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Purpose: To determine whether highly epileptiform electrocorticographical discharge patterns occur in patients with glioneuronal tumors (GNTs) and focal cortical dysplasia (FCD) and whether specific histopathological features are related to such patterns., Methods: The series consists of operated patients with pharmacoresistant epilepsy because of FCD or GNT between 1992 and 2003. Electrocorticography was reviewed for presence of continuous spiking, bursts, recruiting discharges, or sporadic spikes. Surgical specimens were reviewed for the presence of balloon cells, (coexisting) cortical dysplasia, and relative frequencies of neurons, glia, and microglia., Results: Continuous spiking was seen in 55% versus 12% of patients with FCD and GNT, respectively (p = 0.005). Bursts and recruiting discharges were seen in a similar proportion of patients with FCD or GNT. Ninety-one percent of patients with continuous spiking showed (coexisting) cortical dysplasia in contrast to 42% of patients without this pattern (p = 0.004). The presence of balloon cells and glia or microglia content were not associated with discharge patterns., Conclusion: Continuous spiking, bursts, and recruiting discharges occur in patients with FCD and GNT. Continuous spiking was seen significantly more often in patients with FCD. When continuous spiking is found with GNT, it is likely to be associated with dysplastic regions with a high neuronal density.

Purpose: Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug-resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges., Methods: The patients were followed up for a prolonged period at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed interictal and ictal EEG abnormalities. In one patient, EEG and stereo-EEG (SEEG) recordings of seizures were compared., Results: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single-noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No differences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location., Conclusions: The distinctive clinical features and epileptic outcomes in each group of patients confirm the reliability of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and adjacent cortical areas.

Purpose: On MRI, focal cortical dysplasia (FCD) is characterized by a combination of increased cortical thickness, hyperintense signal within the dysplastic lesion, and blurred transition between gray and white matter (GM-WM). The visual identification of these abnormal characteristics may be difficult, and it is unclear to what degree these features occur among different FCD lesions. Our purpose was to investigate the pattern of occurrence of abnormal MRI characteristics in FCD by using a set of computational models and to generate quantitative lesion profiling., Methods: A set of voxel-wise operators was applied to high-resolution 3D T1-weighted MRI in 23 patients with histologically proven FCD and 39 healthy controls, creating maps of GM thickness, maps of relative intensity highlighting areas with hyperintense signal, and maps of gradient magnitude modeling the GM-WM transition. All FCD lesions were segmented manually on the T1-weighted MRI., Results: FCD volumes ranged from 734 mm3 to 80,726 mm3 (mean, 8,629 mm3 +/- 16,238). The manually segmented FCD lesions were used to estimate features in the lesional area and to determine possible local variations of each feature by means of a histogram. In 78% of the patients, FCD lesions were characterized by simultaneous GM thickening, hyperintense signal, and blurring of the GM-WM transition. Moreover, in all patients, the FCD lesion had at least two of these three characteristics., Conclusions: The three features occurred regardless of the lesion volume, and they characterized not only large FCD lesions, but also subtle ones that had been overlooked by conventional radiologic inspection before surgery.

We reviewed the epileptogenic cortical malformations for which a causative gene has been cloned or a linkage obtained. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with epilepsy in female patients and prenatal lethality in most males. About 90% of patients have focal epilepsy. Filamin A mutations have been reported in all families and in approximately 20% of sporadic patients. A rare recessive form of BPNH also has been reported. Most cases of lissencephaly-pachygyria are caused by mutations of LIS1 and XLIS genes. LIS1 mutations cause a more severe malformation posteriorly. Most children have isolated lissencephaly, with severe developmental delay and infantile spasms, but milder phenotypes have been recorded. XLIS usually causes anteriorly predominant lissencephaly in male patients and subcortical band heterotopia (SBH) in female patients. Thickness of the band and severity of pachygyria correlate with the likelihood of developing Lennox-Gastaut syndrome. Mutations of the coding region of XLIS are found in all reported pedigrees and in 50% of sporadic female patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia; accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the RELN gene. Schizencephaly has a wide anatomoclinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Initial reports of heterozygous mutations in the EMX2 gene need confirmation. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to Xq28 in some pedigrees, autosomal recessive inheritance in others, and association with 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy, often Lennox-Gastaut syndrome. Recessive bilateral frontal polymicrogyria has been linked to chromosome 16q12.2-21.

