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Platform Session 4 (36Ц43).

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35. A Blinded, Crossover, Placebo-Controlled Study of
the Effectiveness of the Ketogenic Diet (KJD)
Freeman J, Vining E, Goodman S, Kossoff E, Pyzik P,
Xiaobu Y (Baltimore, MD)
Objective: A blinded, crossover, placebo-controlled study of
the effectiveness of the ketogenic diet (KGD). Methods; 20
children with Lennox Gastaut Syndrome, having ⬎15 EEG
documented seizures/d were fasted for 36 hrs, and KGD introduced. Glucose or saccharine was added in randomized,
blinded fashion to negate (placebo) or sustain the effect of
the diet (treatment). Patients were evaluated after 5 days in
each arm with a fast in-between. Parental seizure detections
(PS) and EEG seizures (ES) were assessed. Results: The
group median for ES went from 20 (1,149) to 6(0,507) for
placebo to treatment, from 11(0,233) to 11(0,44) for treatment to placebo. The group median of PS went from 11
(3,75) to 7 (0, 52) for placebo to treatment, from 8 (0,37) to
15 (0,18) for treatment to placebo. There was no significant
difference between the two arms in number of ES (p⫽0.7)
and marginal difference in PS (p⫽0.07). There was significant reduction in median seizures overall (30 to 10 seizures/
day, p ⬍ 0.0001) between baseline and introduction of the
diet. No patient had absent betahydroxybutyrate during the
glucose arm. Conclusions: The initial fasting to start the
KGD was followed by a significant seizure reduction. The
randomized component of the trial showed no reduction in
EEG-identified, but moderate statistical evidence for a reduction in parent-identified seizures. Administration of 60 grams
of glucose/d did not completely eliminate ketones, and may
not counter the original effects of fasting.
DOI: 10.1002/ana.11479
Neurogenetics and Movement
Friday, October 20, 2006
3:30 – 5:30 pm
36. Presynaptic Dopamine D2 Receptors Selectively
Excite or Inhibit Striatal Glutamatergic
Bamford NS, Joyce JA, Palmiter RD (Seattle, WA)
Striatal excitation by glutamate released from cortical terminals is directly regulated through dopamine D2 receptors. To
determine how a change in dopamine availability affects glutamatergic neurotransmission, we combined optical measurements of presynaptic corticostriatal release in combination
with postsynaptic whole-cell patch-clamp recordings in striatal medium spiny neurons. The activity-dependent release
of the endocytic tracer FM1-43 out of corticostriatal terminals allows a measure of terminal kinetics quantified by the
halftime decay of fluorescence intensity (t1/2). For models of
dopamine depletion and excess, we used dopamine-deficient
transgenic mice and mice exposed to chronic methamphetamine (20mg/kg for 10 days).
In slices from control mice, synaptic dopamine reduced
exocytosis from a subset of cortical terminals with a low
probability of release (t1/2⫽203sec vs. 260sec for dopamine;
P⬍0.001) and reduced excitatory postsynaptic currents and
low amplitude miniature endplate potentials (minis;
P⬍0.001). In slices from dopamine-deficient mice, synaptic
dopamine inhibited release from all terminals (t1/2⫽338 sec;
P⬍0.001), reducing both high and low amplitude minis
(P⬍0.001). Slices from chronic methamphetamine-treated
mice had depressed glutamatergic neurotransmission
(t1/2⫽318 sec; P⬍0.001), and addition of dopamine resulted
in a paradoxical increase in corticostriatal release (t1/2⫽277
Thus, chronic alterations in dopamine availability affect
normal striatal release kinetics. Under control conditions, dopamine preferentially inactivates weak corticostriatal afferents. In states of dopamine deficiency, dopamine inactivates
all corticostriatal afferents. Conversely, following prolonged
periods of dopamine excess, dopamine facilitates corticostriatal release from all afferents. These altered responses of corticostriatal afferents to dopamine may underlie some of the
dysfunction observed in diseases such as attention-deficithyperactivity disorder, Tourette syndrome and Parkinsonism.
