Department of Neurology American Academy of Neurology 2013

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Abstracts – American Academy of Neurology 2013

These abstracts represent selected research presented by Boston Children’s Hospital at the American Academy of Neurology in 2013 (San Diego, March 16 to 23).

Headache

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[S25.006] Factors Influencing the Ordering of MRI Studies in Pediatric Patients with Headache from Two Medical Home/Community Health Center Populations: Costs and Outcomes

David Urion, Boston

OBJECTIVE: To evaluate factors influencing ordering of MRI studies in pediatric patients with headache in 2 urban medical home environments.

BACKGROUND: A previous report examined access to pediatric neurology care in two urban medical home environments, using co-located (on-site) v. hospital-based consultations. That report demonstrated that a co-located model was superior in 1) time to new appointment, 2) kept appointment rate (new and return), 3) use of the ED, and 4) rates of hospitalization. This led to an 8-fold difference per annum per patient for overall neurologic costs in a patient population usually considered challenging in terms of containing costs and improving outcomes .

DESIGN/METHODS: Records of the two cohorts were reviewed for all patients with diagnoses related to headache. Ordering of MRI, visits to the ED, MRI results, and charges for office visits, ED visits, and MRI studies were tabulated.

RESULTS: The co-located care model had 173 cases of headache over the 5-year study period, the traditional referral model 169. The co-located care cohort generated 17 visits to the ED over this period, the traditional cohort 306. This produced a substantial differential in cost of care. The co-located group saw 5 MRI studies ordered, all from ED visits. The traditional care model saw 102 MRI studies generated: 89 from ED visits, 10 by neurology providers , and 3 by primary care providers. All MRI studies were devoid of significant pathological findings in both groups.

CONCLUSIONS: A co-located care model contained costs significantly, used ED resources less often, and was associated with no difference in diagnostic outcome. The chief source of MRI studies ordered were not PCP offices, but rather the ED. A model of care which keeps this cohort of patients from ED utilization for a chronic health problem was thus associated with cost reduction without adverse effects on outcome.

[P02.098] Ictal Vasoconstriction of the Left Middle Cerebral Artery on Magnetic Resonance Angiography in Pediatric Confusional Migraine: A Case Series of Five Patients

Karen Spencer, Boston, Mark Schomer, Boston, Anna Minster, Newton, MA

OBJECTIVE: To demonstrate several cases of confusional migraines in children that were associated with ictal vasoconstriction in the left middle cerebral artery territory on MRA.

BACKGROUND: Confusional migraines are a relatively uncommon presentation of migraines in pediatrics. We present five cases of confusional migraine, all of whom had MRI and MRA imaging during the ictal event. All five cases demonstrated vasoconstriction in the L MCA territory. Two of these cases had post-ictal imaging, which demonstrated resolution of the vasoconstriction within 24 hours of the event. A few case reports have demonstrated similar phenomena in the past, but this is the first to document both ictal and post-ictal findings.

DESIGN/METHODS: Case series.

RESULTS: Five patients, aged 7-17 years, presented to a tertiary care center with confusional migraines. Symptoms consisted of a headache followed by impaired comprehension, and dysfluent speech as well as amnesia surrounding the event. Two of the five patients also had associated right-sided weakness and paresthesias. On neurological examination, all patients demonstrated varying degrees of impaired comprehension and dysfluent speech, with one of the five patients demonstrating an UMN pattern of weakness of her right side. All five patients received an MRI and MRA during the event, which demonstrated decreased caliber of the left MCA. All patients had resolution of their symptoms in less than twenty-four hours. Two patients received follow-up imaging immediately following the event, which demonstrated resolution of the vasoconstriction.

CONCLUSIONS: Our cases demonstrate vasoconstriction in the L MCA territory during a confusional migraine. Vasoconstriction has also been described in some case reports of hemiplegic migraines, lending further credence to the relationship between hemiplegic and confusional migraines. These cases reinforce the role of neurovascular changes in the pathophysiology of migraines.

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Autism

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[S15.001] Autistic-Like Behavior and Cerebellar Dysfunction in Purkinje Cell Tsc1 Mutant Mice

Peter Tsai, Boston, Court Hull, Boston, YunXiang Chu, Cambridge, MA, Wade Regehr, Boston, Mustafa Sahin, Boston

OBJECTIVE: The contribution of cerebellar dysfunction to autism pathogenesis is unclear. Utilizing a mouse model of Tuberous Sclerosis Complex, we investigated the cerebellar contribution to autism.

BACKGROUND: Autism spectrum disorders are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Although implicated in these disorders, the contribution of cerebellar dysfunction to autism remains unclear. Tuberous Sclerosis is a genetic disorder associated with high rates of comorbid autism.

