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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
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
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
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.
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
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
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
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