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Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy., Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%)., Results: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients., Conclusions: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

The prevailing understanding of generalized epilepsy is shaped by the traditional definition that "the responsible neuronal discharge takes place, if not throughout the entire grey matter, then at least in the greater part of it and simultaneously on both sides". This view is no longer tenable since concurrent findings using multiple methods have accumulated to reveal the role of bilateral networks of distributed and selective cortical and subcortical structures in so-called generalized ictogenesis. Most of this research has been focused on juvenile myoclonic epilepsy (JME), which today is commonly considered the archetypical syndrome of the idiopathic generalized epilepsies. Based upon recent research in the fields of clinical epileptology, neuropsychology and psychiatry, clinical neurophysiology, neuroimaging and epilepsy genetics this article, for the first time, unites these new findings into a comprehensive nosological view. Genetically determined dysfunctions of important cognitive systems like visuomotor coordination and linguistic communication appear now as key mechanisms of seizure generation in JME. This review suggests a new paradigm to consider JME as a system disorder of the brain analogous to other neurological system disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We postulate that "system epilepsies" (SystE) are due to an enduring propensity to generate seizures of functionally characterized brain systems. Data supporting this hypothesis-that some types of epilepsy depend on the dysfunction of specific neural systems-are reviewed. The SystE hypothesis may drive pathophysiologic and clinical studies that can advance our understanding of epilepsies and can open up new therapeutic perspectives., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Human emotion perception is a topic of great interest for both cognitive and clinical neuroscience, but its electrophysiological correlates are still poorly understood. The present study is aimed at evaluating if measures of synchronization and indexes based on graph-theory are a tool suitable to study and quantify electrophysiological changes due to emotional stimuli perception. In particular, our study is aimed at evaluating if different EEG connectivity patterns can be induced by pleasant (consonant) or unpleasant (dissonant) music, in a population of healthy subjects, and in patients with severe disorders of consciousness (DOCs), namely vegetative state (VS) patients. In the control group, pleasant music induced an increase in network number of connections, compared with the resting condition, while no changes were caused by the unpleasant stimuli. However, clustering coefficient and path length, two indexes derived from graph theory, able to characterise segregation and integration properties of a network, were not affected by the stimuli, neither pleasant nor unpleasant. In the VS group, changes were found only in those patients with the less severe consciousness impairment, according to the clinical assessment. In these patients a stronger synchronization was found during the unpleasant condition; moreover we observed changes in the network topology, with decreased values of clustering coefficient and path length during both musical stimuli.Our results show that measures of synchronization can provide new insights into the study of the electro physiological correlates of emotion perception, indicating that these tools can be used to study patients with DOCs, in whom the issue of objective measures and quantification of the degree of impairment is still an open and unsolved question.

We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not., (© 2010 Movement Disorder Society.)

Seizures induced by musical stimulation are usually correlated to temporal epilepsy, although the precise localization of their epileptogenic networks are not well characterized. Brain imaging studies show that regional cerebral blood flow (rCBF) recorded during musicogenic seizures is increased in putative epileptogenic foci, as well as in other brain regions not directly related to seizure activity. These studies, however, afford only a virtual temporal relation between ictal discharges and rCBF changes, given that brain images are correlated with off-line EEG recordings. To obviate this problem, the simultaneous multimodal recording of the episode of musicogenic epilepsy is mandatory. The present study describes the EEG-fMRI co-recording of musicogenic elicited seizures in a case of simple partial epilepsy. Our results show that EEG features recorded in epileptogenic areas are largely coupled with rCBF increase. Furthermore, rCBF modifications in other regions suggest that additional aspects of musical processing are also elicited during musicogenic seizures.

In the nineteenth and early twentieth centuries, many important discoveries in nervous system structure and function involved the electrical properties of nerve tissue. The application of these advances, as well as those in electronic amplification and recording, led to the discovery of the human electroencephalogram (EEG) by Hans Berger, a German psychiatrist. Originally received with skepticism, the EEG became a subject of intense interest, and after World War II, became a leading clinical and experimental tool in neurology. Today, it remains important especially in the study and treatment of epilepsy. Though the EEG has also given rise to more sophisticated applications, these remain based on Berger's initial work, one of the great discoveries of medical history.

