Obstructive sleep apnea in children with epilepsy: prospective pilot trial.

BACKGROUND: Obstructive sleep apnea (OSA) is prevalent in adults with epilepsy, especially refractory, but limited data exist in children with epilepsy. AIMS: We conducted a prospective pilot study in children with epilepsy to identify the prevalence of OSA and its relationship to the use of antiepileptic drugs (AEDs) and epilepsy types. METHODS: We used Michigan Pediatric Sleep Questionnaire (PSQ) in children with epilepsy. Patients were classified by seizures frequency as mild (0-1 seizure/month) or severe, refractory epilepsy (> 1 seizures/month). We used PSQ ≥ 0.33 as a cutoff point to assess the risk of OSA. RESULTS: Of 84 children, 52 were classified as mild and 32 as severe. Prevalence of OSA was significantly higher in the severe (43.8%) vs the mild group (30.7%, P < 0.05). Children on >1 AED had significantly higher prevalence of OSA (45.8%) than children on ≤1 AED (30.6%, P < 0.05). There was no significant correlation between the prevalence of OSA and seizure types. CONCLUSIONS: OSA is more prevalent in refractory epilepsy and in children who are on multiple AEDs. While further studies are needed to confirm these findings and to assess the consequences of OSA, we believe it is important to screen the children with epilepsy for OSA.

Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.

OBJECTIVE: To review evidence on the assessment of the child with status epilepticus (SE). METHODS: Relevant literature were reviewed, abstracted, and classified. When data were missing, a minimum diagnostic yield was calculated. Recommendations were based on a four-tiered scheme of evidence classification. RESULTS: Laboratory studies (Na(++) or other electrolytes, Ca(++), glucose) were abnormal in approximately 6% and are generally ordered as routine practice. When blood or spinal fluid cultures were done on these children, blood cultures were abnormal in at least 2.5% and a CNS infection was found in at least 12.8%. When antiepileptic drug (AED) levels were ordered in known epileptic children already taking AEDs, the levels were low in 32%. A total of 3.6% of children had evidence of ingestion. When studies for inborn errors of metabolism were done, an abnormality was found in 4.2%. Epileptiform abnormalities occurred in 43% of EEGs of children with SE and helped determine the nature and location of precipitating electroconvulsive events (8% generalized, 16% focal, and 19% both). Abnormalities on neuroimaging studies that may explain the etiology of SE were found in at least 8% of children. RECOMMENDATIONS: Although common clinical practice is that blood cultures and lumbar puncture are obtained if there is a clinical suspicion of a systemic or CNS infection, there are insufficient data to support or refute recommendations as to whether blood cultures or lumbar puncture should be done on a routine basis in children in whom there is no clinical suspicion of a systemic or CNS infection (Level U). AED levels should be considered when a child with treated epilepsy develops SE (Level B). Toxicology studies and metabolic studies for inborn errors of metabolism may be considered in children with SE when there are clinical indicators for concern or when the initial evaluation reveals no etiology (Level C). An EEG may be considered in a child with SE as it may be helpful in determining whether there are focal or generalized epileptiform abnormalities that may guide further testing for the etiology of SE, when there is a suspicion of pseudostatus epilepticus (nonepileptic SE), or nonconvulsive SE, and may guide treatment (Level C). Neuroimaging may be considered after the child with SE has been stabilized if there are clinical indications or if the etiology is unknown (Level C). There is insufficient evidence to support or refute routine neuroimaging in a child presenting with SE (Level U).

Autoregulation of cerebral blood flow in fetuses with congenital heart disease: the brain sparing effect.

Fetuses with congenital heart disease (CHD) have circulatory abnormalities that may compromise cerebral oxygen delivery. We believe that some CHD fetuses with decreased cerebral oxygen supply have autoregulation of blood flow that enhances cerebral perfusion (brain sparing). We hypothesize that cerebral autoregulation occurs in CHD fetuses, and the degree of autoregulation is dependent on the specific CHD and correlates with intrauterine head circumferences. CHD fetuses were compared to normal fetuses. Data included cardiac diagnosis, cerebral and umbilical artery Doppler, head circumference, weight, and gestational age. The cerebral-to-placental resistance ratio (CPR) was assessed as a measure of cerebral autoregulation. CPR = cerebral/umbilical resistance index (RI) and RI = systolic-diastolic/systolic velocity (normal CPR > 1). CPR > 1 was found in 95% of normal vs 44% of CHD fetuses. The incidence of CPR < 1 was greatest in hypoplastic left or right heart fetuses. Compared to normal, cerebral RI was decreased in CHD fetuses. The CPR vs gestational age relationship, and the relationship among weight, head circumference, and CPR differed across normal and CHD fetuses. Fetuses > 2 kg with CHD and a CPR < 1 had smaller head circumferences than normal. Brain sparing occurs in CHD fetuses. Fetuses with single ventricular physiology are most affected. Inadequate cerebral flow in CHD fetuses, despite autoregulation, may alter brain growth.

