Faculty Bibliography

UNLABELLED:PET has been used for the presurgical localization of epileptic foci for more than 20 y; still, its clinical role in children with intractable epilepsy remains unclear, largely because of variable analytic approaches and different outcome measures. The purpose of the present study was to evaluate and optimize the performance (lateralization and lobar localization value of epileptic foci) of objective voxel-based analysis of (18)F-FDG PET scans in a pediatric epilepsy population. METHODS:Twenty children with intractable focal epilepsy (mean age ± SD, 11 ± 4 y; age range, 6-18 y) who underwent interictal (18)F-FDG PET, followed by 2-stage epilepsy surgery with chronic subdural electrocorticographic monitoring, and were seizure-free after surgery were included in this study. PET images were analyzed using both a visual-analysis and a statistical parametric mapping (SPM) method. Lateralization value and performance of lobar localization (in lateral and medial surfaces of all lobes, total of 8 regions in each epileptic hemisphere), calculated for 3 different statistical thresholds, were determined against intracranial electrocorticography-determined seizure-onset region and surgical resection site. RESULTS:SPM using a statistical threshold of P less than 0.001 provided 100% correct lateralization, which was better than visual assessment (90%). Although visual and SPM analyses (with both P < 0.001 and P < 0.0001 thresholds) performed similarly well (with a sensitivity and specificity of 74% or above) in the localization of seizure-onset regions, SPM detected 7 of 9 seizure-onset regions, mostly in medial cortices, that were missed by visual assessment. Also, SPM performed equally well in both hemispheres, compared with visual analysis, which performed better in the left hemisphere. No statistical difference in performance was observed between visual and SPM analyses of children with abnormal versus normal MRI findings or of children with gliosis versus developmental pathology. Clinical variables, such as age, duration of epilepsy, age of seizure onset, and time between PET and last seizure, showed no correlation with sensitivity or specificity of either visual analysis or SPM analysis. CONCLUSION/CONCLUSIONS:SPM analysis, using a young adult control group, can be used as a complementary objective analytic method in identifying epileptogenic lobar regions by (18)F-FDG PET in children older than 6 y.

The fronto-striato-thalamic circuit has been implicated in the pathomechanism of Tourette Syndrome (TS). To study white and gray matter comprehensively, we used a novel technique called Tract-Based Spatial Statistics (TBSS) combined with voxel-based analysis (VBA) of diffusion tensor MR images in children with TS as compared to typically developing controls. These automated and unbiased methods allow analysis of cerebral white matter and gray matter regions. We compared 15 right-handed children with TS (mean age: 11.6 ± 2.5 years, 12 males) to 14 age-matched right-handed healthy controls (NC; mean age: 12.29 ± 3.2 years, 6 males). Tic severity and neurobehavioral scores were correlated with FA and ADC values in regions found abnormal by these methods. For white matter, TBSS analysis showed regions of increased ADC in the corticostriatal projection pathways including left external capsule and left and right subcallosal fasciculus pathway in TS group compared to NC group. Within the TS group, ADC for the left external capsule was negatively associated with tic severity (r= -0.586, P = 0.02). For gray matter, VBA revealed increased ADC for bilateral orbitofrontal cortex, left putamen, and left insular cortex. ADC for the right and left orbitofrontal cortex was highly correlated with internalizing problems (r = 0.665; P = 0.009, r = 0.545; P = 0.04, respectively). Altogether, this analysis revealed focal diffusion abnormalities in the corticostriatal pathway and in gray matter structures involved in the fronto-striatal circuit in TS. These diffusion abnormalities could serve as a neuroimaging marker related to tic severity and neurobehavioral abnormalities in TS subjects.

BACKGROUND:Sturge-Weber syndrome (SWS) with unilateral hemispheric involvement is a clinical model of early onset, chronic, often progressive hemispheric injury, resulting in variable neuro-cognitive impairment. AIMS/OBJECTIVE:To evaluate if abnormal diffusion and metabolism of the thalamus, a central relay station with extensive cortical connections, may serve as a simple imaging marker of neuro-cognitive dysfunction in SWS. METHODS:We obtained both diffusion tensor imaging and FDG PET in 20 children (11 girls; age range: 3-12.4 years) with unilateral SWS. Diffusion parameters as well as FDG uptake were measured in thalami, compared to normal control values, and correlated with the extent of cortical hypometabolism, deep venous abnormalities and cognitive (IQ) as well as fine motor functions. RESULTS:Children with SWS had significantly higher thalamic glucose metabolic asymmetry than controls (p=0.001). Thalamic metabolic asymmetries correlated positively with the asymmetry of thalamic diffusivity (p=0.001) and also with the extent of cortical hypometabolism (p<0.001). Severe thalamic asymmetries of glucose metabolism and diffusion were strong predictors of low IQ (metabolism: p=0.002; diffusivity: p=0.01), even after controlling for age and extent of cortical glucose hypometabolism in children with left hemispheric involvement. Ipsilateral thalamic glucose hypometabolism was also associated with impairment of fine motor functions (p=0.002). CONCLUSIONS:Both diffusion and glucose metabolic abnormalities of the thalamus are closely related to cognitive functions, independent of age and cortical metabolic abnormalities, in children with unilateral SWS. Thalamic metabolic asymmetry is a robust but simple imaging marker of neuro-cognitive outcome in children with early unilateral hemispheric injury caused by Sturge-Weber syndrome.

