Effects of adjunctive eslicarbazepine acetate on neurocognitive functioning in children with refractory focal-onset seizures.

PURPOSE: This was a phase-II, randomized, double-blind (DB), placebo-controlled study aimed to evaluate neurocognitive effects of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS). METHODS: Children (6-16years old) with FOS were randomized (2:1) to ESL or placebo. Treatment started at 10mg/kg/day, was up-titrated up to 30mg/kg/day (target dose), and maintained for 8weeks, followed by one-year open-label follow-up. The primary endpoint was change from baseline to the end of maintenance period in the composite Power of Attention assessed with the Cognitive Drug Research (CDR) system. Behavioral and emotional functioning and quality of life (QOL), secondary endpoints, were assessed with Child Health Questionnaire-Parent Form 50 (CHQ-PF50), Child Behavior Checklist (CBCL), and Raven's Standard Progressive Matrices (SPM). Efficacy was evaluated through changes in standardized seizure frequency (SF), responder rate, and proportion of seizure-free patients. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). RESULTS: One hundred and twenty-three patients were randomized. A noninferiority analysis failed to reject the null hypothesis that the change from baseline in the Power of Attention score in the ESL group was at least 121ms inferior to the placebo group for all age groups. The CDR scores showed no differences between placebo and ESL in Power of Attention (1868.0 vs 1759.5), Continuity of Attention (1.136 vs -1.786), Quality of Working Memory (-0.023 vs -0.024), and Speed of Memory (-263.4 vs -249.6). Nonsignificant differences between placebo and ESL were seen for CHQ-PF50, CBCL scores, and Raven's SPM. Episodic Memory Index showed significant negative effect on ESL. Efficacy results favored the ESL group (SF least square [LS] means 1.98 vs 4.29). The TEAEs had a similar incidence between treatment groups (41.0% vs 47.5%). CONCLUSIONS: Overall ESL did not produce statistically significant effects on neurocognitive and behavioral functioning in patients with epilepsy aged 6 to 16years. Additionally, ESL was effective in reducing seizure frequency and was well-tolerated.

Rufinamide in refractory childhood epileptic encephalopathies other than Lennox-Gastaut syndrome.

BACKGROUND: To report on the first multicenter Italian experience with rufinamide as adjunctive drug in children, adolescents and young adults with refractory childhood-onset epileptic encephalopathies other than Lennox-Gastaut syndrome. METHODS: Thirty-eight patients (19 males, 19 females), aged between 4 and 34 (mean 13.7 ± 8.3, median 12.5), all affected by different types of childhood-onset refractory epileptic encephalopathies other than Lennox-Gastaut syndrome, were treated with rufinamide as adjunctive drug for a mean period of 11.4 months (range 3-26 months). RESULTS: Fifteen of 38 patients (39.5%) had a ≥ 50% seizure reduction in countable seizures. Complete seizure freedom was achieved in one of these patients (2.6%). Three patients (7.9%) had a 25-49% seizure reduction, whilst seizure frequency remained unchanged in 15 (39.5%) and increased in five patients (13.1%). Eleven patients (28.9%) reported adverse side effects. Vomiting was reported in five patients (13.1%); drowsiness, decreased appetite and irritability with migraine manifested in other four patients. They were transient and mild in all cases. CONCLUSION: Rufinamide may be an effective and well-tolerated adjunctive drug for the treatment of refractory childhood-onset epileptic encephalopathies other than Lennox-Gastaut syndrome. Rufinamide was most effective in patients with drop-attacks and (bi)frontal spike-wave discharges.

Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome.

AIM: The aim of the study was to evaluate the surgical treatment of epilepsy and detection of possible early surgery predictive elements in patients with tuberous sclerosis complex (TSC). MATERIALS AND METHODS: Forty-two TSC patients with epilepsy were selected and divided into two main groups: definite and fruste forms. Definite forms were divided into different groups: patients with pharmacologically controlled epilepsy, patients with pharmacoresistant epilepsy excluded from surgery after an extensive presurgical assessment, and patients with a pharmacoresistant epilepsy who underwent surgery. We compared the definite TSC groups to identify elements that predict surgical candidacy. Second, we compared all operated patients to assess surgical outcome. CONCLUSION: We found several factors that could predict a surgical intervention even if identification of patients with refractory epilepsy who can benefit from surgery is an evolving process. Also, several positive factors for good surgical outcome were identified. Patients with the fruste form had excellent surgical outcome.

Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations.

Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).

Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.

OBJECTIVE: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. METHODS: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. RESULTS: 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). CONCLUSIONS: Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

Auditory attention at the onset of West syndrome: correlation with EEG patterns and visual function.

At the onset of West syndrome a specific impairment of visual function has been clearly demonstrated, while other aspects of sensorial development, and in particular of the auditory function, have been less studied. The aim of this study was to evaluate auditory function and orienting responses at the onset of West syndrome, and to relate the results with EEG patterns, visual function and neurodevelopmental competence. A prospective multicentric study was performed on 25 successively enrolled infants with West syndrome; all the patients underwent a full clinical assessment, including MRI and video-EEG, visual function and auditory orienting responses (AORs) as well as Griffiths' developmental scales. The whole assessment performed at the onset of spasms (T0) was repeated after two months (T1). AORs resulted significantly impaired both at T0 and T1. At the onset of spasms a highly significant relationship of auditory attention with visual function and neurodevelopmental competence was shown in both cryptogenic and symptomatic forms, but it was no longer present after two months. Our results may suggest a possible pervasive effect of the epileptic disorder on sensory processing, associated to a deficit of neurodevelopment. Although we failed to show a significant correlation between auditory orienting responses and EEG patterns, some evidence seems to support at least partially an influence of the epileptic disorder per se on the genesis of the sensorial impairment. A longer follow up and a larger cohort will be useful for a better clarification of these findings.

Evaluation of nutritional status in children with refractory epilepsy.

BACKGROUND: children affected by refractory epilepsy could be at risk of malnutrition because of feeding difficulties (anorexia, chewing, swallowing difficulties or vomiting) and chronic use of anticonvulsants, which may affect food intake and energy metabolism. Moreover, their energy requirement may be changed as their disabilities would impede normal daily activities. The aim of the present study was to evaluate nutritional status, energy metabolism and food intake in children with refractory epilepsy. METHODS: 17 children with refractory epilepsy (13 boys and 4 girls; mean age 9 +/- 3,2 years; Body Mass Index 15,7 +/- 3,6) underwent an anthropometric assessment, body composition evaluation by dual-energy X-ray absorptiometry, detailed dietetic survey and measurement of resting energy expenditure by indirect calorimetry. Weight-for-age, height-for-age (stunting) and weight-for-height (wasting) were estimated compared to those of a reference population of the same age. RESULTS: 40% of children were malnourished and 24% were wasted. The nutritional status was worse in the more disabled children. Dietary intake resulted unbalanced (18%, 39%, 43% of total daily energy intake derived respectively from protein, lipid and carbohydrate). Adequacy index [nutrient daily intake/recommended allowance (RDA) x 100] was < 60% for calcium iron and zinc. CONCLUSION: many children with refractory epilepsy would benefit from individual nutritional assessment and management as part of their overall care.

Atypical Manifestations in Glut1 Deficiency Syndrome.

Glucose transporter type 1 deficiency syndrome is a genetically determined, treatable, neurologic disorder that is caused by an insufficient transport of glucose into the brain. It is caused by a mutation in the SCL2A1 gene, which is so far the only known to be associated with this condition. Glucose transporter type 1 deficiency syndrome consists of a wide clinical spectrum that usually presents with cognitive impairment, epilepsy, paroxysmal exercise-induced dyskinesia, acquired microcephaly, hemolytic anemia, gait disturbance, and dyspraxia in different combinations. However, there are other clinical manifestations that we consider equally peculiar but that have so far been poorly described in literature. In this review, supported by a video contribution, we will accurately describe this type of clinical manifestation such as oculogyric crises, weakness, paroxysmal kinesigenic and nonkinesigenic dyskinesia in order to provide an additional instrument for a correct, rapid diagnosis.

Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene.

OBJECTIVE: To examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1(FLN1) gene. BACKGROUND: Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys. METHODS: Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH. RESULTS: In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy. CONCLUSION: Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.

Prospective study of first-line vigabatrin monotherapy in childhood partial epilepsies.

This was a prospective open comparative pilot study to assess the efficacy and tolerability of first-line vigabatrin monotherapy in childhood partial epilepsies. Two groups of patients were recruited over the same period. The vigabatrin monotherapy group comprised 40 patients (18 male, 22 female; mean age at last visit 7.5 years); the comparative carbamazepine monotherapy group comprised 40 consecutive clinic patients (22 male, 18 female; mean age at last visit 7.8 years). Seizures disappeared in 82% of vigabatrin patients and in all carbamazepine patients with idiopathic partial epilepsy, and in 50% of vigabatrin patients and 55% of carbamazepine patients with symptomatic partial epilepsy. Interictal EEG abnormalities decreased in vigabatrin patients more than in carbamazepine patients (P < 0.05). Tolerability was good in vigabatrin patients, but four out of 37 showed mild irritability by the end of the trial. Persistent sedation was observed in eight of the 40 patients receiving carbamazepine. No patient had drug therapy discontinued because of side-effects. During vigabatrin long-term monotherapy, efficacy and good clinical tolerability were maintained. These results suggest that vigabatrin may be an alternative first-line treatment for childhood partial epilepsies. Further blinded comparative randomized trials are needed.

Ethosuximide is effective in the treatment of epileptic negative myoclonus in childhood partial epilepsy.

The aim of our study was to evaluate the effectiveness of ethosuximide in the treatment of epileptic negative myoclonus, a motor disorder that can occur in childhood partial epilepsy. We introduced ethosuximide in nine patients with partial epilepsy of varying etiology (idiopathic, cryptogenic, symptomatic) who presented with epileptic negative myoclonus. The drug was added to the patients' preexisting antiepileptic drugs, which were maintained unchanged for the following 6 months. Epileptic negative myoclonus disappeared in all patients 15 to 30 days after ethosuximide was started. Plasma ethosuximide levels ranged from 55 to 89 micrograms/mL. The clinical response was not influenced by the patients' preexisting treatment or by the etiology of the epilepsy. No side effects were observed, and none of the patients presented a recurrence of epileptic negative myoclonus during follow-up. Furthermore, in five patients we observed the disappearance of partial seizures; in the remaining patients seizures were reduced by more than 75%. Electroencephalograms showed a decrement or disappearance of focal paroxysmal abnormalities. Our results suggest that ethosuximide is effective in the treatment of epileptic negative myoclonus and that it should be considered as a first-choice drug in the treatment of this motor disorder.

Electrophysiologic study of central motor pathways in ataxia-telangiectasia.

To date, corticospinal tract functional integrity in ataxia-telangiectasia has not been studied. Thorough evaluation of central motor pathways is also lacking in neuropathologic and clinical studies. Using electromagnetic stimulation, we assessed the integrity of the corticospinal tracts in eight patients with ataxia-telangiectasia. Cortical and peripheral compound motor action potentials were recorded from the abductor pollicis brevis muscle. Recordings of the shortest F-wave latency and of the compound motor action potential distal latency were made from the abductor pollicis brevis muscle after electrical stimulation of the median nerve at the wrist. A significant increase in central motor conduction time was observed in four patients, two of whom had clinical findings compatible with a pyramidal lesion. This study demonstrates involvement of the central motor pathways in ataxia-telangiectasia, which appears to be more frequent late in the course of the disease.

A correlated fluctuation of language and EEG abnormalities in a case of the Landau-Kleffner syndrome.

Despite growing interest in the Landau-Kleffner syndrome there have been few reports dealing with language disorders in recent years. The authors present a clinical case of a child with Landau-Kleffner syndrome focusing particularly on the relationship between language disorders and electroencephalographic abnormalities. The authors emphasize that the language disorders primarily affect the receptive sphere and that there seems to be a relationship between abnormalities during sleep with a deterioration in verbal comprehension.

