Hypothalamic hamartoma: is the epileptogenic zone always hypothalamic? Arguments for independent (third stage) secondary epileptogenesis.

Gelastic seizures associated with hypothalamic hamartomas (HHs) are a clinicoradiologic syndrome presenting with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, electroencephalography (EEG) abnormalities, precocious puberty, behavioral disturbances, and progressive cognitive deterioration. Surgery in adults provides seizure freedom in only one third of patients. The poor results of epilepsy surgery could be explained by an extrahypothalamic epileptogenic zone. The existence of an independent, secondary epileptogenic area with persistent seizures after resection of the presumably primary lesion supports the concept of a "hypothalamic plus" epilepsy. "Hypothalamic plus" epilepsy could be related to either an extrahypothalamic structural lesion (visible on magnetic resonance imaging [MRI] or on neuropathology) or if the former is absent, to a functional alteration with enhanced epileptogenic properties due to a process termed secondary epileptogenesis. We report two patients with gelastic seizures with HH (gelastic seizures isolated or associated with dyscognitive seizures of temporal origin). Both patients underwent two-step surgery: first an endoscopic resection of the HH, followed at a later time by temporal lobectomy. Both patients became seizure-free only after the temporal lobectomy. In both cases, neuropathology failed to demonstrate a significant structural lesion in the temporal lobe. To our knowledge, for the first time, these two cases suggest the existence of independent secondary epileptogenesis in humans.

Misleading features of neuroimaging and electroencephalography: insulinoma misdiagnosed as temporal lobe epilepsy.

Epilepsy is a common disorder but diagnosis remains largely clinical. Although MRI and EEG significantly aid the diagnosis of epilepsy, these techniques may also be misleading and indicate abnormalities not related to phenomenology. Consequences of erroneous diagnosis of epilepsy may lead to aggressive and escalating pharmacotherapy with potentially serious side effects. Metabolic disorders, which may mimic epilepsy, should always be considered as they are potentially curable and may be fatal if untreated. We report a case of an insulinoma, misdiagnosed as temporal lobe epilepsy. We highlight the risks associated with misinterpretation of neuroimaging and EEG and outline an approach to differentiate between symptoms of insulinoma or neuroglycopenia and temporal epileptic seizures.

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism.

PURPOSE: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. METHODS: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). KEY FINDINGS: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10(-7)). SIGNIFICANCE: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.

Eyelid fluttering, typical EEG pattern, and impaired intellectual function: a homogeneous epileptic condition among the patients presenting with eyelid myoclonia.

PURPOSE: This retrospective study aims to review the electroclinical features of patients presenting with eyelid myoclonia (EM) with and without absences. METHODS: The Italian chapter of the International League Against Epilepsy (ILAE) has been conducting an electroclinical study of patients with EM. Among these, we searched for and selected the patients presenting with both impairment of intellectual functions and a peculiar ictal electroencephalography (EEG) pattern, that is, a discharge of fast generalized polyspikes/polyspikes and waves. RESULTS: We found 18 patients matching this electroclinical picture. All the patients were photosensitive. All of them had associated generalized, mostly nocturnal, tonic-clonic seizures. During the evolution, 13 patients presented episodes of EM status. Despite adequate antiepileptic treatment, the patients remained drug resistant for many years or throughout the evolution. The degree of impairment of intellectual functions varied from borderline level to moderate mental retardation. DISCUSSION: The patients we described herein can be considered a homogeneous group in the more heterogeneous group of patients presenting with EM. Further clinical and, more probably, genetic studies will clarify whether this condition could be considered a specific and homogeneous condition in the more heterogeneous group of patients presenting with EM.

Landau-Kleffner syndrome is not an eponymic badge of ignorance.

In a 1992 editorial article, Landau expressed the hope of collective agreement in the medical community about Landau-Kleffner syndrome (LKS) in terms of diagnosis criteria, etiology, pathophysiology and rational therapy. Since then, neurophysiological and neuroimaging studies have led to the view that LKS is an acquired aphasia, secondary to an epileptic disturbance affecting a cortical area involved in verbal processing. This fits with the hypothesis of a "functional ablation" caused by epileptic activity. Under these criteria, epileptic aphasia becomes a subgroup of the continuous spike-waves syndrome in which epileptic discharges originate from the temporal cortex. Genetic predisposition for KLS could be related to hyperexcitability and synchronization of interneurons within the perisylvian cortices, which generate the spike-waves. Activation of these waves during NREM sleep, following thalamo-cortical uncoupling, might then alter the blood brain barrier and provoke an autoimmune reaction. Interneuron hyperactivity might in turn have an antiepileptic protective effect, associated with the inhibition of a specific function, and spike-waves activity over the long term might eventuate in focal atrophy. This morphological defect might explain the poor verbal outcome in some cases of LKS. From this study we recommend a multicenter control study of good design and methodology be carried out to compare the efficacies of early versus delayed (3 months) corticosteroid treatment in patients with typical LKS that is being treated by clobazam (or diazepam) monotherapy.

