The occurrence and characteristics of auras in a large epilepsy cohort.

OBJECTIVES: Despite several studies, estimates of the frequency with which auras occur in conjunction with epilepsy continue to be imprecise. The aim of this study was to assess the occurrence and characteristics of auras in a large population-based epilepsy cohort. MATERIALS AND METHODS: Subjects with verified epilepsy were recruited from population-based twin registries in the USA, Denmark and Norway. Using a structured interview in which a list of auras was provided, subjects were asked about the warning symptoms preceding their epileptic attacks. RESULTS: 31% of the total sample (n = 1897) and 39% of those with active epilepsy (n = 765) had experienced an aura. Six percent reported more than one type. Non-specified auras were most frequently reported (35%), followed by somatosensory (11%) and vertiginous (11%). While the majority of those reporting auras (59%) had focal epilepsies, auras of a mostly non-specific nature were experienced by 13% of those with generalized epilepsies. CONCLUSION: Auras serve an important purpose in that they may prevent seizure-related injuries and could provide an indication as to where the seizures originate. The occurrence of auras often is underestimated, especially in children and those with learning disabilities.

Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

BACKGROUND AND PURPOSE: The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. MATERIALS AND METHODS: Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. RESULTS: Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. CONCLUSIONS: Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

Safety and tolerance of multiple doses of intramuscular fosphenytoin substituted for oral phenytoin in epilepsy or neurosurgery.

BACKGROUND: Safety, tolerability, and pharmacokinetics of fosphenytoin sodium, a water-soluble phenytoin prodrug, were investigated after a temporary substitution of intramuscular fosphenytoin for oral phenytoin sodium in 240 epileptic or neurosurgical patients taking oral phenytoin sodium (100-500 mg/d). METHODS: Patients were randomly assigned to 1 of 2 parallel groups. During screening and follow-up, patients were maintained on a regimen of oral phenytoin at an individualized dose. During treatment, the phenytoin-treated patients received intramuscular placebo and their prescribed dose of oral phenytoin; the fosphenytoin-treated patients received oral placebo and intramuscular fosphenytoin equimolar to their phenytoin dose. RESULTS: Both groups had similar types and frequencies of mild to moderate adverse events. Fosphenytoin was as well tolerated as intramuscular placebo at the injection site. Intramuscular fosphenytoin equimolar to a patient's oral phenytoin dose produced equal or greater plasma phenytoin concentrations. CONCLUSIONS: Dosing adjustments are not required when intramuscular fosphenytoin is temporarily substituted or oral phenytoin therapy is resumed. Intramuscular fosphenytoin is a safe and well-tolerated alternative to oral phenytoin when oral administration is not feasible.

Antiepileptic drug therapy in the United States: a review of clinical studies and unmet needs.

The goal of epilepsy treatment is complete seizure control with minimal adverse drug reactions. Because no drug is entirely free of adverse effects, the clinician must aim for a balance between efficacy and tolerability. In approximately 40% of patients, however, monotherapy with conventional antiepileptic drugs either is not tolerated or does not provide optimal seizure control. Polypharmacy may be necessary in as many as 30% of patients. As clinicians look to new agents that may produce an overall improved quality of life, they must continue to balance efficacy and adverse effects in evaluating the usefulness of the new vs the established drugs.

The clinical efficacy of lamotrigine as an antiepileptic drug.

Product license applications for lamotrigine have been filed or approved in more than 50 countries throughout the world. In preclinical models, this drug demonstrates activity against both maximal electroshock and pentylenetetrazol seizures. The primary action of lamotrigine is, most likely, blockade of sodium channels, with resultant inhibition of glutamate and aspartate release. As would be expected from this spectrum of activity, the drug has shown clinical efficacy in both partial and generalized seizures and in a variety of epilepsy syndromes. Particularly promising results have been demonstrated in difficult-to-control epilepsy syndromes with mixed seizures. Half-life of lamotrigine in adults receiving monotherapy is approximately 24 hours. Its half-life is decreased by approximately 50% when it is used in combination with enzyme-inducing antiepileptic drugs, such as phenobarbital, carbamazepine, and phenytoin; in contrast, valproate extends the half-life of lamotrigine by two- to three-fold. Its administration has no effect on the metabolism of other antiepileptic drugs, with the exception of a possible minor increase in the proportion of carbamazepine-10,11-epoxide. The usual maintenance dosage of lamotrigine is 200 to 500 mg daily given in two divided doses. In US open studies of adult patients with treatment-refractory partial epilepsy, increased seizure control was demonstrated with higher dosages. Extension studies have shown even better efficacy with daily doses of approximately 700 mg. Multiple studies and clinical usage have shown lamotrigine to be well tolerated, with patients reporting a sense of well-being during drug therapy. The most frequently reported adverse events are CNS-associated side effects and rash.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of seizures and epilepsy in children and adolescents.