Accurate identification of cortical malformations in children with epilepsy can be crucial for successful clinical management. Although standard head-coil magnetic resonance imaging (MRI) at 1.5 tesla (T) can be used to view the macrostructure of the brain, phased array technology at both 1.5 and 3T significantly improves signal-to-noise ratio (SNR). As a result, spatial resolution and contrast can be optimized to increase visual detection of subtle macrostructural changes that occur with small epileptogenic lesions. In addition, these improvements in SNR allow more accurate quantitative analysis of brain macrostructure and more accurate assessment of brain microstructure using newer sophisticated imaging techniques. For example, phased array imaging enables more accurate diffusion tensor imaging (DTI), and 3T imaging, when combined with phased array technology, enables more informative diffusion spectroscopic imaging (DSI). Recent technological improvements therefore result in improved lesion detection and enable assessment of cerebral growth trajectories and associated longitudinal changes in tissue microstructural organization that occur in association with various types of epilepsy. This article presents a brief comparison of imaging techniques currently in use, both clinically and experimentally, to diagnose, treat, and increase our understanding of the neuropathology of epilepsy in the developing brain.

Purpose: Severe cortical dysplasia (CD) is characterized by the presence of cytomegalic neurons and balloon cells. These aberrant cells could participate in the generation of epileptic activity. The aim of this study was to morphologically and electrophysiologically characterize cells in pediatric CD tissue., Methods: We used infrared video-microscopy to visualize normal and abnormal-appearing cells. To characterize electrophysiological properties, we used whole-cell patch clamp recordings in tissue slices obtained from 42 cases of pediatric CD (ages 0.2-14 years). The pipette contained biocytin for determination of morphological features., Results: Approximately 25% of recorded cells displayed morphologic differences compared with normal-appearing pyramidal neurons, and were divided as follows: immature, misoriented, dysmorphic, cytomegalic, and balloon cells. Immature cells displayed electrophysiological membrane properties typical of developing neurons. Misoriented pyramidal neurons and pyramidal neurons with dysmorphic processes displayed properties similar to normal-appearing pyramidal neurons. In contrast, cytomegalic neurons and balloon cells displayed abnormal membrane properties. Balloon cells had a very high input resistance and lacked voltage-gated Na+ and Ca2+ currents. Cytomegalic neurons had a very high membrane capacitance, very low input resistance, and showed signs of hyperexcitability, as exemplified by the occurrence of repetitive, slowly inactivating Ca2+ spikes when depolarized., Conclusions: We suggest that cytomegalic neurons but not balloon cells have the potential to be epileptic generators, although probably not instigators, in severe CD tissue.

Purpose: Grey matter heterotopia are well-defined malformations of the cortex often associated with severe epilepsy. Defects have been identified in genes, including DCX and FLN1, that influence radial migration of postmitotic cells from the ventricular zone to the cortical plate. A proportion of cortical gamma-aminobutyric acid (GABA)-containing interneurons may arise from the ganglionic eminence of the ventral telencephalon. We aimed to identify the subtypes and localisation of interneurons within grey matter heterotopia relative to cortex., Methods: By using quantitative immunohistochemistry, we studied the density and distribution of interneurons within six cases of grey matter heterotopia in postmortem tissue from patients with epilepsy., Results: In many cases, a suggestion of focal rudimentary laminar arrangement and small reelin-positive cells was identified within the heterotopia. Immunohistochemistry for glutamic acid decarboxylase(65/57), parvalbumin, calbindin, and calretinin showed inhibitory neurons of all subtypes represented within the heterotopia, and of normal morphology. The mean densities of interneurons were overall similar to those of the overlying cortex, but the interneurons showed less organisation and were more randomly orientated compared with cortex., Conclusions: Interneurons within heterotopia probably arise from the ventricular zone, but their abnormal local organization may influence the epileptogenicity of these lesions.

