Many patients with mesial temporal lobe epilepsy continue to have seizures despite medical therapy. For these patients, one recourse is surgical resection of the mesial temporal lobe, with its attendant risks. Noninvasive treatment with Gamma Knife radiosurgery is under active investigation as a possible alternative to open surgery. Accumulated evidence from multiple studies shows radiosurgery to be comparable in outcomes to surgical resection. A definitive randomized, controlled trial, the Radiosurgery or Open Surgery for Epilepsy (ROSE) trial, is currently underway, and further investigation of this promising treatment is crucial in our advancement of alternative therapies to treat refractory epilepsy.

John D. Rolston

Mark Quigg

Nicholas M. Barbaro

Gamma Knife Radiosurgery for Mesial Temporal Lobe Epilepsy

Small animal neuroimaging has become increasingly available to researchers, expanding the breadth of questions studied with these methods. Applying these noninvasive techniques to the open questions underlying epileptogenesis is no exception. A major advantage of small animal neuroimaging is its translational appeal. Studies can be well controlled and manipulated, examining the living brain in the animal before, during, and after the disease onset or disease treatment. The results can also be compared to data collected on human patients. Over the past decade, we and others have explored metabolic patterns in animal models of epilepsy to gain insight into the circuitry underlying development of the disease. In this paper, we provide technical details on how metabolic imaging that uses 2-deoxy-2[18F]fluoro-D-glucose (18FDG) and positron emission tomography (PET) is performed and explain the strengths and limitations of these studies. We will also highlight recent advances toward understanding epileptogenesis through small animal imaging.

Martine M. Mirrione

Stella E. Tsirka

Neuroimaging in Animal Seizure Models with 18FDG-PET

Epilepsy of the temporal lobe (TLE) is the most common form of focal epilepsy, and  in adults, it most frequently develops after injury. However, the mechanisms by which a normal functioning brain turns into an epileptic one still remain obscure. Recent studies point to vascular involvement and particularly blood-brain barrier (BBB) dysfunction in the development of epilepsy. The BBB is a specialized structure which functions to control the neuronal extracellular milieu. BBB dysfunction is found in many diseases of the central nervous system, including stroke, traumatic injuries, tumors and infections. Interestingly, all these insults may initiate an epileptogenic process which eventually leads to spontaneous, recurrent seizures. This epileptogenic time frame usually lasts weeks, months, or even years in man, and days to weeks in rodents and may serve as a “window of opportunity” for the prevention of epilepsy. However, no prevention strategy exists, stressing the importance of research into the mechanisms of epileptogenesis. Here, we will underscore recent experiments suggesting that BBB dysfunction directly induces epileptogenesis. We will provide new evidence to support the hypothesis that BBB breakdown and specifically exposure of temporal lobe structures to the most common serum protein, albumin, is sufficient to induce epileptogenesis.

Itai Weissberg

Aljoscha Reichert

Uwe Heinemann

Alon Friedman

Blood-Brain Barrier Dysfunction in Epileptogenesis of  the Temporal Lobe

Although the ketogenic diet (KD) has been widely accepted as a legitimate and successful therapy for epilepsy and other neurological disorders, its mechanism of action remains an enigma. The use of the KD causes major metabolic changes. The most significant of them seems to be the situation of chronic ketosis, but there are others as well, for instance, high level of polyunsaturated fatty acids (PUFAs). These &#8220;primary&#8221; influences lead to &#8220;secondary&#8221;, in part adaptive, effects, for instance changes in mitochondrial density and gene expression. Clinically, the influences of the diet are considered as anticonvulsive and neuroprotective, although neuroprotection can also lead to prevention of seizures. Potential clinical implications of these mechanisms are discussed.

