A scoring system for early prognostic assessment after neonatal seizures

OBJECTIVE: The aim of this study was to devise a scoring system that could aid in predicting neurologic outcome at the onset of neonatal seizures. METHODS: A total of 106 newborns who had neonatal seizures and were consecutively admitted to the NICU of the University of Parma from January 1999 through December 2004 were prospectively followed-up, and neurologic outcome was assessed at 24 months’ postconceptional age. We conducted a retrospective analysis on this cohort to identify variables that were significantly related to adverse outcome and to develop a scoring system that could provide early prognostic indications. RESULTS: A total of 70 (66%) of 106 infants had an adverse neurologic outcome. Six variables were identified as the most important independent risk factors for adverse outcome and were used to construct a scoring system: birth weight, Apgar score at 1 minute, neurologic examination at seizure onset, cerebral ultrasound, efficacy of anticonvulsant therapy, and presence of neonatal status epilepticus. Each variable was scored from 0 to 3 to represent the range from “normal” to “severely abnormal.” A total composite score was computed by addition of the raw scores of the 6 variables. This score ranged from 0 to 12. A cutoff score of =4 provided the greatest sensitivity and specificity. CONCLUSIONS: This scoring system may offer an easy, rapid, and reliable prognostic indicator of neurologic outcome after the onset of neonatal seizures. A final assessment of the validity of this score in routine clinical practice will require independent validation in other centers.

Mortality risk after neonatal seizures in very preterm newborns

We analyzed clinical and instrumental data of 403 consecutive newborns with gestational age from 24 to 32 weeks, admitted to the University-Hospital of Parma between January 2000 and December 2007, to evaluate the possible relationship between neonatal mortality and occurrence of neonatal seizures in very preterm newborns. Seventy-four subjects died during hospital stay. Seizures were present in 35 neonates, in whom the mortality rate was 37.1%. Multivariate analysis revealed that birth-weight

Preterm infants with video-EEG confirmed seizures:outcome at 30 months of age

Our aim was to identify early predictors of poor neurodevelopmental outcome and of subsequent epilepsy in very early preterm and late preterm newborns with neonatal seizures.

Neonatal seizures and post-neonatal epilepsy:a seven-year follow-up study

BACKGROUND: Seizures are one of the most common symptoms of acute neurological disorders in newborns. This study aims at evaluating predictors of epilepsy in newborns with neonatal seizures. METHODS: we recruited consecutively eighty-five neonates with repeated neonatal video-EEG-confirmed seizures between Jan 1999 and Dec 2004. The relationship between clinical, EEG and ultrasound data in neonatal period and the development of post-neonatal epilepsy was investigated at 7 years of age. RESULTS: Fifteen patients (17.6%) developed post-neonatal epilepsy. Partial or no response to anticonvulsant therapy (OR 16.7, 95% CI: 1.8-155.8, p= .01; OR 47, 95% CI: 5.2-418.1, p<.01 respectively), severely abnormal cerebral ultrasound scan findings (OR: 5.4; 95% CI: 1.1-27.4; p<.04), severely abnormal EEG background activity (OR: 9.5; 95% CI: 1.6-54.2; p= .01) and the presence of status epilepticus (OR: 6.1; 95% CI: 1.8-20.3; p<.01) were found to be predictors of epilepsy. However, only the response to therapy seemed to be an independent predictor of post-neonatal epilepsy. CONCLUSION: Neonatal seizures seem to be related to post-neonatal epilepsy. Recurrent and prolonged neonatal seizures may act on an epileptogenic substrate, causing further damage, which is responsible for the subsequent clinical expression of epilepsy.

Brain mechanisms of altered consciousness in generalised seizures

In spite of the inherent difficulties in achieving a biologically meaningful definition of consciousness, recent neurophysiological studies are starting to provide some insight in fundamental mechanisms associated with impaired consciousness in neurological disorders. Generalised seizures are associated with disruption of the default state network, a functional network of discrete brain areas, which include the fronto-parietal cortices. Subcortical contribution through activation of thalamocortical structures, as well as striate nuclei are also crucial to produce impaired consciousness in generalised seizures.

Reducing suffering in animal models and procedures involving seizures, convulsions and epilepsy

This report is based on discussions and submissions from an expert working group consisting of veterinarians, animal care staff and scientists with expert knowledge relevant to the field and aims to facilitate the implementation of the Three Rs (replacement, reduction and refinement) in the use of animal models or procedures involving seizures, convulsions and epilepsy. Each of these conditions will be considered, the specific welfare issues discussed, and practical measures to reduce animal use and suffering suggested. The emphasis is on refinement since this has the greatest potential for immediate implementation, and some general issues for refinement are summarised to help achieve this, with more detail provided on a range of specific refinements.

Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures

An enhanced tonic GABA-A inhibition in the thalamus plays a crucial role in experimental absence seizures, and has been attributed, on the basis of indirect evidence, to a dysfunction of the astrocytic GABA transporter-1 (GAT-1). Here, the GABA transporter current was directly investigated in thalamic astrocytes from a well-established genetic model of absence seizures, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and its non-epileptic control (NEC) strain. We also characterized the novel form of GABAergic and glutamatergic astrocyte-to-neuron signalling by recording slow outward currents (SOCs) and slow inward currents (SICs), respectively, in thalamocortical (TC) neurons of both strains. In patch-clamped astrocytes, the GABA transporter current was abolished by combined application of the selective GAT-1 and GAT-3 blocker, NO711 (30µM) and SNAP5114 (60µM), respectively, to GAERS and NEC thalamic slices. NO711 alone significantly reduced (41%) the transporter current in NEC, but had no effect in GAERS. SNAP5114 alone reduced by half the GABA transporter current in NEC, whilst it abolished it in GAERS. SIC properties did not differ between GAERS and NEC TC neurons, whilst moderate changes in SOC amplitude and kinetics were observed. These data provide the first direct demonstration of a malfunction of the astrocytic thalamic GAT-1 transporter in absence epilepsy and support an abnormal astrocytic modulation of thalamic ambient GABA levels. Moreover, while the glutamatergic astrocyte-neuron signalling is unaltered in the GAERS thalamus, the changes in some properties of the GABAergic astrocyte-neuron signaling in this epileptic strain may contribute to the generation of absence seizures.

Zonisamide as a treatment for partial epileptic seizures:A systematic review

Although the majority of people with epilepsy have a good prognosis and their seizures can be well controlled with pharmacotherapy, up to one-third of patients can develop drug-resistant epilepsy, especially those patients with partial seizures. This unmet need has driven considerable efforts over the last few decades aimed at developing and testing newer antiepileptic agents to improve seizure control. One of the most promising antiepileptic drugs of the new generation is zonisamide, a benzisoxazole derivative chemically unrelated to other anticonvulsant agents. In this article, the authors present the results of a systematic literature review summarizing the current evidence on the efficacy and tolerability of zonisamide for the treatment of partial seizures. Of particular interest within this updated review are the recent data on the use of zonisamide as monotherapy, as they might open new therapeutic avenues. © 2014 Springer Healthcare.

Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities

Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations. Methods: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients. Results: We classified patients as: SMEI/SMEB = 55; GEFS+ = 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations. Conclusion: We obtained a frequency of 71% SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes. © 2007 International League Against Epilepsy.

Clinical utility of implantable neurostimulation devices as adjunctive treatment of uncontrolled seizures

About one third of patients with epilepsy are refractory to medical treatment. For these patients, alternative treatment options include implantable neurostimulation devices such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation systems (RNS). We conducted a systematic literature review to assess the available evidence on the clinical efficacy of these devices in patients with refractory epilepsy across their lifespan. VNS has the largest evidence base, and numerous randomized controlled trials and open-label studies support its use in the treatment of refractory epilepsy. It was approved by the US Food and Drug Administration in 1997 for treatment of partial seizures, but has also shown significant benefit in the treatment of generalized seizures. Results in adult populations have been more encouraging than in pediatric populations, where more studies are required. VNS is considered a safe and well-tolerated treatment, and serious side effects are rare. DBS is a well-established treatment for several movement disorders, and has a small evidence base for treatment of refractory epilepsy. Stimulation of the anterior nucleus of the thalamus has shown the most encouraging results, where significant decreases in seizure frequency were reported. Other potential targets include the centromedian thalamic nucleus, hippocampus, cerebellum, and basal ganglia structures. Preliminary results on RNS, new-generation implantable neurostimulation devices which stimulate brain structures only when epileptic activity is detected, are encouraging. Overall, implantable neurostimulation devices appear to be a safe and beneficial treatment option for patients in whom medical treatment has failed to adequately control their epilepsy. Further large-scale randomized controlled trials are required to provide a sufficient evidence base for the inclusion of DBS and RNS in clinical guidelines.

Phenobarbital for neonatal seizures:response rate and predictors of refractoriness

Background : Phenobarbital is the first-line choice for neonatal seizures treatment, despite a response rate of approximately 45%. Failure to respond to acute anticonvulsants is associated with poor neurodevelopmental outcome, but knowledge on predictors of refractoriness is limited. Objective : To quantify response rate to phenobarbital and to establish variables predictive of its lack of efficacy. Methods : We retrospectively evaluated newborns with electrographically confirmed neonatal seizures admitted between January 1999 and December 2012 to the neonatal intensive care unit of Parma University Hospital (Italy), excluding neonates with status epilepticus. Response was categorized as complete (cessation of clinical and electrographic seizures after phenobarbital administration), partial (reduction but not cessation of electrographic seizures with the first bolus, response to the second bolus), or absent (no response after the second bolus). Multivariate analysis was used to identify independent predictors of refractoriness. Results : Out of 91 newborns receiving phenobarbital, 57 (62.6%) responded completely, 15 (16.5%) partially, and 19 (20.9%) did not respond. Seizure type (p = 0.02), background electroencephalogram (EEG; p ≤ 0.005), and neurologic examination (p ≤ 0.005) correlated with response to phenobarbital. However, EEG (p ≤ 0.02) and seizure type (p ≤ 0.001) were the only independent predictors. Conclusion : Our results suggest a prominent role of neurophysiological variables (background EEG and electrographic-only seizure type) in predicting the absence of response to phenobarbital in high-risk newborns.