37. Asialotransferrin, a Novel CSF Biomarker for
eIF2B Related Disorders in Vanishing White Matter
Disease/ Childhood Onset Ataxia and Central Nervous
System Hypomyelination
Vanderver, A; Schiffmann, R; Boespflug-Tanguy, Fogli, A;
Timmons, M; Maletkovic, J, Hathout, Y (Washington, DC;
O INSERUM, France; Bethesda, MD)
Background: Vanishing White Matter disease (VWM) or
Childhood onset Ataxia and Central nervous system Hypomyelination (CACH) is related to mutations in the five
genes of EIF2B. A recently described cerebrospinal fluid
(CSF) biomarker, a deficiency of CSF asialotransferrin, is a
rapid alternative to the sequencing of the 57 exons of the
EIF2B genes. This biomarker’s ability to discriminate between leukoencephalopathies indistinguishable on clinical
and radiologic grounds was tested. Methods: Magnetic resonance imaging and clinical findings were reviewed. EIF2B
sequencing was performed. Nine patients with mutation
proven CACH/VWM and four patients with a clinically indistinguishable but mutation negative leukodystrophy were
ascertained. Banked CSF samples were studied. Aliquots
from CSF samples were separated by two-dimensional gel
electrophoresis (2-DG). The resulting gel array images were
compared using 2-DG image analysis software. Results: The
EIF2B mutated CACH/VWM patients had a unique transferrin isoform pattern relative to EIF2B negative CACH/
VWM-like patients, with a relative decrease in asialotransferrin isoforms. The ratio of asialo to sialo-transferrin in the
VWM and VWM-like samples were statistically significantly
different (t (11) ⫽ 6.88, p⬍0.0001). Conclusion: CACH/
VWM is a disorder caused by mutations in EIF2B genes and
appears to be related to an abnormal endoplasmic reticulum
stress response. The association between eIF2B mutation and
decreased asialotransferrin in the CSF supports the hypothesis that this disease is the result of altered protein translation
and modifications. Transferrin isoform abnormalities may be
used as a rapid screening tool in clinical cases suggestive of
Program and Abstracts, Child Neurology Society
38. Phenylbutyrate Modulates Multiple Neuronal
Survival Gene Expression in SMA Cells
Ganta M, Grzeschik SM, Heavlin WD, Wang CH
(Stanford, CA)
Spinal muscular atrophy (SMA) is a motor neuron disease
caused by mutations of the survival motor neuron (SMN1)
gene and decreased SMN protein production. Sodium phenylbutyrate (SPB) has been shown to increase SMN expression in SMA fibroblasts. In animal studies, SPB and its prodrugs increase the survival of SMA mice without affecting
their Smn gene expression. SPB treatment increases antioxidant and anti-apoptotic gene expressions in mouse models
of Huntington’s disease and ALS. Therefore, SPB may exert
its clinical functions through multiple gene modulations. In
this study, we investigate the effects of SPB treatment on
SMN2 and several genes related to oxidative stress and cellular apoptosis using cultured lymphocytes derived from
SMA patients. Eighteen lymphoblastoid cell lines established
from 15 SMA patients (4 type I, 5 type II and 5 type III)
and 4 controls were treated with SPB in six concentrations
and over three time points. RT-PCR and quantitative densitometry were used to measure SMN mRNA species and
other gene products. SPB treatment resulted in dosedependent and time-related increases in SMN full-length to
truncated mRNA ratios. SPB treatment also resulted in significant increases in the expression of glutathione-Stransferase (Gstm3) and manganese superoxide dismutase
(MnSOD) genes. Fas-activated death domain-like apoptosis
regulator (Cflar) and protein kinase C (PKC) genes were significantly down-regulated. Changes in proteasome subunit a
type3 (Psma3) and caspase 9 did not reach statistical significance. These findings suggest that therapeutic efficacy of
phenylbutyrate may result from both increase in SMN2 gene
expression and up-regulation of cellular antioxidant defense
39. Clonidine in ADHD Treatment- Efficacy and
Safety Outcomes
Vierhile, A, Palumbo D, Sallee FR, Pelham W, Bukstein O,
McDermott M, Daviss WB, CAT Study Group
(Rochester, NY; Cincinnati, OH; Buffalo, NY;
Pittsburgh, PA)
Attention Deficit Hyperactivity Disorder (ADHD) is one of
the most common neurobehavioral disorders of childhood.
Methylphenidate and clonidine are commonly used treatments for ADHD, alone and in combination, yet little safety
and efficacy data have been available. Therefore, we conducted an NIH-funded, multi-center, double-blind, placebo
controlled study to determine safety and efficacy of clonidine
alone and in combination with methylphenidate, in treating
children with primary ADHD.
In a 16 week trial, 122 children with ADHD (ages 7-12
years) were randomly assigned to receive clonidine alone,
methylphenidate alone, both medications or placebo. We
compared groups regarding response rate and adverse events.
Overall, subjects receiving methylphenidate (either with
clonidine or alone) reported the greatest improvement in
their ADHD symptoms on the ASQ-T (Conners Abbreviated Symptom Questionnaire for Teachers). Those subjects
on clonidine faired better than those not receiving clonidine,
but the results were not statistically significant. Adverse
events of at least moderate severity were reported more often
in patients taking clonidine with somnolence and fatigue being the common complaints. There was a greater drop in
Annals of Neurology
Vol 60 (suppl 3)
heart rate from baseline to week 16 in groups on clonidine,
but no significant ECG changes or other cardiovascular outcomes. There were no interactions between clonidine and
methylphenidate in cardiovascular outcomes.
