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Aim: The aim of this study was to analyze electroclinical features of a group of patients with West syndrome (WS) who subsequently developed Lennox-Gastaut syndrome (LGS) during the transition between both syndromes., Methods: A retrospective and descriptive study was conducted of a series of patients diagnosed with WS who developed LGS seen at Hospital de Pediatría Prof. Dr. JP Garrahan between January 2012 and January 2019. The medical charts of 170 patients with WS were analyzed. In 63 (37 %) of the children WS evolved to LGS., Results: During the transition from WS to LGS four well-defined electroclinical patterns were recognized. The first corresponded to a group of patients with multiple seizure types, including epileptic spasms associated with multifocal paroxysms; the electroclinical pattern in second group showed mainly focal seizures associated with focal discharges in the EEG; the third group showed predominance of epileptic spasms and myoclonic seizures associated with diffuse spike-and-wave and polyspike-and-wave paroxysms; and the remaining group was characterized by a mixed electroclinical pattern including features of the other three groups. All patients had a neuropsychological deficit. Worsening of cognition and behavior was observed during the transition period in 11, 8, and 5 patients of groups 1, 3, and 4, respectively., Conclusion: Our study of the transition period from WS to LGS allowed us to recognize four well-defined electroclinical patterns. The early recognition of the different patterns could, in the future, support a more precocious prognostic evaluation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Anti-seizure drugs (ASDs) are widely used and known to increase inhibitory tone on neuro-circuits and reduce aberrant synchronous firing in epilepsy. Some ASDs act as agonist at the GABA A receptor. Stiripentol, known to increase GABA A receptor activity as well as the metabolites of GABA A receptor agonists, is often used in the treatment of an epileptic encephalopathy, Dravet syndrome (DS), which is caused by mutations mainly in SCN1A and in other genes such as GABRG2. We have recently generated a Gabrg2 +/Q390X knockin mouse model associated with DS in humans. The objective of the study was to explore the effects of stiripentol in DS with GABA A receptor functional deficiency because of the etiology heterogeneity in DS. Monotherapy (stiripentol or Diazepam) and polytherapy (stiripentol and diazepam) treatments were tested in Gabrg2 +/Q390X mice challenged with pentylenetetrazol (PTZ) seizure induction in conjunction with video-monitoring synchronized electroencephalogram (EEG) recordings. A combination of stiripentol and diazepam greatly reduced seizure-related events in Gabrg2 +/Q390X mice following PTZ administration and increased survival. However, the treatment of stiripentol alone was mostly ineffective in alleviating seizure-related events except that it reduced mortality in PTZ challenged Gabrg2 +/Q390X mice. The study suggests that stiripentol could be only used as add-on therapy for DS with GABA A receptor functional deficiency, which is consistent with the most established clinical application of stiripentol. The study highlights the importance of mechanism-based precision treatment for DS considering the highly heterogeneous nature of etiology in DS and the fact that mutations in different genes give rise to the same clinical phenotype., (Copyright © 2019. Published by Elsevier B.V.)

