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A large randomized study was conducted in patients with newly diagnosed infantile spasms to compare 2 doses of vigabatrin in achieving spasm cessation. High (100-148 mg/kg/d) and low (18-36 mg/kg/d) oral doses of vigabatrin were evaluated in a randomized, single-blind study of 14 to 21 days with subsequent open-label treatment up to 3 years. Spasm cessation was defined as 7 consecutive days of spasm freedom beginning within the first 14 days, confirmed by video-electroencephalogram. A total of 221 subjects comprised the modified intent-to-treat cohort. More subjects in the high-dose group achieved spasm cessation compared with the low-dose vigabatrin group (15.9% [17/107] vs 7.0% [8/114]; P = .0375). During follow-up, 39 of 171 (23%) subjects relapsed; 28 of 39 (72%) regained spasm freedom. Adverse events were primarily mild to moderate in severity. Vigabatrin had a dose-dependent effect in spasm reduction. Spasm cessation occurred rapidly and was maintained in the majority of infants.

This phase III, open-label, multicenter, outpatient study evaluated the 12-month safety of valproate using divalproex sodium sprinkle capsules for partial seizures, with or without secondary generalization, in children aged 3-10 years (n = 169). Laboratory parameters and vital signs were assessed, and the Wechsler Scales of Intelligence, the Developmental Profile-II, movement-related items from the Udvalg for Kliniske Undersøgelser, and the Behavior Assessment System for Children were administered. Efficacy was measured by the 4-week seizure rate. The most common treatment-emergent adverse events in the 169 study patients were typical childhood illnesses: pyrexia (18%), cough (17%), and nasopharyngitis (14%). The most common adverse events not considered typical childhood illnesses were vomiting (14%), tremor (9%), somnolence (8%), and diarrhea (8%). Of the 169 patients, 11 (6.5%) were hospitalized with serious treatment-emergent adverse events. Although elevated ammonia levels were observed in 31 treated patients, and mean increases in uric acid concentrations and decreases in platelets were observed, the majority of patients were asymptomatic. Except for tremor, no increases in movement-related adverse effects were observed. Small numeric improvements were reported in the Wechsler Scales and the Behavior Assessment System for Children. The safety findings in this 12-month study are generally consistent with previous reports of valproate in adult and pediatric epilepsy patients.

Purpose: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS)., Methods: Medical records and 332 cranial MRIs from 205 infants (aged 16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated., Results: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects., Discussion: Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

This open-label study was designed to evaluate the long-term tolerability and efficacy of lamotrigine in 1- to 24-month-old infants with partial seizures. The study enrolled both lamotrigine-naïve patients and patients who had been previously exposed to lamotrigine in a randomized, double-blind, placebo-controlled study. Patients (n = 204) received lamotrigine according to a dosing schedule that depended on prior experience with lamotrigine and concurrent antiepileptic drug therapy for up to 48 weeks or their second birthday, whichever occurred last. Total duration of lamotrigine exposure (which included exposure during the placebo-controlled study in lamotrigine-experienced patients) was >/=24 weeks in 92% of patients, >/=48 weeks in 70% of patients, and >/=72 weeks in 20% of patients. A total of 20 (10%) patients (8 lamotrigine-naïve patients and 12 lamotrigine-experienced patients) transitioned to lamotrigine monotherapy. The most common adverse events were pyrexia (45% of patients), upper-respiratory tract infection (28%), and ear infection (22%). The only adverse event considered reasonably attributable to study medication in >2% of patients was irritability (n = 10; 5% of patients). No cases of serious rash were reported. The median percent reduction from baseline in partial seizure frequency in the sample as a whole was 74%. Seizure frequency was reduced by >/=50% from pre-lamotrigine baseline in 62% of patients in the sample as a whole, 60% of the lamotrigine-naïve subgroup, and 63% of the lamotrigine-experienced subgroup. In the sample as a whole, 13% of patients were seizure free during the Treatment Phase. Investigators considered clinical status at the last clinic visit to be improved (mildly, moderately, or markedly) relative to prelamotrigine clinical status in 76% of patients (150/197) and to be unchanged in 19% (37/197). In this study-the first large prospective investigation of the long-term tolerability and efficacy of an antiepileptic drug in a patient population 2 years and younger-lamotrigine administered for up to approximately 72 weeks was well tolerated and associated with good seizure control.

