Salvatore Mangano

Levetiracetam during 1-year follow-up in children, adolescents, and young adults with refractory epilepsy.

PURPOSE To evaluate the efficacy and safety of levetiracetam (LEV) in refractory crypto/symptomatic, partial or generalised epilepsy in children, adolescents and young adults. METHODS We performed a prospective open label add-on study in 99 patients (age 12 months to 32 years, mean 14 years) with partial or generalised, crypto/symptomatic seizures. Levetiracetam was added to no more than two baseline AEDs and the efficacy was rated according to seizure type and frequency. RESULTS LEV was initiated at the starting dose of 10mg/kg/day with 5-day increments up to 50 mg/kg/day, unless it was not tolerated. Concomitant therapy was generally not modified throughout the study. After a mean follow-up period of 6.7 months (range 3 weeks to 29 months), 11 patients (11.1%) were free of seizures (cryptogenic partial epilepsy, 5; symptomatic partial epilepsy, 6). A more than 75% seizure decrease was found in 14 patients (14.1%) and >50% in 8 (8.1%). Seizures were unchanged in 38 (38.4%), and worsened in 23 (23.2%). Mild and transient adverse side effects were found in 17 patients (17.2%), mostly represented by irritability and drowsiness. CONCLUSION LEV appears to be well tolerated in children and adolescents with severe epilepsy and seems to be a broad spectrum AED, though in our experience, it was more effective against partial seizures with or without secondarily generalisation. LEV efficacy in other epilepsy syndrome should be evaluated further in homogeneous, more selected patients.

Incontinentia pigmenti: clinical and neuroradiologic features

Developmental brain malformations and destructive processes of unknown etiology were described in incontinentia pigmenti (IP). Two patients, a male and a female, with characteristic skin lesions and central nervous system (CNS) involvement are reported. Neuroradiological examinations revealed hypoplasia of corpus callosum, neuronal heterotopias, and periventricular white matter damage. No specific infectious, inflammatory, or metabolic abnormalities were identified. These neuroradiographic findings may suggest that an ischemic pathogenetic mechanism occurred prenatally. We speculate that the brain damage in IP may occur during CNS development and in successive stages. Magnetic resonance imaging appears more useful to detect white matter lesions and brain malformations in patients with IP.

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.

Rufinamide in children and adults with Lennox-Gastaut syndrome: first Italian multicenter experience.

This is the first multicenter Italian experience with rufinamide as an adjunctive drug in children, adolescents and adults with Lennox-Gastaut syndrome. The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3-21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10mg/kg body weight, evenly divided in two daily doses and then increased by 10mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day. After a mean follow-up period of 12.3 months (range 3-21 months), the final mean dose of rufinamide was 33.5mg/kg/24h (range 11.5-60) if combined to valproic acid, and of 54.5mg/kg/24h (range 21.8-85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50-99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25-50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count. Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritability and loss of appetite. In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox-Gastaut syndrome and produced only mild or moderate adverse side effects.

A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability

Mutations in the KCNQ2 gene encoding for voltage‐gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.

Zonisamide in children and young adults with refractory epilepsy : An open label, multicenter Italian study

PURPOSE To report on the first multicenter Italian experience with zonisamide as an add-on drug for refractory generalised or partial epilepsy in children, adolescents and young adults. METHODS The patients were enrolled in a prospective, add-on, open-label treatment study from eight Italian centres for children and adolescent epilepsy care. Eighty-two young patients (45 males, 37 females), aged between 3 and 34 years (mean 13.1 years), all affected by partial (47) or generalised (35) refractory epilepsy, were enrolled in the study. ZNS was added to the baseline therapy at a starting dose of 1 mg/kg/day twice daily. This dose was increased by 2 mg/kg every 1-2 weeks over a period of up 3 months, according to the patients response and tolerability, up to a maximum dose of 12 mg/kg. ZNS was given at the mean daily dose of 5.7/mg/kg/24 h (range 1-12 mg/kg). RESULTS After a mean follow-up period of 11.9 months (range 2-64 months), 9 patients (10.9%) were seizure-free. The number of seizures decreased by 50-99% in 31 cases (37.8%), by 25-49% in 5 cases (6.1%), remained the same in 29 cases (35.4%) and increased in 8 cases (9.7%). After 15 months of follow-up, 61 patients (74.4%) were still taking ZNS, while the remaining 21 (25.6%) had stopped. Twenty-two patients (26.8%) reported adverse effects while taking ZNS. They generally appeared during the first weeks of treatment, and were mild to moderate. The most frequent adverse effects were irritability and a reduced appetite. CONCLUSION ZNS effectively reduced seizure frequency in this pediatric population with both partial and generalised crypto/symptomatic refractory epilepsy. Its overall tolerability was good.