Phenobarbital reduces EEG amplitude and propagation of neonatal seizures but does not alter performance of automated seizure detection

Objective: Phenobarbital increases electroclinical uncoupling and our preliminary observations suggest it may also affect electrographic seizure morphology. This may alter the performance of a novel seizure detection algorithm (SDA) developed by our group. The objectives of this study were to compare the morphology of seizures before and after phenobarbital administration in neonates and to determine the effect of any changes on automated seizure detection rates. Methods: The EEGs of 18 term neonates with seizures both pre- and post-phenobarbital (524 seizures) administration were studied. Ten features of seizures were manually quantified and summary measures for each neonate were statistically compared between pre- and post-phenobarbital seizures. SDA seizure detection rates were also compared. Results: Post-phenobarbital seizures showed significantly lower amplitude (p < 0.001) and involved fewer EEG channels at the peak of seizure (p < 0.05). No other features or SDA detection rates showed a statistical difference. Conclusion: These findings show that phenobarbital reduces both the amplitude and propagation of seizures which may help to explain electroclinical uncoupling of seizures. The seizure detection rate of the algorithm was unaffected by these changes. Significance: The results suggest that users should not need to adjust the SDA sensitivity threshold after phenobarbital administration.

Initial approach to irst-time seizures in pediatrics

Objective: Prove that conducting complementary studies at laboratories and imaging studies are unnecessary in irst-time unprovoked seizures, since there is no change in the evolution and prognosis of the disease, as well as the study of our population, the incidence rate and the proportion of our patients that have been studied and given maintenance treatment, so it can be determined whether or not our population should follow the suggestions of the American Academy of Pediatrics and the Spanish Pediatric Association. Methods: An observational study, including patients diagnosed with irst-time unprovoked seizures. They were followed up on by the emergency department and information was collected from their clinical history and compared with the results of the different studies between patients that suffered just one seizure and the ones that had recurrent seizures. Results: Thirty one patients were included, 14 males and 17 females. The average age was 5.5 years old. The 100% of patients were studied, and the groups were compared. The signiicant study was the electroencephalogram (EEG) with a p=0.02 (signiicance p<0.05), incidence of 41%. Conclusions: The study and diagnosis of irst-time unprovoked seizures is based on clinical manifestations. The EEG is important in the study and classiication of unprovoked seizures. Our population has an incidence and recurrence rate similar to that in the bibliography, and for that reason, this study suggests that the diagnostic and therapeutic guidelines of the American Academy of Pediatrics and the Spanish Pediatric Association should be followed.

An in-depth characterisation of neonatal seizures by early continuous video-EEG analysis

Introduction Seizures are harmful to the neonatal brain; this compels many clinicians and researchers to persevere further in optimizing every aspects of managing neonatal seizures. Aims To delineate the seizure profile between non-cooled versus cooled neonates with hypoxic-ischaemic encephalopathy (HIE), in neonates with stroke, the response of seizure burden to phenobarbitone and to quantify the degree of electroclinical dissociation (ECD) of seizures. Methods The multichannel video-EEG was used in this research study as the gold standard to detect seizures, allowing accurate quantification of seizure burden to be ascertained in term neonates. The entire EEG recording for each neonate was independently reviewed by at least 1 experienced neurophysiologist. Data were expressed in medians and interquartile ranges. Linear mixed models results were presented as mean (95% confidence interval); p values <0.05 were deemed as significant. Results Seizure burden in cooled neonates was lower than in non-cooled neonates [60(39-224) vs 203(141-406) minutes; p=0.027]. Seizure burden was reduced in cooled neonates with moderate HIE [49(26-89) vs 162(97-262) minutes; p=0.020] when compared with severe HIE. In neonates with stroke, the background pattern showed suppression over the infarcted side and seizures demonstrated a characteristic pattern. Compared with 10 mg/kg, phenobarbitone doses at 20 mg/kg reduced seizure burden (p=0.004). Seizure burden was reduced within 1 hour of phenobarbitone administration [mean (95% confidence interval): -14(-20 to -8) minutes/hour; p<0.001], but seizures returned to pre-treatment levels within 4 hours (p=0.064). The ECD index in cooled, non-cooled neonates with HIE, stroke and in neonates with other diagnoses were 88%, 94%, 64% and 75% respectively. Conclusions Further research exploring the treatment effects on seizure burden in the neonatal brain is required. A change to our current treatment strategy is warranted as we continue to strive for more effective seizure control, anchored with use of the multichannel EEG as the surveillance tool.

Treatment trials for neonatal seizures: the effect of design on sample size

Neonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (Td) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, Td and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in Td between groups in analysis will be valid and minimise sample size.