Idiopathic focal epilepsies: the “lost tribe”

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010 ), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many “treats” for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age‐related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow‐wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro‐temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau‐Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro‐clinical features warranting inclusion. In addition, a number of less well‐defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The term “benign” is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research. A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence‐free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice. Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the “unknown cause” classification and strongly suggest a genetic aetiology. The IFE are strongly age‐related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age‐related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state‐of‐the‐art thinking on the topics explored. The symposium led to the formation of international working groups under the umbrella of “Luke's Idiopathic Focal Epilepsy Project” to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high‐frequency oscillations, and parental resources (see www.childhood-epilepsy.org ). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.     

“Gating” of human short-latency somatosensory evoked cortical responses during execution of movement. A high resolution electroencephalography study

The present study aimed at investigating gating of median nerve somatosensory evoked cortical responses (SECRs), estimated during executed continuous complex ipsilateral and contralateral sequential finger movements. SECRs were modeled with an advanced high resolution electroencephalography technology that dramatically improved spatial details of the scalp recorded somatosensory evoked potentials. Integration with magnetic resonance brain images allowed us to localize different SECRs within cortical areas. The working hypothesis was that the gating effects were time varying and could differently influence SECRs. Maximum statistically significant (p<0.01) time-varying gating (magnitude reduction) of the short-latency SECRs modeled in the contralateral primary motor and somatosensory and supplementary motor areas was computed during the executed ipsilateral movement. The gating effects were stronger on the modeled SECRs peaking 30–45 ms (N30–P30, N32, P45–N45) than 20–26 ms (P20–N20, P22, N26) post-stimulus. Furthermore, the modeled SECRs peaking 30 ms post-stimulus (N30–P30) were significantly increased in magnitude during the executed contralateral movement. These results may delineate a distributed cortical sensorimotor system responsible for the gating effects on SECRs. This system would be able to modulate activity of SECR generators, based on the integration of afferent somatosensory inputs from the stimulated nerve with outputs related to the movement execution.     

Gap junctions: the “kiss of death” and the “kiss of life”

Cells expressing herpes simplex-thymidine kinase (HSV-tk) can be killed “in vitro” within 5 days of treatment with 20 μM ganciclovir (GCV) and transmit this toxicity to adjacent cells lacking HSV-tk; this phenomenon was termed “bystander effect” or “kiss of death”. On testing a large number of cell lines in vitro, a wide range of sensitivity to GCV-mediated bystander killing has been reported. Although intercellular transfer of GCV metabolites through gap junction channels seems to be a likely mechanism for the “kiss of death”, some studies suggest that other pathways may contribute to induced apoptosis of neighboring cells. To further investigate the mechanism underlying cell death mediated by HSV-tk and to evaluate the efficacy of gap junction channels formed by different connexins in this process, we have stably transfected a virtually uncoupled mouse neuroblastoma cell line (N2A cells) with different connexin-types expressed by neural cells (Cx32, Cx37, Cx40, Cx43) and co-cultured these cells with N2A cells stably transfected with Cx37 and HSV-tk. Here, we confirm our previous studies and those of others that the extent of cell death and sensitivity to GCV depend on the degree of connexin expression in transfectants. Further, we show that the bystander effect also depends on which connexin is expressed; reported disparities regarding the extent of GCV-mediated cellular apoptosis are likely due both to the degree of functional coupling and the type of connexin expressed. These results support the notion that gap junction hemichannels formed of certain connexins are more likely than others to pair functionally with Cx37, and suggest co-transfection strategies that might prove effective in sensitizing tumor cell populations to GCV. In addition, potential applications are discussed for use of the “good Samaritan effect”, a mechanism by which bystander cells have been suggested to prevent cytotoxicity.     