Major frontal lobe tracts and corpus callosum (CC) were investigated in 32 children with autism spectrum disorder (ASD, mean age: 5 years), 12 nonautistic developmentally impaired children (DI, mean age: 4.6 years), and 16 typically developing children (TD, mean age: 5.5 years) using diffusion tensor imaging tractography and tract-based spatial statistics. Various diffusion and geometric properties were calculated for uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFO), arcuate fasciculus (AF), cingulum (Cg), CC, and corticospinal tract. Fractional anisotropy was lower in the right UF, right Cg and CC in ASD and DI children; in right AF in ASD children; and in bilateral IFO in DI children, compared with TD children. Apparent diffusion coefficient was increased in right AF in both ASD and DI children. The ASD group showed shorter length of left UF and increased length, volume, and density of right UF; increased length and density of CC; and higher density of left Cg, compared with the TD group. Compared with DI group, ASD group had increased length, volume, and density of right UF; higher volume of left UF; and increased length of right AF and CC. Volume of bilateral UF and right AF and fiber density of left UF were positively associated with autistic features.

The usefulness of magnetic resonance imaging tractography is demonstrated in the presurgical planning of an 8-year-old girl with intractable epilepsy. Imaging and intracranial electrode monitoring suggested a left hemispherectomy for complete control of her seizures. Although this child was hemiplegic, she retained considerable motor function in her right hand, and her parents and the epilepsy team voiced significant concern that she would lose right-hand function after a hemispherectomy. Tractography indicated near-complete absence of her left corticospinal tract and a more robust than normal corticospinal tract in the right hemisphere. This finding suggested that her right motor function had reorganized to the right hemisphere and the ipsilateral corticospinal tract. After surgery, her seizures were completely controlled, and no change in right motor activity was evident compared with her presurgical status. Tractography helped determine the extent of cortical resection and predict the extent of motor functional loss.

BACKGROUND:Multiple rare copy number variants (CNVs) including genomic deletions and duplications play a prominent role in neurodevelopmental disorders such as mental retardation, autism, and schizophrenia, but have not been systematically studied in Tourette syndrome (TS). METHODS:We performed a genome-wide screening of single nucleotide polymorphism (SNP) genotyping microarray data to identify recurrent or de novo rare exonic CNVs in a case-control association study of patients with TS. RESULTS:We identified 5 exon-affecting rare CNVs that are either de novo or recurrent in 10 out of 111 patients with TS but were not found in 73 ethnically matched controls or in the entries of the Database of Genomic Variants (containing 21,178 CNVs at 6,558 loci). Three out of the 5 CNVs have been implicated previously by other studies in schizophrenia, autism, and attention-deficit hyperactivity disorder, suggesting that these CNVs produce a continuum of neuropsychiatric disturbances that manifest in different ways depending on other genetic, environmental, or stochastic factors. CONCLUSIONS:Rare, recurrent exonic copy number variants are associated in a subset of patients with Tourette syndrome.

Previous studies in Tourette syndrome have reported lateralized abnormalities of neurotransmitters and microstructure of the cortico-striato-thalamo-cortical circuit. The authors analyzed the relationship between serotonin synthesis and microstructural changes in the subcortical structures (caudate nucleus, lentiform nucleus, and thalamus) related to this circuit, using alpha-[(11)C]methyl-L-tryptophan positron emission tomography (PET) and diffusion tensor imaging, respectively, in 16 children with Tourette syndrome. Correlations between diffusion tensor imaging and alpha-[(11)C]methyl-L-tryptophan PET asymmetry values were found in the caudate nucleus. The findings suggested higher serotonin synthesis on the side of more abnormal diffusion, characterized by lower fractional anisotropy and parallel diffusivity but higher perpendicular diffusivity. Altogether, these imaging abnormalities suggest asymmetric immature microstructure in the caudate nucleus associated with abnormally increased serotonin synthesis in Tourette syndrome. The observed diffusion tensor imaging changes are likely related to abnormal connectivity in the cortico-striato-thalamo-cortical circuit, which may result in cortical disinhibition and increased serotonin synthesis; this could provide a new therapeutic target.

Institutional rearing is associated with neurocognitive and behavioral difficulties. Although such difficulties are thought to reflect abnormal neurologic development resulting from early social deprivation (ED) and there is evidence for functional abnormality in children with histories of ED, the impact of early deprivation on brain anatomy has received little study in humans. The present study utilized an objective and sensitive neuroimaging analysis technique (Tract-Based Spatial Statistics) to evaluate white matter fractional anisotropy (FA) and diffusivity in a group of right-handed children with histories of ED (n = 17; mean age = 10.9 + 2.6 years) as compared with age-matched healthy controls (n = 15; mean age = 11.7 + or - 2.8 years). Participants underwent magnetic resonance imaging diffusion tensor imaging sequences and comprehensive neuropsychological evaluations. Results revealed reduced FA in frontal, temporal, and parietal white matter including components of uncinate and superior longitudinal fasciculi, in children with histories of ED, providing further support for limbic and paralimbic abnormalities in children with such histories. Furthermore, white matter abnormalities were associated with duration of time in the orphanage and with inattention and hyperactivity scores. It is suspected that the observed white matter abnormalities are associated with multiple depriving factors (e.g., poor prenatal care, postnatal stress) associated with institutional caregiving.

Positron emission tomography (PET) is a relatively noninvasive imaging test that is able to detect abnormalities in different organs based on derangements in the chemical functions and/or receptor expression at the cellular level. PET imaging of the brain has been shown to be a powerful diagnostic tool for detecting neurochemical abnormalities associated with various neurologic disorders as well as to study normal brain development. Although its use in detecting neurological abnormalities has been well described in adults and pediatrics, its application in the newborn nursery has not been explored adequately. Early detection of brain injury secondary to intrauterine and perinatal insults using PET imaging can provide new insight in prognosis and in instituting early therapy. In this review, the authors describe applications of PET imaging in the newborn nursery specifically related to the detection of metabolic changes seen in hypoxic ischemic encephalopathy, neonatal seizures, and neuroinflammation in the neonatal period.