In conclusion, clonidine, used either in conjunction with
methylphenidate or alone, is generally well tolerated and safe
for children with ADHD and should be considered as a
treatment option.
40. Survival Motor Neuron Protein (SMN) Depletion
in Neuronal Cells by siRNA Inhibition: An In Vitro
Model for SMA
Acsadi, G, Xingli L, Roumen A, Loeb J, Dombkowski A
(Detroit, MI)
Genetic defects in the telomeric survival motor neuron (SMN)
gene are responsible for lower motor neuron death in spinal
muscular atrophy (SMA). SMN protein is a component of
RNA processing complexes, as well as axonal cones. SMN may
affect the growth and pathfinding of axons however, the process by which this occurs is not yet clear. Objective: To study
the molecular effects of SMN loss in neuronal cell cultures
with particular emphasis on axon functions and apoptosis.
Methods: We developed an in vitro neuronal culture system
for studying the effect of SMN loss on survival, apoptosis and
axonal functions of cells. We utilized a mouse cell line (NSC34), which resembles developing motor neurons. The SMN
expression of NSC-34 cells was lowered by small interfering
RNA (siRNA) technology. Differential expression profiling
was obtained by a mouse oligonucleotide array (Agilent). Results: Up to 55-70 % drop in SMN protein was observed at
96 hours after transfection of siRNA. We identified significant
changes in gene expression of 394 genes affecting various cell
functions (cell cycle and proliferation). There was a marked
change in the mRNA levels of some axonal proteins (e.g. dynactine and tubulin). Conclusion: An in vitro system for
studying the functions of SMN protein has been developed
and used successfully to study the molecular consequences of
reduced SMN levels in neuronal cells. Early alterations in cell
cycle and some axonal genes have been recognized. Further
validation of these data is necessary in anterior horn cells of
SMA animal models.
41. Frontal Dopaminergic Abnormality in Tourette
Syndrome: A Postmortem Analysis
Yoon D, Gause C, Leckman J, Singer H (Baltimore, MD
and New Haven, CT)
Although the precise neurobiological mechanism underlying
Tourette syndrome (TS) remains elusive, cortico-striatothalamo-cortical circuits have been hypothesized as the site of
neuropathic localization. There is expanding evidence to suggest a cortical dysfunction in TS including neuropsychological and motor testing, oculomotor paradigms, and nuclear
imaging studies. Our goal was to confirm a frontal abnormality by analyzing multiple postmortem brain regions in TS
subjects and their matched controls.
Postmortem tissue samples from frontal (BA4, 6, 9, 10,
11, and 12) and occipital (BA17) regions were obtained from
three individuals with TS (two males ages 29 and 35 and a
female age 63, all with childhood onset) and three age- and
sex-matched controls. Samples were analyzed by semiquantitative immunoblotting with advanced volumetric/densitometric measurements of dopamine (D1, D2), serotonin
(5HT-1A) and alpha-adrenergic (␣-2A) receptors, the dopamine transporter, a monoamine terminal marker (vesicular
monoamine transporter type 2, VMAT-2), and vesicular
docking and release proteins (VAMP-2, synaptotagmin,
SNAP-25, syntaxin, synaptophysin). Data from each TS
sample was calculated as a percentage of its control.
A dopaminergic abnormality was identified in all three TS
subjects with increases (greater than 130% of its matched
control) in DAT, D1DR, and D2DR. ␣-2A protein density
was also increased in several frontal regions.
Dopaminergic fibers arise from the ventral tegmentum
and innervate the frontal cortex, exciting pyramidal neurons
and inhibiting interneurons. Our data support the hypothesis
of a dopaminergic dysfunction in the frontal lobe and a
likely role in the pathophysiology of TS.