Object: The object of this study was to identify prognostic factors for survival among children with recurrent medulloblastoma., Methods: Postprogression survival and patient, tumor, and treatment factors were examined in 46 cases of recurrent medulloblastoma (mean age of patients at diagnosis 6.5 years, mean age at progression 8.4 years). Differences were calculated by Kaplan-Meier log-rank analysis. Multivariate analysis was performed using the Cox proportional hazard model., Results: The probability of 5-year survival was 26.3%. Forty-one patients received salvage therapy and five patients received hospice care only. Log-rank analysis showed an association between prolonged patient survival and recurrence limited to the primary site (p = 0.008), initial therapy including the Pediatric Oncology Group (POG) regimen for the treatment of brain tumors in infants ("Baby POG;" p = 0.037), and treatment with radiation therapy (RT) following initial progression (p = 0.015). Cox regression analysis showed a significant association between prolonged survival and only one variable--tumor recurrence restricted to the primary site (p = 0.037). There was no significant association between prolonged survival and any other variables, including patient sex, age at progression, interval from tumor diagnosis to progression, initial tumor stage, and salvage treatment with chemotherapy. Subgroup analysis revealed that site of tumor progression was also prognostic for survival among the subgroup of patients older than 3 years of age at diagnosis who were initially treated with RT and chemotherapy (p = 0.017, log-rank test)., Conclusions: Some children with recurrent medulloblastoma will be long-term survivors, and certain features are associated with likelihood of survival. Patients whose tumors recur at only the primary tumor site have an increased chance of prolonged survival.

Mutations in the voltage-gated sodium channel gene SCN1A are a major cause of severe myoclonic epilepsy of infancy (Dravet syndrome) and generalized epilepsy with febrile seizures plus. This study reports the identification of six de novo SCN1A mutations in patients with severe myoclonic epilepsy of infancy, including a tetranucleotide deletion in exon 26. The same deletion was previously observed in two unrelated patients and appears to result from slipped-strand mispairing of a direct repeat during deoxyribonucleic acid replication. Review of the literature indicates that recurrent mutations account for 25% of SCN1A mutations in severe myoclonic epilepsy of infancy, including six sites of deamination at CpG dinucleotides.

Purpose: The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs., Patients and Methods: Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis., Results: One hundred forty-one children were identified (mean +/- SD age, 7.6 +/- 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P =.035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P =.001 for all). Tumors in the optic pathways were associated with a shorter PFS (P =.001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P =.001 and.019, respectively)., Conclusion: Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.

Background: Nonperioperative strokes are rare yet potentially devastating events for children with central nervous system (CNS) tumors. The incidence of and risk factors for nonperioperative strokes in children with CNS tumors is unknown., Methods: The authors performed a retrospective review of children from their institution with CNS tumors. The incidence of stroke in the nonperioperative period and the influence of patient demographic factors, coexisting genetic diseases, tumor type, and treatment modality on the subsequent occurrence of a stroke were determined., Results: Eight hundred seven consecutive patients from the authors' institution with CNS tumors were observed for a combined 3224 nonperioperative years. Thirteen patients (1.6%) had a nonperioperative stroke, for an incidence of 4.03 strokes/1000 years of nonperioperative patient follow-up. Eight patients were males, and the median age at diagnosis of a CNS tumor was 4.8 years (range, 0.3-18.6 years). The median duration from diagnosis of a CNS tumor until the occurrence of stroke was 2.3 years (range, 0.3-15.8 years). Among numerous potential risk factors individually examined by chi-square analysis, only treatment with radiation therapy was associated with the subsequent development of a stroke (chi-square, P = 0.007). By logistic regression analysis, treatment with radiation therapy and a diagnosis of an optic pathway glioma were the only statistically significant variables associated with a stroke., Conclusions: Strokes are much more common among children with CNS tumors. Children treated with radiation therapy and those with optic pathway gliomas have a higher association with the occurrence of a subsequent nonperioperative stroke. Because children with optic pathway gliomas may be at particularly high risk of stroke after radiation therapy, the desired beneficial therapeutic effects of irradiation must always be weighed against its potentially adverse effects, including stroke., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10353)