The use of topiramate in refractory status epilepticus.

In cases of refractory status epilepticus (RSE) unresponsive to sequential trials of multiple agents, a suspension of topiramate administered via nasogastric tube was effective in aborting RSE, including one patient in a prolonged pentobarbital coma. Effective dosages ranged from 300 to 1,600 mg/d. Except for lethargy, no adverse events were reported.

Utility of electroencephalography in the pediatric emergency department.

To assess the role of electroencephalography (EEG) in the pediatric emergency department, we reviewed the records of all patients having an EEG in the pediatric emergency department of our hospital between 1995 and 1997. EEG findings, clinical presentations, and follow-up data were analyzed, and patients were distributed into three groups according to clinical presentation: group 1 included patients with new-onset seizures, group 2 included patients with known epilepsy presenting with worsening seizures and altered mentation, and group 3 comprised patients with acute confusional states. Overall, 56 patients with 57 EEGs were included. In group 1 (n = 36), 20 (55.6%) had an abnormal EEG. The risk of recurrence was much higher in children with abnormal EEGs (80% vs. 31%) (P < .01). In retrospect, among all of the patients receiving the diagnosis of epilepsy, 76% had an abnormal emergency department EEG. Four in group 2 (n = 14) and one in group 3 (n = 7) were proven to have nonconvulsive status epilepticus and were treated accordingly. No patients in group 1 had nonconvulsive status epilepticus. Ongoing seizures were promptly excluded in the remainder. The EEG directly contributed to the diagnosis in 84% of all referrals in the pediatric emergency department, either being abnormal and leading to a diagnosis of a seizure disorder or confirming low suspicion for seizures. Thus, a prompt EEG should be considered in children with new-onset seizures and unexplained altered consciousness.

Treatment of epilepsy in the multiply handicapped.

The medical management of epilepsy in the multi-handicapped patient requires careful evaluation, classification, and pharmacologic treatment. It is estimated that 20-40% of patients with mental retardation and cerebral palsy have epilepsy. This review reports the clinical trial data and personal experience related to the use of newer AEDs in the chronic management of epilepsy syndromes in children and adults, as well as information available on the treatment of seizures in individuals with mental retardation and associated handicaps. Furthermore, clusters of seizures, prolonged seizures and status epilepticus are more commonly seen in the multiply handicapped and mentally retarded population and require special attention. The new antiepileptic drugs felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide show specific advantage in some multiply handicapped patients, be it for seizure control or medication tolerance. Furthermore, new modalities of treatment for prolonged seizures allow better efficacy both outside of hospital and within hospital facilities. The treatment of epilepsy in multi-handicapped and retarded adults and children has significantly advanced in the past few years, and much of this improvement can be attributed to improved knowledge and monitoring of new antiepileptic drugs. Conventional anticonvulsants remain first line therapy for most clinicians, but newer AEDs must broaden the therapeutic option and do allow improved therapy for some multiply handicapped patients.

Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.

This is a multicenter, open-label, add-on trial, investigating the safety and efficacy of ganaxolone (GNX) in a population of children with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms. A total of 20 children aged 7 months to 7 years were enrolled in this dose-escalation study, after baseline seizure frequencies were established. Concomitant antiepilepsy drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of 4 weeks, then maintained for 8 weeks before tapering and discontinuation. Seizure diaries were maintained by the families, and spasm frequency was compared with the baseline period. The occurrence of adverse events was clinically monitored, and global evaluations of seizure severity and response to treatment were obtained. A total of 16 of the 20 subjects completed the study, 15 of whom had refractory infantile spasms at the time of study enrollment. Spasm frequency was reduced by at least 50% in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated, and adverse events attributed to GNX were generally mild. Ganaxolone was safe and effective in treating this group of refractory infantile spasms patients in an open-label, add-on trial. Further investigation with randomized, controlled study design is warranted.

