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A letter to the editor is presented in response to an article about the review of the "Encyclopaedia of Occupational Health and Safety," in the June 1984 issue.

The neuronal ceroid lipofuscinoses (NCLs) are incurable pediatric neurodegenerative diseases characterized by accumulation of lysosomal material and dysregulation of autophagy. Given the promising results of treatment with trehalose, an autophagy inducer, in cell and animal models of NCL, we conducted an open-label, non-placebo-controlled, non-randomized 12-month prospective study in NCL patients receiving oral trehalose (4 g/day). All were treated with a commercially available formulation for 6 months, followed by a 6-month washout. The primary endpoint was the presence of severe adverse reactions during treatment; secondary endpoints were clinical changes documented using the validated Unified Batten Disease Rating Scale and the Hamburg scale. Leveraging on our recent multiomic studies identifying convergent biomarkers in NCLs, fluid biomarker changes were taken as additional secondary endpoints. Of the 17 patients enrolled, 11 completed the study. Oral intake of trehalose in NCL patients with different genetic forms and at different disease stages was found to be well tolerated over 6 months. Oral trehalose is associated with subjective benefits reported by caregivers, but not with improvement or worsening on clinical scales. Analysis of potential biomarkers demonstrated significant differences between patients and controls at baseline, but we observed no modifications over time, or correlations with clinical scales and treatment. In our pilot experience in a heterogeneous disease group of NCL, oral trehalose seemed safe for patients. While subjective improvements were reported by caregivers, larger multicenter randomized placebo-controlled studies, and perhaps additional clinical tools covering multiple functions affected by the disease, will be needed to identify possible improvements in clinical scale scores and biomarkers., Competing Interests: Declarations. Conflict of interest: The authors have no conflict of interest. Ethical approval: The study was approved by the Tuscany Region Ethics Committee. The patient gave informed consent for diagnostic testing and research studies. The study was conducted in accordance with the Helsinki Declaration of 1964, as revised in October 2013 in Fortaleza, Brazil., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The objective of this study is to characterize the electro-clinical phenotype of individuals affected by the rare PPP3CA gene-related developmental and epileptic encephalopathy (DEE)., Methods: We provide a detailed electro-clinical description of four previously unreported subjects, with unremarkable structural brain MRI and a normal screening for inborn errors of metabolism, who carry pathogenic variants within the regulatory domain of the PPP3CA gene, which encodes for calcineurin. We also conducted a literature review via PubMed and SCOPUS (up to December 2023) to collect all the studies reporting clinical details of subjects with PPP3CA pathogenic variants within the regulatory domain., Results: Our in-depth investigation reveals two distinct electro-clinical phenotypes with unique interictal and ictal patterns. Pathogenic variants within the calmodulin-binding domain result in childhood-onset epilepsy with focal and generalized seizures, developmental and intellectual impairments. Pathogenic variants within the regulatory domain lead to early onset drug-resistant severe epilepsy and potentially fatal outcomes. Comparative analysis with existing literature corroborates the notion that truncating mutations, prevalent in the regulatory domain but also possible in the calmodulin-binding domain, consistently associate with more profound disabilities and drug-resistant epilepsy., Conclusion: Our study emphasizes the critical role of pathogenic variants' type and location on the severity of PPP3CA-related DEE. We also speculate, based on peculiar EEG patterns, on potential pathophysiological mechanisms involving calcineurin dysfunction and calcium homeostasis. In order to improve our understanding of this rare DEE, we need both collaborative efforts to gather larger cohorts and further experimental studies., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Biallelic CNTNAP2 variants have been associated with Pitt-Hopkins-like syndrome. We describe six novel and one previously reported patients from six independent families and review the literature including 64 patients carrying biallelic CNTNAP2 variants. Initial reports highlighted intractable focal seizures and the failure of epilepsy surgery in children, but subsequent reports did not expand on this aspect. In all our patients (n = 7), brain MRI showed bilateral temporal gray/white matter blurring with white matter high signal intensity, more obvious on the T2-FLAIR sequences, consistent with bilateral temporal lobe dysplasia. All patients had focal seizures with temporal lobe onset and semiology, which were recorded on EEG in five, showing bilateral independent temporal onset in four. Epilepsy was responsive to anti-seizure medications in two patients (2/7, 28.5%), and pharmaco-resistant in five (5/7, 71.5%). Splice-site variants identified in five patients (5/7, 71.5%) were the most common mutational finding. Our observation expands the phenotypic and genetic spectrum of biallelic CNTNAP2 alterations focusing on the neuroimaging features and provides evidence for an elective bilateral anatomoelectroclinical involvement of the temporal lobes in the associated epilepsy, with relevant implications on clinical management., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) currently present a therapeutic challenge. A pharmaceutical cannabidiol (CBD) specialty (Epidyolex®) has been approved by the FDA and EMA for the treatment of seizures in these syndromes. However, in Italy, the use of galenic formulations versus the pharmaceutical CBD has not been clearly regulated., Aim: To share and disseminate expert' opinions on how to use and administer pharmaceutical CBD in patients with DS and LGS as well as identifying a possible strategy for the switch from galenic to pharmaceutical specialty., Methods: A nominal group technique (NGT) was used, involving eight Italian adult and pediatric neurologists. Two questionnaires were consecutively administered and the Clinician' responses were discussed in a final meeting in order to draw the own conclusions., Results: The use of a pharmaceutical CBD is considered preferable to galenic formulations, in terms of reproducibility, safety, and control of the delivered dose., Conclusion: The use of a pharmaceutical CBD in DS and LGS patients is useful for both seizure treatment and quality of life (QoL) improvement. However, further studies are needed to confirm the improvement in QoL and the best strategy for switching from a galenic formulation to pharmaceutical CBD.

