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Platform Session 3 (28Ц35).

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PLATFORM SESSION 3:
Epilepsy and Epileptic
Syndromes
Friday, October 20, 2006
3:30 – 5:30 pm
28. Simultaneous EEG and fMRI Recordings of
Childhood Absence Seizures
Novotny EJ, Berman R, Negishi M, Levy SR, Constable RT,
Blumenfeld H (New Haven, CT)
Introduction: Absence seizures consist of brief 5-10 s episodes of unresponsiveness, associated with a 3-4 Hz spikewave discharges on EEG. The fundamental mechanisms of
impaired attention in childhood absence epilepsy (CAE) are
not known. By understanding the fundamental mechanisms
and brain regions crucial for impaired attention in this patient population, new treatments may be developed. Methods: We propose using simultaneous EEG and functional
MRI (EEG-fMRI) in children with typical absence seizures
on and off medication. Simultaneous EEG-fMRI data was
acquired using a 3T MR system with continuous EPI BOLD
sequence. EEG artifact was removed by post-processing using
temporal PCA-based gradient noise removal. fMRI data during seizure and baseline intervals was analyzed using SPM2.
Results: We tested 13 patients with CAE of which 3 had
seizures during scanning and obtained a total of 11 seizure
episodes (4-12 sec) during 4 sessions. We found significant
ictal BOLD signal increases in bilateral thalamus. Moderate
increases were also seen in the cingulate, lateral frontal, and
parietal cortex. Decreased BOLD signal was present in the
retrosplenial cortex, and to a lesser degree in the bilateral
frontoparietal cortex. Patients most commonly showed significant fMRI increases in the bilateral anterior frontal cortex, anterior cingulate, dorsolateral frontal and parietooccipital cortex, left fusiform gyrus, bilateral medial
thalamus, upper brainstem, and cerebellum. Conclusions:
These results demonstrate the feasibility of obtaining high
quality EEG-fMRI during individual absence seizures in children and support the hypothesis that absence seizures may
involve specific thalamocortical networks.
29. Alpha-methyl-L-tryptophan Positron Emission
Tomography (AMT-PET) Predicts Surgical Outcome in
Children with Intractable Neocortical Epilepsy
Sundaram S, Chugani D, Munian Govindan R, Asano E,
Juhasz C, Chakraborty P, Muzik O, Sood S, Chugani HT
(Detroit, MI)
Objective: Accurate pre-operative localization of epileptogenic cortex in neocortical epilepsy is essential to improve
surgical outcome. We assessed whether PET scanning with
[11C]methyl-L-tryptophan (AMT) can predict surgical outcome. Methods: 31 children (23 males, age: 9 months – 16
years) with intractable epilepsy of neocortical origin underwent AMT-PET scans prior to resective epilepsy surgery. All
patients also underwent standard pre-surgical evaluation.
MRI was normal in 12 patients. Patients were divided into
AMT positive (n⫽16) and AMT negative (n⫽15) groups
based on whether there was focal cortical increase of AMT
uptake. Areas of increased AMT uptake were marked objectively as regions with abnormal asymmetry using in-house
written software, and AMT uptake ratios (AMT uptake in
lesion/ AMT uptake in normal homotopic cortex) were calculated. Mann-Whitney test was used to compare outcomes
between AMT positive and AMT negative groups. Results:
The mean follow-up period is 22⫹/-5 (Mean ⫹ SD)
months. Mean AMT uptake ratio in the AMT positive
group was 1.15 ⫹ 0.05 (Mean ⫹ SE). Mean Engel scores in
AMT positive and negative groups were 1.6 ⫹ 0.26 (Mean
⫹ SE) and 2.6 ⫹ 0.29 (Mean ⫹ SE) respectively. Surgical
outcome in the AMT positive group was significantly better
than in the AMT negative group (p ⫽ 0.013). Conclusions:
Children with positive AMT-PET scans have better surgical
outcome compared to children with negative AMT scans.
Presumably, this is because of improved localization of the
epileptic focus with AMT PET and guidance of intracranial
electrodes placement to define the epileptogenic zone to be
resected.
