Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study.

Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable. Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997-2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1-21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.

Improvement of quality of life in adolescents with epilepsy after an empowerment and sailing experience.

PURPOSE: Epilepsy in adolescents affects their psychological health, independence, and emotional adjustment. Psychological and self-management interventions might give benefits to adolescent with epilepsy in terms of quality of life, emotional well-being, and reduced fatigue. "Fondazione Tender To Nave Italia" promotes a project using sailing activities as an empowerment opportunity. The main aim of our study was to examine the empowerment effects on quality of life of adolescents with epilepsy attending sailing activities, and to compare the results perceived by adolescents and their parents. METHODS: Fifty-eight patients with a diagnosis of epilepsy were included in an empowerment project titled "Waves rather than spikes" from June 2013 to July 2018. Intellectual level was based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. Patients were administered Pediatric Quality of Life Inventory (PedsQL), adolescent and parent version. Behavioral data were collected by parent-report Child Behavior Checklist (CBCL). RESULTS: Thirty female and 28 male patients with a mean age of 15 years, referred to "Bambino Gesù Children's Hospital" in Italy, were included. Thirty-three (56.9%) patients had a history of refractory epilepsy; 34 (56.2%) received polytherapy, 19 (32.7%) monotherapy, and 5 (8.6%) were not taking antiepileptic drugs. Intellectual functioning was normal in 43 (74.1%), borderline in 9 (15.5%), and mildly impaired in 6 (10.3%). Results from PedsQL adolescent report revealed significant postintervention improvement for total score (p = 0.023) and in two domains: physical health (p = 0.0066) and emotional functioning (p = 0.015). Results from PedsQL parent report showed significant postintervention improvement for the domain of school functioning (p = 0.023). In the multivariate model, a low CBCL value was predicting a higher score in the health subscore difference between pre- and postempowerment activity (p = 000.8). CONCLUSION: Empowerments activities are crucial in order to reduce the burden of epilepsy in adolescents, and to improve quality of life. These are critical factors for a well-managed transition phase to adulthood.

A validation study of the clinical diagnosis of Dup15q syndrome: Which symptoms matter most?

PURPOSE: Dup15q syndrome is a rare genetic disease with a fairly nonspecific phenotype, clinical heterogeneity, and a wide spectrum of severity. However, no formal characterization has been attempted to select clusters of symptoms, signs and instrumental tests, to be used in the differential diagnosis with other neurodevelopmental disorders. Thus, our purpose was to identify symptoms, signs and instrumental findings, singly or in various combinations, favoring the early diagnosis of the Dup15q syndrome and the indication for genetic testing. METHODS: 25 patients with Dup15q syndrome and 25 age and sex matched controls with other neurodevelopmental disorders were the study population. Patients' history, clinical and instrumental assessment were examined by five expert child neurologists blind to the genetic diagnosis. Each rater was asked to make the diagnosis in three subsequent steps: 1. Revision of the medical records; 2. Examination of the videorecorded clinical findings; 3. Assessment of the instrumental tests. Inter-rater agreement was measured with the Kendall's coefficient of concordance) and the Kappa statistic. Sensitivity, specificity and predictive values for symptoms, signs and instrumental findings, singly or in various combinations, were measured. RESULTS: The Kendall's coefficient for the diagnosis of Dup15q syndrome was 0.43 at step 1 was 0.43, at step 2 was 0.42, at step 3. Patients with past feeding difficulties, hypotonia during the neonatal period, and epilepsy had >80 % probability of having the Dup15q syndrome. CONCLUSION: Feeding difficulties, hypotonia and epilepsy, though unspecific, can be used as signals of Dup15q syndrome and focused search of genetic abnormalities.

De novo Absence Status Epilepticus in a pediatric cohort: Electroclinical pattern in a multicenter Italian patients cohort.

PURPOSE: Absence Status epilepticus (AS) is a form of Non Convulsive Status Epilepticus defined as a prolonged, generalized and non-convulsive seizure, with an altered content of consciousness. We aim to describe a group of healthy children, who presented recurrent and unprovoked de novo AS as the only manifestation of their epilepsy, with an excellent response to antiepileptic drugs. METHOD: We retrospectively reviewed the electroclinical and genetic features of 13 pediatric patients, referring to our epilepsy centers from 2005 to 2019, on the following criteria: (1) regular psychomotor development, (2) one or more unprovoked AS as the only epileptic manifestation, (3) normal blood testing, (4) normal neuroimaging, (5) EEG recording, (6) available follow-up (1-14 years). RESULTS: Patients are 7 females and 6 males, aged 7-22, with a mean age at AS onset of 9,3 years. All of them started an antiepileptic therapy, with an excellent response to Valproic Acid (VPA) or Ethosuximide (ETS). 5 patients did not start the therapy immediately after the first AS and they presented recurrent AS (from 2 to 4 episodes). 10 of them performed aCGH, karyotype, NGS panel or Whole Exome Sequencing. CONCLUSIONS: We suggest that de novo AS may be a well-defined age-related and self-limited epilepsy syndrome, with a good prognosis and excellent response to therapy, but it comes with a high risk of relapsing if not adequately treated with antiepileptic drugs.