Dynamic analysis of glioma cells: Looking into “movement phenotypes”

One of the major obstacles to the successful treatment of diffuse gliomas is their highly infiltrative property. It is one of the important therapeutic strategies to inhibit infiltration of glioma cells and make it possible to locally control a lesion. To achieve this, we first need to observe and describe detailed movement profiles of glioma cells in the brain tissue at the cellular level. Then we further need to determine extra and intracellular molecules that play a key role in glioma cell invasion. Live cell imaging is a powerful technique to investigate the basic movement pattern of glioma cells as well as the effects of therapeutic interventions on their migration. In this review, we describe a technical aspect of live cell imaging with special regard to time‐lapse video imaging and discuss the relevance of the methods to glioma studies.     

“Strong” and “weak” synaptic differentiation in the crayfish opener muscle: Structural correlates

The single excitor motoneuron to the limb opener muscle in the crayfish Procambarus clarkii provides multiterminal innervation to individual muscle fibers. At low impulse frequencies, these neuromuscular synapses generate a threefold larger junctional potential in fibers of the proximal region of the muscle compared to those in the central region. Focal extracellular recording from synapse-bearing “boutons” showed more quantal release at low frequencies in the proximal region. Structural correlates for the physiological differences were sought. Fluorescence microscopy of surface innervation stained with a vital fluorescent dye, 4-Di-2-Asp, showed that density of innervation was not greater in the proximal region and thus could not account for the overall differences in synaptic strength. Freeze fracture studies showed that the intramembrane organization of excitatory synapses and their active zones was qualitatively similar in proximal and central sites. Serial section electron microscopy of several innervation sites in proximal and central regions showed homogeneity in number and size of synapses. However, presynaptic dense bars (at release sites, or active zones) were longer and occurred at a higher density in proximal than in central synapses. The differences in number and length of presynaptic dense bars correlate positively with the differences in synaptic strength represented by junctional potential amplitudes and quantal contents of individual surface recording sites. Since many individual proximal synapses have multiple dense bars, co-operativity among these may serve to enhance transmitter output. It is concluded that occurrence of dense bars is a significant pre synaptic correlate of synaptic strength in this neuron. © 1994 Wiley-Liss, Inc.     

Life events and schizophrenia: The “triggering” hypothesis

The present paper reviews the life event research specific to schizophrenia with the goal of assessing the extent to which recent empirical studies have implicated life stress variables as precipitants of acute episodes of the disorder (i.e. the “triggering” hypothesis). Different methodological strategies used in life events research are reviewed along with the substantive findings from quasi-experimental and controlled studies of schizophrenic patients. It is concluded that stressful life events have been found to be part of the pool of factors associated with the onset of acute schizophrenic episodes, but evidence is still lacking to indicate that this association is a necessary or direct one. Recommendations are made regarding the types of future studies required to fill the gaps in the existing literature.     

“The Epilepsies”: Kinnier Wilson’s landmark epileptology

Kinnier Wilson, better known for his eponymous disease, in fact devoted much of his career to the study of epilepsy. In his long campaign to alter the general perception of epilepsy, he spent much time and effort decrying the use of "epilepsy" as a single disease, pleading for individual consideration for its sufferers. In addition, he undertook an extensive reconsideration of many of the basic principles of his mentor and friend the great John Hughlings Jackson. Eventually his status as the European expert in epilepsy earned him the signal honour of authorship (in English) of the important chapter entitled "The Epilepsies" in the 1935 flagship German language textbook of neurology that appeared immediately prior to the advent of the EEG. This chapter and the one in his posthumously published textbook of 1940 are landmarks of epileptology of that era.     

