Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months.

OBJECTIVE: This randomized, double-blind, placebo-controlled trial was conducted to assess the efficacy and tolerability of adjunctive lamotrigine for the treatment of partial seizures in infants aged 1 to 24 months. METHODS: The study used a responder-enriched design in which all patients received adjunctive lamotrigine during an open-label phase (n = 177; maximum maintenance dose 5.1 mg/kg/day for those on non-enzyme-inducing antiepileptic drugs [AEDs] or valproate and 15.6 mg/kg/day for those on enzyme-inducing AEDs). Patients meeting response criteria were randomly assigned to double-blind treatment for up to 8 weeks with continued lamotrigine (n = 19) or to withdrawal from lamotrigine (placebo; n = 19) while background AEDs were maintained. RESULTS: The proportion of treatment failures (patients who met escape criteria or withdrew before completing the double-blind phase) was lower with lamotrigine (58%) than with placebo (84%). This finding was not significant in the primary analysis (two-sided chi(2) test [primary endpoint]). A post hoc sensitivity analysis of the primary endpoint was also performed (p = 0.045 by one-sided, mid-p corrected Fisher exact test). The median time to meet escape criteria was longer with lamotrigine (42 days) than with placebo (22 days) (p = 0.059). During the last 28 days of the open-label phase, 53% of the patients had a >or=50% reduction in frequency of partial seizures with lamotrigine. Additional reduction in partial seizure frequency was observed during the double-blind phase compared with the last 4 weeks of the open-label phase among those randomly assigned to lamotrigine (32% with a >or=25% reduction) but not those randomly assigned to placebo (5% with a >or=25% reduction). Lamotrigine was well tolerated, with an adverse event profile comparable to that observed in older pediatric patients. CONCLUSION: Lamotrigine was well tolerated, and the data indicate that it may be efficacious in the treatment of partial seizures in infants aged 1 to 24 months.

Biotin-responsive basal ganglia disease: case report and review of the literature.

Biotin-responsive basal ganglia disease is a rare entity of which 10 cases have been reported in the literature. We report a case of biotin-responsive basal ganglia disease with similarities and differences compared to the previously reported cases by Ozand et al. Our case presented much earlier, was milder and responded better to lower doses of biotin, compared to the cases reported previously. Since our case showed differences with those in the literature, it might represent a new entity or a milder form of the same entity.

Marked benefits in physical activity and well-being, but not in functioning domains, 2 years after successful epilepsy surgery in children.

In this first study comparing epilepsy-specific quality-of-life measures of children after epilepsy surgery (2.4 years after focal resection) with those of a matched comparison group of nonoperated patients, seizure severity, medication side effects, overall quality of life, general health, physical activity, and well-being were better in surgical patients (70.6% seizure free vs 8.3%). Cognitive, social, and behavioral functioning did not differ, suggesting that these may require additional interventions during postsurgical follow-up.

Risk factors for development of subclinical hypothyroidism during valproic acid therapy.

OBJECTIVE: To identify risk factors for subclinical hypothyroidism (SCH) (thyroid-stimulating hormone levels >5 mIU/mL) in patients receiving valproate (VPA) therapy. STUDY DESIGN: During a period of 2 years, consecutive patients with epilepsy receiving VPA and a control group of patients with diseases other than epilepsy attending a tertiary care neurology clinic were screened for SCH. The 2 groups were compared. The association between SCH and specific risk factors was investigated with bivariate and multivariate analyses. RESULTS: Thirty-six of 143 patients receiving VPA (25.2%, mean age +/- SD: 8.5 +/- 6.6 years) and none of the 35 control subjects had SCH (P < .001). Predictors of SCH were younger age (OR: 1.15, cutoff age 3.9 years); duration of treatment between 6 and 24 months versus <6 months (OR: 2.98) and >24 months (OR: 2.66); VPA polytherapy with enzyme-inducing agents (OR: 6.08), or polytherapy with non-enzyme-inducing agents (OR: 3.34) compared with VPA monotherapy. Most (88.2%) patients with duration of therapy >2 years were older than 3.9 years. CONCLUSION: Risk factors for SCH were young age, co-medication with antiepileptic drugs, and duration of therapy between 6 and 24 months. Screening patients with these risk factors may be warranted.

Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls.

Lafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous EPM2A mutation and patients with apparently homozygous EPM2B mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to EPM2B mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD.