DESIGN/METHODS: Methods: We generated mice lacking Tsc1, one of the genes mutated in Tuberous Sclerosis, in cerebellar Purkinje cells.

RESULTS: Homozygous, but not heterozygous, loss of Tsc1 in Purkinje cells resulted in increased neuronal stress, Purkinje cell loss, and motor deficits. However, both heterozygous and homozygous mutant animals displayed autistic-like behaviors, including abnormal social interaction, repetitive behavior, and abnormal vocalizations, in addition to decreased Purkinje cell excitability. Treatment of mutants with the mTOR inhibitor, rapamycin, prevented both pathological and behavioral deficits.

CONCLUSIONS: These findings demonstrate novel roles for Tsc1 in Purkinje cell function and define, for the first time, a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

[S15.003] Identification of Distinct Network Topology and Resilience Features in Tuberous Sclerosis and Autism

Jurriaan Peters, Boston, Maxime Taquet, Louvain-la-Neuve, Belgium, Shafali Jeste, Los Angeles, CA, Iván Sánchez Fernández, Boston, Charles A. Nelson, Boston, Jacqueline Tan, Amsterdam, Netherlands, Mustafa Sahin, Boston, Simon Warfield, Boston

OBJECTIVE: To study brain functional networks of electroencephalographic (EEG) connectivity through graph measures, in patients with Tuberous Sclerosis Complex (TSC) with and without autism spectrum disorder (ASD), and in patients with non-syndromic ASD.

BACKGROUND: Graph theory can characterize complex brain networks, making it highly suitable to investigate altered connectivity in neurologic disorders. There is mounting evidence for a current model of ASD as a developmental disconnection syndrome. However, the effects of abnormal connectivity on network properties have not been well studied.

DESIGN/METHODS: EEG data were collected from TSC patients with ASD (n=14) and without ASD (n=29), from patients with non-syndromic ASD (n=16), and from controls (n=46). EEG connectivity was characterized by the mean coherence, the ratio of inter- over intrahemispheric coherence and the ratio of long- over short-range coherence. Next, graph measures and resilience analysis were computed of the functional networks. To distinguish effects related to ASD from those related to TSC, a two-way ANCOVA with age as a covariate was applied.

RESULTS: Analysis of network properties revealed differences specific to TSC and ASD, and these differences were very consistent across subgroups. In TSC, regardless of the diagnosis of ASD, mean coherence, global efficiency, and clustering coefficient were decreased and the average path length was increased. These findings indicate an altered network topology. In ASD, both with and without a concurrent diagnosis of TSC, decreased long- over short-range coherence and markedly increased network resilience were found.

CONCLUSIONS: The altered network topology in TSC represents a functional correlate of structural abnormalities, and may play a role in the pathogenesis of neurological deficits. The increased resilience in ASD may reflect an excessively degenerate network with local overconnection and decreased functional specialization. This joint study of TSC and ASD networks provides a unique window to common neurobiological mechanisms in autism.

[P02.100] Atypical Face Processing in Children with Tuberous Sclerosis Complex

Shafali Jeste, Los Angeles, Sanjay Prabhu, Boston, MA, Matt Gregas, Boston, Mustafa Sahin, Boston, Charles Nelson, Boston

OBJECTIVE: In this study, we investigated the neural correlates of face processing in children with Tuberous Sclerosis Complex (TSC).

BACKGROUND: We focused on face processing for two reasons. First, there is an extensive literature on atypical face perception in ASD. Secondly, face processing represents a construct that requires a combination of low-level and higher-order visual processing, each of which could be impaired in TSC given the aberrant structural connectivity in visual projections shown in the TSC mouse model.

DESIGN/METHODS: We studied 19 children with TSC under age 4 and 20 age matched controls using an event related potential paradigm of familiar-unfamiliar faces. Six children with TSC (32%) had ASD. Components of interest included the temporal-occipital P1, N290 and P400. A repeated measures analysis of variance was performed with amplitude and latency as dependent variables. Groups analyzed included: (1) Controls; (2) TSC; (3) TSC/ASD; (4) TSC/no ASD; (5) TSC with temporal lobe tubers; (6) TSC with occipital lobe tubers.

RESULTS: There was a main effect of diagnostic group for the N290 latency, with the TSC group showing a longer N290 latency than controls (276 msec vs. 259 msec; p=0.05). There was also a region by group interaction (F=3.63, p=0.04), with the TSC group failing to show the expected hemispheric differences in face processing. On subgroup analysis, the longest N290 latency was seen in (1) children with ASD/TSC and (2) children with temporal lobe tubers, regardless of ASD diagnosis.