Certain epilepsy types occur more commonly or exclusively in children and adolescents. Proper diagnosis of the specific seizure type and the etiology of the seizure is the cornerstone for appropriate management of these patients. When treatment is determined to be necessary, antiepileptic drug (AED) selection should focus on the agent(s) that will provide the best risk:benefit ratio. A number of new AEDs are now available for use in patients who are refractory to or intolerant of classic medications. These recent additions to the therapeutic armamentarium are also receiving consideration as first-line therapy in some indications. As with the classic AEDs, optimizing efficacy and safety of the new compounds requires adherence to recommended dosing regimens and careful monitoring for adverse effects.

Fosphenytoin use in children.

Phenytoin is widely used for the prevention and treatment of acute seizures in children. Although it has the advantage of being available in parenteral form, it cannot be given through the i.m. route. Furthermore, problems with venous accessibility and maintenance may complicate i.v. administration of phenytoin in newborns and very sick infants. Fosphenytoin, a new phenytoin prodrug, can be safely administered through the i.m. route, and, because of the physical characteristics of its formulation, it offers advantages over phenytoin for i.v. administration. Clinical studies with i.v. and i.m. fosphenytoin demonstrate that the efficacy, safety, and pharmacokinetics of this drug are similar in 5- to 18-year-old children and in young adults. The safety and pharmacokinetic profile of i.v. and i.m. fosphenytoin in younger children and infants is currently being investigated.

Characterization of seizures associated with biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited disorder that is often characterized by neurologic abnormalities. We reviewed the clinical features of 78 symptomatic children, 11 new patients and 67 previously reported cases, to determine the frequency, type, age at onset, and the responsiveness of seizures to antiepileptic drugs and biotin therapy. Forty-three of the 78 (55%) symptomatic children had seizures, and seizures were the presenting symptom in 38% of the enzyme-deficient patients and 70% of those who had had seizures at some time. EEGs were available for 21 of these children. Sixteen were abnormal. The initially abnormal EEGs in eight of 12 infants became normal or improved with biotin therapy, whereas four continued to be abnormal. In 21 (49%) patients, the seizures were not well controlled with antiepileptic drugs. Biotin therapy stopped the seizures within 24 hours in 12 of 16 (75%) of those whose seizures were uncontrolled by anticonvulsants (five children died prior to diagnosis). Although the metabolic and cutaneous abnormalities were corrected in the remaining four children, they continued to have neurologic abnormalities. Biotinidase deficiency and a trial of biotin (5 to 10 mg) should be considered in infants less than 1 year of age with poorly controlled seizures, and biotinidase deficiency should be included in the differential diagnosis of an infant or child with unexplained seizures.

Childhood hypertensive stroke with neurofibromatosis.

A child with neurofibromatosis had hypertension and acute hemiplegia resulting from both renal and cerebral vascular occlusive disease. This case illustrates the importance of recognizing surgical antihypertensive therapy was attempted, and may have contributed to rapid neurologic deterioration. Children with neurofibromatosis and hypertension require a careful neurologic evaluation, including computed tomography, before therapy.

Evidence for a genetic predisposition for status epilepticus.

The role of genetic factors in determining risk for status epilepticus (SE) was examined in twins identified using the population-based Virginia Twin Registry. Concordance rates for SE were 0.38 for monozygotic (MZ) and 0.00 for dizygotic (DZ) twins, with the rate in MZs being significantly increased over DZs. The prevalence of SE in MZ co-twins of affected individuals was as high as 0.55. Clinical presentation of SE was evaluated, and no association was found between occurrence of SE and age at onset or seizure etiology. Genetic factors contribute to risk for SE.

Postictal pulmonary edema in children.

Pulmonary edema complicating generalized tonic-clonic seizures has rarely been reported in children, although it has been well documented in adults. We report two patients, aged 8 and 9 years, who developed clinical and radiographic evidence of the condition. Fever, leukocytosis, and arterial hypoxemia are seen in the absence of cardiac dysfunction or infection. Rapid and complete recovery is to be expected if supportive therapy is instituted. Since these patients had no underlying cardiac pathology, control of the seizures will prevent further episodes.

The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins.