Purpose: Subtle microdysplastic features are found in some patients with hippocampal sclerosis (HS) and refractory temporal lobe epilepsy. The significance of these findings is unknown. We investigated their frequency, relation to the pattern of HS, and clinical associations., Methods: One-hundred forty patients with histologically confirmed HS (mean age at operation, 35 years; 85 women) were analyzed. The presence of HS and subtle structural abnormalities (SSAs) in the mesial temporal lobe and in the lateral neocortical tissue was assessed in detail. Antecedents, seizure characteristics, two verbal memory tests, and outcome in HS patients with and without SSAs were determined., Results: SSAs were found in 60 (43%) of the 140 HS patients, being mesial only in 32 of the 60 cases, and lateral only in nine cases; the remaining 19 cases had both mesial and lateral abnormalities. The frequency of SSA was not related to the pattern of HS or other tested variables. Prolonged febrile convulsions were present in 26 (44%) patients with SSAs, and in 26 (34%) patients (not significant) without SSAs. The outcome after surgery did not differ between patients with SSAs (incidence rate ratio for seizure recurrence, 0.9; 95% confidence interval, 0.5-1.6) compared with patients without SSAs (reference ratio, 1)., Conclusions: Forty-three percent of HS patients have SSAs in their lobectomy specimens. The presence of SSAs does not predict clinical characteristics, such as presence of prolonged febrile convulsions, postsurgical outcome, or neuropsychological performance, nor does it correlate with the histologic pattern of HS.

Purpose: Extensive multilobar cortical dysplasia in infants commonly is first seen with catastrophic epilepsy and poses a therapeutic challenge with respect to control of epilepsy, brain development, and psychosocial outcome. Experience with surgical treatment of these lesions is limited, often not very encouraging, and holds a higher operative risk when compared with that in older children and adults., Methods: Two infants were evaluated for surgical control of catastrophic epilepsy present since birth, along with a significant psychomotor developmental delay. Magnetic resonance imaging showed multilobar cortical dysplasia (temporoparietooccipital) with a good electroclinical correlation. They were treated with a temporal lobectomy and posterior (parietooccipital) disconnection., Results: Both infants had excellent postoperative recovery and at follow-up (1.5 and 3.5 years) evaluation had total control of seizures with a definite "catch up" in their development, both motor and cognitive. No long-term complications have been detected to date., Conclusions: The incorporation of disconnective techniques in the surgery for extensive multilobar cortical dysplasia in infants has made it possible to achieve excellent seizure results by maximizing the extent of surgical treatment to include the entire epileptogenic zone. These techniques decrease perioperative morbidity, and we believe would decrease the potential for the development of long-term complications associated with large brain excisions., (Copyright 2004 International League Against Epilepsy)

Phased-array imaging at 1.5 and 3 T significantly improves image quality compared with that in routine 1.5-T head coil studies. These improvements significantly increase lesion detection in patients with focal epilepsy. Semiautomated image-analysis techniques have the potential to improve lesion detection, assess lesion burden more accurately, characterize cortical abnormalities, and determine the location and extent of associated cortical and deep gray nuclei involvement. With increasing interest in understanding the role white matter plays in epileptogenesis and seizure propagation, diffusion tensor imaging may yield useful information about changes in white matter organization. Our current multimodality imaging combines these structural imaging advances with coregistered neurophysiological information obtained with magnetoencephalography and with simultaneous EEG recordings. Our initial experience suggests that multimodality imaging will improve our ability to detect and define the extent of epileptogenic lesions.

Focal epilepsy can present with a rapidly progressing course of intractable epilepsy in children. We present a typical example of such a patient with focal seizures due to a frontal lobe cortical lesion of developmental origin. MRI and SPECT revealed abnormalities in the right frontal lobe. Surgical resection resulted in excellent outcome.

