Mark S. Scher
during prenatal life. For the epileptologist to fully appreciate developmental epileptogenesis, one must apply an ontogenetic approach (i.e. "nature-nurture-niche") in order to study the epileptic condition from a fetal neurology perspective. Genetic susceptibility can involve pre-fertilization and post-fertilization mechanisms that dictate the timing and form of major malformations associated with specific epileptic syndromes. Maternal, fetal, and placental disease conditions also contribute to either brain malformations or injuries, depending on events during the first or second half of pregnancy. Sequential stages during prenatal brain development, from embryonic through perinatal periods, specify which gray and white matter structures may be adversely altered, with later expression of seizures in the context of motor, cognitive and behavioral deficits. Translational research from bench to bedside should consider the acquired causes of pediatric and adult epilepsies in the context of the patient’s genetic environment.
Mona Sazgar, Peter L. Carlen, Richard Wennberg
association of ictal panic and anxiety symptoms with partial seizures lateralized to the right temporal lobe.
<i> Methods:</i> From 112 consecutive patients with intractable temporal lobe epilepsy (59 right, 53 left) referred for video-EEG monitoring, five patients were identified whose seizures had been diagnosed as panic attacks in the past. Their ictal symptomatology included feelings of panic and impending doom, hyperventilation, palpitation, diaphoresis, shortness of breath and generalized paresthesiae. Ictal panic was not identified in 72 patients with extratemporal epilepsy investigated during the same period.
<i> Results:</i> EEG documented a right anterior to mid-temporal focus in all five patients. Brain MRI or pathology showed right mesial temporal sclerosis in four and a right temporal ganglioglioma in one. Ictal tachycardia was documented with EEG-EKG recording in the latter patient, prior to right anterior temporal lobectomy and amygdalohippocampectomy. Reinvestigation of this patient five years later for recurrent seizures, no longer associated with panic symptomatology, showed right temporal ictal onsets with seizure spread to the left temporal lobe, now associated with ictal bradycardia.
<i> Conclusions:</i> Our case series provides further evidence to support a relationship between panic attack symptomatology and ictal involvement of the right mesial temporal region [Published with video sequences].
Stéphane Kremer, Marc Braun, Philippe Kahane, F. Guillemin, Jean-François Le Bas, Alim Louis Benabid
in order to detect subtle MRI abnormalities such as atrophy, which could be indicative of its implication in the epileptogenic area. The population consisted of 20 epileptic patients (31.2 9.4 years) and 20 normal volunteers (31.8 7.7 years). The epileptic patients underwent intracerebral recordings, and were sub-divided into five patients presenting with seizures involving the CG (CG 1), seven patients in whom the CG was only secondarily involved (CG 2) and eight patients in whom the CG was not invoved at all (CG 3). All subjects were investigated by MRI (1.5 tesla Gyroscan Philips): axial T1w 3D Gradient Echo acquisitions, thickness 1.5 mm, reconstructions in all planes. At first, we described the sulcal limits of the CG, trying to define a "normalised CG". In a second step, we segmented the CG intrasulcal grey matter using the "Surgiscope Scopeplan" (Elekta). We compared (Mann and Whitney U test [α=0.05]), the CG volumes of CG 1 to CG 2 + 3, and the volume of CG 1 and of CG 1 + 2 + 3 to that of normal volunteers. There was no significant difference between CG 1 and CG 2 + 3 (
<i>P</i> = 0.89), between CG 1 and normal volunteers (
<i>P</i> = 0.75) or between CG 1 + 2 + 3 and normal volunteers (
<i>P</i> = 0.83). The volumetric analysis showed no atrophy of the CG in epileptic patients and did not distinguish the group in whom seizures involved the CG, from the other groups.
