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.

ACTH versus vigabatrin therapy in infantile spasms: a retrospective study.

ACTH is the standard treatment for infantile spasms (IS) in North America. Recent reports showed that vigabatrin is a valuable treatment for IS, but comparative studies with ACTH are limited. In this study, we compare the effectiveness of ACTH versus vigabatrin on IS. Our results support that vigabatrin is as effective as and better tolerated than ACTH. Because of their similar efficacy, we believe that vigabatrin should be the first intention drug for the treatment of IS.

A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group.

BACKGROUND AND OBJECTIVE: Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. METHODS: Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. RESULTS: The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). CONCLUSION: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.

The epileptiform significance of intermittent rhythmic delta activity in childhood.

Intermittent rhythmic delta activity is reported in various disorders and is classified as a nonspecific abnormal electroencephalographic pattern. We have investigated its clinical and electroencephalographic features in childhood. Intermittent rhythmic delta activity was identified in 54 children over a period of 48 months. Epilepsy was present in 81%, 4% had only a single generalized tonic-clonic seizure, and 15% had no seizures. Generalized seizures were more common than partial seizures (83% versus 13%; 4% were mixed). The largest group of patients had idiopathic epilepsy. Epileptiform features were present in 70%. No patient identified prospectively has had a space-occupying lesion. Intermittent rhythmic delta activity should be considered an epileptiform pattern in children, most commonly occurring as an interictal pattern in primary generalized epilepsy.

Prolonged treatment of refractory status epilepticus in a child.

Barbiturate anesthesia, which is commonly used for refractory status epilepticus, is an effective treatment, but with many significant complications. The relationship between the duration of this extreme therapy and the ultimate outcome of refractory status epilepticus has not been well studied. We report a 7-year-old girl who presented with refractory status epilepticus secondary to presumed encephalitis with a focal lesion on cranial magnetic resonance imaging. She was treated for 70 days with high-dose antiepileptic drugs and recovered with a residual seizure disorder. This case suggests that, if the status epilepticus is due to a reversible cause such as encephalitis, neurologic recovery may occur despite this very prolonged course of extreme therapy.

Electroencephalogram and clinical focalities in juvenile myoclonic epilepsy.

Partial seizures and asymmetric abnormalities seen on electroencephalogram (EEG) are infrequent in juvenile myoclonic epilepsy, but when present, can lead to a misdiagnosis of partial seizures. We report four patients with juvenile myoclonic epilepsy who had generalized spike or polyspike and wave discharges on EEG in addition to clinical and EEG evidence of focality. The clinical course and response to therapy was similar to that in typical juvenile myoclonic epilepsy.

Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence.

Cyclosporin A is associated with an acute encephalopathy including seizures and alterations in mental status, herein referred to as cyclosporin A acute encephalopathy and seizure syndrome. The clinical history, electroencephalogram (EEG), and neuroimaging findings in 19 children with cyclosporin A acute encephalopathy and seizure syndrome over a 10-year period were reviewed in order to delineate clinical characteristics, imaging features, and to determine the risk of seizure recurrence in this population. All 19 had motor seizures associated with other features of cortical and subcortical dysfunction. The acute mean cyclosporin A level was 342 microg/L, but was within the "therapeutic" range in five cases. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) in the acute or subacute phase revealed lesions characteristic of cyclosporin A toxicity in 14 cases. Acute EEG abnormalities were present in all and included epileptiform discharges or focal slowing. Patients were followed for a median of 49 months (1-9 years). Follow-up imaging (n = 10) showed lesion resolution or improvement in the majority while EEG (n = 10) had normalized in only three. Seizures recurred in six patients and only in those with persistent EEG or imaging abnormalities. No patient had a second episode of cyclosporin A associated neurotoxicity or seizure. It appears that a significant risk of seizure recurrence exists following cyclosporin A acute encephalopathy and seizure syndrome and primarily in those children with persistent EEG or imaging abnormalities.