A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Monoallelic mutations on TMEM63A have been recently reported as cause of a previously unrecognized disorder named "infantile-onset transient hypomyelination". Clinical and neuroradiological presentation is described as highly similar to Pelizaeus-Merzbacher Disease but evolution over time was surprisingly benign with a progressive spontaneous improving course. We report on a new TMEM63A-mutated girl. The clinical picture was similar to the one already described except for the presence of recurrent episodes of unilateral eyelid twitching, and for the evidence of spinal cord involvement on MRI. These are interesting findings helping in distinguishing this condition from classic PMD since early disease stages. However, additional observations are needed to confirm if these are common features of this condition., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Intracranial penetration during attempted nasotracheal intubation is a potentially devastating complication, which should be carefully evaluated and the risk should be addressed in neonatal resuscitation trainings., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: A survey of European Pain Federation 2019 attendees was conducted to identify unmet needs in chronic pain patients. Materials & methods: Four questions were asked focusing on functional impairment in chronic pain, including who are at increased risk and ways to better identify and manage these patients. Results: In total 143 respondents indicated that key issues were lack of knowledge, lack of resources/time to assess and manage chronic pain and lack of sufficient tools to identify patients at risk for functional impairment. Education and training of primary care physicians, simplified guidelines and practical tools for assessment and use of multidisciplinary teams to treat chronic pain were recommended. Conclusion: There are many unmet needs in the management of functional impairment in chronic pain patients.

Leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) neurological autoimmunity in adults has been associated with various clinical syndromes involving central, peripheral and autonomic nervous system, while data in children is limited. We perform the first systematic literature review on paediatric LGI1 and CASPR2 autoimmunity, with focus on clinical data, in order to contribute to the definition of clinical features of LGI1 and CASPR2 autoimmunity in paediatric age and favour early diagnosis. Additionally, we report the youngest-to-date case of Morvan syndrome. We identified 37 published paediatric cases of LGI1 and/or CASPR2 autoimmunity. Most frequent syndromes were encephalitis in LGI1-positive and isolated epilepsy in CASPR2-positive children, while syndromes with predominant peripheral symptoms were most frequent in double-positive children. With the limitations imposed by the low number of cases, differences to published adult cohorts included: absence of faciobrachial dystonic seizures and hyponatremia in patients with LGI1-positive encephalitis; slightly higher proportion of isolated epilepsy syndromes in CASPR2-positive patients; absence of tumour in the whole cohort., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly., Methods: We use family-based whole-exome sequencing to identify candidate variants., Results: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein., Conclusion: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors., Methods: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency., Results: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124)., Significance: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objective: To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations., Methods: Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel., Results: The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism., Conclusions: KCNB1 -related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