We evaluated the long-term prognosis of patients featuring the association of absences and myoclonic epilepsy of infancy. Our cohort consisted of 10 male subjects with mean age at seizure onset of 29 months. Follow-up data included seizure outcome and EEG findings. All individuals received antiepileptic drugs (AEDs) as monotherapy (6 patients) or polytherapy (4 patients) for a mean period of 24 months. Over a 30-60 month evaluation period (mean: 43 months), all patients were seizure-free. Follow-up data after withdrawal of antiepileptic therapy were obtained for a mean period of 22 months. None of the children did develop other age-related epileptic syndrome after AEDs discontinuation. Furthermore, follow-up EEG data after drugs withdrawal were normal and none of the patients showed cognitive impairment. In conclusion, we confirm that absence seizures may occur in association with myoclonic epilepsy of infancy. This condition shows excellent prognosis with either favourable neurologic development and seizure outcome in these children., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: we characterized multifocal myoclonus in Dravet syndrome (DS) that was never systematically typified before., Methods: we studied EEG-EMG recordings of 19 consecutive patients, aged 2-29 years, with DS associated with SCN1A gene mutations to detect and evaluate myoclonus based on the spectrum of EMG activity on antagonist muscle pairs and cortico-muscular coherence (CMC)., Results: multifocal action myoclonus was detected in all patients corresponding to brief EMG bursts, which occurred synchronously on antagonist muscles at a frequency peaking in beta band. There was significant CMC in beta band, and a cortico-muscular transfer time consistent with a cortical origin of the jerks. The somatosensory evoked potentials (SSEPs) were giant in only one patient who also showed exaggerated long-loop reflexes (LLRs). The nine patients who had experienced myoclonic seizures showed greater CMC., Conclusions: The cortical myoclonus consistently observed in patients with DS shows features that are similar to those characterizing progressive myoclonus epilepsy, but differs because it does not have a severely worsening course and is not commonly associated with increased SSEPs or enhanced LLRs. This kind of myoclonus is an intrinsic feature of DS associated with SCN1A mutations, and may be a cause of disability., Significance: We hypothesize that myoclonus is generated in cortical motor areas by hyper-synchronous oscillations, which are possibly due to sodium channel dysfunction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To study the different epilepsy syndromes that included epileptic spasms (ES) in clusters without hypsarrhythmia (WoH)., Methods: Between 2/1990 and 7/2013, we registered 48 patients with the electroclinical diagnostic criteria of ES in clusters WoH., Results: We recognized two subgroups. In the first subgroup of 30 patients, ES started at a mean age of 10.6 months (range, 2-40 months). Ictal EEG recordings showed diffuse high-amplitude slow waves in 15 patients, diffuse slow waves followed by voltage attenuation in six patients, diffuse fast rhythms in five, diffuse slow waves with superimposed fast rhythms in three, and diffuse sharp waves in one. In the second subgroup of 18 patients, nine had electroclinical features of Lennox-Gastaut syndrome, four had epilepsy with myoclonic and atonic seizures, two had Dravet syndrome, one 6-year-old boy had a non-convulsive status epilepticus characterized by atypical absences associated with ES, one had epilepsy with migrating seizures of infancy, and one patient had clinical features of subacute sclerosing panencephalitis with ES. ES started at a mean age of 6.3 years (range, 0.5-13 years). The ictal EEG recording during the ES showed diffuse fast rhythms in 10 cases, diffuse slow waves with superimposed fast rhythms in four, and diffuse slow waves in four., Conclusion: Our study shows two subgroups of children with ESWoH. The first subgroup had a well-defined electroclinical syndrome predominantly in infancy, and in the second subgroup ES was one more seizure type associated with an epileptic encephalopathy other than West syndrome predominantly occurring in childhood., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To describe clinical and EEG phenotypes of a family with an unusual familial epilepsy syndrome characterized by myoclonus and dystonia., Methods: Family members underwent electroclinical phenotyping including review of EEGs and MRI. DNA from family members was genotyped using Illumina OmniExpress genotyping arrays. Parametric and nonparametric linkage analyses were performed using MERLIN., Results: The disorder followed autosomal dominant (AD) inheritance and affected seven individuals over two generations. Seizures began at a mean of 14.5 years. Six individuals had spontaneous myoclonic seizures, of which five also had photic-induced myoclonus and four had photic-induced occipital seizures. Six individuals had convulsive seizures; generalized in two and focal in four. Photosensitivity was prominent with generalized spike wave and polyspike wave in four individuals of which two also had occipital spikes. MRI scans were normal in the four individuals tested. Extensive metabolic investigation was normal. Juvenile myoclonic epilepsy (JME) occurred in two; and JME overlapping with idiopathic photosensitive epilepsy (IPOE) in four individuals. All three affected males had a more severe disorder than the four affected females. Two males had a progressive neurological disorder with progressive myoclonus epilepsy and deterioration in their early 30s. They developed episodes of paroxysmal cervical dystonia with cognitive decline during periods of poor seizure control. One plateaued after years of poor seizure control but remained intractable with periods of deterioration. The other deteriorated with episodes of status dystonicus and status epilepticus, ataxia and a progressive ophthalmoplegia before succumbing at 38 years. Parametric linkage analysis identified three peaks achieving a maximum LOD score of 1.21. Nonparametric analysis identified eight peaks achieving LOD scores above 0.80. These were not statistically significant., Conclusions: This is a novel autosomal dominant familial epilepsy syndrome. "Myoclonic occipital photosensitive epilepsy with dystonia" (MOPED) involves a spectrum of phenotypes from JME, sometimes with an IPOE overlap, to progressive myoclonus epilepsy with paroxysmal dystonia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A consanguineous family from Turkey having two children with intellectual disability exhibiting myoclonic, febrile and other generalized seizures was recruited to identify the genetic origin of these phenotypes. A combined approach of SNP genotyping and exome sequencing was employed both to screen genes associated with Dravet syndrome and to detect homozygous variants. Analysis of exome data was extended further to identify compound heterozygosity. Herein, we report identification