Platform Session 2: (#9?16) 9. Lovastatin normalizes the brain spontaneous low-frequency fluctuations in children with neurofibromatosis type 1 Acosta MT (Washington, DC), Chabernaud C (New York, NY), Mennes M (New York, NY) Kardel P (Washington, DC), Gaillard WD (Washington, DC), Kalbfleisch ML (Fairfax VA), Van Meter JW (Washington, DC), Packer RJ (Washington, DC), Milham MP (New York, NY), Castellanos FX (New York, NY) Objectives: In the NF1 mouse model, lovastatin improves cognitive deficits. As part of a Phase 1 safety open label trial, seven participating children with NF1 underwent fMRI scans pre- and post-treatment. We present the examination of functional connectivity (FC) in Default Network (DN) architecture, which has been implicated in typical brain maturation. Method: Participants underwent a 7-minute EPI scan at baseline and after treatment. Task-induced variance from the event-related data was removed leaving only ??continuous resting-state?? data. The task-related BOLD response was modeled to regress out the associated variance. Functional connectivity analyses were carried out on this ??resting-state?? signal using 11 DN regions of interest. For each participant and age-matched healthy control, voxel-wise correlations were calculated for the time series of each seed, creating subject-level FC maps. Group-level analyses used a randomeffects ordinary least squares model. Results: Lovastatin increased positive RSFC within DN regions along the anterior-posterior axis, with significant increase of long-range positive relationships between core regions. Lovastatin produced more focal local RSFC in the dorsomedial prefrontal cortex and the PCC. The pattern of connectivity in the NF1 participants for the on-drug condition closely resembled the age-matched healthy controls. Conclusions: Lovastatin administration in this sample appeared to normalize anterior-posterior and local FC within the DN. The pattern of results is consistent with normalization of developmental processes and apparent benefits in a mouse model. Interpretation is tentative because of the sample size; however, these results warrant that continued examination of the potentially beneficial effects of lovastatin in NF1. 10. Deep brain stimulation demonstrates partial amelioration of motor dysfunction in a mouse model of Rett syndrome Arehart EJ, Leiter JC, Green AI (Lebanon, NH) Objective: Rett syndrome (RTT) is a genetic disease that disrupts brain maturation leading to severe mental retardation and motor impairment in females. Neurotransmission imbalance is thought to play a critical role in pathogenesis. Recent work in animals suggests the process may be reversible. High frequency stimulation (HFS) of the brain modulates neural circuits and neurotransmitter release. We propose that HFS will reverse motor impairment in a mouse model of RTT, possibly by restoring balanced neurotransmission. Methods: Deep brain stimulation (DBS) uses electrodes implanted in the brain and HFS to modulate neural circuits. Eighteen MECP-2 null mice underwent surgical bilateral electrode implantation in the striatum and were randomized to three treatment groups: six were treated with HFS for 15 min/day, six were treated with HFS for one hour/day, and six received surgery, but did not undergo HFS. Six MECP2 null mice and six WT mice did not undergo surgery and served as positive and negative conC 2011 Child Neurology Society S112 V trols. Animals were evaluated using the wire-hang test, open field test, daily weight and disability score. Results: Mice treated with HFS as compared to littermatched controls demonstrated improved neuromuscular performance (p<0.001), improved mobility (p<0.002), improved weight gain (p<0.002), a decrease in their general disability score (p<0.01), and increased survival (p<0.001). The performance improvements lasted for twenty-four hours after the period of DBS. Conclusion: This work represents the first use of HFS to treat RTT and may eventually lead to clinical investigations of DBS in children with RTT to improve their long-term function and survival. 11. Everolimus showed long-term efficacy and safety in the extension phase of a prospective, openlabel phase I-II study of patients with subependymal giant-cell astrocytomas associated with tuberous sclerosis complex Krueger DA, Tillema J, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson K, Byars A, (Cincinnati, OH), Sahmoud T (Florham Park, NJ), Franz DN (Cincinnati, OH) Objective: To study long-term safety and efficacy of everolimus treatment in patients with subependymal giant-cell astrocytomas (SEGAs) associated with tuberous sclerosis complex. Methods: Long-term extension of a prospective, openlabel, phase I-II trial in patients who received everolimus starting at 3 mg/m2/day for treatment of SEGA. Results: Study cut-off was 31-Dec-2010, at which time 25 of 28 patients initially enrolled were still receiving everolimus (median dose 5.29 mg/m2/day [range, 2.1?12.3], median duration 1041 days [range, 142?1434]). Primary SEGA volume was reduced from baseline by 30% in 79.2%, 64.7%, and 77.8% and by 50% in 50%, 41.2%, and 55.6% of patients at 24, 30, and 36 months, respectively. Median duration (up to progression or cut-off date) of SEGA reduction 30% was 23.7969.8 months. Seizure activity