Two randomized vitamin D trials in ambulatory patients on anticonvulsants: impact on bone.

OBJECTIVE: To investigate the effects of two doses of vitamin D given over 1 year on bone density in ambulatory patients on long-term antiepileptic drug (AED) therapy. METHODS: We conducted two parallel, randomized, controlled trials in 72 adults (18 to 54 years old) and 78 children and adolescents (10 to 18 years) on long-term AED therapy. They received either low-dose vitamin D 400 IU/day or high-dose vitamin D 4,000 IU/day (adults) and 2,000 IU/day (children/adolescents). Bone mineral density (BMD) was measured using dual-energy x-ray absorptiometry. RESULTS: In adults, baseline BMD was lower than that of age- and gender-matched controls vs either a Western or an ethnically identical population. After 1 year, there were significant increases in BMD at all skeletal sites compared to baseline in the high-, but not in the low-dose treatment group. However, BMD at 1 year remained below normal. In children, baseline BMD was normal vs age- and gender-matched controls and showed significant and comparable increases in both treatment groups. CONCLUSIONS: In ambulatory adults on antiepileptic drugs, high-dose vitamin D therapy substantially increased bone mineral density at several skeletal sites. In children, both doses resulted in comparable increases in bone mass.

Exacerbation of vocal tics after temporal lobectomy.

We describe a woman with intractable temporal lobe epilepsy secondary to dysgenesis of the left temporal lobe who had a marked and long-term exacerbation of her preexisting vocal tics after a temporal lobectomy that completely controlled her seizures. The patient was determined to have right-sided speech dominance by the Wada test. This is, to our knowledge, only the second reported case of exacerbation of tics after resection of the nondominant temporal lobe.

Effect of antiepileptic drugs on bone density in ambulatory patients.

BACKGROUND: Long-term antiepileptic drug (AED) use causes multiple abnormalities in calcium and bone metabolism that have been most extensively described in institutionalized patients. The objective is to determine the effect of AED on vitamin D levels and bone density in ambulatory patients and to compare the effects of enzyme-inducing and -noninducing AED and of single vs multiple therapy on bone density. METHODS: A cross-sectional evaluation was conducted of 71 patients (42 adults and 29 children/adolescents) on anticonvulsant therapy for at least 6 months who presented to neurologists at a tertiary referral center. Bone mineral density (BMD) as well as serum 25 hydroxy-vitamin D (25-OHD) levels were measured. A detailed questionnaire assessing calcium intake as well as previous and current intake of antiepileptic medications was administered to all patients. RESULTS: Over 50% of adults and children/adolescents had low 25-OHD levels, but this finding did not correlate with BMD. Antiepileptic therapy decreased BMD in adults. Generalized seizures, duration of epilepsy, and polypharmacy were significant determinants of BMD, more so at skeletal sites enriched in cortical bone. Subjects on enzyme-inducing drugs such as phenytoin, phenobarbital, carbamazepine, and primidone tended to have lower BMD than those on noninducers such as valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, and ethosuximide. CONCLUSION: Epilepsy and its therapy, including the newer drugs, are risk factors for low bone density, irrespective of vitamin D levels. Skeletal monitoring with the institution of appropriate therapy is indicated in patients on chronic antiepileptic therapy.

Classification of epilepsy syndromes and role of genetic factors.

In this report the types of epilepsy syndromes seen in children in a tertiary referral center in Beirut, Lebanon were studied and the importance of consanguinity and family history in the occurrence of these syndromes was investigated. Records of 230 pediatric patients evaluated during a 1-year period with the diagnosis of single seizure, febrile seizure, or epilepsy were reviewed. Each patient was classified according to the International League Against Epilepsy classification. The occurrence of consanguinity, of family history of febrile seizures or epilepsy, and of other variables was noted. Thirty-six percent of patients were diagnosed with localization-related epilepsy, 21.7% with generalized epilepsy, 11.7% with undetermined generalized or focal, and 24.3% with special syndromes. Twelve percent of patients were diagnosed with idiopathic, 15.1% with symptomatic, and 30.3% with cryptogenic epilepsies. Consanguinity was more common in patients with symptomatic and cryptogenic epilepsies than in patients with idiopathic epilepsies or with incidental seizures (P < 0.05). Family history of epilepsy was more common in patients with symptomatic, cryptogenic, and idiopathic epilepsies than in patients with incidental seizures (P < 0.05). Family history of febrile seizures but not consanguinity was more common in patients with febrile seizures (P < 0.05). We conclude that genetic factors are important not only in idiopathic epilepsies and febrile seizures but also in cryptogenic and symptomatic epilepsies.