of two paternally inherited genetic variants in SCN1A (rs121917918; p.R101Q and p.I1576T), one of which was previously implicated in Dravet syndrome. Interestingly, the previously reported clinical variant (rs121917918; p.R101Q) displayed mosaicism in the blood and saliva of the father. The study supported the genetic diagnosis of affected children as Dravet syndrome possibly due to the combined effect of one clinically associated (rs121917918; p.R101Q) and one novel (p.I1576T) variants in SCN1A gene. This finding is important given that heterozygous variants may be overlooked in standard exome scans of consanguineous families. Thus, we are presenting an interesting example, where the inheritance of the condition may be misinterpreted as recessive and identical by descent due to consanguinity and mosaicism in one of the parents., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Mutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented with isolated bilateral or focal myoclonia, which could evolve to long-lasting attacks without loss of consciousness, with a peculiar reflex component, and were associated with generalized tonic-clonic seizures. This entity was named "familial infantile myoclonic epilepsy" (FIME). More recently, TBC1D24 mutations have been shown to cause a variable range of disorders, including epilepsy of various seizure types and severity, non-syndromic deafness, and DOORS syndrome. We report on the electro-clinical features of two brothers, born to first-cousin parents, affected with infantile-onset myoclonic epilepsy. The peculiar epileptic presentation prompted us to perform direct sequencing of the TBC1D24 gene. The patients had very early onset of focal myoclonic fits with variable topography, lasting a few minutes to several hours, without loss of consciousness, which frequently evolved to generalized myoclonus or myoclonic status. Reflex myoclonia were noticed in one patient. Neurological outcome was marked by moderate intellectual disability. Despite the high frequency of seizures, repeated EEG recordings showed normal background rhythm and rare interictal spikes and waves. We found a homozygous missense mutation, c.457G>A/p.Glu153Lys, in the two affected brothers. This observation combined with recent data from the literature, suggest that mutations in TBCD24 cause a pathological continuum, with FIME at the "benign" end and severe drug-refractory epileptic encephalopathy on the severe end. Early-onset myoclonic epilepsy with focal and generalized myoclonic seizures is a common characteristic of this continuum., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A group of five DS patients whose first development was already reported were longitudinally followed up till the scholar age. Beside the general and epileptic clinical evolution, visual and cognitive functions were investigated in order to define their trajectory and possibly provide information about mechanisms of cognitive decline as well as to improve prognosis and tertiary prevention. Neuropsychological assessment was performed with a test battery investigating the development of visual function that progressively integrates into extrastriate components and higher cognitive skills (global form and motion coherence, stereopsis, crowding cards, ABCDEFV battery, general intelligence and specific cognitive tests). Main results showed a fall in visuo-motor items including global motion coherence and specific cognitive skills, presenting a continuity of the visual function deterioration extended from basic abilities to visuo-motor dorsal pathway skills. Moreover, a case whose previous visual and cognitive functions had been in the normal range began showing a visual deterioration with increasing age, followed by the cognitive decline; that prevents from excluding in early ages a poor development in presence of a normal visual function. A dorsal stream vulnerability seems thus shown in this sample of DS patients, like in other genetic syndromes (Williams, Prader Willi. fragile-X), providing new information about mechanisms underlying cognitive decline and suggesting a possible strategy to improve their neuropsychological outcome. Larger cohorts may confirm whether these findings are part of a specific pattern of DS neuropsychological phenotype., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: The aim of the study was to perform a detailed assessment of cognitive abilities and behaviour in a series of epileptic patients with Dravet syndrome (DS) in order to establish a possible cerebellar-like pattern., Methods: Nine children with DS without major behavioural disturbances and with cognitive abilities compatible with the assessment of specific cognitive skills (IQ>45) were enrolled in the study, in parallel with another group of nine epileptic patients (cryptogenic or symptomatic with minor brain injuries) consecutively admitted into the hospital matched for chronological age and IQ. All cases underwent neurological examination, long term EEG monitoring, neuroimaging and genetic analysis as well as a neuropsychological assessment including specific cognitive skills., Results: On neurological examination 8 of the 9 DS patients had cerebellar signs, which were mild in six and more severe in the other two cases. DS patients had a constant discrepancy between verbal and performance items scales (verbal better than visual-spatial) that was not found in the control group. As to specific cognitive competence, the DS patients differ from the control group in the pattern of cognitive defects involving four main areas of cognitive abilities (a) expressive language with relatively spared comprehension, (b) visual-spatial organization, (c) executive function defects, (d) behavioural disorders., Cunclusions: The pattern of cognitive difficulties found in DS patients is consistent with what is reported in literature as cerebellar cognitive syndrome and may account for a possible cerebellar origin (at least as co-factor) of the cognitive decline observed in DS patients, as suggested by other clinical and experimental studies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: To describe the clinical and electroencephalographic (EEG) features of reflex myoclonic epilepsy in infancy (RMEI) and long-term cognitive outcome., Methods: We enrolled 31 children from 16 neuropediatric centres in Italy, who underwent clinical and video-EEG evaluation. Cognitive assessment was performed in all patients using standardized psychometric tests., Results: The age at onset ranged from 3 to 24 months of age. Seizures were characterised in all patients by symmetric myoclonic seizures (MS), triggered by sudden unexpected acoustic (38.7%) or tactile stimuli (29%) or both (29%). Spontaneous attacks were reported in 32.2% of the cases. Ictal EEG showed generalized high-amplitude 3 Hz polyspike and wave discharges, synchronous with brief rhythmic bursts of electromyographic activity. Patients were re-evaluated after a period of 7.2 ± 5.6 years. The prognosis for seizure control was excellent in all cases and reflex MS