Nelia Zamponi

Vagus nerve stimulation: clinical experience in drug-resistant pediatric epileptic patients.

INTRODUCTION Vagus nerve stimulation (VNS) is an effective alternative treatment for patients with partial refractory epilepsy. Nevertheless, information regarding VNS in children is still limited. MATERIALS AND METHODS The clinical efficacy, safety and neuropsychological effects of VNS in 34 children (mean age 11.5 years) with drug-resistant epilepsy were studied. Mean follow-up was 30.8 months. Nine patients have been diagnosed with Lennox-Gastaut Syndrome, nine patients were affected by severe partial epilepsy with bisynchronous EEG and drop attacks, and 16 patients suffered from partial epilepsy without bisynchronous EEG and fall seizures. Forms were designed for prospective data collection on each patients history, seizures, implants, device settings, quality of life (QOL), neuropsychological assessment and adverse events. Surgical technique was performed both by standard two incisions and single neck incision. RESULTS Mean reduction in total seizures was 39% at 3 months, 38% at 6 months, 49% at 12 months, 61% at 24 months and 71% at 36 months. Significant better results were obtained in partial epilepsy, with and without drop attacks, than in Lennox-Gastaut syndrome--three patients being seizure-free. No operative morbidity was reported. Side-effects were minor and transient--the most common were voice alteration and coughing during stimulation. In two patients, electrode breakage occurred 3 years after surgical procedure; in both cases, a new device was implanted after removing the vagal electrode coils and generator. CONCLUSION VNS can be considered an appropriate strategy as an add-on treatment in children affected by drug-resistant partial epilepsy and ineligible for resective epilepsy surgery.

Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children

To gain insight into the long‐term impact of vagus nerve stimulation (with VNS Therapy) in children with drug‐resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow‐up period of up to 24 months.

The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial

To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long‐term health‐related quality of life (HRQoL).

Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy

The aim of this multicentric, retrospective, and uncontrolled study was to evaluate the efficacy and safety of levetiracetam (LEV) in 81 children younger than 4 years with refractory epilepsy. At an average follow-up period of 9 months, LEV administration was found to be effective in 30% of patients (responders showing more than a 50% decrease in seizure frequency) of whom 10 (12%) became seizure free. This efficacy was observed for focal (46%) as well as for generalized seizures (42%). In addition, in a group of 48 patients, we compared the initial efficacy (evaluated at an average of 3 months of follow-up) and the retention at a mean of 12 months of LEV, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Twenty-two patients (46%) were initial responders. After a minimum of 12 months of follow-up, 9 of 48 patients (19%) maintained the improvement, 4 (8%) of whom remained seizure free. A loss of efficacy was observed in 13 of the initial responders (59%). Maintained LEV efficacy was noted in patients with focal epilepsy and West syndrome. LEV was well tolerated. Adverse events were seen in 18 (34%) patients. The main side effects were drowsiness and nervousness. Adverse events were either tolerable or resolved in time with dosage reduction or discontinuation of the drug. We conclude that LEV is safe and effective for a wide range of epileptic seizures and epilepsy syndromes and, therefore, represents a valid therapeutic option in infants and young children affected by epilepsy.

Complications of vagal nerve stimulation for epilepsy in children

Vagal nerve stimulation (VNS) is a surgical option to treat drug-resistant epilepsy. A few side effects have been described, mainly as anecdotal reports. We analysed our material concerning a juvenile population to identify the most common and most important complications, discussing them with the literature. Thirty-six patients were studied (18 months–18 years old). The children were assessed before the VNS implant and 3, 6, 12, 24 and 36 months after surgery. The mean follow-up was 30 months. Four patients required a second surgery: two for changing the device 3 years after implant; one for revision of an imperfect implant; one for removing a non-functioning device. In one patient a transient vocal cord paralysis was observed. Hoarseness was the main complaint (38.8%). More infrequent was mild sleep apnoea (8.3%), sternocleidomastoid muscle spasm, drooling and snoring in one patient each. Skin scars were reported with a different frequency according to the surgical technique. At variance with the literature reports, we did not observe infections. Side effects of VNS can be minimised, but not avoided completely, with a correct technical procedure, which in turn depends upon a thorough knowledge of vagus nerve anatomy.

