Nonconvulsive seizures are common in critically ill children.

BACKGROUND: Retrospective studies have reported the occurrence of nonconvulsive seizures in critically ill children. We aimed to prospectively determine the incidence and risk factors of nonconvulsive seizures in critically ill children using predetermined EEG monitoring indications and EEG interpretation terminology. METHODS: Critically ill children (non-neonates) with acute encephalopathy underwent continuous EEG monitoring if they met institutional clinical practice criteria. Study enrollment and data collection were prospective. Logistic regression analysis was utilized to identify risk factors for seizure occurrence. RESULTS: One hundred children were evaluated. Electrographic seizures occurred in 46 and electrographic status epilepticus occurred in 19. Seizures were exclusively nonconvulsive in 32. The only clinical risk factor for seizure occurrence was younger age (p=0.03). Of patients with seizures, only 52% had seizures detected in the first hour of monitoring, while 87% were detected within 24 hours. CONCLUSIONS: Seizures were common in critically ill children with acute encephalopathy. Most were nonconvulsive. Clinical features had little predictive value for seizure occurrence. Further study is needed to confirm these data in independent high-risk populations, to clarify which children are at highest risk for seizures so limited monitoring resources can be allocated optimally, and to determine whether seizure detection and management improves outcome.

Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest.

BACKGROUND: Hypoxic ischemic brain injury secondary to pediatric cardiac arrest (CA) may result in acute symptomatic seizures. A high proportion of seizures may be nonconvulsive, so accurate diagnosis requires continuous EEG monitoring. We aimed to determine the safety and feasibility of long-term EEG monitoring, to describe electroencephalographic background and seizure characteristics, and to identify background features predictive of seizures in children undergoing therapeutic hypothermia (TH) after CA. METHODS: Nineteen children underwent TH after CA. Continuous EEG monitoring was performed during hypothermia (24 hours), rewarming (12-24 hours), and then an additional 24 hours of normothermia. The tolerability of these prolonged studies and the EEG background classification and seizure characteristics were described in a standardized manner. RESULTS: No complications of EEG monitoring were reported or observed. Electrographic seizures occurred in 47% (9/19), and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). Seizures commenced during the late hypothermic or rewarming periods (8/9). Factors predictive of electrographic seizures were burst suppression or excessively discontinuous EEG background patterns, interictal epileptiform discharges, or an absence of the expected pharmacologically induced beta activity. Background features evolved over time. Patients with slowing and attenuation tended to improve, whereas those with burst suppression tended to worsen. CONCLUSIONS: EEG monitoring in children undergoing therapeutic hypothermia after cardiac arrest is safe and feasible. Electrographic seizures and status epilepticus are common in this setting but are often not detectable by clinical observation alone. The EEG background often evolves over time, with milder abnormalities improving and more severe abnormalities worsening.

Magnetoencephalography for pediatric epilepsy: how we do it.

Magnetoencephalography (MEG) is increasingly being used in the preoperative evaluation of pediatric patients with epilepsy. The ability to noninvasively localize ictal onset zones (IOZ) and their relationships to eloquent functional cortex allows the pediatric epilepsy team to more accurately assess the likelihood of postoperative seizure freedom, while more precisely prognosticating the potential functional deficits that may be expected from resective surgery. Confirmation of clinically suggested multifocality may result in a recommendation against resective surgery because the probability of seizure freedom will be low. Current paradigms for motor and somatosensory testing are robust. Paradigms allowing localization of those regions necessary for competent language function, though promising, are under continuous optimization. MR imaging white matter trajectory data, created from diffusion tensor imaging obtained in the same setting as the localization brain MR imaging, provide ancillary information regarding connectivity of the IOZ to sites of rapid secondary spread and the spatial relationship of the IOZ to functionally important white matter bundles, such as the corticospinal tracts. A collaborative effort between neuroradiology, neurology, neurosurgery, neuropsychology, technology, and physics ensures successful implementation of MEG within a pediatric epilepsy program.

Randomized dose-controlled study of topiramate as first-line therapy in epilepsy.

OBJECTIVES: To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design. MATERIALS AND METHODS: We conducted a multinational, randomized, double-blind trial in adults and children (> or =6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to > or =2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized. RESULTS: Kaplan-Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day (P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day (P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P = 0.009) and in those with generalized-onset tonic-clonic seizures (P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. CONCLUSION: Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.

Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility.

PURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. METHODS: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry. RESULTS: SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82. CONCLUSION: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.

Dysplasia: a common finding in intractable pediatric temporal lobe epilepsy.

BACKGROUND: Risk factors for temporal lobe epilepsy (TLE) include history of CNS infection, family history of epilepsy, and history of febrile convulsions (FC). Pre-existing cortical dysplasia (CD) may also predispose to refractory TLE, independent of other risk factors for epilepsy. METHODS: The authors reviewed the neuropathologic features of surgical tissue from temporal lobectomies of 33 pediatric patients with refractory TLE, with and without a history of epilepsy risk factors. RESULTS: CD was found in 64% (21/33) of all patients with refractory TLE, including 73% (11/15) patients with a history of FC, 66% (2/3) patients with CNS infections, and 83% (5/6) patients with a family history of epilepsy. Disrupted cortical lamination, dystrophic and maloriented neurons, and balloon cells characterized the CD found in the temporal neocortex. CONCLUSION: CD was seen in 21 of 33 surgical specimens from children with refractory TLE, including those with and without other epilepsy risk factors.

The early identification of candidates for epilepsy surgery.

The effectiveness of resective surgery for the treatment of carefully selected patients with medically intractable, localization-related epilepsy is clear. Seizure-free rates following temporal lobectomy are consistently 65% to 70% in adults and 68% to 78% in children. Extratemporal resections less commonly lead to a seizure-free outcome, although one recent childhood series reported a seizure-free rate of 62% following extratemporal epilepsy surgery. With both temporal and extratemporal resections, additional patients have a reduction in seizures following surgery but are not completely seizure free. The identification of favorable surgical candidates has been the subject of extensive research, and many investigators have examined predictors of outcome following epilepsy surgery. However, the early identification of the potential epilepsy surgery candidate and the optimal timing of surgery have only occasionally been addressed in the literature. This issue is methodologically challenging to study since studies require large numbers of patients with new-onset partial epilepsy who are followed over time. The purpose of this article is to review the current ability for early prediction of medical intractability in patients with surgically remediable epilepsy. Emphasis will be placed on the early prediction of intractable temporal lobe epilepsy in children and adolescents, since temporal lobectomy remains the prototype epilepsy surgery, and early surgery may improve psychosocial outcome in younger patients.

Response to first drug trial predicts outcome in childhood temporal lobe epilepsy.

OBJECTIVE: To construct a clinical prediction model for the early identification of children destined to develop refractory temporal lobe epilepsy (TLE) 2 years after epilepsy onset. METHODS: Patients with TLE between 1 and 18 years old seen in the Division of Neurology at Children's Hospital of Philadelphia during 1999 were identified through billing records and chart review. Data were abstracted independently on 5 candidate predictor variables for refractory TLE and on seizure frequency outcome at 2 years after epilepsy onset. RESULTS: One hundred twenty patients met inclusion criteria and had at least 2 years of follow-up. Forty-five of 120 patients (37.5%) had refractory TLE at 2 years after onset, and 75 of 120 (62.5%) were seizure free. Three significant predictors of refractory TLE were found on bivariate analysis: an early risk factor for epilepsy (risk ratio = 3.5 [95% CI 2.2, 5.6]), temporal lobe abnormality on MRI scan (2.9 [95% CI 1.9, 4.6]), and failure of the first antiepileptic drug (AED) trial (16.5 [95% CI 6.3, 43.9]). Logistic regression indicated that the best model to predict refractory TLE contained only the variable "failure of first AED trial," with a positive predictive value of 0.89 (95% CI 0.76, 0.96) and negative predictive value of 0.95 (95% CI 0.87, 0.99) to predict "refractory TLE" at 2 years. CONCLUSIONS: Failure of first AED trial accurately predicts refractory TLE at 2 years after onset, based on retrospective cohort data in children. If verified prospectively and with longer follow-up, this finding should support earlier consideration of surgical options.

Subacute sclerosing panencephalitis in an American-born adult.

We describe a case of an adult born in the United States who had subacute sclerosing panencephalitis (SSPE). We discuss the possibility that the patient contracted subclinical measles during the 1989-1991 measles epidemic in the United States.

A 4-year-old with pica, progressive incoordination, and decreased responsiveness.

