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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.

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.

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/m 2 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.

In the days before widespread internet use, iPhones, and iPads, the American Board of Psychiatry and Neurology part II oral board examination provided a unique opportunity for examiners to meet, mingle, and network. Sometimes interesting collaborations developed. Such was the case in 1994 when we had the same hour off on Dr. Alan Percy’s child neurology team. We were discussing infantile spasms and the reports out of Europe that vigabatrin was showing efficacy in treating infantile spasms.1,2 We thought, “Wouldn’t it be neat if we could get access to vigabatrin for our patients?” We knew Hoechst Marion Roussel had submitted a new drug application for vigabatrin for adult patients with complex partial seizures. We expected approval in the United States within 3-4 years and thought it would be great for our infantile spasms patients if we could get access to it while awaiting Food and Drug Administration (FDA) approval. Thus was born the journey that eventually would lead to the Pediatric Epilepsy Research Foundation (PERF). Over the summer of 1994, we developed a compassionate use protocol for treating infantile spasms with vigabatrin. This was presented to a preliminary group of investigators at the 1994 San Francisco Child Neurology Society meeting, most of whom would eventually form the Vigabatrin Infantile Spasms Study Group. Over the next 6 months or so, the details were hammered out and the Vigabatrin Infantile Spasms Study Group was formalized (see Table). Hoechst Marion Roussel agreed to provide an unrestricted grant and three large barrels (55-gallon drums with 165,000 pills) of 500-mg vigabatrin tablets to support the effort.

Desmoplastic infantile gangliogliomas are massive cystic tumors, typically occurring in the cerebral hemispheres of infants. They are remarkable pathologically for a prominent desmoplasia and, in some cases, for a cellular mitotically active component that can be readily interpreted as a malignant neoplasm. Four children less than 1 year of age were diagnosed with desmoplastic infantile gangliogliomas in the Pediatric Oncology Group infant brain tumor study (Protocol number 8633). All had been diagnosed by their respective institutions as having malignant tumors, i.e., Grade III astrocytoma, malignant meningioma, leptomeningeal fibrosarcoma, and gliosarcoma. All had increased intracranial pressure, and two had seizures. The tumors were extremely large, with one measuring 12 x 9 x 9 cm. None had evidence of metastatic disease. One patient had a gross total resection, and the other three had debulking procedures. All four children were treated with chemotherapy (cyclophosphamide, vincristine, cisplatinum, etoposide) for periods ranging from 12 to 24 months. Of those with postoperative measurable disease, one child had a complete response, one a partial response, and one had stable disease at the conclusion of chemotherapy. No child received radiation therapy. All children are alive with progression-free survivals after diagnosis of more than 36, 42, 48, and 60 months, respectively. Although desmoplastic infantile gangliomas are rare, recognition of this tumor type is essential because, despite their massive size and pathologically malignant appearance, they may have a relatively benign clinical course. If total surgical resection can be achieved, further therapy may not be indicated. In those patients in whom residual disease is present, chemotherapy appears to be an effective form of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

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).Medical records and 332 cranial MRIs from 205 infants (agedor=24 months) with IS treated at 10 sites in the United States and Canada were collected. Similarly, 2,074 images from 668 children (aged 2-16 years) and adults (aged16 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.Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p0.001). 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.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.

The object of this study was to identify prognostic factors for survival among children with recurrent medulloblastoma.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.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).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.

Objective: To evaluate the efficacy and tolerability of levetiracetam (LEV) as adjunctive therapy in children (4 to 16 years) with treatment-resistant partial-onset seizures. Methods: This multicenter, randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 14-week double-blind treatment period. During the treatment period, patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day. Results: One hundred ninety-eight patients (intent-to-treat population) provided evaluable data. The reduction in partial-onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy was significant (26.8%; p = 0.0002; 95% CI 14.0% to 37.6%). A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo ( p = 0.0002). Seven (6.9%) LEV-treated patients were seizure-free during the entire double-blind treatment period, compared with one (1.0%) placebo-treated patient. One or more adverse events were reported by 88.1% of LEV-treated patients and 91.8% of placebo patients. The most common treatment-emergent adverse events were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, and pharyngitis. A similar number of patients in each group required a dose reduction or withdrew from the study as a result of an adverse event. Conclusion: Levetiracetam adjunctive therapy administered at 60 mg/kg/day is efficacious and well tolerated in children with treatment-resistant partial seizures.

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.

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. (J Child Neurol 1995;10:382-384).

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.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.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.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.

Objective: The Quality Standards Subcommittee of the American Academy of Neurology develops practice parameters as strategies for patient management based on analysis of evidence. For this practice parameter, the authors reviewed available evidence on evaluation of the first nonfebrile seizure in children in order to make practice recommendations based on this available evidence. Methods: Multiple searches revealed relevant literature and each article was reviewed, abstracted, and classified. Recommendations were based on a three-tiered scheme of classification of the evidence. Results: Routine EEG as part of the diagnostic evaluation was recommended; other studies such as laboratory evaluations and neuroimaging studies were recommended as based on specific clinical circumstances. Conclusions: Further studies are needed using large, well-characterized samples and standardized data collection instruments. Collection of data regarding appropriate timing of evaluations would be important.