Clinical course of young patients with Dravet syndrome after vagal nerve stimulation

Medical treatment of Dravet syndrome is disappointing. Ketogenic Diet and neurostimulation procedures as Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation are in ongoing evaluation. In the present study, the long-term effectiveness of VNS on seizures, cognition and behavior was retrospectively evaluated in eight young patients with DS and medically refractory epilepsy (mean age at VNS implant: 10.28 years, range: 5-25). The average duration of treatment was 54 months (range: 12-120). Compared to baseline (mean: 55; standard deviation: 83, range: 4-200), the mean number of monthly seizures after VNS implantation was 39 ± 67 at 3 months, 42 ± 67 at 6 months and 38 ± 69 at twelve months (not significant comparisons). In particular, VNS produced a mean seizure rate reduction of 12% at three months, 6% at six months, and 31% at twelve months. All patients but three experienced some reduction in seizure burden (range: 33-61%) at twelve months. Seizure outcome after one year of stimulation was rated as Mc Hugh class II (50-79% reduction in seizure frequency) in four patients, class III (<50% reduction) in one patient and class V (no improvement) in three patients. In this small case series of patients with DS, VNS therapy had a clinically significant effect in reducing seizures at twelve months in four of the eight patients. Even in patients in whom seizure reduction was not dramatic, a slight improvement in alertness and communicative skills was seen. The long-term clinical course of two selected cases is discussed.

Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene.

Deletions and duplications/amplifications of the α1‐sodium channel subunit (SCN1A) gene occur in about 12% of patients with Dravet syndrome (DS) who are otherwise mutation‐negative. Such genomic abnormalities cause loss of function, with severe phenotypes, reproductive disadvantage and, therefore, sporadic occurrence. Inherited mutations, occurring in ∼5% of patients with DS, are usually missense; transmission occurs from a mildly affected parent exhibiting febrile seizures (FS) or the generalized epilepsy with febrile seizures plus (GEFS+) spectrum. We identified an intragenic SCN1A deletion in a three‐generation, clinically heterogeneous family. Sequence analysis of SCN9A, a putative modifier, ruled out pathogenic mutations, variants, or putative disease–associated haplotype segregating with phenotype severity. Intrafamilial variability in phenotype severity indicates that SCN1A loss of function causes a phenotypic spectrum in which seizures precipitated by fever are prominent and schematic syndrome subdivisions would be inappropriate. SCN1A deletions should be ruled out even in individuals with mild phenotypes.

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).

Lacosamide in pediatric and adult patients: comparison of efficacy and safety.

PURPOSE This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy. METHOD This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months. RESULTS A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean±SD age was 15.9±6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B. CONCLUSION Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.

Levetiracetam in absence epilepsy

The aim of the study was to assess the efficacy, tolerability, and safety of levetiracetam therapy in children and adolescents with absence epilepsy. Twenty‐one participants (11 male, 10 female) with typical absence seizures were enrolled in this prospective study from seven centres in Italy. The mean age and age range at time of enrolment into the study were 8 years 9 months (SD 0.9) and 5 years 1 month to 13 years respectively. All patients were carefully evaluated at 6 months from baseline, and 12 patients were also re‐evaluated at 12 months after the beginning of therapy with levetiracetam. At the 6‐month evaluation, out of 21 patients studied, 11 were seizure free and one showed ‘decreased’ seizures (more than 50% reduction in seizures). A less than 50% reduction in seizures was observed in nine patients. At the 12‐month evaluation, 10 patients were completely seizure free and two were seizure free with some anomalies in electroencephalograms. Two patients who had shown no improvement at 6 months had decreased seizures at the second follow‐up. Our results suggest that monotherapy with levetiracetam could be effective and well tolerated in patients with childhood absence epilepsy and juvenile absence epilepsy. Prospective, large, long‐term double‐blind studies are needed to confirm these findings.