Treating of focal epilepsy: a patent review.

Focal epilepsy is one of the most frequent specific type of epilepsies, with 30% treatment-resistant patients. There are several directions researchers can follow to improve existing treatment of focal epilepsy: synthesis of new compounds with anticonvulsant activity, repurposing drugs approved for other indications, finding drugs targeted to specific genetic and biochemical defects that underlie focal epilepsy syndromes, development of viral vectors for specific gene therapy, creation of devices and methods for suppression of seizures by electrostimulation and development of methods to increase safety of epilepsy surgery. Improvement of efficacy and safety of current therapies is necessary, as well as developing targeted treatment of genetic epilepsy syndromes that will not only suppress seizures, but stop further epileptogenesis.

Usefulness of ketogenic diet in a girl with migrating partial seizures in infancy.

Migrating partial seizures in infancy (MPSI) are an age-specific epilepsy syndrome characterized by migrating focal seizures, which are intractable to various antiepileptic drugs and cause severe developmental delay. We report a case of MPSI with heterozygous missense mutation in KCNT1, which was successfully managed by ketogenic diet. At age 2months, the patient developed epilepsy initially manifesting focal seizures with eye deviation and apnea, then evolving to secondarily generalized clonic convulsion. Various antiepileptic drugs including phenytoin, valproic acid, zonisamide, clobazam, levetiracetam, vitamin B6, and carbamazepine were not effective, but high-dose phenobarbital allowed discontinuation of midazolam infusion. Ictal scalp electroencephalogram showed migrating focal seizures. MPSI was suspected and she was transferred to our hospital for further treatment. Potassium bromide (KBr) was partially effective, but the effect was transient. High-dose KBr caused severe adverse effects such as over-sedation and hypercapnia, with no further effects on the seizures. At age 9months, we started a ketogenic diet, which improved seizure frequency and severity without obvious adverse effects, allowing her to be discharged from hospital. Ketogenic diet should be tried in patients with MPSI unresponsive to antiepileptic drugs. In MPSI, the difference in treatment response in patients with and those without KCNT1 mutation remains unknown. Accumulation of case reports would contribute to establish effective treatment options for MPSI.

Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.

Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.

Altered language processing in autosomal dominant partial epilepsy with auditory features.

BACKGROUND: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations, frequently associated with mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene. Although affected subjects do not have structural abnormalities detected on routine MRI, a lateral temporal malformation was identified through high resolution MRI in one family. We attempted to replicate this finding and to assess auditory and language processing in ADPEAF using fMRI and magnetoencephalography (MEG). METHODS: We studied 17 subjects (10 affected mutation carriers, 3 unaffected carriers, 4 noncarriers) in 7 ADPEAF families, each of which had a different LGI1 mutation. Subjects underwent high-resolution structural MRI, fMRI with an auditory description decision task (ADDT) and a tone discrimination task, and MEG. A control group comprising 26 volunteers was also included. RESULTS: We found no evidence of structural abnormalities in any of the 17 subjects. On fMRI with ADDT, subjects with epilepsy had significantly less activation than controls. On MEG with auditory stimuli, peak 2 auditory evoked field latency was significantly delayed in affected individuals compared to controls. CONCLUSIONS: These findings do not support the previous report of a lateral temporal malformation in autosomal dominant partial epilepsy with auditory features (ADPEAF). However, our fMRI and magnetoencephalography data suggest that individuals with ADPEAF have functional impairment in language processing.

Molecular genetics of human familial epilepsy syndromes.

Genetic defects have been recently identified in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy. Both receptors are components of neuronal acetylcholine receptor, a ligand-gated ion channel in the brain. Furthermore, mutations of two K+ channel genes also were identified as the underlying genetic abnormalities of benign familial neonatal convulsions. Mutations in the voltage-gated Na+-channel alpha1 and beta1 subunit genes were found as the cause of generalized epilepsy with febrile seizures plus, a clinical subset of febrile convulsions. Mutation of a voltage-gated K+-channel gene can cause partial seizures associated with periodic ataxia type 1 and some forms of juvenile myoclonic epilepsy can result from mutations of a Ca2+ channel. This line of evidence suggests the involvement of channels expressed in the brain in the pathogenesis of certain types of epilepsy. Our working hypothesis is to view certain idiopathic epilepsies as disorders of ion channels (i.e., "channelopathies"). Such a hypothesis should provide a new insight into our understanding of the genetic background of epilepsy.

Ion channels and epilepsy.

Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, mutations in ion channel encoding genes are found in a variety of inherited diseases associated with hyper- or hypoexcitability of the affected tissue, the so-called 'channelopathies.' An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1). These rare disorders provide interesting models to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies can be developed, as has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels.

Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors.

A mutation (S247F) in the channel-lining domain (M2) of the alpha4 nicotinic acetylcholine receptor (AChR) subunit has previously been linked genetically to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To better understand the functional significance of this mutation, we characterized the properties of mutant and wild-type human alpha4beta2 AChRs expressed in Xenopus oocytes. Both had similar expression levels and EC50 values for ACh and nicotine. Substantial use-dependent functional upregulation was found for mutant alpha4beta2 AChRs, but not for wild type. Mutant AChR responses showed faster desensitization, slower recovery from desensitization, less inward rectification, and virtually no Ca2+ permeability as compared with wild-type alpha4beta2 AChRs. Addition of the alpha5 subunit restored Ca2+ permeability to the mutant alpha4beta2alpha5 AChRs. At -80 mV, wild-type alpha4beta2 AChR single channel currents exhibited two conductances, each with two mean open times (gamma1 = 17 pS, tau1 = 3.7 msec, and tau2 = 23.4 msec; gamma2 = 28 pS, tau1 = 1.9 msec, and tau2 = 8.1 msec). In contrast, mutant AChRs exhibited only one conductance of 11 pS, with tau1 = 1.9 msec and tau2 = 4.1 msec. The net effect of the mutation is to reduce AChR function. This could result in the hyperexcitability characteristic of epilepsy if the mutant AChRs were part of an inhibitory circuit, e.g., presynaptically regulating the release of GABA. In the minority of AChRs containing the alpha5 subunit, the overall functionality of these AChRs could be maintained despite the mutation in the alpha4 subunit.

An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics.

The alpha4 subunit of the neuronal nicotinic acetylcholine receptor is the first gene shown to be involved in a human idiopathic epileptic disease. A missense mutation, leading to the replacement of serine 248 by phenylalanine in the second transmembrane segment, had been detected in patients with autosomal dominant nocturnal frontal lobe epilepsy. The properties of the wild type receptor composed of alpha4 and beta2 subunits and the mutant receptor where alpha4 subunits carried the mutation at serine 248 were compared by means of cDNA manipulation and expression in Xenopus oocytes. The mutant receptor exhibited faster desensitization upon activation by acetylcholine and recovery from the desensitized state was much slower than in the wild type receptor. We conclude that the reported mutation causes seizures via a diminution of the activity of the alpha4beta2 neuronal nicotinic acetylcholine receptor.