disappeared spontaneously or after valproate treatment. The cognitive outcome was excellent in 90.3% of children., Conclusions: RMEI appears to be a variety of idiopathic generalized epilepsy with specific features that occurs in developmentally normal children., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We studied clinical and EEG manifestations of absence seizures (AS) in children with Dravet syndrome (DS) to clarify their characteristic features and differences from those of typical AS (TAS). The subjects were 12 children with DS. We retrospectively analyzed electroclinical characteristics of AS. We analyzed a total of 102 ictal EEGs characterized by generalized spike-and-wave (GSW) and semiology of 78 video-taped AS. The mean age at the onset of AS and at the time of the study was 16.2±7.1 months and 40.3±22.1 months, respectively. Ictal EEG showed the focality of initial discharge in 49/102 (48%), a duration ranging from 2 to 180 s (mean: 10.2±22.6 s; median: 4.0 s), frequency ranging from 2 to 4 Hz (median=3.0 Hz), and irregular and disorganized GSW morphology in 66/102 (65%). AS manifested with eyelid-myoclonus and generalized myoclonus in 9/54 (17%) and 34/78 (44%), respectively. In conclusion, AS in DS were characterized by an early-onset age, a high incidence of irregular and disorganized 3 Hz GSW morphology, and the frequent association of generalized myoclonic movement as well as the absence of automatism as compared to TAS. The results should be appreciated in the differential diagnosis of early-onset AS, the treatment of AS in DS and also a further clinical and genetic study for DS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The objective of the study was to explore clinical, electroencephalography (EEG), neuropsychological features and prognosis of myoclonic-astatic epilepsy (MAE). Of 327 children aged between 1 and 9 years with a diagnosis of generalized epilepsy followed between 2000 and 2008, 18 (5.5%) had MAE. Male significantly predominated (88.9%). Age at onset ranged from 2.3 to 4.9 years (mean 3.6 years). Median follow-up period was 6.3 years. In addition to myoclonic-astatic seizures patients had myoclonic seizures (66.7%), drop attacks (72.2%), head drops (77.8%) absences (88.9%), tonic-clonic generalized seizure (77.8%), tonic seizures (38.9%), non-convulsive status epilepticus (16.7%). Seven patients (38.9%) had an epileptic encephalopathy. At onset, interictal epileptiform and slow abnormalities were recorded, respectively, in 100% and 77.8% of patients. EEG abnormalities disappeared in all patients within 4 years since the onset. At long-term follow-up, two patients developed focal abnormalities typical of rolandic epilepsy and two patients photosensitivity. On neuropsychological testing 66.7% of patients had a normal IQ (mean 81.2±17.0, range 47-105, median 84.5) after a mean period of 4.4 years since the last seizure. Sixteen out of 18 patients remitted within 3.5 years since the onset and in two patients tonic seizures persisted. MAE is generalized childhood epilepsy: although cognitive functions might deteriorate, outcome is good regarding seizures., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We present a child with myoclonic seizures, epileptic spasms and generalized epileptiform discharges on scalp EEG. Magnetoencephalography and coherence-phase analysis for scalp EEG suggested focal onset in the left hemisphere. Intracranial video EEG confirmed seizure onset in the left frontal lobe with ictal high-frequency oscillations. Left frontal lobectomy suppressed his seizures. Subsets of myoclonic seizures can be focal in origin despite bilaterally synchronized epileptiform discharges on scalp EEG., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: To characterize very early onset symptomatic epilepsies electroclinically, to identify meaningful factors to delineate epilepsy syndromes under this category, and to test validity of the current syndromic organization of these epilepsies by the International League Against Epilepsy (ILAE)., Methods: Subjects were 38 epileptic patients with seizure onset before 3 months of age. We investigated the age of seizure onset, seizure types, myoclonus, EEG features, neuroimaging studies, outcome of seizures and development. We performed multiple correspondence analysis (MCA) to reveal associations among these characteristics and to find important characteristics to divide this epilepsy group into subgroups., Results: Very early onset epilepsies were characterized by partial seizures and epileptic spasms, especially occurring in combination as a single ictal event (combined seizures), and poor outcome. Suppression-burst (SB), hypsarrhythmia, EEG asymmetry and structural brain abnormalities were common. MCA demonstrated that presence or absence of SB was the most meaningful factor to separate this group into subgroups. MCA on the subgroup with SB revealed a subset with early-onset spasms, partial seizures with single focus, no myoclonus, SB during wakefulness and sleep, no EEG asynchrony, hypsarrhythmia and combined seizures, and another subset with late-onset spasms, partial seizures with multiple foci, myoclonus, EEG asynchrony, no combined seizures, SB during sleep only, no EEG asymmetry, no structural abnormality and no hypsarrhythmia. These corresponded to Ohtahara syndrome and early myoclonic encephalopathy, respectively., Conclusions: Very early onset symptomatic epilepsies have the electroclinical characteristics distinct from those with later onset. This study supported the current ILAE organization on this epilepsy group from statistic approach., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Negative myoclonus (NM) is a sudden brief atonia in muscle that causes jerky lapses of posture. This study employed an electrophysiological technique (silent-period-locked-averaging (SPLA) electroencephalography (EEG)) and a pharmacodynamic imaging technique (123I-IMZ-SPECT) to examine epileptic NM (ENM). Delayed-phase 123I-IMZ-SPECT images, which reflect the specific binding of the tracers to GABA-A receptors, exhibited significant decrease in the left medial frontal area. The deficit in GABA-A receptors indicated that abnormal synchronization was mediated by the lack of inhibitory postsynaptic mechanism. The SPLA-EEG recorded spike-like notches superimposed on the slope of negative slow activity in the contralateral fronto-central region. The slow activity started around 100 ms before and the peak of the spike-like component was 30 ms before the onset of ENM. Since the 123I-IMZ-SPECT shows the actual distribution of the tracers, the abnormal area associated with ENM in this particular patient was supposed to be on the left medial frontal lobe. Scalp EEG, though it cannot always accurately locate the abnormal area, was highly sensitive to be able to detect electrical activities transmitted through neuronal network or volume conductor. Combined use of the two methods provided high resolution both in spatial and temporal domain., (Copyright 2010 Elsevier B.V. All rights reserved.)