Twin studies provide an efficient method for examining the importance of genetic and environmental factors in the etiology of disorders such as epilepsy. Population-based twin registries are especially valuable for studies of this type since effects of reporting and self-selection biases on the resulting data are minimized. Among 14,352 twin pairs contained in the Virginia and Norwegian twin panels for whom questionnaire information was available, there was a history of epilepsy in one or both members of 286 pairs; febrile seizures were reported in 257 pairs. Analyses of questionnaire data revealed no significant differences in concordance rates between Virginian and Norwegian twins for either epilepsy or febrile seizures. Probandwise concordance rates for epilepsy were 0.19 in monozygotic twins and 0.07 in dizygotic twins. Analogous rates for febrile seizures were 0.33 (monozygotic) and 0.11 (dizygotic). These results provide further evidence that genetic factors do have a role in the expression of epilepsy and febrile seizures.

A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia.

This report presents the initial analysis of a prospective, population-based study of status epilepticus (SE) in the city of Richmond, Virginia. The incidence of SE was 41 patients per year per 100,000 population. The frequency of total SE episodes was 50 per year per 100,000 population. The mortality rate for the population was 22%, 3% for children and 26% for adults. Evaluation of the seizure types for adult and pediatric patients demonstrated that both partial and generalized SE occur with a high frequency in these populations. Based on the incidence of SE actually determined in Richmond, Virginia, we project 126,000 to 195,000 SE events with 22,200 to 42,000 deaths per year in the United States. The majority of SE patients had no history of epilepsy. These results indicate that SE is a common neurologic emergency.

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group.

OBJECTIVE: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. BACKGROUND: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. METHODS: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. RESULTS: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. CONCLUSIONS: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

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.

Managing pediatric epilepsy syndromes with new antiepileptic drugs.

The management of epilepsy in the pediatric patient requires careful evaluation, classification, and pharmacologic treatment. Despite best efforts on the part of clinicians, approximately 25% of children remain refractory to appropriate medical therapies. The development of an improved classification system and the emergence of several new antiepileptic drugs have enabled some progress in this area, specifically in children with disorders such as Lennox-Gastaut syndrome and infantile spasms, which are notoriously difficult to control. However, limited data are available that define the optimal use of new antiepileptic agents in pediatric patients. To most effectively treat children with epilepsy syndromes, further research must be completed to validate the positive effects described in case reports, open-label clinical trials, and early controlled clinical trials.

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.

Verification of the fetal valproate syndrome phenotype.

We have evaluated 19 children who were exposed to valproic acid (VPA) in utero to look for manifestations of a fetal valproate syndrome (FVS), as proposed by Di Liberti et al. [1984]. We found no consistent alterations of pre- or postnatal growth with exposure to VPA monotherapy. Postnatal growth deficiency and microcephaly were present however, in two thirds of children exposed to VPA in combination with other anticonvulsants. Developmental delay or neurologic abnormality was found in 71% of those exposed to VPA monotherapy, and in 90% of those exposed to VPA and other anticonvulsants. Craniofacial anomalies, which can be seen with other anticonvulsant exposures, including midface hypoplasia, short nose with a broad and/or flat bridge, epicanthal folds, minor abnormalities of the ear, philtrum or lip, and micrognathia were also found in infants whose mothers used VPA. Prominent metopic ridge and outer orbital ridge deficiency or bifrontal narrowing and certain major anomalies such as tracheomalacia, talipes equinovarus (with intact spine) and lumbosacral meningomyelocele seem to be peculiar to infants with VPA exposure. Other defects such as urogenital anomalies, inguinal or umbilical hernias, and minor digital anomalies that are common to other prenatal anticonvulsant exposures are also occasionally found in those exposed to VPA. Heart defects have been found in infants exposed to nearly every class of anticonvulsant although the types of defects associated with maternal VPA use may be clarified when classified by pathogenetic mechanism. Our findings overall are in agreement with the report of Di Liberti et al. [1984].

Pyridoxine deficiency in children treated with isoniazid.

Isoniazid-induced deficiency of pyridoxine (vitamin B6) is reportedly not uncommon in adults but rare in children. In the present study, 38 children had serum levels of pyridoxine tested while receiving therapy with isoniazid. A biologic assay using the protozoan Tetrahymena thermophila determined pyridoxine status after 2 to 18 months of therapy with isoniazid. Five children (13 percent) were deficient. None had definitive clinical symptoms or signs consistent with pyridoxine deficiency. Three had normal nerve conduction velocity. Children receiving isoniazid in dosages greater than 10 mg/kg/day had a higher incidence of deficiency. Present recommendations for withholding pyridoxine prophylaxis from children receiving isoniazid therapy must be reconsidered in light of these findings, particularly in those children who are debilitated or have a poor nutritional history with a known pyridoxine deficit prior to therapy with isoniazid.