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies-An Italian observational multicenter study.

PURPOSE: To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions. PATIENTS AND METHODS: This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline. RESULTS: 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number=96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1mg (2-12mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue. CONCLUSION: PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy.

Somatic mosaicism of PCDH19 mutation in a family with low-penetrance EFMR.

The occurrence of epilepsy with mental retardation limited to females (EFMR; MIM 300088) has been recently associated to mutations in the PCDH19 gene, located on chromosome X and encoding for protocadherin 19. EFMR shows a rare X-linked inheritance wherein affected females may be segregating a mutation through unaffected transmitting males (Fabisiak and Erickson Clin Genet 38(5):353-358, 1990; Juberg and Hellman J Pediatr 79:726-732, 1971; Ryan et al. Nat Genet 17(1):92-95, 1997). The description of a pedigree segregating PCDH19 mutations from unaffected mothers to patients (Depienne et al. Hum Mutat 32:E1959-1975, 2011; Dibbens et al. Neurology 76:1514-1519, 2011) complicates disease inheritance and genetic counseling. In the present study, we describe a PCDH19 mutation segregating from an asymptomatic mother to an EFMR patient. In order to correlate the healthy phenotype with the genotype of the transmitting mother, we quantified in a few tissues the level of the mutant allele by real-time PCR, disclosing a somatic mosaicism. This finding has a great impact on genetic counseling.

Childhood refractory focal epilepsy following acute febrile encephalopathy.

BACKGROUND: We describe a group of previously normal children who developed severe focal epilepsy after an acute/sub-acute illness resembling encephalitis. METHODS: This is a retrospective study. An acute phase (encephalitis/encephalopathy period) and a chronic phase (chronic focal resistant epilepsy) were defined. RESULTS: Eight patients were enrolled. The median age at onset was 6.6 years (range 8 months-17.6 years). In the acute phase, fever was the first symptom in all cases and was associated with seizures and status epilepticus. All patients had focal seizures arising in both hemispheres. Seizure onset occurred in the frontal and temporal regions. EEGs showed slowing background activity associated with focal or diffuse slow waves with rare epileptiform abnormalities. Cerebrospinal fluid oligoclonal bands were observed in four out of six patients tested. MRI images showed bilateral peri-insular hyperintensity in four cases. Five patients received corticosteroids, and in four cases, they were given along with intravenous immunoglobulins. The median duration of the acute phase was 19 days (range 15-30 days). During the chronic phase, which followed the acute phase without interval, patients presented with drug-resistant focal seizures and neuropsychological deficits, which ranged from hyperactivity and attention deficits to short-term verbal memory deficit, pervasive developmental disorders, and language delay. CONCLUSION: Considering the clinical presentations, EEG findings, and the associated occurrence of non-specific immunological activations, a possible immune-mediated pathogenesis can be hypothesized, although firm conclusions cannot be drawn out.

Protocadherin 19 mutations in girls with infantile-onset epilepsy.

OBJECTIVE: To explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy. METHODS: We studied a cohort of 117 female patients with febrile seizures (FS) and a wide spectrum of epilepsy phenotypes including focal and generalized forms with either sporadic or familial distribution. RESULTS: PCDH19 screening showed point mutations in 13 probands (11%). Mean age at seizure onset was 8.5 months; 8 patients (62%) presented with FS, 4 (33%) with cluster of focal seizures, and 1 with de novo status epilepticus (SE). Subsequent seizure types included afebrile tonic-clonic, febrile, and afebrile SE, absences, myoclonic, and focal seizures. Seven patients (54%) had a clinical diagnosis consistent with Dravet syndrome (DS); 6 (46%) had focal epilepsy. In most patients, seizures were particularly frequent at onset, manifesting in clusters and becoming less frequent with age. Mental retardation was present in 11 patients, ranging from mild (7; 64%) to moderate (1; 9%) to severe (3; 27%). Five patients (38%) had autistic features in association to mental retardation. Mutations were missense (6), truncating (2), frameshift (3), and splicing (2). Eleven were new mutations. Mutations were inherited in 3 probands (25%): 2 from apparently unaffected fathers and 1 from a mother who had had generalized epilepsy. CONCLUSIONS: PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented.