Aim: Migraine affects approximately 10-20% of the general population, including children and adolescents, and an association between migraine and increased risks for cardiovascular disease and stroke have been reported in adult patients. This study aimed to address the lack of data on children with migraine., Methods: This study comprised 30 children and adolescents (16 male) with migraine. We evaluated their biochemical profile, glucose homeostasis, vascular function by flow-mediated dilatation and arterial structure by carotid intima-media thickness (cIMT). A group of 32 age, sex and auxologically matched children (17 male) served as controls., Results: The group of children with migraine had a normal biochemical profile and glucose homeostasis, but presented with significantly thicker cIMT than the control group (0.48 ± 0.07 mm versus 0.45 ± 0.04, p < 0.05)., Conclusion: We observed a significantly thicker cIMT in children with migraine compared with the controls. The brief time interval between the onset of the disease and the time of the study makes it unlikely that repetitive migraine attacks could be responsible for the thickening of the cIMT. Thus, it may be speculated that primitive vascular function abnormalities were wholly or partly responsible for the development of migraine in this paediatric cohort., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Purpose: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients., Methods: We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them., Key Findings: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity., Significance: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study., Methods: Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate., Results: Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo., Conclusion: This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted.

Objectives: Myocardial adenosine is increased in pressure-overload hypertrophy (POH) and exerts important cardioprotective effects that delay transition to left ventricular failure. Adenosine-mediated signaling is attenuated in POH, but whether this depends on receptor or postreceptor defects is unknown. We therefore examined left ventricular adenosine A1-receptor gene and protein expression in experimental POH., Methods: Six week-old Sprague-Dawley rats were subjected to abdominal aortic banding (group B) or sham operation (group S). Echocardiography and left ventricular catheterization were performed 10 weeks later under ketamine anesthesia. Left ventricular and lung weight indices were obtained postmortem. A1-Receptor mRNA and protein expression were measured in samples from left ventricular, right ventricular and aortic arch tissue. Group B rats were subgrouped as having compensated or decompensated hypertrophy according to the absence or presence of lung congestion (lung weight index below or above mean +/- 2SD compared with group S rats)., Results: Both mRNA and protein A1-receptor expression were significantly increased in compensated group B versus group S rats (by, respectively, 37 and 77%; both P < 0.01). This was not observed in decompensated group B rats. No consistent gene or receptor expression changes were observed in right ventricular or aortic tissues., Conclusions: In compensated POH, increased interstitial adenosine concentrations are accompanied by increased expression of the specific receptor mediating the major cardioprotective effects of this autacoid. Such overexpression is no longer detectable once the transition from POH to left ventricular failure has occurred. These observations may have pathophysiological and, in perspective, therapeutic relevance to the course of hypertensive heart disease.

Topiramate, a derivative of the monosaccharide d-fructose, has shown a wide spectrum of antiepileptic efficacy in both animal models and clinical trials. Multiple putative mechanisms of action include voltage-sensitive sodium channel blockade, calcium channel inhibition, increase of potassium conductance, GABA-mediated chloride current increment, glutamate-mediated neurotransmission inhibition and carbonic anhydrase isoenzyme inhibition. In general, the clinical response is maintained in the long-term. The most common side effects include somnolence, fatigue, headache, psychomotor slowing, confusion, difficulty with memory, impaired concentration and attention, speech and language problems and weight loss. If slowly titrated and used at a low-to-medium dosage, it is well tolerated and offers a valid therapeutic option, the relevance of which is comparable to that of the most widely used 'old' antiepileptic drugs. As it is not yet wholly clear which specific epilepsy syndromes may benefit most from topiramate with respect to other drugs, more accurate indications for initial monotherapy would require syndrome-oriented trials and more clinical experience.

Background: The aim in treating epilepsy is to minimise or control seizures with full respect of quality-of-life issues, especially of cognitive functions. Optimal treatment first demands a correct recognition of the major type of seizures, followed by a correct diagnosis of the type of epilepsy or of the specific syndrome., Methods: Review of data from literature and personal clinical experience in treating children with epilepsy., Results: After summarising the general aspects on the diagnosis and treatment of the main forms of childhood epilepsy, we review key issues about management of seizure disorders, including when to start treatment, how to proceed when the first treatment fails, and how to set the targets of treatment. A special section is devoted to the new concept of epileptic encephalopathy and to the influence of "interictal" EEG abnormalities on cognition, behaviour, and motor abilities in children, providing some suggestions on why and how to treat these conditions. A second section approaches the choice of treatment according to the specific syndromes including infantile spasms, focal epilepsies, syndromes with typical absence seizures, the myoclonic epilepsies and the Lennox-Gastaut syndrome., Conclusions: Antiepileptic drugs (AEDs) can efficiently control seizures in most children. However, the specificity of AEDs is relatively limited, although continuing research is leading to a better understanding of the relationship between pathogenesis and the mechanism(s) and site(s) of drug action.