Embedded ensemble encoding hypothesis: The role of the “Prepared” cell

We here reconsider current theories of neural ensembles in the context of recent discoveries about neuronal dendritic physiology. The key physiological observation is that the dendritic plateau potential produces sustained depolarization of the cell body (amplitude 10–20 mV, duration 200–500 ms). Our central hypothesis is that synaptically‐evoked dendritic plateau potentials lead to a prepared state of a neuron that favors spike generation. The plateau both depolarizes the cell toward spike threshold, and provides faster response to inputs through a shortened membrane time constant. As a result, the speed of synaptic‐to‐action potential (AP) transfer is faster during the plateau phase. Our hypothesis relates the changes from “resting” to “depolarized” neuronal state to changes in ensemble dynamics and in network information flow. The plateau provides the Prepared state (sustained depolarization of the cell body) with a time window of 200–500 ms. During this time, a neuron can tune into ongoing network activity and synchronize spiking with other neurons to provide a coordinated Active state (robust firing of somatic APs), which would permit “binding” of signals through coordination of neural activity across a population. The transient Active ensemble of neurons is embedded in the longer‐lasting Prepared ensemble of neurons. We hypothesize that “embedded ensemble encoding” may be an important organizing principle in networks of neurons.     

Electrodiagnosis in the management of focal neuropathies: The “WOG” syndrome

The role of electrodiagnosis in managing patients with focal neuropathies is discussed from the differing perspectives of a peripheral nerve surgeon and a practitioner of electrodiagnostic medicine. Both clinical evaluation and electrodiagnosis are useful methodologies, each having limitations. Dr. Dellon labels the overreliance on electrodiagnosis and the “WOG” (Word of God) syndrome, and describes its signs, symptoms, and treatment. Dr. Brown contends Dr. Dellon's crusade is misdirected. The exchange is an eloquent polemic on the virtues and foibles of these different approaches to evaluating peripheral nerve function and the imperative to practice them in a complementary rather than a contentious manner. © 1994 John Wiley & Sons, Inc.     

Modeling Human Syllogistic Reasoning: The Role of “No Valid Conclusion”

Syllogistic reasoning, that is the drawing of inferences for categorical‐quantified assertions, is one of the oldest branches of deductive reasoning research with a history exceeding 100 years. In syllogistic reasoning experiments, “No Valid Conclusion” (NVC) is one of the most frequently selected responses and corresponds to the logically correct conclusion for 58% of the syllogistic problem domain. To date, NVC is often neglected in computational models or just treated as a by‐product of the underlying inferential mechanisms such as a last resort when the search for alternatives is exhausted. We illustrate that NVC represents a major shortcoming of current models for human syllogistic reasoning. By introducing heuristic rules for predicting NVC, we demonstrate that simple extensions of the existing models result in substantial improvements in their predictive performances. Our results emphasize the need for better NVC handling in cognitive modeling of human reasoning and provide directions for modelers on how to enhance their approaches.     

Rationales, values, and DSM-IV: The case of “medication-induced movement disorders”

The DSM-IV has improved psychiatric diagnostic classification through initiating, among other things, the open disclosure of rationales for nosologic changes. It will be argued that a consideration of values is necessary in justifying nosologic changes, considerations missing from the DSM-IV rationales. In illustration of this, I examine the reasons for including the medication-induced movement disorders (MIMDs) on axis I by using a literature review, then compare the published rationales for including the MIMDs with the DSM-IV Task Force's own guidelines for including categories. Discrepancies are found between the Task Force's guidelines for including categories and the published rationales for including MIMDs. Strict adherence to the Task Force guidelines more strongly supports placing MIMDs in axis Ill. Discussion emphasizes the importance of value commitments in nosology development.     

“Feeling” others' painful actions: The sensorimotor integration of pain and action information

Sensorimotor regions of the brain have been implicated in simulation processes such as action understanding and empathy, but their functional role in these processes remains unspecified. We used functional magnetic resonance imaging (fMRI) to demonstrate that postcentral sensorimotor cortex integrates action and object information to derive the sensory outcomes of observed hand–object interactions. When subjects viewed others' hands grasping or withdrawing from objects that were either painful or nonpainful, distinct sensorimotor subregions emerged as showing preferential responses to different aspects of the stimuli: object information (noxious vs. innocuous), action information (grasps vs. withdrawals), and painful action outcomes (painful grasps vs. all other conditions). Activation in the latter region correlated with subjects' ratings of how painful each object would be to touch and their previous experience with the object. Viewing others' painful grasps also biased behavioral responses to actual tactile stimulation, a novel effect not seen for auditory control stimuli. Somatosensory cortices, including primary somatosensory areas 1/3b and 2 and parietal area PF, may therefore subserve somatomotor simulation processes by integrating action and object information to anticipate the sensory consequences of observed hand–object interactions. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