Purpose: Focal cortical dysplasia (FCD) is known to be a major cause of intractable epilepsy. The cellular mechanism(s) underlying the epileptogenicity of FCD remain largely unknown. Because recent studies indicate that metabotropic glutamate receptor subtypes (mGluRs) play a role in epileptogenesis, we investigated the expression and cellular distribution pattern of mGluRs in FCD specimens., Methods: Immunocytochemical expression of group I and group II mGluR subtypes was investigated in 15 specimens of human FCD obtained during epilepsy surgery., Results: Strong mGluR1alpha and mGluR5 (group I mGluRs) immunoreactivity (IR) was observed in the majority of FCD specimens in dysplastic as well as in heterotopic neurons. mGluR1alpha was expressed in a subpopulation of neurons (mainly large dysplastic cells), whereas mGluR5 was represented in a higher percentage of dysplastic neuronal cells. Group II mGluRs (mGluR2/3) IR was observed less frequently than that in group I mGluRs and generally appeared in <10% of the dysplastic neurons. IR for all three mGluR subtypes was observed in balloon cells. mGluR2/3 appeared to be most frequently expressed in glial fibrillary acidic protein (GFAP)-positive balloon cells (glial type), and mGluR1alpha, in microtubule-associated protein (MAP)2-positive cells (neuronal type). mGluR5 was present in the majority of balloon cells. Occasionally glial mGluR1alpha IR was observed in bizarre glial cells with di- or multinuclei. Reactive astrocytes were intensively stained, mainly with mGluR5 and mGluR2/3., Conclusions: The cellular distribution of mGluR subtypes, with high expression of mGluR1alpha and mGluR5 in dysplastic neurons, suggests a possible contribution of group I mGluRs to the intrinsic and high epileptogenicity of dysplastic cortical regions.

Purpose: We report the case of a male newborn with Ohtahara syndrome and right hemimegalencephaly who presented epileptic negative myoclonus in the first days of life., Methods: Prolonged polygraphic studies were performed, as well as MRI and a full clinical examination., Results: EEG showed a constant and nonreactive pattern of burst suppression. There were several kinds of electro-clinical seizures (generalized myoclonia, short atonias, typical spasm and tonic spasms) at the beginning of the EEG's burst. The periods of EMG silence, lasting less than 300 ms, were associated with stereotyped EEG transients., Conclusions: Epileptic negative myoclonus can be observed also in neonatal age. The short transient impairment of motor function observed in the newborn seems linked to the slow component of spike-wave discharge, but its mechanism is still not clear.

Purpose: The aim of this study was to correlate the electroclinical and radiologic data with the neuropathologic findings and surgical outcome in epileptic patients with epilepsy and Taylor's focal cortical dysplasia (TFCD) and to characterize further the abnormal intermediate filaments expression in the balloon cell present in the peculiar dysplasia., Methods: We retrospectively selected 13 TFCD patients who underwent surgery for intractable epilepsy with the aim of removing the magnetic resonance (MR)-detectable lesion and/or the epileptogenic zone defined by stereoelectroencephalographic recordings. The surgical specimens were analyzed by means of routine neuropathologic and immunocytochemical studies. Antisera against different intermediate filaments also were used in serial adjacent sections to evaluate their coexpression in balloon cells., Results: Histopathologic abnormalities typical of TFCD were found not only within the MR-visible lesions but also in most of the epileptogenic zones with no MR signal alterations. Furthermore, the MR-visible lesions contained a high proportion of cells with an abnormal expression of intermediate filament proteins. After a long follow-up, 10 of the patients are now seizure free., Conclusions: Our findings indicate that highly epileptogenic zones may correspond to tissue alterations not revealed by neuroimaging. Furthermore, the immunocytochemical data show that the dysplastic tissue detected by MR contained high concentrations of cells filled with abnormal intermediate filaments. The detected colocalization of neuronal and glial markers in balloon cells indicates a failure of cellular commitment during development.

