Faculty Bibliography

OBJECTIVE:To investigate cortical association tracts using diffusion tensor imaging (DTI) in children with global developmental delay of unknown etiology. STUDY DESIGN/METHODS:We performed DTI in 20 patients (age range: 18-83 months, mean: 45 +/- 16 months, 12 males) with a history of global developmental delay and 10 typically developing children (age range: 26-99 months, mean: 54 +/- 24 months, 5 males). DTI tractography was performed to isolate major cortical association tracts. RESULTS:In 9 out of 20 patients, arcuate fasciculus (AF) was absent bilaterally and in another 2 patients, it was absent in left hemisphere. In contrast, AF was present bilaterally in all typically developing children. Fractional Anisotropy (FA) of inferior longitudinal fasciculus (ILF) was asymmetric in the control group but not in the developmental delay group (P = .04). FA was significantly reduced in right ILF in developmentally delayed children compared with controls (P = .03). FA of other association tracts was not different between patients and controls (P = NS). The apparent diffusion coefficient (ADC) showed no asymmetry for these tracts in controls or developmentally delayed children (P = NS). CONCLUSIONS:DTI can be used to identify absence of AF and inadequate maturation of ILF in children with global developmental delay of unknown etiology.

A 7-year-old girl presented with a cluster of seizures occurring in one day and followed by the development of paranoid delusions. Her electroencephalogram (EEG) revealed a psychomotor variant. Cranial MRI was normal, but the 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) scan showed hypometabolism in the left inferior frontal cortex. Her psychotic symptoms occurred episodically. Three years later, she developed hypermotor seizures associated with a fearful look. Video/EEG monitoring captured seizures of left frontotemporal onset. Her seizures became drug resistant and she underwent epilepsy surgery. Intracranial electrocorticography captured spontaneous and electrically induced seizures with onset in the left inferior frontal region, which was resected. She became seizure-free and her psychosis resolved. This case illustrates that frontal lobe epilepsy can present solely with psychotic symptoms, which may delay the diagnosis of epilepsy. We suggest that these cases may be underdiagnosed. When epilepsy is suspected and if MRI fails to demonstrate an abnormality, FDG PET scanning and video/EEG monitoring should be considered.

Reorganization involving residual visual pathways with unilateral damage to the primary visual cortex was previously described. Using diffusion tensor imaging, we measured water diffusion-related changes in the optic radiation contralateral to occipital lobe ablation in children with intractable epilepsy. We studied 10 children who had undergone a resection of the unilateral occipital cortex and 13 control subjects. Diffusion tensor imaging was acquired using a 1.5 Tesla magnetic resonance scanner. Fiber bundles representing optic radiation were tracked. Diffusion parameters included mean fractional anisotropy, apparent diffusion coefficient, and diffusion parallel and perpendicular to the fiber tract. In the surgical group, fractional anisotropy values of optic radiation contralateral to the side of resection exhibited a significant positive partial correlation (r = 0.752, P = 0.019) with duration of time between surgery and diffusion tensor imaging acquisition, after controlling for age. The apparent diffusion coefficient and parallel diffusivity were higher in the surgical versus the control group, but did not differ among patients. After unilateral resection of the occipital lobe, the contralateral optic radiation undergoes significant changes in anisotropy. Such structural white-matter changes may represent an adaptive response because of unilateral occipital ablation, and may account for plasticity changes observed in functional magnetic resonance imaging.

Several studies have shown that seizure-induced cellular and molecular changes associated with chronic epilepsy can lead to functional and structural alterations in the brain. Chronic epilepsy, when medically refractory, may be associated with an expansion of the epileptic circuitry to involve complex interactions between cortical and subcortical neuroanatomical substrates. Progress in neuroimaging has led not only to successful identification of epileptic foci for surgical resection, but also to an improved understanding of the functional and microstructural changes in long-standing epilepsy. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) are all promising tools that can assist in elucidating the underlying pathophysiology in chronic epilepsy. Studies using PET scanning have demonstrated dynamic changes associated with the evolution from acute to chronic intractable epilepsy. Among these changes are data to support the existence of secondary epileptogenesis in humans. MRI with DTI is a powerful tool which has the ability to characterize microstructural abnormalities in epileptic foci, and to demonstrate the white matter fibers and tracts participating in the epileptic network. In this review, we illustrate how PET and DTI can be applied to depict the functional and microstructural alterations associated with chronic epilepsy.

