Recent ucdavisneurology_rw items

Epilepsy-Associated Dysfunction in the Voltage-Gated Neuronal Sodium Channel SCN1A

Thu, 20 Nov 2008 00:00:00 +0000

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel subunit (NaV1.1) are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor I1656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS+ mutations (A1685V and V1353L) and L986F, an SMEI-associated...

The Measurement of Everyday Cognition (ECog): Scale Development and Psychometric Properties

Tue, 12 Aug 2008 00:00:00 +0000

This article describes the development and validation of an instrument to assess cognitively mediated functional abilities in older adults, Everyday Cognition (ECog). The ECog is an informant-rated questionnaire comprised of multiple subscales. Confirmatory factor analysis (CFA) was used to examine its factor structure. Convergent validity was evaluated by comparing it to established measures of everyday function. External validity was evaluated by comparing ECog results across different clinical groups (cognitively normal, mild cognitive impairment (MCI), dementia). CFA supported a seven-factor model including one global factor and six domain-specific factors (Everyday Memory, Language, Visuospatial Abilities, Planning, Organization, and Divided Attention). The ECog correlated with established measures of functional status and global cognition, but only weakly with age and education. The clinical groups performed differently in each domain. In addition to the global factor,...

New Molecular Targets for Antiepileptic Drugs: alpha2delta, SV2A and Kv7/KCNQ/M Potassium Channels

Thu, 17 Jul 2008 00:00:00 +0000

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on -aminobutyric acid–mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: 2, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and Kv7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs...

What Clinical Observations on the Epidemiology of Antiepileptic Drug Intractability Tell Us About the Mechanisms of Pharmacoresistance

Thu, 17 Jul 2008 00:00:00 +0000

In the past several years, there have been important advances in the clinical epidemiology of antiepileptic drug resistance, as reviewed by Mohanraj and Brodie. It would appear that by and large, intractability is independent of the choice of antiepileptic drug (AED). Many patients will become seizure free on the first agent tried, irrespective of which one their physician decides to pick. Nonresponders to the first drug are in a different category: it is likely that they will continue to have seizures no matter which medicine or combination of medicines is tried. This simple clinical observation puts important constraints on the possible biological mechanisms for pharmacoresistance. In this essay, I consider the implications of the new clinical research for studies on the neurobiological mechanisms of AED intractability.

Antiepileptic Drugs and Migraine

Tue, 13 May 2008 00:00:00 +0000

Prepared for the 16th International Headache Research Seminar, “Innovative Drug Development For Headache Disorders,” March 23–25, 2007, Copenhagen, Denmark