Roy D. Elterman

Study of the MIB-1 Labeling Index as a Predictor of Tumor Progression in Pilocytic Astrocytomas in Children and Adolescents

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.

Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy

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).

Desmoplastic infantile gangliogliomas: an approach to therapy.

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 for the Treatment of Infantile Spasms: Final Report of a Randomized Trial:

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.

Surgical Treatment of Focal Epilepsy in Children; Results in 37 Patients

This report concerns 37 children and teenagers operated upon for intractable seizures between 1990 and 1994. Follow-up is at least 3 years. Fourteen children underwent pure temporal lobe resections; 71% are seizure free, and 93% have a better than 90% decrease in seizure frequency. The presence of a lesion on magnetic resonance imaging, the side of the lesion, or the presence of abnormal pathology had no influence on the result of resection. 28% of the children who had extratemporal resections are seizure free, and 83% have a greater than 90% decrease in seizure frequency. There was a trend to better results in those with a lesion on magnetic resonance imaging. In the small group with temporal plus extratemporal foci, the results were poor with only 60% showing a greater than 90% reduction in seizure frequency.

Long-term tolerability and efficacy of lamotrigine in infants 1 to 24 months old.

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.

Divalproex Sodium in Children with Partial Seizures: 12-Month Safety Study

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.

Sudden Unexpected Death in Patients With Dandy-Walker Malformation

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).

Unintended Consequences: The Story of PERF

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.