Roberto Horacio Caraballo, Natalio Fejerman, Bernardo Dalla Bernardina, Victor Ruggieri, Ricardo Cersósimo, Carlos Medina, Juan Pociecha
and are associated with a slow-wave transient or sharp and slow-wave complex, followed or not by voltage attenuation. Epileptic spasms usually appear in clusters and are age-dependent. This type of epileptic spasms associated with the particular EEG pattern, hypsarrhythmia, constitutes the basis for the diagnosis of West syndrome. The question is, how to nosologically define those patients who clearly present epileptic spasms in clusters without modified or typical hypsarrhythmia and with or without focal paroxysmal discharges on the interictal EEG. In the present series, the four patients show that epileptic spasms in clusters may occur in infancy, without hypsarrhythmia. They all presented the following features: normal neuropsychological development before onset of epileptic spasms, clusters of epileptic spasms, focal clinical and/or EEG abnormalities, normal neuroradiological imaging, neurometabolic investigations and karyotypes. In three of the patients, seizures were refractory to AEDs. Epileptic spasms in clusters without hypsarrhythmia that start in the first year of life represent a subtype of infantile spasms that generally are refractory to AEDs. It is not yet clear whether it should be considered as a variant of West syndrome or not [Published with Video sequence].
Abnormalities of cortical development and epilepsy
Federico Vigevano, Lucia Fusco, Giorgio Lo Russo, Giovanni Broggi
Renzo Guerrini, Federico Sicca, Lucio Parmeggiani
of MCC is based on embryological brain development, recognising forms that result from faulty neuronal proliferation, neuronal migration and cortical organisation. Hemimegalencephaly, an enlarged dysplastic hemisphere, can present as early onset severe epileptic encephalopathy or as partial epilepsy. In focal cortical dysplasia (FCD), MRI shows focal cortical thickening and simplified gyration. Patients have drug‐resistant, often early onset epilepsy. Complete surgical ablation of FCD is accompanied by remission in up to 90% of patients, but may be technically difficult. Tuberous sclerosis (TS) is a multisystemic disorder primarily involving the nervous system; 60% of patients having epilepsy, with 50% having infantile spasms. TS is caused by mutations in the
<i>TSC2</i> genes; 75% of cases are sporadic.
<i>TSC1</i> mutations cause a milder disease. Bilateral periventricular nodular heterotopia (BPNH) consists of confluent and symmetric nodules of grey matter along the lateral ventricles. X‐linked BPNH presents with epilepsy in females and prenatal lethality in most males. Most patients have partial epilepsy.
<i>Filamin A</i> mutations have been reported in families and sporadic patients. Lissencephaly (LIS ‐‐ smooth brain) is a severe MCC characterised by absent or decreased convolutions. Classical LIS is quite rare and manifests with severe developmental delay, spastic quadriparesis and severe epilepsy.
<i>XLIS</i> mutations cause classical lissencephaly in hemizygous males and subcortical band heterotopia in heterozygous females. Thickness of heterotopic band and degree of pachygyria correlate well with phenotype severity. Schizencephaly (cleft brain) has a wide anatomo‐clinical spectrum, including partial epilepsy in most patients. Polymicrogyria (excessive number of small and prominent convolutions) has a wide spectrum of clinical manifestations ranging from early onset epileptic encephalopathy to selective impairment of cognitive functions. Bilateral perisylvian polymicrogyria may be familial. Patients present with facio‐pharingo‐glosso‐masticatory diplegia and epilepsy, which is severe in about 65% of patients.
Marina Bentivoglio, Laura Tassi, Emanuel Pech, Catarina Costa , Paolo F Fabene, Roberto Spreafico
of transient structures, and successive waves of cell proliferation and migration (followed by cell differentiation and maturation), and apoptotic cell death. The appearance of the proliferative ventricular zone and marginal zone, and of the superficial primordial plexiform layer, is followed by the formation of the prospective layer I, of the subplate, whose neurons are destined to die, and of the cortical plate that will give rise to layers II‐VI. Cells arising in the ventricular zone migrate radially using radial glia as a scaffold, and are destined to form pyramidal cells. Cortical interneurons are mainly generated in the ganglionic eminence and migrate along axonal substrates following tangential routes. Disorders of this complex process lead to a wide range of alterations, and focal derangements of cortical organization have been grouped under the term focal cortical dysplasia (FCD). As the result of a neuropathological revision of FCD cases with intractable epilepsy, a novel classification comprising three subgroups of FCD has been introduced, and is supported by electroclinical and neuroimaging data, as well as by the postsurgical outcome of patients: i) architectural dysplasia, characterized by altered cortical lamination; ii) cytoarchitectural dysplasia, with the occurrence of giant neurons besides cortical dyslamination; iii) Taylor‐type cortical dysplasia, in which altered cortical lamination is consistently associated with the occurrence of giant, dysmorphic and ectopic neurons, and frequently with the so‐called balloon cells.