42. Use of fMRI to Identify Regional Activation of
Cerebral Cortex Involved in Successful Performance of
an Incidental Verbal Memory Task by Children
Maril A, Davis PE, Saygin ZM, Koo J, Mulkern RV,
Waber DP, Rivkin MJ (Boston, MA)
Functional magnetic resonance imaging (fMRI) has been used
effectively to study long term memory in adults. Little investigation has been conducted in children. We employed a subsequent memory fMRI experimental design to study 18 children (ages 7-18 years;2 males; all right-handed) who
performed an incidental verbal memory encoding task. While
in the scanner, children were simultaneously presented pairs of
concrete nouns auditorally with pictures depicting them. For
each noun pair, subjects were to replace the first phoneme of
the second word with the first phoneme of the first word to
yield a specific target concrete noun. After the scan, a surprise
recognition test was given in which target words presented one
at a time were intermixed with foils. Subjects rated each word
as “remembered” or “new”. fMRI data were analyzed for simple task performance and for words remembered using
SPM99. Task performance compared to rest generated increased blood oxygenation level dependent (BOLD) signal in
left prefrontal cortex, supplementary motor cortex, insula, left
parietal lobe, and bilateral occipital cortex. The fMRI map for
target words remembered compared to words forgotten consisted of a left lateralized network of BOLD activation in left
pallidum, left hippocampus/parahippocampus and left parietal
lobe. These data demonstrate a left hemisphere dominant neural network associated with incidental verbal memory encoding in children. While structures associated with verbal encoding in adults, such as left hippocampus and parahippocampus
are also activated in children, children appear to recruit other
loci, such as left subcortical gray matter, for successful incidental verbal encoding.
43. Functional Neuroimaging of Irony Comprehension
in Children with Autism: Role of Medial Frontal Gyrus
Williams DL, Kana RK, Keller TA, Minshew NJ, Just MA
(Pittsburgh, PA)
Background: Comprehension of irony requires common
ground between speaker and addressee in shared beliefs and
knowledge. For example, in the story, Tom and Mike planned
to go on a picnic. In the morning it was raining very hard. Tom
said, “Great weather for a picnic,” the reader must recognize
that the speaker’s mental state differs from the literal interpretation of the statement he makes, a process that may rely on
‘theory of mind’. Several neuroimaging studies have suggested
the role of medial frontal regions in processing theory of
mind, and the hypoactivation of these regions in autism. Objective: Compare activation of brain areas involved in dis-
course processing and theory of mind in individuals with autism and matched controls. Methods: 12 high functioning
children with autism and 12 age and IQ matched control participants read brief stories that concluded with either a literal
or ironic statement made by one of the characters in the story
during fMRI. Results: Behavioral data showed that the participants with autism performed more poorly than controls on
the ironic sentences, but not on the literal sentences. In the
fMRI data, when the processing of ironic utterances was compared to processing of literal utterances, the participants with
autism showed reliably lower activation than the controls in
left medial frontal cortex, right insula and left supramarginal
gyrus. Conclusion: The autism group had less activation in
areas involved in integrative aspects of sentence processing and
in areas involved in ‘theory of mind’.
Source of Funding: NICHD/NIDCD
DOI: 10.1002/ana.11480
Friday, October 20, 2006
3:30 – 5:30 pm
44. Clinical and Radiographic Features of Thrombosis
Propagation in Neonatal and Childhood Cerebral
Sinovenous Thrombosis
Moharir M, Shroff M, MacGregor D, Adams M,
Bharucha P, deVeber G (Toronto, Ontario, Canada)
Background: Cerebral sinovenous thrombosis (CSVT) is increasingly encountered in neonates and children. Adults with
CSVT are treated with anti-coagulants (ACTs) to prevent
thrombus propagation and improve outcome. ACTs are not
offered to most neonates and many children due to lack of
clinical trials. The effects of no treatment on the acute thrombotic process are unknown. Aim: To study the clinical and
radiographic features of thrombus propagation in neonatal and
childhood CSVT. Methods: We conducted a consecutive cohort study of neonates (0-28days) and non-neonates (29 days18years) with CSVT diagnosed by CT venography
(CTV)/MR venography (MRV) from 1992-2005. Patients
without contraindications received standardised anticoagulation based on published institutional protocols. Monitoring
CTV/MRV was performed in untreated patients at 5days. A
study neuroradiologist assessed extent of thrombosis on initial
& each follow-up neuroimaging study and documented propagation or recanalization. Results: CSVT propagation occurred in 10/40 (25%) neonates and 7/22 (32%) nonneonates who were initially untreated, compared to only 1/28
(3%) neonates (p⫽0.04) and 3/55 (5%) non-neonates
(p⫽0.006) who were initially treated. Mean duration from
CSVT diagnosis to propagation was 4days in neonates and
7days in non-neonates. The commonest site of propagation
was superior sagittal sinus (70%). Propagation was asymptomatic in 11/11(100%) neonates and symptomatic in 5/10
(50%) non-neonates. Propagation was associated with new venous infarction in 1/11 (9%) neonates and 4/10 (40%) nonneonates. Conclusions: If untreated, 25% neonates and 32%
older children with CSVT propagate their initial thrombus.
Program and Abstracts, Child Neurology Society
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