CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.

The authors report the successful use of radiosurgery in a child for posterior corpus callosotomy; the early results are good and the patient has not suffered any morbid conditions. The relevant literature pertaining to the use of radiosurgery for treating epilepsy is reviewed. Details of the radiosurgical techniques and prescription dose used are presented, along with 1-year serial neuroirnaging results.

A double-blind, dose-controlled study evaluated topiramate as monotherapy in 470 patients with newly diagnosed (≤ 3 months) epilepsy or epilepsy relapse in the absence of therapy. In addition to having at least 2 lifetime-unprovoked seizures, patients had 1 or 2 partial-onset seizures or generalized-onset tonic-clonic seizures during a 3-month retrospective baseline. The trial included a large cohort (N = 151, 32%) of children and adolescents 6 to 15 years of age. Eligible patients were randomized to treatment groups in which topiramate was titrated to target maintenance dosages of either 400 mg/day (n = 77) or 50 mg/day (n = 74). Patients were followed for at least 6 months. Based on Kaplan-Meier analyses, the primary efficacy endpoint of time to first seizure favored the higher topiramate dose in both the overall population and the cohort of children/adolescents. The probability that children/adolescents remaining in the study were seizure free at 6 months was 78% in the 50-mg target dose group and 90% with the higher dose. At 12 months, the probability of being seizure free was 62% and 85%, respectively. The incidence of treatment-limiting adverse events was 4% in the 50-mg target dose group and 14% in the group assigned to 400 mg as a target dose. The most common adverse events, excluding typical childhood illnesses, were headache, appetite decrease, weight loss, somnolence, dizziness, concentration/attention difficulty, and paresthesia. As shown in this subset analysis, topiramate is effective and well tolerated as monotherapy in children and adolescents.

OBJECTIVE: To evaluate the relationship between baseline seizure frequency and stabilized topiramate dosage and the effect of individualized treatment on tolerability in adults with partial-onset seizures receiving other antiepileptic drugs (AEDs). METHODS: In this 20-week, open-label trial, dosages of medications were adjusted according to clinical response. Dosage and seizure response data were analyzed for 2 groups defined by baseline seizure frequency: <4 and ≥4 seizures per month. RESULTS: In the outcome evaluable population (n = 471), the mean ± SEM stable topiramate dosage was 303 ± 139 mg/d when baseline seizure frequency was <4 seizures/month and 341 ± 153 mg/d when baseline seizure frequency was ≥4 seizures/month (p = 0.005). The most common adverse events were somnolence (8.5%), fatigue (7.3%), nausea (5.3%), and dizziness (5.0%). Cognitive complaints were reported by <3% of patients. When concomitant AED dosages were reduced, 14% of patients discontinued topiramate due to adverse events compared with 23% if the concomitant AED dosage was unchanged or increased. CONCLUSIONS: When clinicians individualize topiramate dosage according to clinical response, the stabilized topiramate dosage as add-on therapy is influenced by baseline seizure frequency. Topiramate tolerability is improved when dosages of concomitant AEDs are reduced.

Childhood epilepsies comprise a broad range of disorders which vary from benign to progressive and disabling. Accurate diagnosis of epilepsy type and determination of aetiology, when possible, are essential for appropriate treatment. The most common seizure type encountered in children is febrile seizures. These represent a benign condition which is not, in fact, epilepsy and usually does not require antiepileptic medication. When partial seizures occur in childhood, benign syndromes with spontaneous remission, such as rolandic epilepsy, must be distinguished from symptomatic epilepsies which may be refractory to medical management. Complex partial seizures in young children may appear different than in adults. The adverse effect profiles and dosing regimens of antiepileptic drugs in children are also different than in adults, and influence the choice of treatment. Epilepsy surgery should be considered for some children with intractible partial seizures. Generalized epilepsies also have a broader spectrum in children. The idiopathic generalized absence epilepsies are usually easy to control with medication. They range from childhood absence epilepsy which tends to remit in adolescence to juvenile myoclonic epilepsy which is a lifelong condition. In contrast, the seizures of West syndrome and Lennox-Gastaut syndrome are difficult to control, and treatment involves therapeutic modalities rarely used in adults such as ACTH and the ketogenic diet. Many childhood epilepsy syndromes have a familial predisposition, and the genetic bases for several disorders have been described.