Non-convulsive status epilepticus associated with tiagabine in a pediatric patient

We report a 4-year-old patient who developed non-convulsive status epilepticus (NCSE) following tiagabine (TGB) as add-on treatment for refractory partial seizures. NCSE occurred while the patient received TGB 0.83 mg/kg/day. In our case, the TGB reduction led to a significant improvement of electroclinical features. The mechanisms of this abnormal effect are not clear. GABA-ergic hyperfunction and/or multiplicity of interlinked brain GABA systems associated with individual specific sensitivity could play a critical role in the pathogenesis of NCSE. This is the first report of NCSE documented by electroencephalogram (EEG) in a child under 12 years of age on TGB treatment.

Benign myoclonic epilepsy in infancy followed by childhood absence epilepsy

Benign myoclonic epilepsy in infancy (BMEI) is a rare syndrome included among idiopathic generalized epilepsies (IGE) and syndromes with age-related onset. Recently, it has been shown that a few patients with BMEI later had other epilepsy types mainly IGE but never childhood absence epilepsy (CAE). We report a patient who at 11 months of age showed isolated myoclonic jerks occurring several times a day. The ictal video-EEG and polygraphic recording revealed generalized discharge of spike-wave (SW) lasting 1-2s associated with isolated bilateral synchronous jerk involving mainly the upper limbs controlled by valproic acid (VPA). At 6 years and 8 months the child developed a new electroclinical feature recognized as CAE. The ictal EEG disclosed a burst of rhythmic 3 Hz generalized SW. Our case is the first patient with BMEI reported in the literature who later developed a CAE. This finding suggests a common neurobiological and genetic link between different age-related epileptic phenotypes.

HYPEREKPLEXIA CAUSED BY DOMINANT-NEGATIVE SUPPRESSION OF GLYRA1 FUNCTION

Hyperekplexia (HE; startle disease; OMIM#149400) is a rare inheritable neurologic disorder characterized by an exaggerated response to sudden stimuli, muscular rigidity, and hyperreflexia, leading to chronic injuries due to unprotected falls. All symptoms are present at birth but gradually decline during the first year of life, although an exaggerated startle response remains during adulthood.1 Dysfunctional inhibitory neurotransmission by glycine (Gly) plays a central role in HE pathogenesis. All patients with HE carry mutations in genes encoding either for α1 (GLYRA1) or β (GLYRB) Gly receptor subunits, presynaptic Gly transporters (SLC6A5), or proteins involved in Gly receptor (GLYR) clustering, such as gephyrin (GPHN) and collybistin (ARHGEF9).1,2 GLYRA1 subunits interact in a heteropentameric complex with homologous β subunits (3α12β). Each subunit comprises an extracellular N-terminus, four α-helical transmembrane segments (TM1 to TM4), and an extracellular C-terminus; TM2 segments are thought to align the Cl− selective pore.1 Different GLYRA1 missense and nonsense mutations have been associated with autosomal dominant, autosomal recessive, and sporadic forms of HE. Missense mutations may show incomplete penetrance and impair channel gating, trafficking, and stability.3 Nonsense mutations have been reported only in recessive cases, in compound heterozygosity with a missense mutation, or in homozygosity in the offspring of consanguineous nonaffected parents and appear unable to cause the startle phenotype in heterozygosis.4,5 A recessive form of HE linked to a GLYRA1 null allele has been described,6 suggesting a nonpathogenic role for haplotype insufficiency. In this study, we investigated the functional consequences of a de novo …

Therapeutic efficacy of magnesium valproate in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of γ-aminobutyric acid (GABA) metabolism, manifests typically as a nonprogressive neurodevelopmental disorder with cognitive deficiency, neuropsychiatric morbidity and epilepsy. Therapy targets symptomatic seizures and neurobehavioral disturbances. We report an adolescent female with SSADHD whose unresponsiveness to a broad spectrum of antiepileptics was circumvented with magnesium valproate (MgVPA). Epilepsy remains well controlled in our patient, with concomitant improvements in behavioral symptoms and an absence of adverse symptoms. MgVPA intervention may have utility in SSADHD.