We report on the use of the voltage-gated calcium channel blocker (Vg-CCB), verapamil, as an add-on anticonvulsant medication in two girls, 4 and 14 years of age, who were affected by severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome, a channelopathy caused by abnormalities in the voltage-gated sodium channel neuronal type alpha1 subunit (SCN1A) gene at 2q24. Both girls had pharmacoresistant epilepsy and developmental delay. Mutation analysis for the SCN1A gene revealed a missense mutation in exon 2 in the 4-year-old girl. Verapamil was co-administered in both children with a prompt response in controlling status epilepticus, myoclonic jerks, and partial and generalized seizures. The therapeutic effect lasted 13 months in the 14-year-old girl, while it is still present after a 20-month follow-up period in the 4-year-old girl who, in addition, has experienced improvement in motor and language development. The verapamil vVg-CCB, which crosses the blood-brain barrier (BBB): (a) inhibits the P-glycoprotein, an active efflux transporter protein expressed in normal tissue, including the brain, which is believed to contribute to the in situ phenomenon of multidrug resistance; and (b) may regulate membrane depolarization induced by abnormal sodium channels functions by modulating the abnormal Ca++ influxes into neurons with subsequent cell resting. This is the first report on long-lasting verapamil therapy in SMEI. The functional consequences of such in vivo modulating effects on Ca++ channels could contribute to rational targeting for future molecular therapeutic approaches in pharmacoresistant epileptic channelopathies.