Harvey B. Sarnat, Laura Flores‐Sarnat
morphology, but these criteria must now be integrated with molecular genetic data to enable an etiological classification that also remains useful to the clinician, radiologist and pathologist, who rely upon imaging and tissue examination for diagnosis. Many cerebral malformations previously thought to be a single disorder are now known to be common end‐results of several independent genetic mutations. Examples are holoprosencephaly and lissencephaly. Gradients of genetic expression along the axes of the neural tube, established at the time of gastrulation, may explain many varieties or anatomical and clinical manifestations of cerebral malformations, including the involvement of non‐neural tissues such as in midfacial hypoplasia, that may be attributed to abnormal neural crest migration. Genes of cellular lineage and of symmetry may explain some hamartomatous malformations, such as tuberous sclerosis and hemimegalencephaly. Modern classification should be applicable to the entire CNS as well as regions; schemes that attempt to artificially isolate the cerebral cortex for a "regional classification" may be erroneous even though the genetic defect primarily affects cortical structures because genetic gradients in the neuraxis are excluded and some involve a more subtle but still important expression in subcortical structures.
Giorgio Battaglia, Stefania Bassanini, Tiziana Granata, Veronica Setola, Alessio Giavazzi, Silvia Pagliardini
nodular heterotopia, a cerebral dysgenesis frequently associated with drug‐resistant focal seizures. In the present study, we investigated the mode of neurogenesis in cerebral heterotopia of MAM‐treated rats, by analyzing post‐natal cytoarchitectural features and time of neurogenesis using bromodeoxyuridine immunocytochemistry. The cytoarchitectural analysis demonstrated the existence, in the early post‐natal period, of white matter cellular bands in close anatomical relationship with the heterotopia, which most likely serve as a reservoir of young, migrating neurons for the newly forming heterotopia. The birth dating analysis demonstrated that the period of generation of neurons within the heterotopia and adjacent white matter bands, was extended in comparison to corticogenesis in normal rat brains. In addition, it demonstrated that the heterotopia were formed through a rather precise outside‐in (for cortical and periventricular heterotopia) and dorso‐ventral (for intra‐hippocampal heterotopia) neurogenetic pattern. We hypothesize that the MAM‐induced ablation of an early wave of cortical neurons is sufficient to alter
<i>per se</i> the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different types of heterotopia. On this basis, we suggest a neurogenetic scheme for MAM‐induced heterotopia that can also explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in humans.
and neuronal proliferation, abnormal neuronal migration and abnormal cortical organisation. Focal or multifocal and generalised forms are recognised in each of these groups. In the first group, generalised forms include microlissencephalies. Among focal‐multifocal abnormalities, neoplastic forms include ganglioglioma and dysembryoplastic neuroepithelial tumours. Non‐neoplastic forms include focal cortical dysplasia and tuberous sclerosis. Malformations due to abnormal migration include lissencephalies; cortical heterotopias are recognised in both focal and generalised forms. Abnormal cortical organisation includes polymicrogyria, in generalised or focal forms, and schizencephalies among the focal forms.
