally by any single dietary treatment. Yet, it is conceivable that alterations in certain dietary constituents could affect the course and impact the outcome of these brain disorders. Further, it is possible that a final common neurometabolic pathway might be influenced by a variety of dietary interventions. The most notable example of a dietary treatment with proven efficacy against a neurological condition is the high-fat, low-carbohydrate ketogenic diet (KD) used in patients with medically intractable epilepsy. While the mechanisms through which the KD works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. The concept that many neurological conditions are linked pathophysiologically to energy dysregulation could well provide a common research and experimental therapeutics platform, from which the course of several neurological diseases could be favorably influenced by dietary means. Here we provide an overview of studies using the KD in a wide panoply of neurologic disorders in which neuroprotection is an essential component.

Neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) are inherited tumor predisposition syndromes that have a major impact on the nervous system but are clinically and genetically distinct disorders. This chapter discusses the clinical characteristics and genetics of the neurofibromatoses and presents the current knowledge about their relationship with epilepsy. As neurofibromin acts as a tumor suppressor, NF1 individuals are at increased risk of developing benign and malignant tumors, particularly pilocytic astrocytomas, although pilomyxoid astrocytomas and glioblastoma multiforme can occur. The treatment of NF1 is based on assiduous monitoring for disease complications and treatment of the specific disease manifestations. NF2 should be distinguished from schwannomatosis, a rare condition characterized by the development of painful schwannomas involving the cutaneous, peripheral, and spinal nerves. The diagnosis of NF2 is made according a combination of skin, eye, and central and peripheral nervous system manifestations.

Purpose of review The aim is to review rational polytherapy of antiepileptic drugs in terms of conventional and novel mechanisms of action, consider combinations that might be beneficial when used as polytherapy, and discuss whether animal models can predict clinical efficacy. Recent findings Many patients with epilepsy require concurrent treatment with more than one antiepileptic drug (rational polytherapy), but there is little information available as to which drugs might work best in combination. Conventional antiepileptic drugs act by blocking sodium channels or enhancing γ-aminobutyric acid function. Some newer antiepileptic drugs have novel mechanisms of action, including impairment of the slow inactivation of sodium channels, binding to the presynaptic vesicle protein SV2A, binding to the calcium channel α2δ subunit, and opening select potassium channels. Several antiepileptic drugs have multiple or uncertain mechanisms of action. Quantitative techniques such as isobolography can be used to compare the efficacy and side effects of antiepileptic drug combinations in animals. However, neither such methods nor antiepileptic drug mechanisms of action have yet proven useful in predicting clinical benefit in patients. Summary Animal models can be used to help predict drug combinations that might be effective clinically, based on novel mechanisms of action. However, at this point, antiepileptic drug choice in patients with epilepsy remains empirical.

The ketogenic diet (KD) is an effective therapy for many children and adults with epilepsy who are refractory to conventional antiepileptic drugs. Possible mechanisms of the KD include direct effects of ketones or lipids on neuronal excitability, enhancement of inhibitory GABAergic function, or alteration of energy metabolism. Another possibility, arising from the fact that carbohydrates are restricted in the KD, is that inhibition of glycolysis (the primary route of glucose catabolism in mammalian cells) might provide an antiepileptic effect. Experiments described in this article show that the glycolysis inhibitor, 2-deoxy-d-glucose, exerts both anticonvulsant and antiepileptic effects in a variety of animal models. Anticonvulsant effects include increase in the afterdischarge threshold in perforant path kindled rats, and decrease in epileptic burst frequency in several models of interictal bursting (including high potassium, 4-aminopyridine, and bicuculline). Antiepileptic effects include the decrease in progression of afterdischarge threshold in kindling of the perforant path, and slowing of kindling progression with perforant path or olfactory bulb stimulation. These findings indicate that 2-deoxy-d-glucose, a safe compound already used for decades in positron emission tomography imaging, might be a novel agent for seizure control in patients with refractory epilepsy.

Seizures in the neonatal period and early childhood are associated with numerous cognitive and behavioral consequences in humans. Parallel studies in animal models have corroborated those deficits, and offer the opportunity to elucidate mechanisms by which seizures induce cognitive impairments in the developing brain. The experimental program described here uses the glutamate analog kainic acid (KA) to induce seizures at various postnatal ages; subsequently, cognitive and behavioral consequences of the seizures are examined. The KA model mimics acquired complex partial seizures with secondary generalization. Using the KA model, investigators have established that cognitive consequences of seizures are age dependent – adult rodents exhibit significant cognitive problems and deficits in learning and memory following KA seizures, while young animals exhibit qualitatively similar though less-severe deficits. These cognitive deficits in the immature brain are independent of neuronal cell death and significant axonal reorganization. The mechanisms by which seizures early in life cause adverse cognitive sequelae are under investigation. Ultimately, the goal is to develop strategies to prevent cognitive deficits in young patients with seizures.

By 2050, elderly people (older than 60 years) will exceed 30% of the total world population. It is now recognized that this population has a high incidence of seizures and epilepsy. Possible reasons include enhanced seizure predisposition, medical comorbidities, structural changes of the brain related to aging, and synergistic effects of concurrent medications. Underlying conditions in aging patients may modify the expression of seizures that have been chronically present in the younger individual, or the aged brain may develop seizures de novo. Metabolism of antiepileptic drugs may be also significantly different in the elderly, with drug interactions becoming a serious issue. The few models in aged animals (mice and rats) that have been investigated to date confirm an increased susceptibility of the aged brain to develop seizures. More research is needed on mechanisms of increased seizure propensity in elderly, and on anticonvulsant drug effects on the aging brain.

Sodium currents are essential for the initiation and propagation of neuronal firing. Alterations of sodium currents can lead to abnormal neuronal activity, such as occurs in epilepsy. The transient voltage-gated sodium current mediates the upstroke of the action potential. A small fraction of sodium current, termed the persistent sodium current (INaP), fails to inactivate significantly, even with prolonged depolarization. INaPis activated in the subthreshold voltage range and is capable of amplifying a neuron's response to synaptic input and enhancing its repetitive firing capability. A burgeoning literature is documenting mutations in sodium channels that underlie human disease, including epilepsy. Some of these mutations lead to altered neuronal excitability by increasing INaP. This review focuses on the pathophysiological effects of INaPin epilepsy.