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The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders., (© 2023 International League Against Epilepsy.)

Objective: Familial adult myoclonic epilepsy (FAME) is an under-recognized disorder characterized by cortical myoclonus, generalized tonic-clonic seizures, and additional clinical symptoms, which vary depending on the FAME subtype. FAME is caused by pentanucleotide repeat expansions of intronic TTTCA/TTTTA in different genes. FAME should be distinguished from a range of differential diagnoses., Methods: The differential diagnoses and frequent presentations leading to misdiagnosis of FAME were investigated from the available literature and reported based on an expert opinion survey., Results: The phenotypic features of FAME, including generalized tonic-clonic and myoclonic seizures, are also seen in other epilepsy syndromes, such as juvenile myoclonic epilepsy, with a resultant risk of misdiagnosis and lack of identification of the underlying cause. Cortical myoclonus may mimic essential tremor or drug-induced tremor. In younger individuals, the differential diagnosis includes progressive myoclonus epilepsies (PMEs), such as Unverricht-Lundborg disease, whereas, in adulthood, late-onset variants of PMEs, such as sialidoses, myoclonus epilepsy, and ataxia due to potassium channel pathogenic variants should be considered. PMEs may also be suggested by cognitive impairment, cerebellar signs, or psychiatric disorders. Electroencephalography (EEG) may show similarities to other idiopathic generalized epilepsies or PMEs, with generalized spike-wave activity. Signs of cortical hyperexcitability may be seen, such as an increased amplitude of somatosensory evoked potentials or enhanced cortical reflex to sensory stimuli, together with the neurophysiological pattern of the movement disorder., Significance: Recognition of FAME will inform prognostic and genetic counseling and diagnosis of the insidious progression, which may occur in older individuals who show mild cognitive deterioration. Distinguishing FAME from other disorders in individuals or families with this constellation of symptoms is essential to allow the identification of underlying etiology., (© 2023 International League Against Epilepsy.)

Our goal was to assess the interrater agreement (IRA) of photoparoxysmal response (PPR) using the classification proposed by a task force of the International League Against Epilepsy (ILAE), and a simplified classification system proposed by our group. In addition, we evaluated IRA of epileptiform discharges (EDs) and the diagnostic significance of the electroencephalographic (EEG) abnormalities. We used EEG recordings from the European Reference Network (EpiCARE) and Standardized Computer-based Organized Reporting of EEG (SCORE). Six raters independently scored EEG recordings from 30 patients. We calculated the agreement coefficient (AC) for each feature. IRA of PPR using the classification proposed by the ILAE task force was only fair (AC = 0.38). This improved to a moderate agreement by using the simplified classification (AC = 0.56; P = .004). IRA of EDs was almost perfect (AC = 0.98), and IRA of scoring the diagnostic significance was moderate (AC = 0.51). Our results suggest that the simplified classification of the PPR is suitable for implementation in clinical practice., (© 2020 International League Against Epilepsy.)

Genetic factors play a major role in the etiology of juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, but so far, genes related to JME remain largely unknown. JME shares electroclinical features with Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1; EPM1), a form of progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and gradual neurologic deterioration. EPM1 is caused by mutations in the gene that codes for cystatin B (CSTB), an inhibitor of cysteine protease. In the present study, we wished to investigate the role of the CSTB gene in patients with JME. Fifty-seven unrelated patients (35 women; mean age ± standard deviation [SD], 24.1 ± 7.7; mean age ± SD at onset, 15.3 ± 2.4) with JME were enrolled. Twenty-three of 57 patients were the probands of families with JME. The molecular diagnosis was carried out to identify the common dodecamer repeat expansion mutation or other disease-causing mutations in the CSTB gene. The molecular analysis did not depict mutations in any of the 57 patients with JME. Our study did not support a role for the CSTB gene in patients with familial or sporadic JME., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