Pallister-Killian syndrome (PKS) is a rare, sporadic, genetic disorder characterized by dysmorphic features, learning disability, and epilepsy. It is caused by a mosaic supernumerary isochromosome 12p (i[12p]). The i(12p) is rarely found in peripheral blood but it is present in skin fibroblasts. Recognition is essential for cytogenetic diagnosis. We describe a male aged 2 years 6 months and a female aged 11 years with PKS and epileptic spasms (ES). This type of seizure is not unusual in patients with brain malformations and with severe developmental delay, but it is sometimes difficult to recognize without video-electroencephalogram studies and could be mistaken for other types of seizure or behavioural manifestations. In these two patients with PKS, spasms had late onset, persisted beyond infancy, and were drug resistant. Clinicians should be aware of this possibility in PKS, which appears to be a rare cause of ES.

Nonconvulsive status epilepticus can be confused with psychiatric disorders. Inappropriate drug treatment can represent a precipitating factor. We describe two patients with idiopathic generalized epilepsy in whom nonconvulsive status epilepticus, aggravated by carbamazepine, was misdiagnosed as psychiatric disorder. A 14-year-old girl experienced a tonic-clonic seizure at age 12 years preceded by monthly episodes of confusion with awkward behavior since age 9 years. She was treated with carbamazepine, and the episodes of confusion became more frequent, leading to a diagnosis of dissociative disorder. An electroencephalogram during one of these episodes revealed nonconvulsive status epilepticus. Substitution of carbamazepine with valproic acid controlled the episodes of status epilepticus. A 23-year-old woman presented at age 16 years with a tonic-clonic seizure. Since early adolescence, she had had episodes of depressive mood, worsening of school performances, and facial tics. Carbamazepine treatment caused worsening of the depressive episodes and facial tics. An electroencephalogram during a typical episode revealed nonconvulsive status epilepticus. Carbamazepine substitution with valproate led to seizure freedom and behavioral improvement. Nonconvulsive status epilepticus should be suspected and searched for in patients with epileptic seizures and ictal or fluctuating behavioral disorders.

Objective: Epileptic negative myoclonus (ENM), a transient muscular atonic phenomenon time-locked to epileptiform EEG abnormalities, is often observed in children with benign childhood epilepsy with centro-temporal spikes (BECTS). In some, for unknown reasons, ENM can be worsened by carbamazepine (CBZ). We describe two children aged 11 and 15 years, in whom CBZ precipitated seizure worsening and ENM. We investigated the morphological and topographic features of the EEG abnormalities while on CBZ and after CBZ withdrawal and compared them with those from 9 children with classical BECTS. The aim of the study was to identify possible electrophysiological specificities in patients who eventually develop ENM during CBZ treatment., Methods: The characterization of EEG abnormalities, related (R) and unrelated to ENM (U), in patients with ENM and rolandic discharges (RD) and in matched controls with BECTS was performed based on polygraphic digital EEG recordings. Off-line time-domain analysis included correlation coefficient between EEG and EMG channels, quantitative analysis on ENM, and topographic analysis on spike-and-wave complexes. Z-score test and paired t test were used when appropriate for statistical analysis on R, U and RD., Results: Recordings in both children with BECTS and ENM while on CBZ showed frequent R discharges (mean interval between R=19.89+/-9.4 s in patient 1; 2.16+/-1.2 s in patient 2). Withdrawal of CBZ produced abatement of R (no R recorded in patient 1; 5.69+/-7.1 s in patient 2) and reduction of the slow wave component of R (P<0.01). Morphology and topography of R and RD differed in field distribution, amplitude (P<0.01) and duration (P<0.01) of the slow wave component. RD and U did not show a significantly different morphology and field distribution., Conclusions: Our findings suggest that an increased cortical inhibition could be the electrophysiological correlate of CBZ-induced ENM. If confirmed on a larger series, the presence of spike-wave (rather than sharp waves) discharges in children with BECTS might be used as an electrophysiological predictor of an abnormal response to CBZ.