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.

An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy.

OBJECTIVE: To conduct an open-label, add-on trial on safety and efficacy of levetiracetam in severe myoclonic epilepsy of infancy (SMEI). PATIENTS AND METHODS: SMEI patients were recruited from different centers according to the following criteria: age > or =3 years; at least four tonic-clonic seizures/month during the last 8 weeks; previous use of at least two drugs. Levetiracetam was orally administrated at starting dose of approximately 10 mg/kg/day up to 50 to 60 mg/kg/day in two doses. Treatment period included a 5- to 6-week up-titration phase and a 12-week evaluation phase. Efficacy variables were responder rate by seizure type and reduction of the mean number per week of each seizure type. Analysis was performed using Fisher exact and Wilcoxon tests. RESULTS: Twenty-eight patients (mean age: 9.4 +/- 5.6 years) entered the study. Sixteen (57.1%) showed SCN1A mutations. Mean number of concomitant drugs was 2.5. Mean levetiracetam dose achieved was 2,016 mg/day. Twenty-three (82.1%) completed the trial. Responders were 64.2% for tonic-clonic, 60% for myoclonic, 60% for focal, and 44.4% for absence seizures. Number per week of tonic-clonic (median: 3 vs 1; p = 0.0001), myoclonic (median: 21 vs 3; p = 0.002), and focal seizures (median: 7.5 vs 3; p = 0.031) was significantly decreased compared to baseline. Levetiracetam effect was not related to age at onset and duration of epilepsy, genetic status, and concomitant therapy. Levetiracetam was well tolerated by subjects who completed the study. To date, follow-up ranges 6 to 36 months (mean, 16.2 +/- 13.4). CONCLUSION: Levetiracetam add-on is effective and well tolerated in severe myoclonic epilepsy of infancy. Placebo-controlled studies should confirm these findings.

Non-epileptic paroxysmal manifestations during sleep in infancy and childhood.

Sleep-related paroxysmal disorders in infancy and childhood have recently been reviewed and classified by the American Sleep Disorders Association. Although in some patients diagnosis is easy to achieve, at times a video/EEG recording of the episodes is required because of the similarity to epileptic seizures. These disorders often represent a challenge for paediatricians as an accurate diagnosis is required. We report a review of the literature and a characterisation of our series of patients. Paroxysmal events during sleep are frequently misdiagnosed as psychogenic fits, epileptic seizures or physiologic events with evident disadvantages for children and families. The widespread use of neurophysiological techniques and better knowledge of the semeiology of epileptic seizures have led us to correctly define these events, which have sometimes been erroneously treated in the past.

Features of the blink reflex in individuals at risk for Huntington's disease.

The aim of the study was to correlate the features of the blink reflex (BR) with the genetic abnormalities and the clinical findings in patients with Huntington's disease (HD) and asymptomatic gene carriers. Twenty patients with HD and 20 relatives were studied. Mutation analysis was performed for the CAG expansion within the HD gene using HD 333-HD 447 as oligonucleotide primers. The BR was elicited transcutaneously by electrical stimulation of the right supraorbital nerve. The recovery curve of the R2 and R3 responses after a conditioning stimulus was evaluated. R2 latency and duration and R3 duration were significantly increased in HD patients and in presymptomatic carriers in comparison with controls; reduced R2 recovery was also clear in both HD and gene-carrier relatives. In HD patients, the R2 latency increase correlated significantly with the severity of facial chorea. The R2 abnormalities are probably caused by impaired suprasegmental control by the basal ganglia over brainstem interneurons, which may precede the onset of involuntary movements, probably conditioning the severity of facial chorea during development of the disease.

Autosomal recessive polymicrogyria with infantile spasms and limb deformities.

We describe two siblings, a girl and a boy, aged 4 and 2 years and 10 months respectively, born from non-consanguineous parents,with diffuse polymicrogyria, lower limb deformities, infantile spasms and developmental delay. Spasms had a good outcome under antiepileptic drug treatment. Clinical and imaging features were of identical severity in both siblings. Muscle biopsy,creatine kinase, metabolic investigations and chromosomal analysis were normal. This combination of anatomo-clinical features and their occurrence in siblings of both sexes suggests an autosomal recessive malformation syndrome.