We report clinical, neurophysiologic, and genetic features of an Italian series of patients with Lafora disease (LD) to identify distinguishing features of those with a slowly progressive course. Twenty-three patients with LD (17 female; 6 male) were recruited. Mean age (± SD) at the disease onset was 14.5 ± 3.9 years and mean follow-up duration was 13.2 ± 8.0 years. NHLRC1 mutations were detected in 18 patients; EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as "mild" and were compared with the remaining LD patients with a typical course. Six of 23 patients were mild and presented significantly delay in the age at onset, lower neurologic disability score at 4 years after the onset, less severe seizure phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to patients with typical LD. However, in both mild and typical LD patients, EEG showed disorganization of background activity and frequent epileptiform abnormalities. Mild LD patients had NHLRC1 mutations and five of six carried homozygous or compound heterozygous D146N mutation. This mutation was found in none of the patients with typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD should be taken into account in clinical practice for appropriate management and counseling., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del; CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Purpose: Epilepsy can impair theory of mind (ToM), but the clinical significance of such a deficit is unknown. This study evaluated the influence of selective ToM deficits on self-appraisal, coping, and quality of life (QoL) in patients with focal epilepsy., Methods: Data were collected from 66 patients with temporal or frontal lobe epilepsy, and from 42 healthy controls. The Faux Pas Task (FPT), Multiple Ability Self-report Questionnaire (MASQ), Coping Responses Inventory-Adult (CRI-Adult), and World Health Organization QoL 100 (WHOQoL 100) evaluated ToM, self-rated cognitive abilities, coping to stressful events, and QoL. Different tests and inventories assessed other cognitive functions, depression, and anxiety., Key Findings: Patients were impaired in the recognition and comprehension of social faux pas. The FPT scores contributed to predict the MASQ, CRI-Adult, and WHOQoL overall scores; the comprehension of others' mental states and interactions score exerted a prominent influence., Significance: In patients with focal epilepsy, selective ToM deficits may have clinical implications, with specific influence on self-appraisal, coping, and overall QoL. ToM evaluation may contribute in explaining some psychobehavioral difficulties and to plan nonpharmacological treatment., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Purpose: Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV 1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced γ-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS., Methods: We have studied heterozygous NaV 1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures., Key Findings: In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase., Significance: We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Purpose: To report the identification of the T1174S SCN1A (NaV 1.1) mutation in a three-generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the pathomechanism., Methods: The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA-201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K)., Key Findings: The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (I(NaP)), consistent with gain of function. The I(NaP) increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions., Significance: Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype-phenotype relationship of SCN1A mutations., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Purpose: To classify the grade of antiepileptic drug (AED) resistance in a cohort of patients with focal epilepsies, to recognize the risk factors for AED resistance, and to estimate the helpfulness of "new-generation" AEDs., Methods: We included 1,155 adults with focal epilepsies who were observed consecutively after 1990 and followed regularly at two epilepsy centers. We systematically collected the clinical, diagnostic, and therapeutic data using a custom-written database. We classified the patients as seizure-free or AED resistant according to the International League Against Epilepsy (ILAE) criteria, and we evaluated the risk factors associated with AED resistance using logistic regression analysis. We further grouped AED-resistant patients in different grades (I, II, and III) according to the number of AEDs already tried as proposed by Perucca., Key Findings: AED resistance occurred in 57.8% of the 729 patients with symptomatic focal epilepsies and was positively associated with electroencephalography (EEG) abnormalities, seizure type, and the presence of mesial temporal sclerosis. Among 426 patients without detectable causes, the percentage of AED resistance was significantly lower (39.2%) and correlated with EEG abnormalities and psychiatric symptoms. Among AED-resistant patients, the majority (64.6%) had tried three or more AEDs, which fit the more severe grade III proposed by Perucca. Among seizure-free patients, more than one-half (57%) needed to try two or more AEDs before reaching seizure control (14.9% needed three or more AEDs). Furthermore, among seizure-free patients who could be previously classified as resistant to two or more AEDs, 52.2% reached seizure freedom while receiving treatment with "new generation" AEDs., Significance: The ILAE classification of AED resistance, as well the graded classification proposed by Perucca, was easily exploitable in our patients, although these classifications systems appear to have a limited value in predicting seizure outcome. Actually, a small but not negligible percentage of patients reached seizure freedom after trying several AEDs (including "new" AEDs), suggesting repeated trials may be necessary for seizure control., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Photosensitive epilepsy (PSE) is the most common form of reflex epilepsy presenting with electroencephalography (EEG) paroxysms elicited by intermittent photic stimulation (IPS). To investigate whether the neuronal network undergoes dynamic changes before and during the transition to an EEG epileptic discharge, we estimated EEG connectivity patterns in photosensitive (PS) patients with idiopathic generalized epilepsy., Methods: EEG signals were evaluated under resting conditions and during 14 Hz IPS, a frequency that consistently induces photoparoxysmal responses (PPRs) in PS patients. Partial directed coherence (PDC), a linear measure of effective connectivity based on multivariate autoregressive models, was used in 10 PS patients and 10 controls. Anterior versus posterior (F3, F4, C3, C4, and P3, P4, O1, O2) and interhemispheric connectivity patterns (F4, C4, P4, O2, and F3, C3, P3, O1) were estimated with focus on beta and gamma band activity., Key