Malformations of the cerebral cortex (MCC) are often associated with severe epilepsy and developmental delay. About 40% of drug-resistant epilepsies are caused by MCC. Classification of MCC is based on embryological brain development, recognising forms that result from faulty neuronal proliferation, neuronal migration and cortical organisation. Hemimegalencephaly, an enlarged dysplastic hemisphere, can present as early onset severe epileptic encephalopathy or as partial epilepsy. In focal cortical dysplasia (FCD), MRI shows focal cortical thickening and simplified gyration. Patients have drug-resistant, often early onset epilepsy. Complete surgical ablation of FCD is accompanied by remission in up to 90% of patients, but may be technically difficult. Tuberous sclerosis (TS) is a multisystemic disorder primarily involving the nervous system; 60% of patients having epilepsy, with 50% having infantile spasms. TS is caused by mutations in the TSC1 and TSC2 genes; 75% of cases are sporadic. TSC1 mutations cause a milder disease. Bilateral periventricular nodular heterotopia (BPNH) consists of confluent and symmetric nodules of grey matter along the lateral ventricles. X-linked BPNH presents with epilepsy in females and prenatal lethality in most males. Most patients have partial epilepsy. Filamin A mutations have been reported in families and sporadic patients. Lissencephaly (LIS smooth brain) is a severe MCC characterised by absent or decreased convolutions. Classical LIS is quite rare and manifests with severe developmental delay, spastic quadriparesis and severe epilepsy. XLIS mutations cause classical lissencephaly in hemizygous males and subcortical band heterotopia in heterozygous females. Thickness of heterotopic band and degree of pachygyria correlate well with phenotype severity. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including partial epilepsy in most patients. Polymicrogyria (excessive number of small and prominent convolutions) has a wide spectrum of clinical manifestations ranging from early onset epileptic encephalopathy to selective impairment of cognitive functions. Bilateral perisylvian polymicrogyria may be familial. Patients present with faciopharingo-glosso-masticatory diplegia and epilepsy, which is severe in about 65% of patients., (Copyright John Libbey Eurotext 2003.)

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria-SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative beta-sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X-inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X-inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal.

Purpose: To report on the association of childhood absence epilepsy and paroxysmal dyskinesia (PD)., Methods: We describe six patients aged 6 to 27 years (mean, 14 years) who were identified in five centers participating in a European study group. Patients had been followed up clinically from the first symptoms and had been studied with video-EEG recordings of absence seizures, videotaping of dyskinetic attacks, and brain magnetic resonance imaging (MRI)., Results: Four patients were sporadic, and two were siblings. Age at onset of absence seizures was unusually early (range, 3 months to 3 years 6 months; mean, 16 months), with four children having their first episodes within the first year of life, and the remaining two by age 3 years 6 months. Resistance to multiple appropriate drugs was seen in five children, in four of whom absences improved remarkably when ethosuximide was added. Absences remitted between age 8 and 13 years in the three patients in whom follow-up was long enough. Different types of PD were seen including paroxysmal kinesigenic dyskinesia (one patient), paroxysmal exercise-induced dystonia (three patients), and paroxysmal tonic upgaze (two siblings). In most patients, PD appeared at a later age than, co-occurred with, and outlasted absence seizures. Only in the two siblings with tonic upgaze, dyskinetic attacks had an earlier onset. PD improved with increasing age and did not usually produce severe disability., Conclusions: There is a widening spectrum of epilepsy and PD syndromes, within which epilepsy has the characteristics of the common idiopathic syndromes, with some atypical features.

Purpose: To study the neurophysiologic characteristics of epileptic myoclonus in patients with Lennox-Gastaut syndrome (LGS) and myoclonic astatic epilepsy (MAE)., Methods: Three patients with symptomatic LGS (mean age, 15 years +/- 4) and three with cryptogenic MAE (mean age, 9 years +/- 3) were studied. Temporal relationships between electroencephalographic (EEG) and electromyographic activity were studied by analyzing latencies of EEG activity related to the onset of single myoclonic jerks, by using burst-locked EEG averaging where necessary., Results: LGS: neurophysiologic analysis indicated that jerks and the accompanying premyoclonic spikes showed latency differences between sides (mean +/- SD, 18 +/- 5 ms for both) with a constant leading side in each patient. The premyoclonic spike latency was 20 +/- 10 ms (mean +/- SD). Topographic voltage mapping of the premyoclonic spike peak showed a unilateral frontal distribution. MAE: muscles from both sides were activated synchronously, and the EEG correlate was a generalized spike-wave, in which the negative peak of the spike preceded the generalized jerks by 30 +/- 2 ms (mean +/- SD). Topographic voltage mapping of the premyoclonic spike peak showed a diffuse distribution of the electrical field, predominating over the anterior regions, but not lateralized., Conclusions: These neurophysiologic findings indicate that epileptic myoclonus in LGS originates from a stable generator in the frontal cortex, to spread to contralateral and ipsilateral cortical areas, whereas myoclonus in MAE appears to be a primary generalized epileptic phenomenon.