Clementina Boniver

Early-onset seizure variant of Rett syndrome: Definition of the clinical diagnostic criteria

BACKGROUND Rett syndrome is a severe neurodevelopmental disorder affecting almost exclusively females. Among Rett clinical variants, the early-onset seizure variant describes girls with early onset epilepsy and it is caused by mutations in CDKL5. METHODS Four previously reported girls and five new cases with CDKL5 mutation, ranging from 14 months to 13 years, were evaluated by two clinical geneticists, classified using a severity score system based on the evaluation of 22 different clinical signs and compared with 128 classic Rett and 25 Zappella variant MECP2-mutated patients, evaluated by the same clinical geneticists. Clinical features were compared with previously described CDKL5 mutated patients. Both the statistical and the descriptive approach have been used to delineate clinical diagnostic criteria. RESULTS All girls present epilepsy with onset varying from 10 days to 3 months. Patients may present different type of seizures both at onset and during the whole course of the disease; multiple seizure types may also occur in the same individual. After treatment with antiepileptic drugs patients may experience a short seizure-free period but epilepsy progressively relapses. Typical stereotypic hand movements severely affecting the ability to grasp are present. Psychomotor development is severely impaired. In the majority of cases head circumference is within the normal range both at birth and at the time of clinical examination. CONCLUSION For the practical clinical approach we propose to use six necessary and eight supportive diagnostic criteria. Epilepsy with onset between the first week and 5 months of life, hand stereotypies, as well as severe hypotonia, are included among the necessary criteria.

Efficacy and safety of topiramate in refractory epilepsy of childhood : Long-term follow-up study

This study aimed to evaluate the long-term efficacy and safety of topiramate in treating children with drug-resistant epilepsy. A multicentric, retrospective, open-label, add-on study was undertaken of 277 children (mean age 8.4 years; range 12 months to 16 years) affected by drug-resistant epilepsy. The efficacy was rated according to the seizure types and epilepsy syndrome. After a mean period of 27.5 months of treatment (range 24—61 months), 11 patients (4%) were seizure free and 56 (20%) had more than 50% reduction in seizure frequency. The efficacy of topiramate treatment was noted in localization-related epilepsy and in generalized epilepsy. In addition, in a group of 114 patients, we compared the initial efficacy (evaluated after a mean of 9 months of follow-up) and the retention at a mean of 30 months of topiramate with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Fifty-five (48%) of 114 patients were initial responders. The retention at a mean of 30 months was 23 of 114 patients (20%), 4 of whom (3.5%) were still seizure free. A loss of efficacy occurred in 32 of the 55 initial responders (58%). It was prominent in patients with generalized epilepsy, such as symptomatic infantile spasms and Lennox-Gastaut syndrome, as well as in those with Dravet syndrome. By contrast, a well-sustained topiramate efficacy was noted among patients with localization-related epilepsy. Globally, adverse events were observed in 161 patients (58%) and were mainly represented by weight loss, hyperthermia, sedation, and nervousness, which, in most cases, disappeared after slowing titration or reducing the dosage of the drug. In conclusion, the present long-term study confirms that topiramate represents a useful drug effective in a wide range of seizures and epilepsy syndromes. Moreover, preliminary data seem to suggest that the efficacy of topiramate, when evaluated in the long-term perspective, is more sustained in localization-related epilepsy than in generalized epilepsy. (J Child Neurol 2005;20:893—897).

A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy

Purpose:  To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy.

Longitudinal Electroencephalographic (EEG) Findings in Pediatric Anti-N-Methyl-d-Aspartate (Anti-NMDA) Receptor Encephalitis The Padua Experience

To contribute to characterize electroencephalographic (EEG) activity in pediatric anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis, we reviewed electroclinical data of 5 children with anti-NMDA receptor encephalitis diagnosed in our department. We identified 4 longitudinal electroencephalographic phases: in the early phase, background activity was normal, with intermixed nonreactive slow waves; in the florid phase, background activity deteriorated with appearance of sequences of peculiar rhythmic theta and/or delta activity unrelated to clinical changes, unresponsive to stimuli and antiepileptic medications; in the recovery phase, these sequences decreased and reactive posterior rhythm re-emerged; electroencephalogram normalized 2 to 5 months after onset. In conclusion, in the presence of evocative clinical history, recognizing a characteristic longitudinal electroencephalographic activity could provide ancillary aspects addressing the diagnosis and the overall management of children with anti-N-methyl-d-aspartate receptor encephalitis; in particular, knowing that peculiar and recurrent paroxysmal nonepileptic rhythmic theta-delta patterns can occur in these patients could help distinguish paroxysmal epileptic and nonepileptic electroencephalographic activity.