30. Children With Focal Seizures May not have the
Primary Motor Cortex for the Hand in the Precentral
GY
Haseeb A, Asano E, Shah A, Juhasz C, Sood S, Chugani HT
(Detroit, MI)
Objectives: Using functional cortical mapping in children
with focal seizures evaluated for epilepsy surgery, we determined whether the primary motor cortex for the hand is
most frequently located in the precentral gyrus. Methods: 55
children with focal seizures aged between 1 year and 19 years
were studied. Patient selection criteria: Subjects underwent
an initial two-stage epilepsy surgery using chronic subdural
EEG monitoring; both intraoperative pictures of brain surface and three-dimensional reconstructed MR images demonstrated a well-defined central sulcus (Talairach and Tournoux, 1988; Yousry et al, 1997); and subdural electrodes
were placed on the pre- and post-central gyri at least 4 cm
above the Sylvian fissure. As a part of presurgical evaluation,
a pair of subdural electrodes was electrically stimulated with
a stimulus frequency of 10Hz. The stimulus intensity was
increased from 6.5 to 16.5mA in a stepwise manner by 5mA.
A brain region with the contralateral hand movement induced by the lowest-intense electrical stimulation was defined as the primary motor cortex. Results: Contralateral
hand movement was induced without afterdischarges in 37
children but not in the remaining 18 children. The MannWhitney test revealed that failure to induce contralateral
hand motor movement was associated with younger age of
subjects (p⬍0.001). The primary motor cortex was confined
to the precentral gyrus in five children (13%), confined to
the postcentral gyrus in 11 children (30%), and located to
both the pre- and post-central gyri in the remaining 21 children (57%). Conclusions: Age is an important factor to determine the success rate of functional motor mapping. Our
study failed to support the generally accepted notion that the
primary motor cortex is most frequently confined to the precentral gyrus. Whether the common involvement of the
postcentral gyrus is due to motor reorganization associated
with epileptic foci, or it represents a normal variation, remains to be determined. Positive motor response associated
with electrical stimulation of the postcentral gyrus is consistent with the observations that TMS-induced electrical current running posterior-anterior direction most frequently induces movement of the contralateral hand.
Program and Abstracts, Child Neurology Society
S137
31. The Acute and Long Term Efficacy of the Novel
AMPAR Antagonist Talampanel in a Model of Neonatal
Seizures
Aujila P, Straw E, Fetell M, Jensen F (Boston, MA and
TEVA Pharmaceuticals)
33. Isolated Language Regression is Strongly
Associated With Electrographic Status Epilepticus in
Sleep
Trevathan E, Ekinci O, Reed N, Zempel J, Thio LL,
Wong M, Isik U, Gurnett, C, Arnold S (St. Louis, MO)
Neonatal seizures as a complication of hypoxic/ischemic encephalopathy can be refractory to conventional AEDs. We
have previously shown that antagonists of the AMPA subtype of glutamate receptors are effective in suppressing seizures and preventing long term epileptogenic effects. AMPAR antagonist efficacy may in part be due to the
overexpression of AMPARs on neurons in the perinatal
brain. Here we tested a novel agent talampanel (GYKI
53773) that is currently in AED Phase II trials in older children and adults. Using a model of hypoxia-induced seizures
in the postnatal day (P) rat, we evaluated the dose-dependent
efficacy of talampanel on acute seizure activity and on secondary increases in status-induced neuronal injury in later
life (P31). Talampanel (1, 5, 7.5, and 10 mg/kg) or vehicle
were administered prior to 15 min global hypoxia (4-6%
O2, n⫽10-17/group). Seizure activity was significantly reduced at 7.5 and 10 mg/kg (p⬍00.1). Following hypoxiainduced seizures at P10, rats typically show enhanced neuronal injury with a “second-hit” seizure in later life.
Importantly, the 7.5 and 10 mg/kg doses of talampanel significantly reversed this enhanced susceptibility to kainate
status-induced neuronal injury in the amygdala (p⬍0.001).
These studies suggest that talampanel may have potential as
an age-sepcific therapeutic agent in neonatal seizures. (Epilepsy Therapy Project, NS31718).
Background and Aims: We determined the factors associated with electrographic status epilepticus in sleep (ESES)
and sleep-activated epileptiform abnormalities (SAEA)
among children with autism and/or regression referred for
EEG-video studies. Methods: Data on all children who were
referred for 24- hour EEG-video monitoring from 19952005 with a question of possible ESES or SAEA were entered into a database for analysis. Senior pediatric neurologists evaluated all children at the time of admission to
determine whether children met diagnostic criteria for autism
or an autistic spectrum disorder (ASD), or if they had isolated language regression (language regression without autistic features). Results: 121 children (64% male) were referred
for EEG-video monitoring to evaluate for possible SAEA or
ESES. 56 of 121 (46%) children had language, autistic,
and/or cognitive/behavioral regression. 66 children had clinical features of autism; 13 children experienced global autistic regression. Of the 33 children with isolated language regression, 19 (58%) had SAEA and 11 (33%) had ESES.