Delayed appearance of interictal EEG abnormalities in early onset childhood epilepsy with occipital paroxysms.

Childhood epilepsy with occipital paroxysms is an age-related idiopathic focal epilepsy. Occipital EEG paroxysms are considered necessary for diagnosis. We carried out a close clinical and EEG follow-up (range, 2-12 years; mean, 6 years 7 months; median, 7 years) in 24 patients (age range, 4-19 years; mean, 11 years 8 months; median, 11 years). In five children with early seizure onset and particularly benign prognosis without any treatment, EEG abnormalities appeared 3-10 months after the first seizure. Four of them exhibited the ictal pattern of versive seizures with vomiting. Our findings confirm that in the early idiopathic focal seizure disorders, interictal EEG abnormalities may be lacking at the beginning of the disorder.

Ring chromosome 9: an atypical case.

A new case of ring chromosome 9 in a 36-month-old child is presented. In addition to the pathognomonic features of this rare disorder (only 21 cases reported), our patient presents some peculiarities, such as corpus callosum hypoplasia and epileptic seizures (infantile periodic spasms). We also observed a reduced level of leukocyte interferon alpha whose synthesis is controlled by a gene on chromosome 9 and which could be responsible for the recurrent respiratory tract infections, typical and sometimes fatal in these patients.

Electrical status epilepticus on eye closure: a case report.

The authors present the clinical case of a boy manifesting eyelid myoclonias on eye closure. The corresponding electroencephalographic recording was characterized by unceasing spike activity, constituting a sort of electrical status epilepticus. There was no loss of consciousness or differences between results of neuropsychological tests with eyes open and closed.

Epilepsia partialis continua in a case of MELAS: clinical and neurophysiological study.

There are few reports in the literature dealing with the association between mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and epilepsia partialis continua (EPC) in children. We report the case of a child presenting with numerous stroke-like episodes associated with EPC which, despite therapy, were not controlled and aggravated the clinical condition of our patient. We present the neuroradiological, biochemical, genetic and muscle biopsy findings, and EEG characteristics, with attention to polygraphic recordings which were done during wake and sleep periods. We consider the correlation with other possible etiological factors relating to EPC and in particular coinvolvement of the basal ganglia as a cause of EPC in our patient.

Acquired epileptic frontal syndrome as long-term outcome in two children with CSWS.

Continuous spikes and waves during slow sleep (CSWS) are a well-known EEG pattern that can be associated with cognitive and behavioural deterioration. We present the long-term clinical, neuropsychological and EEG follow-up of two patients who developed CSWS during childhood. In both the CSWS onset was followed immediately by rapid cognitive and behavioural deterioration. Later the CSWS fragmented or fluctuated and the spike-wave discharges diminished and this was associated with progressive clinical improvement. At the same time bilateral frontal EEG abnormalities appeared awake and in sleep. After the initial period of rapid cognitive and linguistic improvement both patients stabilised. The latest neuropsychological assessment showed a frontal syndrome. The presence of frontal EEG abnormalities superimposed on CSWS, their persistence after CSWS resolution and, in addition, the finding of subtle frontal-type neuropsychological alterations early in recovery may indicate poor long-term outcome.

Epilepsy: a study of adolescence and groups.

We report a 2-year study of 'psychological support' of a group of seven adolescents (five female and two male) with both non-symptomatic generalized and partial epilepsy with onset before puberty. Two child neuropsychiatrists, supervised by a Freudian psychoanalyst specializing in group therapy, conducted the sessions. Sessions were aimed at improving comprehension and acceptance of the condition and its consequences through comparison of thoughts, fantasies, and preoccupations regarding epilepsy, including significance of epileptic seizures and their possible effects on sexuality, pregnancy, mental state, patient resistance to drug therapy, speaking openly about illness, and social and job-related problems. Group dynamics were also examined to improve subject interaction and self-identification. This method varies from the 'self-help' type of intervention which uses an interpretative and reflective approach to interaction of group members.