was studied for the first 6 months only; median seizure frequency decreased at 6 months compared with baseline by 1.0 (range, 17.0?10.8). Adverse events (AEs) were mostly grade 1/2 in severity and were consistent with those previously reported for everolimus. During the entire study, single cases of grade 3 drug-related AEs were reported at <12 months (stomatitis, sinusitis, viral bronchitis, concomitant neutropenia), 25?36 months (stomatitis, pneumonia, limb abscess), and >36 months (neutropenia). There were no drug-related grade 4 events reported and no discontinuations due to everolimus. Conclusions: Long-term everolimus therapy is safe and effective for treatment of SEGAs associated with TSC. Reduction in tumor burden was maintained in patients who received everolimus 3 years, and the drug was well tolerated with no new safety concerns identified. 12. Excess stroke risk in adult survivors of childhood CNS tumors, leukemia and Hodgkin?s lymphoma: results of the Childhood Cancer Survivor Study Mueller S (San Francisco, CA), Fullerton HJ (San Francisco, CA), Stratton K (Seattle, WA), Leisenring W (Seattle, WA), Weathers R (Houston, TX), Stovall M (Houston, TX), Armstrong GT (Memphis, TN), Goldsby RE (San Francisco, CA), Packer RJ (Washington, DC), Robison LL (Memphis, TN), Krull KR (Memphis, TN) Objective: To assess predictors and long-term incidence rates of stroke in childhood cancer survivors. Methods: The Childhood Cancer Survivor Study is a multi-institutional cohort study of childhood cancer survivors (alive 5 years after diagnosis), with a sibling comparison group. The age-adjusted incidence rates of self-reported first-stroke were calculated for brain tumor (n�76), leukemia (n�30) and Hodgkin?s disease (HD) (n�27) survivors, and compared to siblings (n�23) using multivariable Poisson regression models. Multivariable Cox Proportional Hazards models were used to identify independent predictors of stroke. Results: A total of 125 brain tumor, 71 leukemia and 44 HD survivors reported a stroke. The age-adjusted stroke rate per 100,000 person-years at age 22 was 279 (95% C.I. 199?391) for brain tumor survivors, 49 (95% C.I. 31?77) for leukemia, and 23 (95% C.I. 8?72) for HD, compared to 8.2 (95% C.I. 3?21) for siblings. Brain tumor survivors carried a relative stroke risk of 30.1 (95% C.I. 17.8?50.8), leukemia survivors of 8.2 (95% C.I. 4.6?14.5) and HD survivors of 4.4 (95% C.I. 2.5?7.8) compared to siblings. Treatment with radiation increased the stroke risk and this risk continues to increase with longer follow up from diagnosis. The cumulative incidence of stroke in brain tumor survivors treated with 50� Gy was 1.3% (95% C.I. 0.4? 2.1) after 10 years compared to 14.2% (95% C.I. 10.5? 17.9) after 30 years. Conclusion: Children with brain tumors, leukemia or HD have an increased stroke risk, and this excess risk persists for decades after diagnosis. 13. Therapeutic hypothermia is correlated with seizure absence in perinatal stroke. Harbert MJ (San Diego, CA), Tam EWY, Glass HC, Bonifacio SL, Haeusslein LA, Barkovich AJ, Jeremy RJ, Glidden DV, Ferriero DM (San Francisco, CA) Objective: We studied seizure occurrence, neurodevelopmental outcome, and the effect of therapeutic hypothermia in perinatal stroke presenting with encephalopathy. Methods: A nested case-control study was performed within a single-center prospective cohort study of neonatal encephalopathy from 1994?2010. Cases of focal stroke were identified. Each case was matched on the basis of gender and degree of encephalopathy to two controls from the same cohort but without neuroimaging evidence of stroke. Results: Fifteen neonates were diagnosed with focal stroke on magnetic resonance imaging, 5 of whom received therapeutic hypothermia. Of the stroke subjects who received hypothermia, none had seizures in the neonatal period (0 of 5 cases) compared to 7 of the 10 stroke subjects who did not receive hypothermia. Hypothermia was associated with significantly decreased risk of seizures in the neonatal period (p�01). The cases of stroke had Mental Development Index scores (Bayley Scales of Infant Development) that were an average of 26.21 points lower than the matched non-stroke controls (95% CI 8.37, p�007.) This association was not significant after correcting for the presence of neonatal seizures (p�1). Conclusions: This is the first study to demonstrate a positive association between therapeutic hypothermia and perinatal stroke. Further study is needed to evaluate the potential efficacy of hypothermia in perinatal stroke. In a separate finding, neonatal seizures adversely affect cognitive outcomes in stroke presenting with encephalopathy when compared to non-stroke encephalopathic controls. This suggests that the effect of neonatal seizures upon cognitive outcomes may be dependent upon seizure etiology. 