Infantile spasms (IS) are so typically associated with West syndrome that the term IS, properly referred to as a seizure type, is currently used synonymously with this severe infantile epilepsy. This chapter reviews some clinical and experimental observations relevant to IS pathophysiology with particular regard to maturational aspects that may account for IS age-related expression. Neither the cortical nor the brain stem generator hypotheses account for all the clinical features of IS. It is suggested that IS are generated whenever a cortical discharge is able to influence some archaic circuit located putatively in the brain stem through either an excitatory or a disinhibitory mechanism. This may occur with the highest probability during a developmental window in which IS typically occur, when N-methyl-D-aspartate (NMDA) transmission is particularly facilitated due a reduced sensitivity of NMDA receptors to the Mg2+ block. Interestingly, in this age range (0-18 postnatal day in rat), flexion spasms can be elicited experimentally by NMDA administration. These data provide an important key to further investigating IS pathophysiology, thus allowing us to design more effective strategies aimed at counteracting this harmful infantile epilepsy.

Objective: To define the clinical and EEG features of the epileptic syndromes occurring in adult and infantile mitochondrial encephalopathies (ME)., Methods: Thirty-one patients with recurrent and apparently unprovoked seizures associated with primary ME were included in the study. Diagnosis of ME was based on the recognition of a morphologic, biochemical, or molecular defect., Results: Epileptic seizures were the first recognized symptom in 53% of the patients. Many adults (43%) and most infants (70%) had nontypical ME phenotypes. Partial seizures, mainly with elementary motor symptoms, and focal or multifocal EEG epileptiform activities characterized the epileptic presentation in 71% of the patients. Generalized myoclonic seizures were an early and consistent symptom only in the five patients with an A8344G mitochondrial DNA point mutation with classic myoclonus epilepsy with ragged red fibers (MERRF) syndrome or "overlapping" characteristics. Photoparoxysmal EEG responses were observed not only in patients with typical MERRF, but also in adult patients with ME with lactic acidosis and strokelike episodes (MELAS), or overlapping phenotypes, and in one child with Leigh syndrome., Conclusions: Epilepsy is an important sign in the early presentation of ME and may be the most apparent neurologic sign of nontypical ME, often leading to the diagnostic workup. Except for those with an A8344G mitochondrial DNA point mutation, most of our patients had partial seizures or EEG signs indicating a focal origin.

A double methylazoxymethanol (MAM) intraperitoneal injection was prenatally administered to pregnant rats at gestational day 15 to induce developmental brain dysgeneses. Thirty adult rats from 8 different progenies were investigated with a combined electrophysiological and neuroanatomical analysis. The offspring of treated dams was characterized by extensive cortical layering abnormalities, subpial bands of heterotopic neurons in layer I, and subcortical nodules of heterotopic neurons extending from the periventricular region to the hippocampus and neocortex. The phenotype of cell subpopulations within the heterotopic structures was analyzed by means of antibodies raised against glial and neuronal markers, calcium binding proteins, GABA, and AMPA glutamate receptors. Neurons within the subcortical heterotopic nodules were characterized by abnormal firing properties, with sustained repetitive bursts of action potentials. The subcortical nodules were surrounded by cell clusters with ultrastructural features of young migrating neurons. The immunocytochemical data suggested, moreover, that the subcortical heterotopia were formed by neurons originally committed to the neocortex and characterized by morphological features similar to those found in human periventricular nodular heterotopia. The present study demonstrates that double MAM treatment at gestational day 15 induces in rats developmental brain abnormalities whose anatomical and physiological features bear resemblance to those observed in human brain dysgeneses associated with intractable epilepsy. Therefore, MAM treated rats could be considered as useful tools in investigating the pathogenic mechanisms involved in human developmental brain dysgeneses.

We are currently investigating various treatments which could determine, in the rat brain, structural abnormalities mimicking those reported in human brain dysgeneses. We can induce the formation of neuronal heterotopia in the progeny of rats by means of a double injection of the cytotoxic agent methylazoxymethanol acetate (MAM) on embryonic day 15. We have now investigated the anatomical connections of these heterotopia by means of anterograde and retrograde tract tracing techniques. The induced heterotopia along the border of the lateral ventricles shared common anatomical features with the periventricular nodules in human periventricular or subcortical nodular heterotopia (PNH). The tract tracing data demonstrated the existence of reciprocal connections between the neuronal heterotopia and the ipsilateral and contralateral cortical areas, and the presence of abnormal cortico-hippocampal and cortico-cortical connections. On the basis of the connectivity patterns, it may be speculated that some cells in the heterotopia could be neurons originally committed to the cortex, that were interrupted in their migration by the MAM treatment. Given the common morphological features seen in human PNH and MAM-induced brain heterotopia, the anatomical and developmental analysis of MAM-treated rats may shed light on the mechanisms by which human brain dysgeneses develop in human patients.