Background: Infantile spasms are a rare but devastating pediatric epilepsy that, outside the United States, is often treated with vigabatrin. The authors evaluated the efficacy and safety of vigabatrin in children with recent-onset infantile spasms., Methods: This 2-week, randomized, single-masked, multicenter study with a 3- year, open-label, dose-ranging follow-up study included patients who were younger than 2 years of age, had a diagnosed duration of infantile spasms of no more than 3 months, and had not previously been treated with adrenocorticotropic hormone, prednisone, or valproic acid. Patients were randomly assigned to receive low-dose (18-36 mg/kg/day) or high-dose (100-148 mg/kg/day) vigabatrin. Treatment responders were those who were free of infantile spasm for 7 consecutive days beginning within the first 14 days of vigabatrin therapy. Time to response to therapy was evaluated during the first 3 months, and safety was evaluated for the entire study period., Results: Overall, 32 of 142 patients who were able to be evaluated for efficacy were treatment responders (8/75 receiving low-dose vigabatrin vs 24/67 receiving high doses, p < 0.001). Response increased dramatically after approximately 2 weeks of vigabatrin therapy and continued to increase over the 3-month follow-up period. Time to response was shorter in those receiving high-dose versus low-dose vigabatrin (p = 0.04) and in those with tuberous sclerosis versus other etiologies (p < 0.001). Vigabatrin was well tolerated and safe; only nine patients discontinued therapy because of adverse events., Conclusions: These results confirm previous reports of the efficacy and safety of vigabatrin in patients with infantile spasms, particularly among those with spasms secondary to tuberous sclerosis.

Purpose: Children with partial-onset seizures, with or without secondary generalization, participating in a double-blind, placebo-controlled trial of topiramate (TPM) as adjunctive therapy were eligible to participate in an open-label, long-term extension study., Methods: A total of 83 children (mean age, 9 years) continued long-term open-label TPM therapy in which the dosages of TPM and concomitant antiepileptic drugs (AEDs) were adjusted according to clinical response (mean TPM dosage, 9 mg/kg/day)., Results: Seizure frequency over the last 3 months of therapy was reduced > or =50% in 57% of children; 14% of children were seizure-free > or =6 months at the last visit. During treatment periods up to 2 1/2 years (mean, 15 months), 6% of children discontinued because of treatment-emergent adverse events; 13% discontinued because of inadequate seizure control., Conclusions: From these findings, TPM is well tolerated and provides long-term seizure control in children with partial-onset seizures.

Purpose: Children with recurrent or progressive central nervous system (CNS) tumors have an unfavorable prognosis. Based on Pediatric Oncology Group (POG) institutional pilot data, low-dose oral methotrexate (MTX) was studied., Methods: Eight dosages of MTX 7.5 mg/m2 every 6 hours were administered on a weekly schedule for as long as 18 months. Patients in six different brain tumor strata were accrued., Results: The response rates (complete or partial responses) were as follows: astrocytoma 2 of 10, malignant glioma 1 of 19, medulloblastoma 0 of 18, brainstem tumor 0 of 12, ependymoma 1 of 7, and miscellaneous histologic types 0 of 12. The main toxicities, mucositis, myelosuppression, and hepatic transaminase elevation were considered tolerable., Conclusion: Low-dose oral MTX showed no significant activity against malignant glioma, medulloblastoma, brainstem tumors, and miscellaneous histologic types. Indeterminate but low response rates were observed in children with astrocytoma and ependymoma. This regimen will not be recommended for front-line therapy.

An uncommon but well-recognized occurrence in patients with Dandy-Walker malformation is sudden unexpected death. The mechanism of demise has not been established. We report three patients with Dandy-Walker malformation that experienced sudden unexpected death without uncal or tonsillar herniation, the mechanism usually proposed for demise in such situations. Our findings suggest the possibility of vascular compromise as the cause of the sudden unexpected death in these patients. Early and effective relief of the pressure in the posterior fossa may prevent the occurrence of this catastrophic complication.

A 2-year-old boy with microcephaly, developmental delay, and minimal anomalies was found to have an extra submetacentric chromosome equivalent to 18pter----q12. Review of the phenotypes produced by various triplicated 18 regions supports the hypothesis that no one chromosome 18 region is sufficient to produce the phenotype of trisomy 18. The mild phenotype of trisomy 18p, the variable phenotype of trisomy 18pter----q12, and the discontinuous phenotype of triplication for band 18q12 alone emphasizes that the contribution of triplicated loci to the phenotype is neither additive nor invariant.