Findings: PDC analysis revealed an enhanced connectivity pattern in terms of both the number and strength of outflow connections in the PS patient group. Under resting condition, the greater connectivity in the PS patients occurred in the beta band, whereas it mainly involved the gamma band during IPS (i.e., the frequencies ranging from 40-60 Hz that include the higher harmonics of the stimulus frequency). Both at rest and during IPS, the differences between the PS patients and controls were due primarily to clearly increased connectivity involving the anterior cortical regions., Significance: Our findings indicate that PS patients are characterised by abnormal EEG hyperconnectivity, primarily involving the anterior cortical regions under resting conditions and during IPS. This suggests that, even if the occipital cortical regions are the recipient zone of the stimulus and probably hyperexcitable, the anterior cortical areas are prominently involved in generating the hypersynchronization underlying the spike-and wave discharges elicited by IPS., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: Dravet syndrome (DS), a devastating epileptic encephalopathy, is mostly caused by mutations of the SCN1A gene, coding for the voltage-gated Na(+) channel Na(V)1.1 α subunit. About 50% of SCN1A DS mutations truncate Na(V)1.1, possibly causing complete loss of its function. However, it has not been investigated yet if Na(V)1.1 truncated mutants are dominant negative, if they impair expression or function of wild-type channels, as it has been shown for truncated mutants of other proteins (e.g., Ca(V) channels). We studied the effect of two DS truncated Na(V)1.1 mutants, R222* and R1234*, on coexpressed wild-type Na(+) channels., Methods: We engineered R222* or R1234* in the human cDNA of Na(V)1.1 (hNa(V)1.1) and studied their effect on coexpressed wild-type hNa(V)1.1, hNa(V)1.2 or hNa(V)1.3 cotransfecting tsA-201 cells, and on hNa(V)1.6 transfecting an human embryonic kidney (HEK) cell line stably expressing this channel. We also studied hippocampal neurons dissociated from Na(V)1.1 knockout (KO) mice, an animal model of DS expressing a truncated Na(V)1.1 channel., Key Findings: We found no modifications of current amplitude coexpressing the truncated mutants with hNa(V)1.1, hNa(V)1.2, or hNa(V)1.3, but a 30% reduction coexpressing them with hNa(V)1.6. However, we showed that also coexpression of functional full-length hNa(V)1.1 caused a similar reduction. Therefore, this effect should not be involved in the pathomechanism of DS. Some gating properties of hNa(V)1.1, hNa(V)1.3, and hNa(V)1.6 were modified, but recordings of hippocampal neurons dissociated from Na(V)1.1 KO mice did not show any significant modifications of these properties. Therefore, Na(V)1.1 truncated mutants are not dominant negative, consistent with haploinsufficiency as the cause of DS., Significance: We have better clarified the pathomechanism of DS, pointed out an important difference between pathogenic truncated Ca(V)2.1 mutants and hNa(V)1.1 ones, and shown that hNa(V)1.6 expression can be reduced in physiologic conditions by coexpression of hNa(V)1.1. Moreover, our data may provide useful information for the development of therapeutic approaches., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment., Methods: Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations., Key Findings: The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer., Significance: Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: Theory of mind (ToM) is an important prerequisite to social behavior. This study evaluated ToM in patients with temporal (TLE) or frontal lobe epilepsy (FLE) aiming to determine the cognitive aspects, severity, and pathophysiologic mechanisms of ToM impairment in focal epilepsy., Methods: One hundred thirty-eight patients with TLE (n = 109) or FLE (n = 29) and 69 healthy subjects underwent the Faux Pas task (FPT), which evaluates the recognition and comprehension of others' mental states, and neuropsychological tests for other cognitive functions., Key Findings: Factor analysis of all test scores yielded two ToM factors (Recognizing faux pas, FP; Excluding nonexistent FP) distinct from the Control, Language, Matching, and Praxis factors. With respect to healthy subjects, both TLE and FLE patients showed correct exclusion of nonexistent FPs but significantly lower recognition and comprehension of real FPs. FLE patients were also impaired with respect to TLE patients. In the whole patient group, schooling and group membership predicted ToM impairment. In FLE patients, the comprehension of mental states was predicted by disease duration, whereas TLE patients' comprehension of affects and intentions was associated with early age of seizure onset and medial temporal lobe sclerosis (MTLS)., Significance: Focal epilepsy impairs advanced ToM abilities. FLE may affect online performances owing to long-lasting dysfunctions of the prefrontal areas. MTLS may provoke selective ToM deficits due to medial temporal damage, prefrontal dysfunctions, or early interference with cognitive development. Future studies are needed to determine the implications of ToM impairment on behavior and quality of life., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: To characterize the fast EEG activities associated with infantile spasms in West syndrome, and their value in predicting the recurrence and localization of late seizures., Methods: We selected 23 infants who were followed for at least 2 years. Selected EEG recordings underwent autospectra, coherence, and phase analyses in order to assess the changes during follow-up., Results: Short discharges of fast-rhythms (331 +/- 190 ms) with a lateralized onset were detected in 18 of the 23 infants (78.3%). There were no significant differences in the parameters characterizing ICTAL beta-activity (frequency, duration, inter-hemispheric coherence, or transfer time) between the infants with or without seizure recurrence. However, beta-discharges with a consistent location formed part of the ICTAL EEG in all 10 infants with seizure recurrence, but only in eight (61.5%) of those who remained seizure-free (SF) (p < 0.05). In all but one of the infants experiencing seizure recurrence, the ICTAL discharges associated with the late seizures apparently originated from the same hemisphere as that involved at the beginning of the spasm-associated beta-activity, although the precise location varied., Conclusions: Spectral, coherence and phase analyses detected spasm-associated runs of lateralized beta-rhythms in many of our infants with West syndrome. This ICTAL pattern significantly correlated with seizure recurrence. The consistent lateralization of the ICTAL EEG events associated with both the early spasms and late seizures suggests that EEG beta-activities should be considered as indicating local cortical dysfunction in infants who fail to respond to early treatment and often progress toward severe epilepsy.