Isolated paroxysmal arousals as focal epilepsy.

Paroxysmal motor phenomena and arousals during sleep are frequent. The differential diagnoses between benign hypnic transient events, epileptic and non-epileptic seizures represent a common clinical problem. Video-EEG monitoring during sleep, recording several episodes in the same patient, is essential in order to characterize these phenomena. It offers the possibility to compare electro-clinical data, to demonstrate the eventual stereotyped pattern of motor phenomena and their progression in time, and to study EEG-polygraphic correlates. The recently described double split-screen synchronized display (DSSSD) technique represents a useful tool for comparing particular clinical patterns of epileptic seizures when dealing with complex, hypermotor phenomena observed in frontal lobe epilepsy. We reviewed the data of 24 patients admitted during a two-year period (2002-2003) to our epilepsy sleep unit for isolated paroxysmal sleep motor events. Four patients presented with very brief paroxysmal arousals without daytime fits. Three of our patients presented isolated paroxysmal arousals, whereas in one, the events were associated with hypermotor seizures. We present a simplified variant of the DSSSD method (modified DSSSD) that can be used to study episodes of paroxysmal arousals in order to confirm their stereotyped motor pattern. The clinical aspects and the EEG-polygraphy patterns were informative, with the absence of asymmetrical tonic or dystonic posturing of the limbs. Scalp EEG alone does not usually provide much information in patients with isolated paroxysmal arousals. Coupled to the modified DSSSD technique, it may allow confirmation of the diagnosis of frontal epilepsy, as was the case in our four patients. [Published with video sequences].

Towards a definition of the "practical" epileptogenic zone: a case of epilepsy with dual pathology.

Presurgical evaluation for patients with drug-resistant epilepsy requires the definition of various zones that have a variable spatial relationship with the epileptogenic zone. All the available methods to directly measure the actual seizure-onset zone and to define "the minimum amount of cortical tissue that must be resected to produce seizure-freedom" have significant limitations. We report on the case of a patient with dual pathology (hippocampal sclerosis and a post-traumatic scar) and discuss the contribution of the various presurgical investigations that led to surgery and seizure-freedom.

Ictal and interictal perfusion variations measured by SISCOM analysis in typical childhood absence seizures.

Single photon emission computed tomography (SPECT) is currently used in the presurgical evaluation of medically intractable partial epilepsies, but not very often, in generalized epilepsy. In the present study, we used the SISCOM procedure, which represents the fusion of MRI and ictal-interictal difference SPECT images using (99m)Tc-ECD, to study cerebral blood flow changes during the ictal and postictal phases of typical childhood absence seizures. The study was performed on four children with typical, difficult to treat absence seizures, aged 10-13 years at the time of scan. The delay between the onset of absence seizures and the injection of (99m)Tc-ECD was carefully noted. One scan was performed during the ictal phase and showed diffuse blood flow decreases, while the three other scans performed during the postictal phase, showed generalized blood flow increase. These data are consistent with most previous data reporting generalized changes in functional activity, not limited to the thalamo-cortical circuit in which absence seizures originate, and a decrease in cerebral blood flow during the ictal phase. Our data are concordant with the hypothesis that neuronal activity underlying the occurrence of spike-and-wave discharges does not seem to require an increase in metabolic demand and blood flow rates. [Published with videosequences].

Language-induced epilepsy, acquired stuttering, and idiopathic generalized epilepsy: phenotypic study of one family.

PURPOSE: Language-induced epilepsy involves seizure precipitation by speaking, reading, and writing. Seizures are similar to those of reading epilepsy (RE). The nosologic position of language-induced epilepsy is not clear. We performed a clinical and neurophysiological study in a multigenerational family with the association of idiopathic generalized epilepsy (IGE) with ictal stuttering as a manifestation of reflex language-induced epilepsy. METHODS: Nine members on three generations were studied. All patients underwent video-polygraphic EEG recordings (awake and during sleep). A standardized protocol was applied to test the effect of language and non-language-related tasks. RESULTS: Six patients presented language-induced jaw jerking that mimicked stuttering and corresponded to focal myoclonus involving facial muscles. This was associated with an IGE phenotype in four of these patients. Focal EEG spikes were found in all six patients by visual analysis and/or back-averaging techniques. The focal spikes were either asymptomatic (when followed by a slow wave) or symptomatic of facial myoclonia (when isolated). Levetiracetam, used as add-on or monotherapy in four patients, suppressed ictal stuttering. One additional case only had a phenotype of IGE without focal features. CONCLUSIONS: This family study demonstrates the phenotypic heterogeneity of the association of IGE phenotype with ictal stuttering (language-related reflex seizure). Our data suggest that this particular form of reflex epilepsy related to language has more similarities with generalized epilepsies than with focal ones. Neurophysiological investigations should be performed more systematically in patients with acquired stuttering, especially if there is family history of IGE.

SRPX2 mutations in disorders of language cortex and cognition.

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.