Only 1 child with ESES did not have isolated language regression. No child with a diagnosis of global autistic regression had ESES. Isolated language regression was strongly associated with SAEA (odds ratio ⫽ 3.07; 95% CI ⫽ 1.34,
7.00) and with ESES (odds ratio ⫽ 43.5, 95% CI ⫽ 5.33,
355.1). Autistic features were not associated with ESES
(odds ratio ⫽ 0.06, 95% CI ⫽ 0.01, 0.49) and or SAEA
(odds ratio ⫽ 0.31, 95% CI ⫽ 0.14, 0.67). Conclusions:
Isolated language regression, not autism, was strongly associated with SAEA and ESES.
32. The Accuracy of aEEG in Detecting PostAsphyxial Neonatal Seizures
Cherian PJ, Swarte RM, Blok JH, Visser GH
(Rotterdam, The Netherlands)
Objective: To assess the accuracy of amplitude integrated
EEG (aEEG, CFMTM) in neonatal seizure detection in expert hands. Patients and Methods: Full term neonates with
severe birth asphyxia undergoing video-EEG polygraphy for
⬎24 hours. 14/40 babies had seizures recorded on EEG.
Eight-hour EEG segments from these 14 were scored for onset, location, amplitude and frequency of electrographic seizures by a clinical neurophysiologist. aEEG along with single
channel EEG(C3-4) of the same segments were scored independently at paper speeds of 6 cm/hour and 30 cm/hour by
a neurologist and a neonatologist, for seizures and amplitude
of the background activity. Results: A total of 412 seizures
(mean 29 per patient, range 3-144) were scored on EEG. At
6 cm/hour, aEEG showed a median sensitivity of 66%
(mean 53.6, range 0-100, PPV 56.6) for seizure detection. At
30cm/hour, the results were, 72.9% (58.2, 0-100, and 59.5)
respectively. The inter-rater agreement for seizure detection
on aEEG was moderate to good (⬃ 80% agreement for both
paper speeds). The seizures missed by aEEG were ⬍50␮V in
amplitude, involved temporo-occipital or frontal brain regions, or contained excess of EEG artefacts. Classification of
voltage of background activity by aEEG was similar in all
patients except one, at both paper speeds (100% inter-rater
agreement). Conclusions: aEEG has a relatively low sensitivity
for seizure detection in neonates, even in expert hands. However, it appears to be a reliable tool in assessing the background EEG activity which can be of considerable help in
prognostication after birth asphyxia.
S138
Annals of Neurology
Vol 60 (suppl 3)
2006
34. Utility of Prolonged (12-24 hour) EEG in Patients
Referred for Evaluation of Possible Epileptic Aphasia
Dudley-Harrell H, Holland K (Cincinnati, OH)
Objective: An overnight electroencephalogram (EEG) is often
advocated to determine if there is an underlying epileptic encephalopathy in children with autistic spectrum disorders. The
purpose of the study is to determine if an EEG documenting
transition to sleep is an adequate screen. Methods: Consecutive patients referred for evaluation of possible epileptic aphasia were identified from a database of patients who had overnight EEGs from September 2002 through October 2005.
Records were excluded if the entire EEG was not available for
review. The EEG findings during the 40 minute baseline and
transition to sleep were compared to the impression of the
entire EEG (12-24 hours). Results: Of the 266 studies performed, 32% (86) were abnormal. Abnormalities were identified on baseline EEG with transition to sleep in 81 of the 86
(94%) abnormal studies. Five patients had abnormalities identified only during full EEG. None of these patents had a history of language regression and all of their studies had brief or
isolated epileptiform discharges. Overall, the chance of missing
any abnormality with a normal baseline and transition to sleep
EEG was less than 2% (5 of 266). Twelve EEGs had findings
indicative of epileptic encephalopathy. None of these had a
normal EEG during either the baseline or the transition to
sleep. Conclusions: Based on our results, an EEG with transition to light sleep should be a sufficient screen of patients for
an epileptic encephalopathy. Prolonged studies should be reserved for cases in which the screening EEG is abnormal.
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
PLATFORM SESSION 4:
Neurogenetics and Movement
Disorders
Friday, October 20, 2006
3:30 – 5:30 pm
36. Presynaptic Dopamine D2 Receptors Selectively
Excite or Inhibit Striatal Glutamatergic
Neurotransmission
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
sec;P⬍0.001)
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
CACH/VWM.
Program and Abstracts, Child Neurology Society
S139
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