CONCLUSIONS: These promising results demonstrate that children with TSC are slower to process faces, and they lack the hemispheric specialization seen in typical development. We also identify slower face processing in children with TSC and ASD. Here, we have begun to define an electrophysiological biomarker of a perceptual domain critical for normative social development, with the ultimate goal of defining functional pathways to ASD in TSC. Supported by: American Academy of Neurology Clinical Research Training Fellowship: Understanding Neural Correlates of Autism in Children with TSC; DOD CDMRP TSCRP: Characterizing early signs of autism in infants with Tuberous Sclerosis Complex (TSC).

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Epilepsy

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[P03.012] Clinical Characteristics and Treatment Strategies in Refractory Convulsive Status Epilepticus in Children: Results from the Pediatric Status Epilepticus Research Group (pSERG)

Iván Sánchez Fernández, Boston, Nicholas Abend, Philadelphia, Satish Agadi, Houston, Sookee An, Boston, Ravindra Arya, Cincinnati, OH, Jessica Carpenter, Washington, DC, Kevin Chapman, Aurora, CO, William Gaillard, Chevy Chase, MD, Tracy Glauser, Cincinnati, OH, Howard Goodkin, Charlottesville, VA, Mohamad Mikati, Durham, NC, Katrina Peariso, Cincinnati, OH, Sriram Ramgopal, Boston, Margie Ream, Durham, NC, Tobias Loddenkemper, Boston

OBJECTIVE: To describe the clinical characteristics and treatment approach of refractory convulsive status epilepticus (RCSE) in children.

BACKGROUND: There is insufficient literature on the different treatment regimens for pediatric RCSE.

DESIGN/METHODS: We performed a prospective multicenter study and enrolled children with RCSE from 7 different reference hospitals in the United States from June 2011 to September 2012, inclusive. We included all patients with: 1) Status epilepticus (SE) with a convulsive onset, 2) age 30 days to 21 years, and 3) Refractory to, at least, 2 different antiepileptic drugs (AEDs) (benzodiazepines not administered as a continuous infusion was one medication), or required at least one continuous infusion of AEDs.

RESULTS: Forty patients (23 males) ranging in age from 0.2 to 17.7 (median: 2.6) years met our inclusion criteria. At onset, the CSE was continuous (35%) or intermittent seizures without return to baseline (60%). Baseline medical conditions were developmental delay (42.5%), epilepsy (37.5%), prior episode of SE (20%) and cerebral palsy (7.5%). The etiology of SE was structural (22.5%), metabolic (12.5%), genetic (7.5%) and unknown (57.5%). The median (interquartile range) time in minutes from seizure onset to: 1) first AEDs was 17.5 (5-65.3) 2) first non-benzodiazepine was 60 (30-112.5), 3) second non-benzodiazepine was 96 (75.5-322.5), and 4) end of the convulsive status epilepticus was 120 (71.3-207). The AEDs were: 1) first: lorazepam (40.4%), diazepam (19.2%), midazolam (11.5%); 2) first non-benzodiazepine: fosphenytoin (38.5%), phenytoin (17.3%), levetiracetam (5.8%), phenobarbital (3.8%), valproate (1.9%); 3) second non-benzodiazepine: phenobarbital (34.6%), fosphenytoin (9.6%), levetiracetam (9.6%), phenytoin (3.8%), valproate (3.8%). Continuous infusions were used in 14 patients: midazolam (12), pentobarbital (1), and propofol (1). Three patients required a second infusion with midazolam (2) and pentobarbital (1).

CONCLUSIONS: In our series, RCSE was more frequently intermittent, and of undetermined etiology. Although AEDs used followed published guidelines, the period between administration of benzodiazepines and non-benzodiazepines was prolonged. Supported by: Epilepsy Foundation of America.

[P03.015] Does the Reduction of Epileptiform Activity in Patients with Electrical Status Epilepticus in Sleep Treated with High-Dose Diazepam Persist over Time?

Iván Sánchez Fernández, Boston, Jurriaan Peters, Boston, Sookee An, Boston, Ann Bergin, Boston, Masanori Takeoka, Newton, MA, Alexander Rotenberg, Boston, Sanjeev Kothare, Boston, Blaise Bourgeois, Boston, Tobias Loddenkemper, Boston

OBJECTIVE: To evaluate whether acute reduction of epileptiform activity in patients with electrical status epilepticus in sleep (ESES) after treatment with high-dose diazepam (HDDZP) persists on longitudinal follow up.

BACKGROUND: It is currently not known whether reductions in epileptiform activity following HDDZP treatment persist.

DESIGN/METHODS: We enrolled patients with ESES on EEG(minimum spike-wave index: 50%) during eight consecutive years. Inclusion criteria: 1) age 1-21 years, 2) at least one overnight EEG, 3) treatment with HDDZP (1 mg/Kg during the first night followed by 0.5 mg/Kg/night during following nights), and 4) at least one follow-up EEG that included sleep.