Keren Politi

Lilach Shemer-Meiri

Avinoam Shuper

S. Aharoni

The Ketogenic Diet 2011: How It Works

Treatment of epilepsy often imposes an exposure to various antiepileptic drugs and requires long-term commitment and compliance from the patient. Although many new medications are now available for the treatment of epilepsy, approximately 30&#x25; of epilepsy patients still experience recurrent seizures and many experience undesirable side effects.  Treatment of epilepsy requires a multidisciplinary approach.  For those patients with medically refractory seizures, surgical treatment has increased in prevalence as techniques and devices improve.  With increased utilization, proper patient selection has become crucial in evaluating appropriateness of surgical intervention.  Epilepsy syndromes in which surgery has shown to be effective include mesial temporal sclerosis, cortical dysplasia, many pediatric epilepsy syndromes, and vascular malformations.  Monitoring in an epilepsy monitoring unit with continuous scalp or intracranial EEG is an important step in localization of seizure focus.  MRI is the standard imaging technique for evaluation of anatomy.  However, other imaging studies including SPECT and PET have become more widespread, often offering increased diagnostic value in select situations.  In addition, as an alternative or adjunct to surgical resection, implantable devices such as vagus nerve stimulators, deep brain stimulators, and direct brain stimulators could be useful in seizure treatment.

Kristen M. Kelly

Steve S. Chung

Surgical Treatment for Refractory Epilepsy: Review of Patient Evaluation and Surgical Options

One of the main putative causes of therapy refractory epilepsy in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis is the overexpression of multidrug transporters (MDTs) at the blood-brain barrier (BBB). It steps up the removal of antiepileptic drugs (AEDs) out of the brain cells across the BBB resulting in a low concentration of AEDs within the target cells. Some of the mechanisms of AED resistance are most likely to be genetically determined. To obtain more information about the underlying pathophysiology of intractability in epilepsy, we compared the global gene expression profile of human hippocampus and hippocampal-derived microvascular endothelial cells from MTLE with HS patients and controls.
At the level of MDT, a significant up-regulation was found for ABCB1 (P-gp), ABCB2, ABCB3, and ABCB4, which was mainly related to endothelial cells. The data on the MDT were validated and extended by quantitative RT-PCR. Surprisingly, inflammatory factors such as interleukins (IL-1α, IL-1β, IL-6, and IL-18) and cytokines (TNF-α and TGF-β1) were found to be up-regulated in hippocampal parenchyma. The overexpression of P-gp, IL-1β, and IL-6 was also confirmed by immunohistochemistry (IHC). Our results suggest that complex expression changes of ABC-transporters may play a decisive role in pharmacoresistance in MTLE. Further studies on the new and unexpected overexpression of inflammatory cytokines may unlock hitherto undiscovered pathways of the underlying pathophysiology of human MTLE.

Julio Lachos

Michela Zattoni

Heinz-Gregor Wieser

Jean-Marc Fritschy

Thomas Langmann

Gerd Schmitz

Mariella Errede

Daniela Virgintino

Yasuhiro Yonekawa

Karl Frei

Characterization of the Gene Expression Profile of Human Hippocampus in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

There is no consensus as to whether mesial temporal lobe epilepsy (MTLE) leads to executive function deficits. In this study, we adopted an extensive neuropsychological test battery and assessed different executive functions in chronic, unilateral MTLE. Performance of MTLE patients was compared with that of healthy peers and with normative data. Several MTLE patients had scores below cut-off or below the 10th percentile of normative data. Scores of the whole patient group were overall in the average range of normative data. Relative to controls, MTLE patients performed poorly in tests of working memory, cognitive flexibility, categorical verbal fluency, set-shifting, categorization, and planning. These findings raise an important methodological issue as they suggest that executive function deficits in chronic MTLE may be individually variable and that their assessment should include different tests. Deficits in chronic MTLE are not limited to temporal lobe functions, such as memory, but may extend to extra temporal cognitive domains, such as executive functions.

Laura Zamarian

Eugen Trinka

Elisabeth Bonatti

Giorgi Kuchukhidze

Thomas Bodner

Thomas Benke

Florian Koppelstaetter

Margarete Delazer

Executive Functions in Chronic Mesial Temporal Lobe Epilepsy

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

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

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Epilepsy Research and Treatment