Background: Early myoclonic encephalopathy (EME) and the Ohtahara syndrome are currently listed as two separate syndromes in the classification of epilepsies. The most prominent differentiating points are the observations that patients with Ohtahara syndrome experience predominantly tonic seizures; their seizures evolve to infantile spasms and the prognosis is often worse than patients with EME., Summary Points: We performed a literature review of published cases. Although syndromes may have distinct courses, the differentiation early on may be impossible as both myoclonus and tonic seizures may coexist. There is also an overlap in the etiologies. Tonic seizures are considered a manifestation of brainstem dysfunction and it is possible that this is more prominent in Ohtahara syndrome. To date, there are 17 autopsy cases (12 presumed to be Ohtahara cases and 5 EME). Evidence of hindbrain pathology was present in all. Tonic seizures or tonic posturing was a feature of all cases. We suggest that the two syndromes may represent a continuum and that the prominence of tonic seizures in the Ohtahara syndrome may be an indication of brainstem dysfunction which may play an important role in the subsequent transition to infantile spasms.

Objective: We analyzed the electroclinical features, treatment and evolution of patients with Dravet syndrome (DS)., Material and Methods: We evaluated the clinical records of 53 patients that met the diagnostic criteria of DS according to the ILAE classification of 1989 seen at our center between February 1990 and December 2004., Results: Thirty-four male and 19 female patients met the diagnostic criteria of DS. Mean time of follow-up was 10 years. The mean age at onset was 6 months and in all patients the seizures were associated with febrile illness. Myoclonias were found in 39 children. These seizures appeared between the ages of 1 and 5.5 years, with an average of 1 year and 5 months. The seizures were difficult to control with AEDs. All patients presented some degree of mental delay. At the age of 6 years, one of the children in our series presented kinesigenic paroxysmal dyskinesias. Twenty patients were placed on the ketogenic diet (KD). Two did not tolerate the KD and the diet was ineffective in five cases. The other 13 showed different degrees of control of seizures., Conclusion: The present study confirms the severity and intractability of the seizures and the difficulties to make an early diagnosis in DS. The onset of febrile seizures or seizures related to infectious disease or vaccination, focal or generalized, prolonged in time and during the first year of life, is especially suggestive of DS. The final diagnosis is usually made after 2 or 3 years when the electroclinical picture is complete, but earlier diagnosis is desirable. Myoclonias are the most representative type of non-febrile seizures in this syndrome but are not always present. Cognitive development is poor in all patients. Treatment with the KD should be considered early. A ion-channel disorder could explain the association between DS and paroxysmal diskinesias, as seen in one of our patients.