Symptoms in Tourette syndrome (TS) are likely related to abnormalities involving multiple neurotransmitter systems in striatal-thalamo-cortical circuitry. Although prior studies have found abnormal levels of tryptophan, serotonin, and their metabolites in blood, cerebrospinal fluid and brain tissue of TS patients, understanding of focal brain disturbances and their relationship to clinical phenotype remains poor. We used alpha-[(11)C]methyl-L-tryptophan (AMT) positron emission tomography (PET) to assess global and focal brain abnormalities of tryptophan metabolism and their relationship to behavioral phenotype in 26 children with TS and nine controls. Group comparisons on regional cortical and subcortical AMT uptake revealed decreased AMT uptake in bilateral dorsolateral prefrontal cortical and bilaterally increased uptake in the thalamus (P = 0.001) in TS children. The ratio of AMT uptake in subcortical structures to dorsolateral prefrontal cortex was significantly increased bilaterally (P < 0.01) in TS patients also. Behaviorally defined subgroups within the TS sample revealed differences in the pattern of AMT uptake in the fronto-striatal-thalamic circuit. This study demonstrates cortical and subcortical abnormalities of tryptophan metabolism in TS and provides neuroimaging evidence for a role of serotonergic mechanisms in the pathophysiology of TS.

BACKGROUND AND PURPOSE/OBJECTIVE:Although patients with tuberous sclerosis complex (TSC) manifest various structural abnormalities, we hypothesized that white matter (WM) structures that appear normal on conventional MR imaging may be accompanied by microstructural changes, such as gliosis and myelinization defects. Our objective was to determine in vivo whether there was evidence for WM microstructural changes by using diffusion tensor imaging (DTI). MATERIALS AND METHODS/METHODS:We used DTI to evaluate diffusivity and anisotropy in normal-appearing WM (NAWM) of 6 children with TSC and 12 age-matched control subjects. The anterior and posterior limbs of the internal capsule, the external capsule, and the genu and splenium of the corpus callosum were assessed. We hypothesized that previously reported DTI abnormalities of NAWM in patients with TSC may not be equal in all diffusion directions as measured by the major, middle, and minor eigenvalues. RESULTS:When combining NAWM regions in patients with TSC, we observed a significant increase in mean diffusivity (P = .003) and a decrease in anisotropy (P = .03) compared with those of controls. However, the increase in diffusivity was more pronounced in directions orthogonal to the axons measured by the minor and middle eigenvalues (P = .005) than by the major eigenvalue (P = .02). CONCLUSION/CONCLUSIONS:Our findings revealed a decrease in anisotropy and an increase in longitudinal and radial diffusivities in NAWM beyond the location of TSC lesions seen on conventional MR imaging. The axonal microstructural changes suggested by our study may be related to changes in myelin packing due to giant cells accompanied by gliosis and myelination defects known to occur in TSC WM.

OBJECTIVE:We determined whether the primary motor hand area was most frequently located in the precentral gyrus in young patients with intractable focal seizures. METHODS:Sixty-five patients with focal seizures aged between 5 months and 20 years who underwent a two-stage epilepsy surgery using chronic subdural-EEG monitoring were studied. Pairs of subdural electrodes were electrically stimulated, and the brain region with contralateral hand movement induced by the lowest-intense stimulus was defined as the primary motor hand area. RESULTS:Contralateral hand movement was induced without afterdischarges in 50 children but not in the remaining 15 children. The unpaired t-test revealed that failure to induce contralateral hand motor movement was associated with younger age of subjects. Among the 50 patients with a positive motor response, the primary motor hand area was confined to the precentral gyrus in 9 patients, confined to the postcentral gyrus in 24, and located in both the pre- and post-central gyri in the remaining 17. The McNemar's test revealed that the observed frequency of 24 patients showing the primary motor hand area confined to the postcentral gyrus was larger than chance frequency. Logistic regression analysis failed to demonstrate that the observation of the primary motor hand area confined to the postcentral gyrus was associated with the age, the presence of dysplastic lesion or the seizure onset involving the frontal lobe. CONCLUSION/CONCLUSIONS:Our study failed to support the traditionally-accepted notion that the primary motor hand area is most frequently located in the precentral gyrus but rather demonstrated that a substantial proportion of young patients had the primary motor hand area in the postcentral gyrus.