Analysis of the Bispectral Index During Natural Sleep in Children

The Bispectral Index (BIS) is a system used to measure sedation levels. Some investigators recently analyzed changes in the BIS during natural sleep in adults and found that the BIS diminished considerably as sleep became deeper. No such studies have been undertaken to investigate changes in the BIS in sleeping children. The aim of this work was to assess the trend of the BIS in the various stages of sleep in a group of children, performing a descriptive analysis on a limited number of cases. We evaluated 15 children with negative clinical findings and a normal electroencephalogram (EEG) as part of their follow-up for prior episodes of epilepsy, recording the BIS and EEG in a waking state, in the various stages of sleep and on reawaking. For each stage, the mean value, the standard deviation, and the range of BIS values were calculated. The results showed that the BIS decreased progressively as sleep became deeper. The correlation between the stage of sleep and the BIS was significant. On reawaking, a slow increase was apparent in the BIS.

No evidence of a major locus for benign familial infantile convulsions on chromosome 19q12-q13.1

Summary: Purpose: A locus for benign familial convulsions (BFICs) has been recently mapped on chromosome 19q12–13.1 by studying five families of Italian descent. The main goal of this study was to investigate the role of this locus in a set of seven newly identified families with at least three affected cases.

Paediatric anti-N-methyl-d-aspartate receptor encephalitis: The first Italian multicenter case series

BACKGROUND Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. METHODS To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. RESULTS Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. CONCLUSIONS Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.

Electroclinical diagnosis of Angelman syndrome: a study of 7 cases

The authors describe 7 new cases of Angelman syndrome (AS: 3 males and 4 females) diagnosed on the basis of clinical features (dysmorphic facial features, severe mental retardation with absent speech, peculiar jerky movements, ataxic gait and paroxysms of inappropriate laughter) and neurophysiological findings. Failure to detect deletion of the long arm of chromosome 15 or the absence of epileptic seizure were not considered sufficient to exclude a diagnosis of AS. Feeding problems, developmental delay and early signs of ataxia, especially tremor on handling objects and unstable posture when seated, proved effective as clinical markers for early diagnosis of AS. The EEG patterns characteristic of AS were found within the first 2 years of life (under 18 months in the majority of cases). The authors conclude that AS should be included in differential diagnosis in a child aged under 12 months having cryptogenic psychomotor retardation with prevalent language compromise. Repeat EEG recordings are needed to check for the typical trace, and cytogenetic investigations are mandatory.

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine‐rich, glioma‐inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis.

Pathogenic Role of the X-Linked Cyclin-Dependent Kinase-Like 5 and Aristaless-Related Homeobox Genes in Epileptic Encephalopathy of Unknown Etiology With Onset in the First Year of Life

Two genes causally involved in refractory epilepsy with mental retardation, cyclin-dependent kinase-like 5 and aristaless-related homeobox, could account for at least some forms of early onset epileptic encephalopathy that still lack etiological explanation. With the aim of investigating the specific pathogenic involvement of the 2 genes, we have conducted a clinical and molecular study in 80 patients with epileptic encephalopathy of unknown etiology and onset within the first year of life, regardless of the presence of other clinical features or the definition of a precise epileptologic syndrome. A total of 8 different disease-causing mutations were detected in our population, confirming the pivotal role of these genes in the pathogenesis of the epileptic encephalopathies in infancy. Early key clinical and electroencephalographic phenotypical features identified in these patients can contribute to more precise and early diagnoses. This work provides a better phenotypic characterization and more stringent clinical indications for the molecular test.