Temporal lobectomy in early childhood: the need for long-term follow-up.

We retrospectively identified 15 children ages 12 years and under with anticonvulsant resistant epilepsy who underwent a temporal lobectomy at Children's Hospital, Boston, between 1978 and 1993. Our aim was to study the long-term seizure outcome. Data pertaining to preoperative evaluation, electroencephalography (EEG), neuroimaging, surgery, seizure outcome, and postoperative complications were reviewed. Only patients followed for more than 12 months were included. The average duration of follow-up was 57 months. At the last visit, 47% (7 of 15) of the children were seizure free or only had auras: another 33% (5 of 15) had > 90% reduction in seizure frequency. Three patients had < 90% seizure reduction. Four cases were initially seizure free but had subsequent recurrence between 11 and 28 months after the epilepsy surgery. Factors associated with a good outcome include exclusively focal EEG discharges or an imaging suggestive of a low-grade tumor; factors associated with a poor outcome include generalized EEG discharges and a normal magnetic resonance image. Temporal lobectomy is useful in the treatment of early childhood drug-resistant partial epilepsy, but long-term follow-up is necessary as late seizure recurrence may occur up to 28 months after surgery.

Mechanisms of generalized absence epilepsy.

Absence seizures represent bilaterally synchronous burst-firing of an ensemble of reciprocally connected neuronal populations located in the thalamus and neocortex. Recent studies demonstrate that neurons in the reticular thalamic nucleus (nRt), thalamic relay neurons (RNs), and neocortical pyramidal cells comprise a circuit that sustains the thalamocortical oscillatory burst-firing of absence seizures. Recent studies have focused on three intrinsic neuronal mechanisms that increase the likelihood of thalamocortical oscillations. The first mechanism involves T-currents elicited by activating the T-type calcium channel, which appear to trigger sustained burst-firing of thalamic neurons during absence seizures. A second intrinsic mechanism is GABA B receptors which can elicit longstanding hyperpolarization in thalamic neurons required to 'prime' T-channels for sustained burst-firing. A third mechanism involves the ability of GABA A receptors, located on nRt neurons, to mediate recurrent inhibition. Enhanced activation of GABA A receptors on nRt neurons decreases the pacemaking capacity of these cells, therefore decreasing the likelihood of generating absence seizures. Cholinergic mechanisms through modulating cortical excitability and excitatory amino acid mediated mechanisms through depolarizing thalamic neurons also play a role in absence seizures.

Midazolam and pentobarbital for refractory status epilepticus.

Status epilepticus, a serious, life-threatening emergency characterized by prolonged seizure activity, occurs most commonly in pediatric patients. Although initial therapies with agents such as diazepam, phenytoin, or phenobarbital generally terminate seizure activity within 30-60 minutes, patients with refractory status epilepticus (RSE) lasting longer require additional intervention. High-dose pentobarbital has been the most commonly prescribed agent for the management of RSE in children; however, midazolam has emerged as a new treatment option. This review compares the use of midazolam with pentobarbital in published reports of pediatric RSE. Both drugs effectively terminated refractory seizure activity, although pentobarbital use was complicated by hypotension, delayed recovery, pneumonia, and other adverse effects. Midazolam use was effective and well tolerated, affirming its value in pediatric RSE management.

Efficacy of primidone for seizure control in neonates and young infants.