Isolated adipic aciduria.

Adipic acid can appear, in combination with other dicarboxylic acids, in the urine of patients in a number of underlying metabolic diseases. A child with seizures and mental retardation of unknown etiology who was found to have elevated isolated adipic aciduria on investigation for metabolic diseases is reported. A dietary artifact was suspected, and the adipic aciduria resolved after the child was kept on a specific restricted diet for 3 days. This is the third report of isolated adipic aciduria secondary to food. Findings confirm the previous reports of dietary origin of isolated adipic aciduria and should alert clinicians to such artifact before committing patients to unnecessary treatments.

Time sequence and types of memory deficits after experimental status epilepticus.

P35 rats subjected to kainate induced status epilepticus (SE) subsequently underwent four consecutive series of the Morris Water Maze. They demonstrated, compared with controls, an early (P46-49), and subsequent (P60-63) disturbance in acquisition, but not in long term retention, of spatial memory. They eventually achieved performance levels similar to those of controls (P74-77, P91-94). These data support the hypothesis that acquisition, but not long term retention, of spatial material is impaired in this model of temporal lobe epilepsy (TLE), probably due to the hippocampal injury that occurs after SE.

Anticonvulsant action and long-term effects of gabapentin in the immature brain.

The anticonvulsant action and the long-term effects on learning, memory and behavior of the new generation antiepileptic drug gabapentin (GBP) were investigated in immature animals. Kainic acid (KA) was administered to rats on postnatal day (P) 35. Animals were treated with GBP or saline from P36 to P75 and spontaneous seizure frequency was monitored. After tapering the drug, the rats were tested in the water maze and open field test. Brains were then analyzed for histological lesions. Animals treated with GBP following KA-induced status epilepticus had a reduced incidence of spontaneous recurrent seizures, a better pathology score, and less aggressiveness compared to saline-treated controls. Effectiveness of GBP on seizure threshold was tested using flurothyl inhalation in 10 separate age groups of animals ranging from the newborn period to adulthood. Furthermore, GBP plasma concentration peaks were determined in all age groups. At all ages, GBP pre-treated animals demonstrated a higher seizure threshold. Plasma GBP concentrations did not significantly change with age. These data suggest that acute administration of a single therapeutic dose of GBP increases the seizure threshold at all ages studied, while chronic treatment following the status reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.

Alternating hemiplegia of childhood: clinical manifestations and long-term outcome.

We present our analysis of 44 patients with alternating hemiplegia of childhood. The clinical course usually consisted of three phases. The first was dominated by abnormal eye movements and dystonic episodes, the second by hemiplegic spells and psychomotor regression, and the third by persistent developmental delay and fixed neurologic deficits. The age of onset was 0-54 months (mean = 7.9 +/- 13 months). The presenting signs included abnormal ocular movements in 65%, dystonia in 60%, and hemiplegia in 32%. Patients with an early onset of the disorder and an early appearance of hemiplegic spells faired the poorest developmentally. Developmental delay was present in 91%, ataxia in 68%, choreoathetosis in 50%, and seizures in 18%. Laboratory investigations suggested mitochondrial abnormalities and cerebrovascular dysfunction in several patients. Numerous therapies were largely ineffective. Flunarizine reduced the duration, severity, and frequency of the hemiplegic attacks in 78%. Patients who received flunarizine did not differ developmentally from those who did not. Our data suggest that flunarizine does not adversely affect and may favorably influence the outcome in patients with alternating hemiplegia of childhood. Additionally, the occurrence of autosomal-dominant cases of the syndrome, although rare, suggests that, in addition to mitochondrial dysfunction, genetic factors may be important.

Successful use of intravenous immunoglobulin as initial monotherapy in Landau-Kleffner syndrome.