Benign adult familial myoclonic epilepsy (BAFME) were mapped on chromosome 8q24 and 8q23.3-q24.1 in Japanese pedigrees and mapped on 2p11.1-2q12.2 in European pedigrees, respectively. Recently, we recruited a large BAFME pedigree in China. After genotyping 11 microsatellite markers covering the two previously identified chromosome regions, we performed linkage analyses. However, evidence of negative linkage was found in the two previously reported candidate regions (LOD score <-3.0 at no recombination). Our data suggest that the causative gene responsible for BAFME in the Chinese pedigree may be located on a new region other than 8q23.3-q24.1 and 2p11.1-q12.2, indicating the presence of a third locus for BAFME.

Severe myoclonic epilepsy of infancy (SMEI) has been long suspected to have a genetic origin. Recently mutations in the gene encoding a voltage-gated alpha-1 sodium channel subunit-SCN1A-have been identified as a common cause of SMEI. Moreover, a mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor-GABRG2-has been described in a GEFS+ family with a member affected by SMEI. In order to further investigate the role of GABRG2 in the pathogenesis of SMEI, we have screened for mutations 53 SMEI patients who resulted negative for SCN1A mutations. Mutational screening of GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram. Twenty-nine variant chromatograms were identified corresponding to seven different nucleotide variants. None of them leads to an amino acid change or obvious protein dysfunction. No difference in allele frequency was observed for the SMEI patients compared to a control population indicating that these variants are not involved in SMEI. Our study demonstrates that GABRG2 is not a commonly involved in the etiology of SMEI and suggests that other and yet unidentified genes are involved in the syndrome

Progressive myoclonic epilepsies (EPM) are difficult to treat and refractory to most antiepileptic drugs. Besides epilepsy, EPMs also involve continuous neurological deterioration. Oxidative stress is thought to be an important factor in this process. We therefore analyzed a series of antioxidant enzymes in the blood of patients and compared with healthy age matched controls. In addition patients were given high doses of N-acetylcysteine (NAC), a glutathione percursor to determine if symptoms of EPM would improve. Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC. Before treatment, plasma samples were analyzed for glutathione peroxidase activity, catalase activity, extracellular superoxide dismutase (SOD) and CuZn-SOD and compared with the controls. Erythrocyte CuZn-SOD was significantly lower in the EPM patients compared to controls. NAC improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2.

The characteristics of evoked potentials in patients with dentatorubral-pallidoluysian atrophy (DRPLA) were investigated. Twelve patients with DRPLA and three patients with progressive myoclonic epilepsy (PME) attributable to other causes participated in the study. In 11 out of the 12 patients, the diagnosis of DRPLA was genetically confirmed, based on a 56-75 CAG triplet repeat expansion on chromosome 12p; in the remaining patient, the diagnosis was not genetically confirmed but the patient was clinically diagnosed as having DRPLA and was within the same pedigree as one of the 11 genetically confirmed patients. Two out of the three patients with PME, who had been tested for dodecamer repeat expansion in the cystatin B gene, were genetically confirmed as having Unverricht-Lundborg disease (UL); the remaining patient was also clinically diagnosed as having UL, but the patient did not have the aforementioned genetic abnormality. Somatosensory evoked potentials (SEPs) and brainstem auditory evoked responses (BAERs) were recorded. The amplitudes of the SEPs were determined as the peak-to-peak amplitudes between P2 and N2 deflections. The results revealed that high-amplitude SEPs were not evoked in any of the DRPLA patients; on the other hand, high-amplitude SEPs were evoked in all the patients with UL. Moreover, BAERs were absent in seven out of the 12 patients with DRPLA; on the other hand, all UL patients showed BAERs in which all peaks, from I to V, were distinguishable. These results suggest differences in pathophysiology between DRPLA, which predominantly affects the brainstem and subcortical regions, and PME, characterized by cortical hyperexcitability. Thus, evoked potential measurements may be useful to differentiate DRPLA patients from those with progressive myoclonic epilepsy.

Autonomic function was studied by the use of spectral analysis of heart-rate variability in patients with epilepsy in relation to type of epilepsy and anti-epileptic drug therapy. A total of 21 patients with juvenile myoclonic epilepsy (JME) and 21 with temporal lobe epilepsy (TLE) were included; 18 patients were treated with carbamazepine (CBZ), 16 with valproate (VPA) and seven with phenytoin (PHT). One healthy drug free control, matched for age and sex, was selected for each patient. Patients and controls underwent an ambulatory 24 h EKG. Heart-rate variability was analyzed in time and frequency domains. Patients with TLE had significantly lower S.D. of the RR-intervals, lower low frequency power and a lower low frequency/high frequency power ratio than their controls. A lower low frequency/high frequency power ratio was the only significant difference between the JME patient group and their controls. Treatment, however, may have had a considerable influence on the heart rate variability in the epilepsy patients. Patients on CBZ had significantly lower S.D. of RR-intervals, low frequency power and a low frequency/ high frequency power ratio than did their matched healthy drug free controls. The ratio of low frequency/high frequency power was also lower in patients on VPA compared with their controls, but apart from that no differences could be demonstrated between this treatment group and the controls. In conclusion, patients with epilepsy appear to have an altered autonomic control of the heart, with a reduction in some heart-rate variability measures, suggesting a decreased sympathetic tone, which may be related to the drug therapy or the epilepsy as such. Further studies are warranted to explore these changes and their possible relevance for sudden death in epilepsy.

