Jong M. Rho

The Pharmacologic Basis of Antiepileptic Drug Action

Summary: The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever‐growing armentarium of AEDs, necessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action.

Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet.

Despite strong clinical data confirming the anticonvulsant efficacy of a ketogenic diet (KGD) in pediatric patients, corroborative experimental data in young animals are limited. In the present study, the effects of a KGD on flurothyl seizure susceptibility were examined in normal juvenile mice after a dietary duration of 3, 7, or 12 days, and in adult mice for 15 days. In all groups of KGD-treated mice, blood beta-hydroxybutyrate levels were significantly elevated over those measured in controls. The present KGD was anticonvulsant (i.e. delayed onset) against the first (clonic) flurothyl-induced seizure for juvenile mice treated for either 7 or 12 days, but not for juvenile mice and adult mice fed the diet for 3 and 15 days, respectively. While this KGD was not anticonvulsant against the second (tonic extension) seizure induced by flurothyl in any of the juvenile groups, it significantly delayed tonic extension in the adult group. In addition, juvenile mice fed a KGD exhibited a lower mortality rate following flurothyl-induced seizures compared to mice fed a standard diet. In our discussion of animal models of the KGD, we highlight the need to understand better the impact of important variables such as dietary composition, genetic background, and mode of seizure induction in the study of the KGD.

DEVELOPMENTAL SEIZURE SUSCEPTIBILITY OF KV1.1 POTASSIUM CHANNEL KNOCKOUT MICE

Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 α-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (–/–, +/–, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 –/– animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/– mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1.1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.

Lamotrigine‐Induced Tic Disorder: Report of Five Pediatric Cases

Summary: Purpose: To describe the clinical spectrum of lamotrigine (LTG)‐induced tics (an uncommon side effect) in children.

Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice.

Mice lacking the potassium channel subunit KCNA1 exhibit a severe epileptic phenotype beginning at an early postnatal age. The precise cellular physiological substrates for these seizures are unclear, as is the site of origin. Since KCNA1 mRNA in normal mice is expressed in the neocortex, we asked whether neurons in the neocortex of three to four week-old Kcna1-null mutants exhibit evidence of hyperexcitability. Layer V pyramidal neurons were directly visualized in brain slices with infrared differential-interference contrast microscopy and evaluated with cellular electrophysiological techniques. There were no significant differences in intrinsic membrane properties and action potential shape between Kcna1-null and wild-type mice, consistent with previous findings in hippocampal slice recordings. However, the frequency of spontaneous post-synaptic currents was significantly higher in Kcna1-null compared to wild-type mice. The frequency of spontaneous inhibitory post-synaptic currents and miniature (action-potential-independent) inhibitory post-synaptic currents was also significantly higher in Kcna1-null compared to wild-type mice. However, the frequency of spontaneous and miniature excitatory post-synaptic currents was not different in these two groups of animals. Comparison of the amplitude and kinetics of miniature inhibitory and excitatory post-synaptic currents revealed differences in amplitude, rise time and half-width between Kcna1-null and wild-type mice. Our data indicate that the inhibitory drive onto layer V pyramidal neurons is increased in Kcna1 knockout mice, either directly through an increased spontaneous release of GABA from presynaptic terminals contacting layer V pyramidal neurons, or an enhanced excitatory synaptic input to inhibitory interneurons.

Epilepsy: Mechanisms, Models, and Translational Perspectives

This chapter reviews the cellular and synaptic basis for focal and generalized seizure generation with an emphasis on ion channels and synaptic physiology. This background is useful for understanding the scientific basis of epilepsy and its treatment, as discussed in greater detail in subsequent chapters of this book. A seizure, or epileptic seizure, is a temporary disruption of brain function due to the excessive, abnormal discharge of cortical neurons. The clinical manifestations of a seizure depend on the specific region and extent of brain involvement and may include an alteration in alertness, motor function, sensory perception, or autonomic function, or all of these. Any person can experience a seizure in the appropriate clinical setting (e.g., meningitis, hypoglycemia), attesting to the innate capacity of even a normal brain to support epileptic discharges, at least temporarily. Epilepsy is the condition of recurrent (two or more), unprovoked seizures, usually due to a genetic predisposition or chronic acquired pathologic state (e.g., cerebral dysgenesis, brain trauma). Epilepsy syndrome refers to a constellation of clinical characteristics that consistently occur together, with seizures as a primary manifestation. Features of an epilepsy syndrome might include similar age of onset, electroencephalogram (EEG) findings, etiology, inheritance pattern, natural history of the symptoms, and response to particular antiepileptic drugs. Mechanisms leading to the generation of a seizure (ictogenesis) may differ from those predisposing to epilepsy, the condition of recurrent, unprovoked seizures (i.e., epileptogenesis) (Dichter, 2009). A seizure is characterized by aberrant electrical activity within the brain. Such electrical activity is the net product of biochemical processes at the cellular and subcellular levels occurring in the context of large neuronal networks. Seizures often involve interplay between cortical and subcortical structures (Blumenfeld, 2003). The surface EEG is the primary clinical tool with which normal and abnormal electrical activity in the brain is measured. At the cellular level, the two hallmark features of epileptic activity are neuronal hyperexcitability and neuronal hypersynchrony. Hyperexcitability is the abnormal responsiveness (e.g., lower threshold) of a neuron to excitatory input; a hyperexcitable neuron tends to fire bursts of multiple action potentials instead of just one or two. Hypersynchrony refers to the recruitment of large numbers of neighboring neurons into an abnormal firing mode. Ultimately, a seizure is a network phenomenon that requires participation of many neurons firing synchronously. Conventional EEG techniques can detect cortical areas exhibiting hypersynchronous discharges in the form of interictal sharp waves or spikes. Using specialized EEG recording techniques in humans and animals with epilepsy, bursts of very localized discharges have been detected that are not detected by usual EEG methods (Engel et al., 2009). These so-called “fast ripples” (250 to 600 Hz) reflect abnormal interictal discharges in restricted cortical areas which could synchronize and lead to a seizure (see Chapter 21, this volume).

Pharmacodynamic Interactions of Antiepileptic Drugs

Publisher Summary A pharmacodynamic interaction occurs when the pharmacology (effect) of one drug alters the pharmacology of another drug without altering plasma concentrations. The pharmacological effect of a drug is a consequence of interaction(s) with specific molecular target(s), which induces downstream changes in ionic membrane gradients, intracellular signaling pathways, and even transcriptional regulation of specific genes. Often in clinical practice, two or more antiepileptic drugs (AEDs) are combined in an attempt to achieve either seizure reduction or freedom. The concept of rational polytherapy is based on knowledge of drug pharmacology and toxicology and the pathophysiology of the disease involved. For the treatment of epilepsy, it has been defined as the selection of combinations of (AEDs) to treat patients in whom two or three drugs have failed as monotherapy. The combinations should consist of drugs with wide therapeutic index, low potential for toxicity, and drug interactions with the selection of the AEDs based on their mechanisms of action. A few clinical studies have examined pharmacodynamic interactions of AEDs, and the majority of the reported pharmacodynamic effects are based on case reports or observational studies.