Nadia Colombo, Alberto Citterio, Carlo Galli, Laura Tassi, Giorgio Lo Russo, G. Scialfa, Roberto Spreafico
in 1971 as a peculiar malformative disorganisation of the neocortex characterised at histology by loss of cortical lamination and accompanied by giant, dysmorphic neurones and, most frequently, by balloon cells‘ littered throughout the cortex and sub‐cortical white matter. While in the past decades the term cortical dysplasia‘ has referred to various malformations of cortical development, such as agyria, pachygyria, polymicrogyria, heterotopia and hemimegalencephaly, it is now widely accepted that the entity identified by Taylor should be considered separately, from both histological and neuroimaging standpoints. More recently, the recognition of various histological subtypes of focal cortical dysplasia characterised by different degrees of cortical disruption with or without cytological abnormalities has generated several classifications that are still unsatisfactory. With better magnetic resonance capability, subtle and very small focal cortical dysplasias may now be visualised and the differential magnetic resonance aspects of the histological subgroups can be established. We will discuss the problem of histopathological classification and magnetic resonance imaging differentiation of the various subtypes of focal cortical dysplasia in the light of personal data collected from a large series of epileptic patients who underwent surgery and had a histological diagnosis of focal cortical dysplasia.
Judith Helen Cross
dysfunction, predominantly through disturbances in metabolism or blood flow. Techniques available include single photon emission computed tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Although the use of these diagnostic techniques is widely reported for presurgical evaluation, there has been little work with specific reference to malformations of cortical development.
on visual inspection of conventional MRI is difficult due to their subtlety and the complexity of the brain‘s convolutions. Quantitative MR image processing methods have the potential to help identify lesions that may be overlooked by conventional radiological evaluation. To increase the sensitivity of MRI for the detection of subtle lesions of FCD, we recently developed voxel‐based image post‐processing methods, including first‐order texture analysis and morphological processing modeled on known MRI features of FCD. Using these methods we were able to increase the sensitivity over conventional MRI analysis by more than 30%, while maintaining a high degree of reliability. The image processing methods we developed improve visual detection of FCD, even in cases where no lesion is obvious on MRI. Therefore, these techniques could allow a more precise evaluation of patients with partial epilepsy who could benefit from surgery.
Paolo Tinuper, Giuseppe d‘Orsi, Francesca Bisulli, Anna Zaniboni, Antonella Piraccini, Bruno Bernardi, Agostino Baruzzi
data of a series of sixty adult epileptic patients with different types of malformation of cortical development, who had been followed at the Epilepsy Centre of the Department of Neurological Sciences of the University of Bologna, with particular attention to age at seizure onset, mental retardation, response to therapy, and EEG features. The heterogeneity of our population, especially when divided into the different groups of malformation of cortical development, precluded any general conclusions, but we stress the following aspects: 1) epilepsy due to malformation of cortical development may begin in adolescents and young adults; 2) epileptic seizures with clinical and polygraphic features of infantile spasms may persist into adulthood; 3) complex cortical malformation is not necessarily associated with severe epileptic encephalopathy. In periventricular nodular heterotopias, the largest in our series (nine patients), age at onset of seizures, response to therapy and mental deterioration differed according to the presence of nodules confined to the ventricular wall (pure‘ form) or periventricular nodules associated with other cerebral cortical malformations (plus‘ form).
yield and expected benefit of epilepsy surgery for the patient. Recent advances in imaging techniques now allow more accurate placement of the subdural electrodes and also limit the number required.
to assess by imaging, and some focal cortical dysplasias can be missed by magnetic resonance imaging. The combination of high‐resolution magnetic resonance imaging and neurophysiological findings provided by direct intra‐lesional recordings has greatly improved diagnosis and surgical outcome in focal cortical dysplasias. Stereo‐EEG has demonstrated that dysplastic areas show continuous spiking activity persisting after diazepam injection and are the site of ictal discharge onset. Surgery guided by stereo‐EEG made seizure‐free outcome possible for all patients recently investigated and who had undergone surgery in our centre for extra‐temporal partial epilepsy associated with focal cortical dysplasias (10 patients, mean follow‐up: 15 months). Moreover, we demonstrated that limited resections can be performed safely in eloquent cortex without permanent disability. These results demonstrate the usefulness of stereo‐EEG in surgical treatment for focal cortical dysplasias, despite the invasive nature of this procedure.