Purpose: We studied 17 patients with periventricular nodular heterotopia (PNH) to further investigate the electroclinical pictures and semiology of the associated seizures., Methods: PNH was diagnosed by means of magnetic resonance imaging (MRI). The patients' clinical and familial histories were carefully analyzed, and their electroclinical features and course of epilepsy followed for periods ranging from 10 months to 22 years. The electroclinical data were compared with those of previously reported PNH cases., Results: The patients were subdivided into those with bilateral (7) and unilateral (10) PNH. The former were mainly characterized by structural abnormalities in the posterior cerebral fossa and multiple seizure types; the latter were characterized by the paratrigonal location of the malformation and, frequently, by elementary seizures with a visual or auditory onset. Focal seizures were drug resistant in most cases. The interictal EEG abnormalities were always focal and consistent with the location of the PNH. A previously unreported photic driving of posterior background activity was observed in all patients and was always consistent with the PNH location., Conclusions: Our present findings and previously reported data show that bilateral and unilateral PNH cases are different in their morphological and electroclinical features and may be determined by different etiologies. The female predominance, frequent familial occurrence, and positive family history for epilepsy suggest that genetic factors may be involved in the genesis of bilateral and symmetrical PNH, whereas the presence of prenatal risk factors and its location in the watershed paratrigonal area suggest that vascular mechanisms may determine unilateral PNH.

Despite the increasing number of patients affected by neuronal migration disorders (NMDs) recently diagnosed in vivo by means of magnetic resonance imaging (MRI), few detailed data on the correlation between the neuroradiological and the anatomical features in the single NMD case are available. The present paper reports a combined cytoarchitectural and immunocytochemical analysis, by means of antisera recognizing specific neuronal and glial markers, of three MRI diagnosed NMD patients surgically treated for the relief of intractable seizures. The first case was a giant subcortical nodular heterotopia of morphologically normal neurons lacking any type of cortical lamination. The second case was a layered polymicrogyria with an abnormal amount of ectopic neurons in the underlying white matter. The third case was a focal cortical dysplasia characterized by a dramatic disruption of the normal cortical layering associated with marked cytological abnormalities. The present data demonstrate that the macroscopical and microscopical brain abnormalities can be markedly different in different NMD subtypes, and suggest that different anatomical substrates can underlie the intrinsic hyperexcitability of these brain malformations. The relevance of further prospective clinico-morphological studies for a better understanding of the mechanisms determining the development of these brain malformations is underlined.

Purpose: Nine patients affected by schizencephaly were analyzed, and the epileptologic findings prospectively studied, to define the relations between the anatomic brain malformations and clinical outcome., Methods: The schizencephaly was diagnosed by means of magnetic resonance imaging (eight cases) or computed tomography (one case). The clinical histories of all the patients were analyzed, and a psychometric evaluation was made. The electroclinical features and course of epilepsy in the six patients with epilepsy were prospectively followed up for a period ranging from 3 to 14 years., Results: The patients were divided into those who were unilaterally (six) and those bilaterally (three) affected. The former were characterized by mild neurologic deficits and late-onset epilepsy; their epileptologic features were consistent in terms of age of onset, seizure semiology, the absence of secondary generalization, and resistance to antiepileptic treatment. The patients with bilateral schizencephaly associated with other brain malformations were characterized by severe neurologic deficits but were only rarely affected by epilepsy, which was always completely controlled by antiepileptic treatment., Conclusions: Our data show that the extent of anatomic malformation is strictly related to the severity of motor and mental impairment but not to the presence or severity of epilepsy. The absence of prenatal risk factors for brain damage in our series, previously described familial cases of schizencephaly, and the recent report of mutations in homeobox gene EMX2 associated with cases of schizencephaly all indicate that genetic factors may play a key role in the pathogenesis of this brain malformation.

The morphological features of cerebral tissue in the isolated guinea-pig brain maintained in vitro by arterial perfusion are described. Light and electron microscopic analysis of the thalamus, the somatosensory cortex and the limbic cortices (hippocampus, piriform and entorhinal cortices) was performed after different periods of incubation in vitro (1, 7 and 12 h), in parallel with an electrophysiological study. The morphological analysis showed that neuronal elements retained their normal appearance at both cellular and subcellular level in the examined brain regions up to an incubation period of 12 h. Immunoreactivity for GABA was also preserved for up to 12 h of in vitro perfusion. Vasogenic edema and perivascular extracellular swelling appeared after 7 h, together with signs of progressive astrocytic deterioration. These findings show that normal electrophysiological recordings correlate with good anatomical preservation of the isolated guinea-pig brain preparation after prolonged times of arterial in vitro perfusion.