Overview of childhood epilepsy and epileptic syndromes and advances in therapy.

Seizures have a variety of etiologies and manifestations. Descriptions of various epiletic seizures as well as electroencephalographic findings have led to a unifying international classification of epileptic seizures and epilepsy syndromes. The development of this classification system and the emergence of several new antiepiletic drugs have led to progress in the refractory pediatric patient particularly disorders which are traditionally difficult to treat such as infantile spasms and the Lennox-Gastaut Syndrome. However, there is limited data regarding optimal use in children. The childhood epilepsy syndromes are reviewed as well as the newer antiepileptic drug treatments - felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide. Efficacy data and toxicity are discussed from both the adult, and when available, pediatric data.

Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia.

PURPOSE: Previous work suggested that there is a lower mortality for convulsive status epilepticus (SE) with intermittent seizures (intermittent SE) as opposed to SE with continuous seizure activity (continuous SE). A plausible hypothesis to explain this difference is that the shorter ictal time in intermittent SE is responsible for the lower mortality in this group. This study investigates the relative contributions of total ictal time and SE duration to the differing mortalities of intermittent and continuous SE. METHODS: Six hundred forty-five cases of prospectively identified convulsive SE were examined. Nonparametric statistical methods were used to compare continuous SE and intermittent SE variables. Multivariate logistic regression analyses were used to determine which factors were most highly associated with mortality. Intermittent SE cases were analyzed to evaluate the relative contributions of ictal time versus SE duration to mortality. RESULTS: Intermittent SE had a significantly lower mortality than continuous SE (19.6 vs. 31.4%; p < 0.001) in adults but not in children. Intermittent and continuous SE durations did not significantly differ in adult cases but did differ in pediatric cases. Ictal time was significantly shorter than SE duration for intermittent SE in both adults and children. After adjusting for age, etiology, and SE duration, SE type (continuous SE vs. intermittent SE) was shown to have an independent effect on mortality in adults. The relative risk of mortality for continuous SE was 1.79 times that of intermittent SE (p = 0.04). After controlling for SE duration, ictal time did not significantly affect mortality in adults. CONCLUSIONS: Intermittent and continuous convulsive SE were common in both pediatric and adult populations. Intermittent SE had a significantly lower mortality than did continuous SE. This difference in mortality was not completely explained by differences in SE duration, total ictal time, etiology, or age. Further research is needed to identify the factor(s) contributing to the significant difference in mortality between intermittent SE and continuous SE.

Hemodynamic monitoring prior to and at the time of death in status epilepticus.

Status epilepticus (SE) is a common neurological and medical emergency. Despite the significant mortality associated with SE, no human data have been available regarding cardiovascular changes prior to death in patients with this condition. This study was conducted to measure hemodynamic trends in the 24 h prior to death in a series of 24 prospectively evaluated SE patients. Two distinct cardiovascular patterns of mean arterial pressure (MAP) and heart rate (HR) were observed. Ten patients had a gradual decline in MAP and/or HR, and this group was designated as having gradual cardiac decompensation (GCD). The remaining 14 patients showed no significant changes in either MAP or HR up to the time of death. This group of patients was designated as having acute cardiac decompensation (ACD). The changes in MAP and HR over the last 24 h prior to death between the GCD and ACD groups were statistically significant. Ninety percent of the GCD patients had a history of multiple risk factors for arteriosclerotic cardiovascular disease (ASCVD), while only 30% of the ACD group had a history of multiple risk factors for ASCVD. The results provide the first human data of cardiovascular events immediately preceding death in SE patients. We propose that further investigation of the cardiovascular pathophysiology of SE may provide new therapeutic interventions which could decrease the significant mortality associated with SE.

Physiological analysis of Rasmussen's encephalitis: patch clamp recordings of altered inhibitory neurotransmitter function in resected frontal cortical tissue.