Primidone can be used for seizures refractory to standard antiepileptic drugs. We administered primidone, 25 mg/kg/day in 3 divided doses, to 10 patients and obtained serum levels of primidone, phenobarbital, and phenylethylmalonic acid at 1, 2, 4, 6, and 8 hours on day 1, alternate days until discharge, and after 6 weeks. Other antiepileptic drugs were discontinued in 8 of 10 patients with refractory seizures. Mean primidone levels were 10.6 +/- 4.4 micrograms/ml by day 3 and remained stable until discharge. Phenylethylmalonic acid was detected by 6 hours and increased to 11.1 +/- 4.0 micrograms/ml by day 7. Phenobarbital levels in 3 of 10 patients not previously treated with phenobarbital ranged from 0.6-3.4 micrograms/ml by day 5. The mean initial phenobarbital level was 30.1 +/- 10.5 micrograms/ml and had decreased to less than 15 micrograms/ml by day 7. Seizure control occurred within 5 days in 8 of 10 patients and was achieved by day 3 in 6 of 8 patients, coinciding with primidone levels greater than 10 micrograms/ml. No toxic effects of primidone were observed. All levels decreased during subsequent examinations suggesting auto-induction of metabolic systems. Our data indicate that seizure control is best correlated with primidone and phenylethylmalonic acid levels and unrelated to phenobarbital levels in this age group.

Hypoxemia and hemodynamic changes during the hypercarbia stimulation test.

The hypercarbia stimulation test is a valuable technique to document the absence of brainstem responsiveness to elevated levels of carbon dioxide (PCO2); however, its application has been limited by concern that hypoxemia may induce cardiovascular instability. We investigated hemodynamic and oxygen (PO2) changes in 19 patients: group 1 (17 patients) had no spontaneous ventilations at PCO2 values ranging from 37-129 torr; group 2 (2 patients) had spontaneous ventilations at less than 38 torr. Group 1 was separated into 2 subgroups: A (10 patients) with PO2 greater than 153 torr and B (7 patients) with PO2 less than 80 torr. Hemodynamic changes (less than 10% variation in baseline pulse and blood pressure) occurred in 9 of 10 patients in group 1A and all patients in Group 1B. Mean differences in pulse and blood pressure changes between these groups were not significant; therefore, pulse and blood pressure changes are not predictive of hypoxemia and hypercarbia is not necessary to induce spontaneous ventilation in patients with intact medullary function.

Differential diagnosis of staring spells in children: a video-EEG study.

Staring is frequently a nonepileptic manifestation in children. To differentiate epileptic versus nonepileptic staring, we reviewed clinical and video-EEG findings in 143 patients, aged 5 months to 43 years, monitored for staring episodes. In 79 patients staring was of epileptic origin; 46 had partial seizures and 33 atypical absence. Thirty-five had behavioral staring, 8 psychogenic seizures, 1 a migraine equivalent, and in 20 no staring spells were recorded. In all patients with epileptic staring, epilepsy was suspected clinically. Only 22 of the admissions for behavioral staring and 3 for pseudoseizures were to exclude a possible nonepileptic phenomenon. Review of their clinical histories revealed that certain findings strongly support a nonepileptic origin. In conclusion, a careful clinical history will differentiate between epileptic and nonepileptic staring episodes in most patients. Video-monitoring is helpful to adjust treatment or to exclude nonepileptic events in patients with refractory staring spells.

Timing of maintenance phenytoin therapy after intravenous loading dose.

The specific timing of maintenance phenytoin therapy in children has not been addressed. Prevention of a subtherapeutic phenytoin level is important for seizure control. We devised a protocol using an 18 mg/kg loading dose of phenytoin with serial levels (obtained after 2,6,12 hours) and analyzed the results in 20 consecutive patients. A therapeutic level (greater than 10 micrograms/ml) was present in all patients at 2 hours, in 16 of 20 at 6 hours, and in 10 of 20 at 12 hours. The patients were divided into 2 groups by the 12-hour levels: group I: therapeutic level; and group II: subtherapeutic level. The mean 2-hour level in group I was 22.7 micrograms/ml versus 15.6 micrograms/ml in group II (P less than 0.001). The mean decline in plasma concentration in individual patients was 0.7 micrograms/ml/hr in group I versus 1.02 micrograms/ml/hr in group II (P less than 0.05). We now use the 2-hour level to decide the timing of maintenance phenytoin therapy and have devised an equation to estimate the duration of the therapeutic range. Phenytoin can be administered at 12 hours when the 2-hour level is satisfactory or earlier when the 2-hour level indicates that a subtherapeutic level will occur.