RESULTS: Seventeen patients (12 males) were included and underwent 23 cycles of HDDZP treatment. Their median (interquartile range) age at the first cycle of HDDZP treatment was 7.42 (5.59-9.71) years. After 24 hours of treatment, in 15 treatment cycles, a decrease of at least 25% of epileptiform activity was noted. Eleven of these treatment cycles had an available follow-up EEG at least 3 months after treatment and 8 (72.73%) demonstrated persistent decreases in epileptiform activity while 3 (27.27%) relapsed back to baseline epileptiform activity. Nine cycles had a reduction of at least 50% at 4 months. Of the 6 treatment cycles with a minimum 6-month follow-up EEG, all 6 (100%) had persistent reduction in epileptiform activity. The treatment with HDDZP was continued over 1 month (in 4 cycles of treatment), 2 months (6), 3 months (4), 5 months (2) and was discontinued during the first week in 7 cycles. The heterogeneous follow-up schedule did not allow statistical comparisons, yet patients who responded acutely continued to have persistent response.

CONCLUSIONS: In patients with sufficient follow-up on EEG, the majority of children treated with HDDZP had a persistent reduction of spike-wave index. Acute reduction in epileptiform activity suggested persistence of this effect on longitudinal follow-up. Supported by: Iván Sánchez Fernández is funded by a grant for the study of Epileptic Encephalopathies from "Fundación Alfonso Martín Escudero

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Brain malformations

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[S25.005] Clinical, Radiological and Genetic Results in a Cohort of 50 Patients with Nonsyndromic and Syndromic Polymicrogyria

Dina Amrom, Montreal, Jacques Michaud, Montreal, Grant Mitchell, Montreal, Emmanuelle Lemyre, Montreal, Annapurna Poduri, Chestnut Hill, MA, Jennifer Partlow, Boston, MA, Vijay Ganesh, Boston, MA, Bernard Dan, Brussels, Brabant, Belgium, Giorgi Kuchukhidze, Innsbruck, Austria, Iris Unterberger, Innsbruck, Austria, Eugen Trinka, Salzburg, Austria, Nicolas Deconinck, Brussels, Brabant, Belgium, Catherine Christophe, Brussels, Belgium, Bruno Pichon, Brussels, Belgium, Francois Dubeau, Montreal, Donatella Tampieri, Montreal, Jean-Claude Decarie, MontrealWilliam Dobyns, Seattle, WA, Frederick Andermann, Hampstead, QC, Canada, Christopher Walsh, Boston, MA, Eva Andermann, Montreal

OBJECTIVE: To study the clinical, radiological and genetic data in a cohort of 50 patients with nonsyndromic and syndromic polymicrogyria (PMG).

BACKGROUND: Common clinical features of PMG include seizures, developmental delay, oromotor dysfunction and motor disabilities. PMG is a malformation of cortical development characterized by numerous small gyri that can be attributed to environmental causes, single gene disorders with various patterns of inheritance, or chromosomal rearrangements, usually sporadic.

DESIGN/METHODS: Inclusion of any type of PMG, excluding confirmed congenital CMV/toxoplasmosis. We performed detailed review of medical records; karyotype and/or CGH and/or genomic SNP microarray; and specific gene analysis when indicated.

RESULTS: We studied 46 sporadic patients and two families with two siblings each. Their PMG pattern was variable. 24/50 (48%) had associated brain malformation(s), including 5/24 nodular heterotopia , 4/24 microcephaly, 2/24 corpus callosum dysgenesis, 2/24 brainstem hypoplasia, 2/24 hemimegalencephaly, 1/24 focal cortical dysplasia, 1/24 optic chiasm hypoplasia. 10/50 (20%) had PMG as part of a syndrome. One karyotype showed a reciprocal translocation 46,XY t(8;22)(p23.1;p11.2). Of 27 CGH microarray results, 23 (85%) were normal. The detected CGH anomalies included a 22q11del, 1p36del, a 2p21del of unknown significance, and a 2p13.3-p16.3duplication. We fine mapped a subgroup of bilateral perisylvian polymicrogyria (BPP) patients to 2p16.1-p16.3. We identified a novel TUBB2B mutation in exon 4 in a sporadic patient with PMG and associated anomalies of the basal ganglia and brainstem; neither parent carried this mutation.

CONCLUSIONS: Polymicrogyria is markedly heterogeneous. Our results support previous suggestions of PMG loci on chromosomes 22q11 and 1p36. We have narrowed a novel locus for BPP to 2p13.1-p16.3. These data can help to identify the causative genes located in these regions. We found a novel and de novo TUBB2B mutation in a patient with complex PMG. Identification of associated brain malformations and phenotypic anomalies can help to orient the genetic diagnosis. Supported by: Children's Hospital Boston (CHB), Division of Genetics; Réseau de Médecine Génétique Appliquée, Quebec.

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