Rasmussen's encephalitis (RE) is a progressive, rare childhood disease characterized by severe epilepsy, hemiplegia, dementia, and inflammation of the brain. While one mechanism underlying the pathogenesis of RE has been hypothesized to be mediated by production of excitotoxic GluR3 autoantibodies to the AMPA receptor, other neuropathological etiologies have also been indicated. Whole-cell patch clamp recordings of GABA(A) receptor mediated responses were conducted in neurons acutely isolated from an RE patient, and compared to properties of non-focal human temporal cortical neurons. RE neurons appeared similar anatomically to control cortical neurons. Significant differences in GABAergic responses were evident between RE and control neurons. GABA was significantly more potent in RE than in control cortical neurons (EC50 of 13 microM vs 23 microM, respectively). In addition, the overall efficacy of GABA was significantly decreased in RE neurons, associated with a decrease in postsynaptic GABA current density in RE neurons (5.1 pA/microm2) in comparison to controls (9.2 pA/microm2). Augmentation of GABA responses by the benzodiazepine, clonazepam (CNZ), was significantly reduced in RE in comparison to control neurons (34% vs 99% augmentation at 100 nM). The RE-associated reduced functional efficacy and altered pharmacology of neuronal GABA(A) receptors is consistent with overall disinhibition in RE neurons, and could contribute to the generation of the severe epileptic activity evident in this disorder.

New drug therapy for acute seizure management.

Several new agents have recently become available for the long-term treatment of epilepsy. Until now, there has been little change for the acute management of seizures. Three new agents may alter our present practice. Fosphenytoin has recently been approved as a substitute for parenteral phenytoin. It provides similar efficacy without the risk for infusion site injury while allowing greater flexibility in intravenous solutions. Intravenous valproate adds flexibility for patients on valproate, allowing patients to be rapidly loaded. In addition, it will prevent patients from having to change seizure medications when intervening medical illness or surgery do not allow medications by mouth. Viscous diazepam solution for rectal administration will allow for safe and effective treatment for seizures at home and will potentially decrease emergency department services and hospitalization.

Diagnosis and treatment of epilepsy in children and adolescents.

Seizures have a variety of aetiologies and may have various manifestations. Some are recurrent and represent the different types of epilepsy, whereas others are isolated events. Descriptions of various epileptic seizures, as well as their corresponding electroencephalograms (EEGs), have recently led to a unifying international classification of epileptic seizures and epilepsy syndromes. These classifications are extremely important for the practitioner working with the paediatric patient, as they allow for optimal evaluation and treatment. This article reviews the epilepsies and epilepsy syndromes with special attention to age of onset and prognosis. Special circumstances such as status epilepticus, which represents a true medical emergency, are reviewed. The first step in the pharmacological management of seizures is to establish the diagnosis of epilepsy. The recurrence of seizures (or the risk), seizure type and specific syndrome help guide initial treatment choices. There is no drug of choice, but some drugs have proven more effective for certain types of seizure. Monotherapy is preferable, and combination therapy should only be used if monotherapy with first-line drugs fails. Candidates for the newer antiepileptic drugs (e.g. felbamate, gabapentin, lamotrigine and vigabatrin) include patients resistant to older agents or who are unable to tolerate them. The exact place in therapy of these newer agents is uncertain, but in many patients they provide better seizure control and are better tolerated.

Neutropenia in a patient receiving intravenous immune globulin.

A child with Guillain-Barre syndrome treated with intravenous immune globulin (IVIG) developed neutropenia (absolute neutrophil count = 390), which resolved 3 days after completion of the therapy. Potential mechanisms for the development of neutropenia during the use of IVIG therapy are discussed. In this case, testing of the IVIG used revealed the presence of a high concentration of anti-neutrophil antibodies compared to other samples. It is recommended that white blood cell and neutrophil counts be monitored daily during the use of such therapy.

Ocular and disseminated candidiasis in an immunosuppressed cat.

Ocular and systemic candidiasis was diagnosed in an immunosuppressed and diabetic 12-year-old cat that initially was examined because of polyuria, polydipsia, and urinary tract disease. Bilateral recurrent corneal erosions and chorioretinitis, urinary tract infections attributable to bacteria or Candida sp, and renal dysfunction developed during the next 2 months. Examination of corneal scrapings revealed spherical to oval, budding, yeast-like cells. The cat's condition progressively deteriorated, and it was euthanatized. Toxoplasmosis was diagnosed by fecal flotation and from serum titers, and pituitary-dependent hyperadrenocorticism was detected at postmortem histologic evaluation. Candida budding yeasts and pseudohyphae with blastospores were detected in the corneas, vitreous bodies, retinas, CNS, pharynx, trachea, esophagus, kidneys, and urinary bladder at postmortem examination.