Stefano Francione, Lino Nobili, Francesco Cardinale, Alberto Citterio, Carlo Galli, Laura Tassi
clinical details have been identified for Taylor‘s focal cortical dysplasia, and in a recent article we reported a better post‐surgical outcome in Taylor‘s focal cortical dysplasia than in other histological subtypes of cortical dysplasias. In the present study, we analysed the intra‐lesional electrical activity directly recorded inside Taylor‘s focal cortical dysplasia during a stereo‐EEG diagnostic procedure in 21 patients selected from among the 27 cases in which post‐operative neuropathological examination demonstrated this kind of lesion. Our data show the existence of a peculiar interictal pattern characterised by the presence of repetitive and rhythmic spike and poly‐spike and wave, frequently associated with short bursts of fusiform micro poly‐spikes. Moreover, an almost pathognomonic ictal pattern (mid‐amplitude 14‐18 Hz rhythmic activity followed by a low voltage recruiting fast activity) is present in 12 of these 21 patients. These electrical peculiarities suggest a high level of epileptogenicity of Taylor‘s focal cortical dysplasia and could possibly explain the high percentage of post‐surgical success among patients with this kind of lesion.
Abnormalities of cortical development and epilepsy
Giorgio Lo Russo, Laura Tassi, Massimo Cossu, Francesco Cardinale, Roberto Mai, Laura Castana, Nadia Colombo, Manuela Bramerio
has been used in reference to a wide range of alterations of the cortical mantle. Focal cortical dysplasias represent the main group of malformations of cortical development, but there are also other types of alterations, such as heterotopias, double cortex or polymicrogyria. Defining candidacy for surgical therapy and tailored resection requires thorough pre‐surgical evaluation so that the approach will be individualised for each patient. We present our series of 126 patients with malformation of cortical development selected from 321 consecutively operated patients. Within this group encompassing different types of malformation of cortical development, including periventricular heterotopia (nine patients), polymicrogyria (three patients), hemimegalencephaly (one patient) and subcortical band heterotopia (one patient), the largest group was 81 individuals with focal cortical dysplasia. For this last group, we propose a simplified classification defining 42 architectural dysplasias, 12 cytoarchitectural dysplasias and 27 Taylor‘s focal cortical dysplasias. In addition, at routine neuropathological investigation, the only morphological alteration shown by 31 patients was diffuse neuronal heterotopia. All patients underwent scalp EEG and video‐EEG, and 75 patients (59.5%) also underwent stereo‐EEG. Magnetic resonance imaging and stereotactic stereoscopic angiography represented the indispensable premises for further studies, in particular stereo‐EEG, and for planning surgery and tailoring resection. Magnetic resonance imaging was unhelpful in 17 out of 81 patients with focal cortical dysplasia and in seven out of 31 with neuronal heterotopia, while signal alterations were present in all other cases. Common characteristics corresponding to clinical‐histopathological homogeneous subgroups were found within the focal cortical dysplasia group. In patients with architectural dysplasia, the epileptogenic zone was mainly in the temporal lobe and there was a lower seizure frequency than in patients with Taylor‘s focal cortical dysplasia. Patients with Taylor‘s type had an epileptogenic zone that was mainly extra‐temporal, and a distinctive interictal stereo‐EEG. The best outcome was observed in patients with Taylor‘s type dysplasia: 69% seizure‐free (Engel class Ia) after at least 1 year of follow‐up, compared with 45% of cytoarchitectural dysplasia and 49% of architectural dysplasia patients.
Jean Guy Villemure, Kathleen Meagher‐Villemure, Jose Luis Montes, Jean‐Pierre Farmer, Giovanni Broggi
hemispherectomy, either functional hemispherectomy or peri‐insular hemispherotomy. The median age at surgery was 4.5 years old and the interval between seizure onset and surgery, 3 years. All patients underwent a presurgical evaluation that led to the suggestion of disconnective hemispherectomy. Over 70% of patients have remained in Engel‘s seizure outcome class I since surgery and another 18% have had a satisfactory seizure outcome. There was one unexplained death and one case of early hydrocephalus. Hemispherectomy offers the possibility to improve seizure control in the majority of patients undergoing surgery for extensive dysplastic pathology of the hemisphere. Disconnective techniques reduce the rate of complications in this specific pathology.