Paroxysmal tonic upgaze (PTU) is a childhood oculomotor syndrome of unclear etiology characterized by episodic tonic upward eye deviation with neck flexion. Neuroimaging findings are often normal and the electroencephalography during episodes is typically normal. We describe a 2-year-old boy who presented with macrocephaly, hypotonia, developmental delay and episodes of eye fluttering, head nodding and unresponsiveness. Video-EEG captured absence seizures and he was treated with valproate, which led to improvement of his seizures. However, two weeks after treatment, he developed paroxysmal episodes of "eyes up and chin down" movements lasting for hours at a time which were captured by home video. The episodes were relieved by sleep and exacerbated by fever, stress and even tactile stimulation. Increasing the dose of valproate resulted in increased frequency of the episodes. A repeat video-EEG disclosed the non-epileptic nature of these events. Discontinuation of valproate dramatically decreased the episodes. This case illustrates that paroxysmal tonic upgaze of childhood may co-exist with early onset absence epilepsy. Furthermore, valproate treatment may be associated with the development or unmasking of PTU suggesting that the pathophysiology of PTU may involve abnormal GABA neurotransmission. [Published with videosequences].

BACKGROUND:The natural course of Sturge-Weber syndrome (SWS) is poorly understood, although neurological symptoms are often progressive. AIMS/OBJECTIVE:To track longitudinal changes in brain glucose metabolism measured with positron emission tomography (PET) and their relation to clinical changes during the early course of SWS. METHODS:Fourteen children (age 3 months to 3.9 years at enrollment) with SWS and unilateral leptomeningeal angioma underwent two consecutive glucose metabolism PET scans with a mean follow-up time of 1.2 years. Longitudinal changes of the extent of cortical glucose hypometabolism on the angioma side were measured and correlated with age, clinical seizure frequency and hemiparesis. RESULTS:An increase in the size of the hypometabolic cortex was seen in 6 children, coinciding with an age-related increase in cortical glucose metabolism measured in unaffected contralateral cortex. These 6 patients were younger both at the initial (mean age 0.75 vs. 2.8 years; p<0.001) and the second scan (mean age 1.8 vs. 4.2 years; p=0.001) than those with no change in the extent of hypometabolic cortex (n=6). The area of cortical hypometabolism decreased in the two remaining children, and this was associated with resolution of an initial hemiparesis in one of them. Seizure frequency between the two scans was higher in children who showed progressive enlargement of cortical hypometabolism, as compared to those with no progression (p=0.008). CONCLUSIONS:In SWS, detrimental metabolic changes occur before 3 years of age coinciding with a sharp increase of developmentally regulated cerebral metabolic demand. Progressive hypometabolism is associated with high seizure frequency in these children. However, metabolic abnormalities may remain limited or even partially recover later in some children with well-controlled seizures. Metabolic recovery accompanied by neurological improvement suggests a window for therapeutic intervention in children with unilateral SWS.

The hallmark of Sturge-Weber syndrome is leptomeningeal angiomatosis. Over 15 years, four children were identified (2 boys, age 2.9-6 years) with unilateral facial port-wine stain, referred for presumable Sturge-Weber syndrome but who were also autistic. Computed tomography and magnetic resonance imaging scans failed to show evidence of leptomeningeal angioma in all four children. Three of the children had a history of seizures. Detailed neuropsychologic testing of three children revealed a similar presentation, characterized by developmental disturbance, particularly involving delayed onset of language, and early-emerging social atypicality. Positron emission tomography scanning of cerebral glucose metabolism revealed hypometabolism in the bilateral medial temporal regions, anterior cingulate gyrus, frontal cortex, right temporal cortex, and cerebellum. The pattern of glucose hypometabolism differed from that of 12 children with infantile autism (age 2.7-7.9 years) who had mild left medial temporal but more severe right temporal cortical hypometabolism and showed a reversal of normal frontotemporal asymmetry of glucose metabolism. Unilateral facial port-wine stain and autism with no intracranial angioma on conventional imaging may represent a rare clinical entity distinct from both infantile autism and previously described variants of Sturge-Weber syndrome.