Evidence of Morphologic Differences in Children with Down Syndrome who Develop Infantile Spasms. Nicholas Phillips1,3 , Asim Choudhri2, James Wheless1, Namrata Shah1, Zoltan Patay3. 1. Le Bonheur Neuroscience Institute, Department of Pediatric Neurology, University of Tennessee, Memphis TN 2. Department of Neuroradiology, Le Bonheur Children’s Hospital, University of Tennessee, Memphis TN 3. Department of Radiological Science, St. Jude Children’s Research Hospital, Memphis, TN nphillips@uthsc.edu ABSTRACT Infantile spasms is the most frequent epilepsy syndrome in children with Down Syndrome. Compared to their cohorts with Infantile Spasm, Down Syndrome children have better seizure control. Additionally, early initiation of treatment has been demonstrated to contribute to better developmental outcomes and prevention of late seizure development. In this study we examined the hippocampal volumes and morphology of children with Down Syndrome and Infantile Spasms compared to other children with Down Syndrome to determine if hippocampal differences were present at onset of disease and if hippocampal dysmorphology was more predominant in the Down Syndrome group. Twelve subjects were included in this study. Six patients had diagnosis of DS with IS and six patients had a diagnosis of IS without DS. Four IS without DS patients were classified as cryptogenic and two as symptomatic. Each group contained 3 males and 3 females. Hippocampal volumes were significantly lower in the DS with IS group (p = 0.0046). And hippocampal malrotation was more likely to be present in DS with IS group (p=0.0361). Introduction Infantile Spasms in Down Syndrome Down syndrome (DS) is the most common genetic cause of mental retardation1. The prevalence of epilepsy in children with DS is higher than the general population, but lower than in other causes of mental retardation. Seizure onset is reported to occur within a year of birth in 40% of epileptic DS. A majority of these patients will suffer from Infantile Spasms (IS). Often IS with DS can be attributed to secondary lesions however many lack any identifiable risk factors2. Most neuroimaging studies have demonstrated global brain volume reduction and disproportionate reduction in the cerebellum, brainstem, frontal lobe and hippocampus3. Interestingly, among mental retardation syndromes, only DS exhibits hippocampal dysfunction. Additionally, studies of DS children, demonstrate that these low hippocampal volumes are not attributed to neurodegenerative changes, but likely are due to early developmental differences. However no definitive study of hippocampal structures of DS with IS patients has been conducted to date. We hypothesized that DS with IS patients would have abnormal hippocampal volumes and morphology compared to IS patients without DS. Methods Subjects 12 subjects were included in this study 6 had diagnosis of IS with DS (age 1.07 +/- 0.65) 6 had diagnosis of IS without DS (age 1.05 +/- 1.00) 4 IS without DS were classified as cryptogenic 2 IS without DS were classified as symptomatic Each group contained 3 males and 3 females. An IRB approved retrospective cohort study was conducted to evaluate hippocampal rotation and volumes in patient with DS with IS, and symptomatic and cryptogenic IS without DS. Controls were matched for age and gender. Data Analysis Axis of rotation and volume was assessed on coronal thin section STIR, with secondary confirmation using sagittal T1 and coronal FLAIR by a board certified pediatric neuroradiologist blinded to the diagnosis. Volume loss and axis of rotation were scored in using a 4 point Likert scale (0 normal, 1 mild, 2 moderate, 3 severe)4. Intrasubject asymmetry in shape, volume and signal intensity was also evaluated. Continuous variables were compared with a 2-tailed t-test. Discrete variables were compared using a Fisher's exact test. Results Hippocampal Volume Loss Hippocampal Rotation Abnormality Present Present Group Yes No Group Yes No IS with DS 12 0 IS with DS 10 2 IS no DS 5 7__ IS no DS 4 8__ Twelve subjects were included in this study. Six patients had diagnosis of DS with IS ( age 1.07 years +/- 0.65) and six patients had a diagnosis of IS without DS (age 1.05 years +/- 1.00). Four IS without DS patients were classified as cryptogenic and two as symptomatic. Each group contained 3 males and 3 females. Hippocampal volumes were significantly lower in the DS with IS group (p = 0.0046). And hippocampal malrotation was more likely to be present in DS with IS group (p=0.0361). 2a. 2b. Figure 2. This figure demonstrates the differences in hippocampal morphology. (a) Coronal FLAIR imaging of subjects with Down Syndrome and Infantile Spasms demonstrating significant malrotation and volume loss compared to (b) this STIR image of a subject with Infantile Spasms without Down Syndrome. Discussion This study reviewed the hippocampal structures of 12 subjects diagnosed with Infantile Spasms. We were able to demonstrate in this retrospective cohort study, that children with Down Syndrome and Infantile Spasms have morphologically different hippocampi compared to children with Infantile Spasms without Down Syndrome. These findings may be a demonstration of reported immunohistological evidence of pathologic changes in the GABAergic interneurons in all hippocampal subregions in Down Syndrome patients who suffer from Infantile Spasms5. 1. Hippocampal Volume Loss None Mild Moderate Severe 0 1 2 3 ______ Subject 1 __ __ __ __ Subject 2 __ __ __ __ Subject 3 __ __ __ __ __________________________________________________________________________________________ References 1. Arya R., Kabre M., Gulati S., Epilepsy in Children With Down Syndrome. Epileptic Disorders 2011;13(1):1-7 2. Carmant L., Infatile Spasms. Arch Neurol. 2002;59:317-318 3. De Wit MCY., et al., Cortical Brain Malformations. Arch Neurol. 2008;65,(3):358-366 4. Likert R., A Technique for the Measurement of Attitudes. Arch Psych. 1932;140:1-55 5. Pennington BF., et al., The Neuropsychology of Down Syndrome: Evidence for Hippocampal Dysfunction. Child Development 2003;74(1):75-93 Figure 1. This figure is an exampled of the Likert item used for this study. The neuroradiologist (the respondent) is asked to evaluate according to a subjective criteria and the level of agreement or disagreement is measured. The Likert scale is the sum of responses on several Likert items.