The neural correlates of “mind blanking”: When the mind goes away

Mind blanking (MB) is the state where our minds are seemingly “nowhere,” and attention calls no perceptual input into conscious awareness. It is little investigated, perhaps partly because it is difficult to detect the mysterious periods of blanking. In this study, we found that our participants could intentionally produce a state of MB whose neural correlates were deactivation of Broca's area and parts of the default mode network (namely, the hippocampus) which would be active during mind wandering (MW), in addition to activity in another region in the default mode network (namely, anterior cingulate cortex). Because the behavioral finding replicates a previous report of ours, we suggest that the simple instructions that we used to induce MB should be effective. From the neuroimaging data, we conclude that we cannot define the content of our thoughts during MB because our inner speech system does not work at that time. Another possibility is that we actually think of nothing in the MB state. Although more sophisticated studies would be needed to uncover the mechanism of such a phenomenon, the present study provides a methodology and clues for understanding MB and related concepts such as MW, awareness, and metacognitive ability.     

“Jerky” dystonia in children: Spectrum of phenotypes and genetic testing

Hyperkinetic dystonia is characterized by phasic, tremulous, and “jerky” movements in addition to twisting postures. We studied longitudinally 23 index patients with hyperkinetic dystonia from a quaternary pediatric movement disorder clinic in Ireland. Four clinical categories emerged: (1) Eight patients were diagnosed with myoclonus‐dystonia, of whom seven carried heterozygous epsilon sarcoglycan (SGCE) mutations, including a novel deletion of exon 10. Gait disorder, unsteadiness, or frequent falls before 18 months were detected in all SGCE mutation carriers, whereas the typical neck‐predominant presentation developed only years later. (2) One patient classified as benign hereditary chorea, because jerks were choreiform and continuous rather than action‐induced, carried a heterozygous stop mutation of the TITF‐1 gene (Y114X, exon 2). (3) Three mutation‐negative patients were grouped as “myoclonic dystonia” with jerks only in the body regions affected by dystonia. (4) Eleven patients presented with a novel combination of dystonia and low amplitude poly‐mini myoclonus of the upper limbs and pectoral muscles (D‐PMM). In early childhood up to 3 years of age, an initial presentation with predominant gait impairment with only subtle jerks should prompt consideration of SGCE mutation analysis in addition to testing for DYT1 mutations. A causative gene for D‐PMM remains to be identified. © 2008 Movement Disorder Society     

The “Pathological Gambling and Epidemiology” (PAGE) study program: design and fieldwork

The German federal states initiated the “Pathological Gambling and Epidemiology” (PAGE) program to evaluate the public health relevance of pathological gambling. The aim of PAGE was to estimate the prevalence of pathological gambling and cover the heterogenic presentation in the population with respect to comorbid substance use and mental disorders, risk and protective factors, course aspects, treatment utilization, triggering and maintenance factors of remission, and biological markers. This paper describes the methodological details of the study and reports basic prevalence data. Two sampling frames (landline and mobile telephone numbers) were used to generate a random sample from the general population consisting of 15,023 individuals (ages 14 to 64) completing a telephone interview. Additionally, high‐risk populations have been approached in gambling locations, via media announcements, outpatient addiction services, debt counselors, probation assistants, self‐help groups and specialized inpatient treatment facilities. The assessment included two steps: (1) a diagnostic interview comprising the gambling section of the Composite International Diagnostic Interview (CIDI) for case finding; (2) an in‐depth clinical interview with participants reporting gambling problems. The in‐depth clinical interview was completed by 594 participants, who were recruited from the general or high‐risk populations. The program provides a rich epidemiological database which is available as a scientific use file. Copyright © 2015 John Wiley & Sons, Ltd.