The pathophysiological and neuroanatomical bases of reading epilepsy (RE) are unclear. We performed video-EEG, high quality MRI and [11C]diprenorphine PET in a patient with RE to detect structural and functional abnormalities. EEG showed multifocal seizure onset bilaterally in temporal and fronto-central regions. MRI was normal, whereas [11C]diprenorphine PET revealed peri-ictal opioid binding decreases in both temporal lobes and the left frontal lobe. These findings confirm that RE is due to abnormal activity in the network subserving reading.

Epilepsy with myoclonus is thought to be linked to the motor system. At birth, development of the central nervous system in humans is far from being achieved. Post-natal changes take place at different levels in this neuronal system. These modifications suggest that the motor cortex is a highly dynamic structure during post-natal development. They may account for the age-dependence of various epileptic syndromes. (1) The number of synapses increases during the early post-natal years and then decreases to reach the adult level around puberty. (2) Neurons differentiate and synthesize various neurotransmitters. (3) Dendrites grow actively and participate in the formation of local cortical circuits. (4) Electrophysiological properties of cortical neurons change during the first months of rodent development. This could reflect modifications of the ion channels present in the cell membrane. (5) The pyramidal tract myelinate and exuberant collaterals are selectively removed. These two processes are dependent on neuronal electrical activity. It has been demonstrated that selective collateral stabilization is promoted by glutamate release and stimulation of the N-methyl-D-aspartate (NMDA) receptor. So, seizures occurring during the neonatal period may interact with these normal developmental features. Furthermore, neuronal electrical activity and seizures stimulate the transcription of specific messenger RNAs coding for neurotrophic factors like nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF). The overproduction of neurotrophic factors leads to maldevelopment of the cortex.

Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5% of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral change. Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.

Baltic myoclonus epilepsy (BME) is a neurodegenerative disease characterized by tonic-clonic seizures, myoclonus and a progressive course. The aim of the present study was to assess the clinical symptoms and signs of possible involvement of the autonomic nervous system (ANS) and objectively evaluate autonomically mediated cardiovascular reflexes in this syndrome. Fifteen patients with BME and 14 healthy control subjects were studied. Thirteen (87%) of the patients had symptoms suggesting ANS dysfunction. The most common symptoms were postural dizziness and sweating disturbances. The heart rate variation during deep breathing was lower in patients than in controls. The heart rate response and systolic blood pressure response during tilting were similar in both groups. Our results suggest a mild parasympathetic hypofunction and an intact sympathetic function in ambulatory patients with BME.

The effects of large doses of L-phenylalanine and of aspartame on seizure susceptibility and severity have been assessed in baboons Papio papio from Senegal which show photosensitive epileptic responses similar to primary generalised epilepsy in man. L-Phenylalanine, 50, 150 or 450 mg/kg, or aspartame, 300 or 1000 mg/kg, were administered orally. Peak plasma L-phenylalanine concentrations of approximately 2000 mumoles/l occurred 1-4 h after the highest dose of L-phenylalanine or aspartame. The plasma L-phenylalanine to large neutral amino acid ratio increased approximately 30-fold at this time. Compared with water administration there were no changes in epileptic responses 1-5 h after either treatment. In this primate model of epilepsy acute increases in plasma phenylalanine concentration are neither pro- nor anticonvulsant.

Juvenile myoclonic epilepsy is a well defined, age related epileptic syndrome. Case reports are presented, demonstrating the onset of this syndrome very early in life as well as in old age. Consequently, since the correct diagnosis is of decisive importance with regard to optimal treatment, the search for this syndrome should not be confined to juvenile patients.