Vagus nerve stimulation in pediatric epilepsy: a review.

Therapeutic options for intractable epilepsy include new and investigational antiepileptic drugs, ketogenic diet, epilepsy surgery, and, now, vagus nerve stimulation, which is approved by the U.S. Food and Drug Administration for the treatment of refractory partial seizures in adolescents and adults. The exact mechanisms of action are unknown. Although the use of vagus nerve stimulation in children has increased, including those younger than 12 years of age or those with generalized epilepsy, there has been no large controlled pediatric study to date. The identification of favorable prognostic indicators, especially in children, would be useful. Preliminary results suggest that children with Lennox-Gastaut syndrome may have a favorable response, with improvement in both seizure control and global evaluation scores. Improved global evaluation scores have occurred even without an associated improvement in seizure control.

West syndrome following deep hypothermic infant cardiac surgery.

Postoperative seizures are among the more common complications of cardiac surgery in children. These seizures have traditionally been considered benign, transient phenomena with little, if any, prognostic significance. We report 4 infants with early postoperative seizures following cardiac surgery who later developed the previously unreported complication of West syndrome, with infantile spasms, hypsarrhythmia, and developmental delay. This group constitutes 6% of 67 infant spasms evaluated over a 5-year period at Boston Children's Hospital. The postoperative seizures in these 4 patients were more difficult than usual to control with antiepileptic therapy; otherwise no intra- or perioperative features distinguished these infants who later developed West syndrome from infants with apparently benign "postpump seizures."

Psychogenic seizures: video telemetry observations in 27 patients.

Psychogenic seizures are unusual during the first decade of life. To compare the clinical features of psychogenic seizures in young children with those of teenagers, the long-term electroencephalographic and video monitoring studies of all patients younger than 18 years of age with recorded episodes diagnosed as psychogenic seizures were reviewed from a single hospital during the past 7 years. The 27 patients were divided into 2 age groups: group A, 6-9 years (n = 5), and group B, 10-17 years (n = 22). All patients had habitual episodes recorded during monitoring. Although the adolescents displayed clinical patterns similar to adult patients with psychogenic seizures, the children demonstrated a clinical pattern characterized mainly by prolonged staring and unresponsiveness. The most common behaviors in the adolescent group were tremor (45%), intermittent stiffening (41%), and out-of-phase movements of the extremities (36%). Fifteen percent of the patients had a history of seizures. This study suggests that young children with psychogenic seizures have clinical profiles different from that of teenagers.

Value of plasmapheresis in hepatic encephalopathy.

Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however, despite plasmapheresis, 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore, plasmapheresis may be a useful adjunct in the treatment of liver failure, potentially improving the pretransplantation status of the patient.

Technetium-99m HmPAO brain SPECT and outcome of hemispherectomy for intractable seizures.

With recent descriptions of the modified hemispherectomies and hemicorticectomy, there has been renewed interest in hemispherectomy for treatment of intractable seizures with hemiparesis. Because long-term outcome remains uncertain, patient selection remains difficult. 99mTc-HmPAO brain SPECT has been a helpful adjunct in the evaluation of epilepsy surgery candidates. We report SPECT scan findings in 7 patients who underwent hemispherectomy and compare these results with scalp EEG findings. Six patients had unilateral SPECT findings and all had a favorable outcome, regardless of surface EEG findings.

Perinatal cerebrovascular disease in the neonate. Parenchymal ischemic lesions in term and preterm infants.

Acute cerebrovascular injury in term and preterm infants is a cause of significant morbidity. Treatment efforts in the past have focused on attempts to prevent such injury by interceding during labor in term infants and improving neonatal care in preterm infants. Epidemiologic studies suggest that these strategies have had little impact. A new strategy--drug treatment of acute ischemic brain injury--is on the horizon. The recognition and prognostication in ischemic neonatal brain injury takes on a new importance in this light.