This article reports a typical case of subacute sclerosing panencephalitis (SSPE). The patient contracted measles as an infant during the 1989 to 1991 United States measles epidemic. At 4 1/2 years of age, he developed behavioral changes and quickly progressed through the typical clinical stages of SSPE. His EEG was characteristic. Serum and CSF measles immunoglobulin G were markedly elevated. He remains alive but is vegetative. To our knowledge, this is the first case of SSPE stemming from the 1989 to 1991 measles epidemic. Because infants--the group at highest risk to develop SSPE--were most severely affected by this measles outbreak, other cases of SSPE stemming from this epidemic may occur.

Language-related cognitive declines after left temporal lobectomy in children.

Presented is a case series demonstrating that clinically significant language-related cognitive declines not detected by intelligence quotient (IQ) testing occur after left temporal lobectomy in school-aged children. In this series, comprehensive preoperative and postoperative neuropsychologic evaluations were completed in eight school-aged patients who underwent temporal lobectomy (five left, three right) for temporal lobe epilepsy. Mean age at surgery was 13 years, 11 months +/- 2 years, 1 month. Testing included measurement of IQ, verbal learning, naming, visual memory, sight word recognition, reading comprehension, and calculation. All five left temporal lobectomy patients demonstrated significant language-related cognitive declines on postoperative neuropsychologic testing, including deficits in verbal IQ (one patient), verbal learning (four patients), naming (one patient), and reading comprehension (one patient). These deficits were clinically evident in four of the five left temporal lobectomy patients, leading to declines in educational performance. IQ testing alone did not reliably identify these deficits. No significant declines were found after surgery in three right temporal lobectomy patients. Average or high preoperative functioning may have predisposed patients to postoperative deficits in this series, whereas magnetic resonance imaging or pathologic abnormalities did not protect against postoperative deficits. Outcome studies of temporal lobectomy in childhood should use comprehensive neuropsychologic testing to identify cognitive deficits.

Hippocampal cell density and subcortical metabolism in temporal lobe epilepsy.

PURPOSE: Correlations between hippocampal cell density and subcortical metabolism in patients with temporal lobe epilepsy (TLE) were studied to explore possible links between subcortical function and the regulation of hippocampal excitability. METHODS: Resected hippocampal cell densities were correlated with cortical and subcortical regional cerebral metabolic rate for glucose (CMRglu), as measured by [18F]-fluorodeoxyglucose positron emission tomography (18-FDG-PET), in 39 patients with intractable TLE who underwent anterior temporal lobectomy (ATL). CMRglu was measured ipsilateral and contralateral to the resected temporal lobe. Linear regression techniques were used for statistical analysis. RESULTS: Hilar cell densities correlated positively and significantly with CMRglu in the bilateral thalamus, putamen and globus pallidus, and the ipsilateral caudate. Dentate granule cell densities correlated positively and significantly with CMRglu in the bilateral thalamus and putamen. There was no significant correlation between cell densities and CMRglu in any cortical region, including the hippocampus. CONCLUSIONS: We postulate that hippocampal cell loss results in decreased efferent synaptic activity to the thalamus and basal ganglia, causing decreased neuronal activity in these structures with consequent hypometabolism. This synaptic activity has a significant bilateral component. Subcortical hypometabolism in patients with TLE may reinforce the epileptogenic potential of mesial temporal lobe discharges.

Effects of the submarine environment on renal-stone risk factors and vitamin D metabolism.

The effects of total sunlight deprivation on urinary risk factors for nephrolithiasis and vitamin D metabolism were studied in 20 healthy male subjects. Blood and 24-h urine samples were collected before submarine deployment and 68 days later while still at sea. No subject received sunlight exposure during the test interval. Significant decreases in daily urinary excretion of calcium, uric acid, sodium, sulfate, and phosphorus were found. The relative supersaturation ratio of monosodium urate also fell. There was no change in urinary citrate or urine volume. Mean serum levels of 25-hydroxyvitamin D [25(OH)D] declined from 31 to 19 pg/ml (P < 0.0001), parathyroid hormone increased from 22 to 30 pg/ml (P < 0.0001), and osteocalcin (GLA) increased from 2.7 to 3.3 ng/ml (P = 0.005). Mean serum levels of 1,25 dihydroxy-vitamin D were unchanged. Four subjects had 25(OH)D levels below 10 ng/ml by the end of the submarine patrol. These findings suggest that exposure to the submarine environment produces physiologic changes that decrease the risk for renal stone formation. The data are consistent with the role of vitamin D metabolism in sunlight deprivation and demonstrate that compensatory mechanisms are well established within 68 days.