Purpose: To report in detail the electroclinical features of a large family in which we recently identified a missense mutation (M145T) of a well-conserved amino acid in the first transmembrane segment of domain I of the human SCN1A. We showed that the mutation is associated with a loss of SCN1A function., Methods: The family originates from southern Italy and contains 35 members spread over four generations. Of the 14 affected individuals, the 13 still living members (7 males, mean age 36.6 +/- 20.4) underwent a complete electroclinical evaluation., Results: All 13 affected family members had febrile seizures (FS) up to the age of 6 years. Age at onset of FS ranged from 5 to 45 months with a mean age of 12.8 +/- 12.9 months. One of the 13 was affected by post-traumatic epilepsy. Three of the 13 later developed temporal lobe epilepsy (TLE) with both simple focal seizures, and also very rare focal complex or nocturnal secondary generalized tonic-clonic seizures. In two of the three patients who later developed TLE, the MRI studies revealed mesial temporal sclerosis., Conclusions: Our findings illustrate that SCN1A mutations can cause simple FS associated with TLE, which differ from the characteristic clinical spectrum of GEFS+. It is open to conjecture if this unusual phenotype might at least in part be related to the fact that M145T is the first missense mutation found in DIS1 of SCN1A.

The discovery of genetically determined epileptic syndromes associated with specific mutations of genes codifying for subunits of voltage or ligand-activated ion channels highlights the role of ion channels in epileptogenesis. In vitro and in vivo models of channel pathology have been used to define the functional consequence of the mutations identified in human epilepsies. The evaluation of gene-channel mutations based on molecular and physiological techniques have provided significant knowledge on the cellular mechanisms leading to inherited human epilepsies, and possibly to nongenetic human epilepsies due to "acquired" channel pathologies. We review some of the studies that have explored human epileptic disorders through experimental manipulations of these channels, highlighting some of the difficulties that have arisen using "in vitro" preparations or rodent models. These findings underscore the need for further studies to address the mechanisms involved in mutated-channel dysfunctions.

Purpose: EPM2B mutations have been found in a variable proportion of patients with Lafora disease (LD). Genotype-phenotype correlations suggested that EPM2B patients show a slower course of the disease, with delayed age at death, compared with EPM2A patients. We herein report clinical and genetic findings of 26 Italian LD patients., Methods: Disease progression was evaluated by means of a disability scale based on residual motor and cognitive functions and daily living and social abilities, at 4 years from the onset. Mutational analysis was performed by sequencing the coding regions of the EPM2A and EPM2B genes., Results: Age at onset ranged from 8.5 to 18.5 years (mean, 13.7+/-2.6). The mean duration of follow-up was 7.1+/-3.9 years. Daily living activities and social interactions were preserved in five of 24 patients. The remaining patients showed moderate to extremely severe limitations of daily living and social abilities. Sixteen (72%) of 22 families showed mutations in the EPM2B gene, and five (22%), in the EPM2A gene. One family showed no mutations. A novel EPM2B mutation also was identified., Conclusions: In our series, EPM2B mutations occurred in 72% of families, thus indicating that EPM2B is the major gene for LD in the Italian population. Moreover, we found that six of 17 EPM2B patients preserved daily living activities and social interactions at 4 years from onset, suggesting a slow disease progression. Additional clinical and functional studies will clarify whether specific mutations may influence the course of the disease in LD patients.

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: 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.

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.