It is estimated that one in five patients referred to specialist epilepsy clinics for refractory seizures have psychogenic nonepileptic seizures (PNES). Despite the high prevalence, little is known about the prognosis of patients with PNES. In this paper we set out to systematically assess published original studies on the prognosis and outcome predictors of patients with PNES. Our literature search across the databases Medline, PsycINFO, and EMBASE generated 18 original studies meeting the search criteria.  Prognosis was found to be poor in adults, but good in children. Predictors of poor outcome included the presence of coexisting epilepsy or psychiatric comorbidities, violent seizure phenomenology, dependent lifestyle, and poor relationships. Overall, too much reliance is placed on seizure remission as an outcome measurement for patients with PNES, and the impact of many of the outcome predictors requires evaluation using larger studies with longer followup.

Joseph Durrant

Hugh Rickards

Andrea E. Cavanna

Prognosis and Outcome Predictors in Psychogenic Nonepileptic Seizures

Despite much research, there remains controversy over the role of gap junctions in seizure processes. Many studies report anticonvulsant effects of gap junction blockade, but contradictory results have also been reported. The aim of this study was to clarify the role of connexin36 (Cx36) gap junctions in neocortical seizures. We used the mouse neocortical slice preparation to investigate the effect of pharmacological (mefloquine) and genetic (Cx36 knockout mice (Cx36KO)) manipulation of Cx36 gap junctions on two seizure models: low-magnesium artificial cerebrospinal fluid (ACSF) and aconitine perfusion in low-magnesium ACSF. Low-magnesium- (nominally zero) and aconitine- (230&#x2009;nM) induced seizure-like event (SLE) population activity was recorded extracellularly. The results were consistent in showing that neither mefloquine (25&#x2009;&#x3bc;M) nor genetic knockdown of Cx36 expression had anticonvulsant effects on SLE activity generated by either method. These findings call into question the widely held idea that open Cx36 gap junctions promote seizure activity.

Logan J. Voss

Noortje Mutsaerts

James W. Sleigh

Connexin36 Gap Junction Blockade Is Ineffective at Reducing Seizure-Like Event Activity in Neocortical Mouse Slices

Autosomal dominant lateral temporal epilepsy (ADTLE) is an inherited epileptic syndrome characterized by ictal auditory symptoms or aphasia, negative MRI findings, and relatively benign evolution. Mutations responsible for ADLTE have been found in the LGI1 gene. The functions of the Lgi1 protein apparently are mediated by interactions with members of the ADAM protein family: it binds the postsynaptic receptor ADAM22 to regulate glutamate-AMPA currents at excitatory synapses and also the ADAM23 receptor to promote neurite outgrowth in vitro and dendritic arborization in vivo. Because alteration of each of these neuronal mechanisms may underlie ADLTE, ADAM22 and ADAM23 are candidate genes for this syndrome. In a previous work, we excluded a major role of ADAM22 in the aetiology of ADLTE. Here, we performed linkage analysis between microsatellite markers within or flanking the ADAM23 gene and ADLTE in 13 Italian families. The results exclude ADAM23 as major causative gene for ADLTE.

Laura Rigon

Andrea Vettori

Giorgia Busolin

Gabriella Egeo

Patrizia Pulitano

Lia Santulli

Elena Pasini

Pasquale Striano

Angela la Neve

Valeria Vianello Dri

Clementina Boniver

Antonio Gambardella

Paola Banfi

Simona Binelli

Carlo Di Bonaventura

Salvatore Striano

Fabrizio  de Falco

Anna T. Giallonardo

Oriano Mecarelli

Roberto Michelucci

Carlo Nobile

ADAM23, a Gene Related to LGI1, Is Not Linked to Autosomal Dominant Lateral Temporal Epilepsy

Epilepsy is one of the major neurological disorders, affecting roughly 1-2% of the world's population, of which approximately 20–25% of patients are drug resistant. A variety of drugs have been used to activate and identify the epileptic area in patients during presurgical evaluation. We studied the cerebral blood flow (CBF) by single photon-emission computed tomography (SPECT) and bioelectrical brain activity responses to etomidate in 
11 patients. Etomidate (0.1 mg/kg) was administered while patients were monitored by video-electroencephalography with foramen ovale electrodes (FOEs). After etomidate administration, a brief period of high-frequency activity was observed, followed by a generalized, high-voltage delta pattern. Increased regional CBF was observed bilaterally in thalamus, putamen, and posterior hippocampus. Besides, the only interhemispheric difference was observed in the posterior hippocampus, where CBF decreased in the epileptic temporal lobe. Activation by etomidate induces a specific and repetitive response in the bioelectrical activity. In addition, CBF changes induced by etomidate may serve as a diagnostic tool in the near future.

Ivan Herrera-Peco

Rybel Wix Ramos

Luis Domínguez-Gadea

María Luisa Meilán

José Luis Martínez-Chacón

Eva de Dios

Rafael G. Sola

Jesús Pastor

What Do Changes in Brain Perfusion Induced by Etomidate Suggest about Epilepsy in Human Patients?

Intracranial pharmacotherapy is a novel strategy to treat drug refractory, localization-related epilepsies not amenable to resective surgery. The common feature of the method is the use of some type of antiepileptic drug (AED) delivery device placed inside the cranium to prevent or stop focal seizures. This distinguishes it from other nonconventional methods, such as intrathecal pharmacotherapy, electrical neurostimulation, gene therapy, cell transplantation, and local cooling. AED-delivery systems comprise drug releasing polymers and neuroprosthetic devices that can deliver AEDs into the brain via intraparenchymal, ventricular, or transmeningeal routes. One such device is the subdural Hybrid Neuroprosthesis (HNP), designed to deliver AEDs, such as muscimol, into the subdural/subarachnoid space overlaying neocortical epileptogenic zones, with electrophysiological feedback from the treated tissue. The idea of intracranial pharmacotherapy and HNP treatment for epilepsy originated from multiple sources, including the advent of implanted medical devices, safety data for intracranial electrodes and catheters, evidence for the seizure-controlling efficacy of intracerebral AEDs, and further understanding of the pathophysiology of focal epilepsy. Successful introduction of intracranial pharmacotherapy into clinical practice depends on how the intertwined scientific, engineering, clinical, neurosurgical and regulatory challenges will be met to produce an effective and commercially viable device.

Nandor Ludvig

Geza Medveczky

Jacqueline A. French

Chad Carlson

Orrin Devinsky

Ruben I. Kuzniecky

Evolution and Prospects for Intracranial Pharmacotherapy for Refractory Epilepsies: The Subdural Hybrid Neuroprosthesis

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Epilepsy Research and Treatment