14. Efficacy and safety of Clobazam for seizures associated with Lennox-Gastaut Syndrome (LGS): results of a Phase III study Conry JA (Washington, DC), Ng YT (Phoenix, AZ), Drummond R, Stolle J, Owen JR, Weinberg MA (Deerfield, IL) Objectives: To demonstrate the efficacy and safety of clobazam for LGS, we conducted a Phase III controlled trial. Methods: Three oral dosages of clobazam were compared with placebo as adjunctive therapy for LGS. Following a 4week baseline phase, patients who had 2 drop seizures per week were randomized to placebo or 1 of 3 dosages of clobazam (0.25, 0.5, 1.0 mg/kg/day), up to 40 mg/day maximum. Treatment included a 3-week titration, followed by a 12-week maintenance period. Primary endpoint was percentage decrease in mean weekly frequency of drop seizures during the maintenance phase (vs. baseline) for the modified intention-to-treat (mITT) population (all patients who had entered maintenance phase). Safety included physical examinations, laboratory evaluations, and AE information. Statistical significance was prespecified as p0.01 for the primary endpoint. Results: 301 patients were screened, 238 were randomized, 217 comprised the mITT population, and 177 completed the study. At baseline, patients? mean age was 12.4 years, and 60.5% were male. Demographics and clinical characteristics were similar between groups. There was a statistically significant decrease in mean weekly drop-seizure frequency for all three groups receiving clobazam vs. placebo: 68.3% for high dosage (p<0.0001); 49.4% for medium dosage (p�0015); and 41.2% for low-dosage (p�0120), vs. 12.1% for placebo. Somnolence, lethargy, drooling, upper respiratory infections, and behavioral abnormalities were the most frequent treatment-emergent AEs reported for cloblazam. Conclusions: Clobazam 0.5 and 1.0 mg/kg/day statistically significantly decreased the weekly frequency of drop seizures associated with LGS. No new safety signals were observed vs. the Phase II study. 15. Emergency management of febrile status epilepticus: results from the FEBSTAT study Seinfeld S (Richmond, VA), Pellock JM (Richmond, VA), Shinnar S (Bronx, NY), Sun S, Deng X (Richmond, VA), Hesdorffer D (New York, NY), O?Dell C (Bronx, NY), O?Hara K (Richmond, VA), Nordli D (Chicago, IL), Frank M (Norfolk, VA), Gallentine W (Durham NC), Moshe SL (Bronx, NY, FEBSTAT Study Team Objective: To analyze pre-hospital and emergency department (ED) management of febrile status epilepticus (FSE). Methods: Subjects were children age 1 month to 5 years who are part of a prospective, multicenter study of consequences of FSE which was defined as a febrile seizure or series of seizures without recovery in between lasting >30 minutes. We reviewed the emergency medical service (EMS) and ED management, including seizure recognition, medication administration and respiratory support. Preliminary data (93 of 200 patients) from two sites were analyzed. The remaining cases at the 3 other sites are currently being reviewed. Results: EMS recognized a seizure on arrival 66% of the time. During EMS transport 92% of the patients had convulsions. The average time from seizure onset to initial dose of seizure medication by EMS or ED was 57 minutes. The mean seizure duration was 78 minutes when medication was administered prior to presentation to the ED and 99 minutes if no medication was administered (p value 0.12). Program and Abstracts, Child Neurology Society S113 Seizure duration was longer in patients that received respiratory support (mean 115 vs 78 minutes, p-value 0.016). Conclusions: FSE is a neurological emergency requiring prompt recognition and treatment. Seizure duration is related to the requirement of respiratory support. This study demonstrates a delay in FSE treatment. Studies of status epilepticus in adults have shown that early treatment reduces the need for respiratory support and ICU which emphasizes the urgency of early recognition and treatment.Supported by Grant NS 43209 (PI: S Shinnar MD PhD) from NINDS 16. Answering parents? important questions after their child has status epilepticus Camfield PR, Camfield CS (Halifax, NS) Objective: To answer 4 questions parents often ask about unprovoked status epilepticus. Methods: The Nova Scotia Childhood Epilepsy Study (population-based) identified patients with 1 episodes of unprovoked status, focal epilepsy, normal intelligence and follow up 10 years. Results. 156 cases had a mean follow up of 2765 years with 1 death from status. 31 (20%) had 1 episodes of status. 15 had status as their first unprovoked seizure. S114 Annals of Neurology Vol 70 (suppl 15) 2011 Question 1. Will this happen again? 20 (65%) had only 1 episode of status, 6 had 2, 5 had 3?10. Question 2. Will there be brain damage? At onset 9/31 (29%) status patients and 27/124 (22%) non-status patients were clinically assessed to have learning disorders. At the end of follow up, 10 (32%) status and 41 (33%) non-status patients had learning disorders. Question 3. Will the epilepsy be harder to control? As a proxy measure we assessed number of AEDs used throughout the clinical course ? 14/31(45%) status patients used 2 AEDs versus 76/124 (61%) non-status patients (p�1). The distribution of patients using 3?11 AEDs was similar. Question 4. Will the likelihood of remission be decreased? Remission was defined as seizure-free without AEDs at the end of follow up. Excluding those with epilepsy surgery (3 status, 8 non-status) the remission rate for status patients was 15/28 (54%) versus 77/116 (66%) in non-status (p�2). Conclusions: Despite its frightening and recurring nature, status epilepticus appears to have little influence on long term intellectual or seizure outcome of focal epilepsy in normally intelligent children. Parents may relax.