In the past year, several new antiepileptic drugs have emerged that have potential benefits for children with epilepsy. The spectrum of adverse effects is the principal feature that differentiates among the older drugs used to treat partial and related seizures, including simple partial, complex partial, and partial secondarily generalized seizures. Based on studies in adults with refractory seizures, the new or investigational compounds felbamate, gabapentin, lamotrigine, and vigabatrin should be active against these types of seizures in children, but none of them have been subjected to pediatric randomized controlled trials, and no studies have been done that compare new and old drugs in this category. Thus, the new drugs hold promise in children with these types of seizures, but their role relative to old drugs has not been elucidated. Several of the new drugs are active against myoclonic and generalized tonic-clonic seizures, but thus far, none have been proven to possess antiabsence activity in children. Open-label investigations suggest that lamotrigine may be helpful in Lennox-Gastaut syndrome, and vigabatrin in infantile spasms. Only felbamate has been evaluated in a randomized controlled study in children, in which it has proven beneficial against astatic and generalized tonic-clonic seizures in children with Lennox-Gastaut syndrome. Whereas investigations of these and other novel drugs are ongoing, this is an active and exciting period in pediatric antiepileptic drug development.

Four unrelated children were thought to have valproate-associated hepatotoxicity. They presented with recurrent partial secondarily generalized status epilepticus and epilepsia partialis continua followed by mental and motor regression. Despite treatment with multiple antiepileptic medications, they continued to have seizures. After initiation of valproic acid (VPA), all 4 manifested liver failure within 3 months. Two of these children each had 1 sibling who was not exposed to VPA, but who developed the same clinical picture including liver failure. At the time of autopsy, all 6 children had similar neuropathological findings with focal areas of spongiosis and neuronal loss, diffuse gliosis, and Alzheimer type II cells. One VPA-treated patient underwent a successful liver transplantation only to die from relentlessly progressive neurological deterioration. We propose that many of the reported patients with VPA-associated hepatotoxicity represent undiagnosed patients with early childhood hepatocerebral degeneration, the Huttenlocher variant of Alpers' syndrome. This disease manifests by obstinate partial seizures, recurrent partial secondarily generalized status epilepticus, epilepsia partialis continua, psychomotor deterioration, and hepatic dysfunction that is exacerbated by VPA administration. The accelerated demise from liver failure in the nontransplanted patients before the central nervous system pathology fully evolves makes the diagnosis of this rare condition difficult. The occurrence of disease in the unexposed siblings suggests recessive inheritance.

The goal of antiepileptic drug administration is to prevent seizures without drug-related side effects. This statement says nothing about the production of a particular drug concentration in the patient’s blood or about measuring it. Drug levels are only adjuncts that help answer questions in certain situations. Too many routine, expensive drug levels are being obtained, and their misuse causes unnecessary trouble.

Summary: About 75% of patients with epilepsy have seizures during childhood, often requiring antiepileptic therapy. Children possess all the drug‐specific pharmacokinetic features of adults (e.g., nonlinearity of phenytoin elimination and autoin‐duction of carbamazepine metabolism), plus other factors (e.g., age, intercurrent illness, comedication) that influence dosage. Kinetic differences are maximal in newborns and infants, with limited drug elimination in premature and full‐term babies, soon followed by accelerated elimination during infancy and childhood, before lower adult elimination rates develop during late childhood or early adolescence. Most children with epilepsy require two‐ to fourfold larger doses relative to bodyweight than adults, to achieve comparable drug levels and therapeutic effects. Although rapid growth may require increased dosage, the need is limited as relative clearance declines with age. Children of any age, but particularly premature and newborn babies, show greater individual variability in drug handling and therefore in dose requirements than adults. Clinical response and antiepileptic drug concentrations should both be monitored carefully in children.