We report a patient with early infantile epileptic encephalopathy (EIEE) with suppression-burst (Ohtahara syndrome) associated with olivary-dentate dysplasia and agenesis of mamillary bodies is reported. Although those with Ohtahara syndrome are a heterogeneous group, virtually all reported cases are secondary to neuronal migrational disorders, sometimes only identified by detailed neuropathologic examination, as in this case report, which describes mamillary body agenesis as a not-yet-recognized anomaly associated with Ohtahara syndrome. All children with Ohtahara syndrome should have high-resolution magnetic resonance imaging (MRI) and detailed postmortem neuropathologic examinations.

Purpose: Increased availability of surgically resected epileptogenic tissues reveals often unsuspected cortical dysplasia (CD). There is some controversy about the ontogenic stages in which these occur. Although most take place during neuroblast proliferation and migration, there is some evidence for some CD occurring during postmigrational intrinsic cortical organization. It has been shown that various kinds of focal cortical manipulations in rats, if performed within 3-4 postnatal days, lead to the genesis of various cortical malformations including a four-layered microgyrus or an unlayered CD. It is not known whether such events also might occur in the human brain., Methods: Two children sustained minor head trauma within 4 postnatal days and later developed intractable epilepsy, which was relieved by surgery. Neuropathologic analysis of the resected tissues revealed an unsuspected microdysplastic cortex immediately adjacent to a focal, modest meningeal fibrosis, presumably secondary to the old closed head trauma., Results: The main histologic features were a disorganized, unlayered cortex; abnormal clusters of neurons, often with complex, randomly oriented proximal dendritic patterns with absent apical orientation; the presence of a number of heterotopic small and large neurons in the white matter; absence of inflammatory infiltrates, of hemosiderine, of reactive gliosis, or of an excessive number of blood vessels. The morphologic features in these surgical specimens suggest that these focal malformations occur because of a regional disorder of postmigrational intrinsic cortical remodeling., Conclusions: The clinical histories and the pathologic findings lend some support to the hypothesis that minor morbid events occuring in the immediate postnatal period may lead to microdysplasia in the human similar to those induced in rat pups. The animal model could be helpful to clarify the genesis of some cases of CD and of the epileptogenicity often manifesting later in life.

Purpose: Polymicrogyria (PMG) is often associated with symptomatic focal epilepsy and neurologic dysfunction. We investigated the clinical and laboratory features of a group of children with congenital hemiparesis, unilateral polymicrogyria on magnetic resonance imaging (MRI), and a peculiar epileptic syndrome., Methods: Twelve patients (seven girls and five boys) with a mean age of 7.8 years (range, 5-13 years) were studied. All patients underwent clinical evaluation, computed tomography (CT) and MRI scanning, and neuropsychological assessment at initial examination. Patients were followed up from 1 to 7 years (mean, 4.5 years)., Results: Partial motor seizures with secondary generalization with onset between age 1 and 6 years (mean age, 2 years) were recorded in all patients. The course of epilepsy was similar in all patients with development of atypical absences, negative myoclonus, and gait difficulties. EEG recording demonstrated continuous spike-wave or bilateral abnormality throughout. Frequent relapses of the atonic and myoclonic seizures were seen in seven patients. However, during follow-up, seven patients were seizure free, and the others have not developed this particular seizure pattern. A single case underwent cortical resection 23 months ago and has had no seizures since then. Mental retardation was mild in nine and moderate in three patients., Conclusions: Children with unilateral polymicrogyria may develop a syndrome of negative myoclonus seizures that appears to be age specific and responsive to antiepileptic drug (AED) treatment. Despite limited follow-up time, a good outcome was observed in most cases.

The role of the glutamate receptor GluR3 in Rasmussen's encephalitis is actively under investigation. Autoimmune processes with this receptor as the target are currently theorized. We provide an additional case of pathologically proved Rasmussen's encephalitis (with concomitant cortical dysplasia) in the presence of antibodies against the GluR3 receptor.