Stereoelectroencephalography (SEEG) provides the neurosurgeon with crucial information for directing surgical strategies aimed at removing the epileptogenic foci. In lesional epilepsies the epileptogenic area does not necessarily correspond with the lesional area as defined by imaging techniques. In the case of good correspondence, lesion-directed surgery may be beneficial for the associated epilepsy even without the guide of presurgical SEEG. According to personal observation, this seems to be the case for epileptogenic cavernous angiomas, while for low grade gliomas the criteria for SEEG indication are still to be defined. The SEEG definition of the primary epileptogenic area is based on the detection of leading epileptic potentials by optimally placed depth electrodes. Experimental results demonstrate that epileptic discharges recorded from the hippocampus as the apparent leading phenomena may in fact result from subtle changes in excitability taking place upstream in the piriform cortex. This may lead to misjudgment of the location of primary epileptogenic areas unless suitable techniques of SEEG analysis are applied.

Neurological derangement has been reported in haemodialysed patients receiving intravenous desferrioxamine (DFO) for aluminium-related disorders. The possible direct effects of desferrioxamine on EEG recordings were investigated in ten haemodialysed patients who underwent a DFO test 2 h after the end of dialysis. According to a commonly accepted protocol, 40 mg/kg body-weight of desferrioxamine was infused in 60 min. EEG recording was continuously performed, starting 30 min before and stopping 30 min after the desferrioxamine infusion. Besides visual inspection, EEG records were digitised, tapered, and spectrally analysed with Digital PDP 11/73 microcomputer. Basal EEG recording was normal in all patients. In three patients a progressive EEG slowing was detected by visual inspection during desferrioxamine infusion; in these cases automatic analysis revealed a 50% increase in power of slower frequencies 30 min after starting the infusion, when no changes in plasma aluminium concentrations are detected; a complete recovery was observed 30 min after desferrioxamine withdrawal. In one patient bilateral paroxysms of slow waves appeared, so we stopped desferrioxamine infusion. Two of the three patients who developed EEG abnormalities also had an increased aluminium body burden (positive DFO test). Results indicated that desferrioxamine per se can modify EEG in haemodialysis patients and that its effect is not mediated by acute increases of plasma aluminium concentrations. The finding of a positive DFO test in two of three patients with EEG changes may suggest that an aluminium-induced blood-brain barrier derangement could have played a role. However, prompt recovery after ceasing desferrioxamine infusion strongly suggests a direct role of desferrioxamine in the induction of EEG changes.(ABSTRACT TRUNCATED AT 250 WORDS)

A 67-year-old man had repeated cerebral ischemic attacks, which resulted in a clinical picture combining paralysis of visual fixation, optic ataxia and impairment of visuospatial orientation, consistent with the definition of Balint's syndrome. Postmortem examination showed multiple lesions involving the occipital cortex of both sides and the white matter underlying the right insular cortex. EOG recording demonstrated a marked impairment of refixation saccades and saccades on verbal command. Smooth pursuit movements were completely abolished. Visual fixation was randomly achieved after many erratic exploratory movements and steadily maintained on the target (spasmodic fixation). During spasmodic fixation, EOG recording detected an ocular flicker resulting in a continuous instability of eye position. It is suggested that these findings may all be accounted for by the loss of panoramic vision due to a bilateral impairment of cortical areas 18 and 19.

A procedure is described which aims to classify an EEG recorded during neurosurgery, for example intracerebral aneurysm clipping. A parametric approach is used; it employs auto-regressive (AR) modelling and Kalman filtering to quantify directly the dynamics of the EEG generating mechanism, supposing it to be a linear, time-invariant system driven by white noise. The results of this EEG processing are analysed together with simultaneous values of arterial blood pressure (ABP) as surgery of this kind is carried out under conditions of controlled hypotension. The object is to compare the sensitivity of ABP data with that obtained from the EEG and so provide an early warning of a potentially dangerous non-physiological state induced by the hypotensive drug (in this case sodium nitroprusside). Some methodological comments on the correct implementation of these algorithms are given and the procedure is compared with similar approaches which have appeared in the literature during the last few years. Particular emphasis is placed on the power spectral analysis of the signal by pointing out a method for spectral decomposition, related to AR power density estimation, which permits the separation of single spectral components in terms of central frequencies and their associated power. Other potential applications of this method are in long term EEG monitoring for the detection of changes due for example to drug infusion, to fast transient events, or to changes in the stationary condition.