PURPOSE: There is a need for new and more effective therapies for Landau-Kleffner syndrome. In this article we present the first case in which a patient with Landau-Kleffner syndrome was given intravenous immunoglobulin (IVIG) as his first and only therapy and responded to it. METHODS: This previously healthy, left-handed boy presented at 31 months of age with a 3-month history of auditory agnosia, behavioral abnormalities, and progressive, eventually complete loss of speech. Electroencephalography (EEG) showed frequent and, in sleep, continuous right central and temporal spike slow wave discharges. Metabolic workup, magnetic resonance imaging, and auditory evoked potentials were normal. Cerebrospinal fluid IgG index was high (18%). The patient was treated with IVIG, as his initial and only therapy, receiving 500 mg/kg/day over four consecutive days. RESULTS: On the third day of IVIG, the patient started using single words, and on the fourth, two-word sentences. Two weeks later his speech and behavior returned to normal. At the end of 4 days of IVIG therapy, EEG was within normal limits. Two months later, however, he had a severe relapse clinically and by EEG. He promptly responded to another course of IVIG. A subsequent cerebrospinal fluid IgG index showed normalization (6%). Three months later he had essentially normal speech and behavior. CONCLUSIONS: Repeated, immediate, and remarkable clinical and EEG responses of this patient suggest that IVIG was helpful as first-line therapy in the treatment of Landau-Kleffner syndrome. It also supports the hypothesis that immunological mechanisms contributed to his symptoms.

Unusual presentation of Kearns-Sayre syndrome in early childhood.

Congenital glaucoma and insulin-dependent diabetes mellitus were the predominant presenting signs in a patient with Kearns-Sayre syndrome. Thereafter, he developed short stature, pigmentary retinopathy, progressive external ophthalmoplegia, and ataxia. The diagnosis was confirmed by detecting a deletion of mitochondrial DNA in muscle, thus demonstrating that Kearns-Sayre syndrome can have the unusual presenting signs described above.

Consequences of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor blockade during status epilepticus in the developing brain.

To investigate if AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activation contributes to acute manifestations and long term consequences of status epilepticus (SE), we administered the AMPA receptor antagonist NBQX to P35 rats undergoing kainic acid (KA)-induced SE. NBQX (30 mg/kg/dose) given intraperitoneally (i.p.) at 30, 60 and 90 min after i.p. KA injection (12 mg/kg) reduced severity of SE. When tested as adults, rats that had received KA and NBQX were similar to controls with no long term impairment in visuospatial memory (assessed by the water maze test), or histologic damage in the CA1 or CA3 hippocampal subfields. However, both P35 groups, those receiving KA alone and those receiving KA and NBQX, had similar rates of spontaneous recurrent seizures (SRS). In P15 rats, NBQX resulted in increased acute mortality from KA associated SE. These results indicate that the effects of NBQX on KA-induced SE are age dependent, and that non-NMDA receptor activation contributes to the acute manifestations and to the long term sequelae seen after KA-induced SE in the prepubescent rat brain.

Electroencephalographic discharges of temporal lobe seizures in children and young adults.

We investigated the discharge morphology and propagation patterns of electroencephalographic seizures of temporal lobe onset in 21 children and young adults who underwent invasive long-term EEG monitoring (LTM). Of those, 15 subsequently underwent anterior temporal lobectomy. The onset was focal in 63%. The most frequent discharge morphology was low amplitude beta (30%) or rhythmic/semirhythmic theta discharge (30%). Thirteen patients displayed several sequences of propagation with different spreading stages along a fixed path. Initial spreading to the ipsilateral frontal lobe was associated with a higher frequency of secondary generalization than initial spreading to the contralateral temporal lobe (P = 0.18). A comparison of 13 patients older than 18 years of age with 8 patients younger than 14 years showed a trend towards a lower rate of propagating from the temporal lobe (P = 0.13) in the younger age group. Discharge morphology was not correlated with age, focality, or outcome of surgery.

Early onset neonatal spontaneous pneumopericardium.

Neonatal pneumopericardium is a rare clinical condition which usually occurs in association with other air leaks, especially when there is severe lung pathology, post vigorous resuscitation, or in presence of assisted ventilation. We report the first case of isolated, spontaneous pneumopericardium occurring in the absence of a history of neonatal resuscitation, mechanical ventilation, or of significant lung pathology. In this neonate the pneumopericardium had a relatively benign course resolving on oxygen therapy. We also review the literature and highlight the differences between the early onset, often spontaneously resolving cases, and the late onset usually severe cases.