Faculty Bibliography

PURPOSE/OBJECTIVE:Interictal increase of (11) C-alpha-methyl-l-tryptophan (AMT) on positron emission tomography (PET) can be seen in cortical epileptic foci, and is particularly common in cortical developmental malformations. Therefore, in the present study, we evaluated the clinical and histopathologic correlates of AMT-PET abnormalities in children with intractable epilepsy undergoing resective surgery. METHODS:Thirty children (mean age: 6.7 ± 3.2 years) were included in this study. All patients received AMT-PET as part of their presurgical evaluation and subsequently underwent epilepsy surgery. Magnetic resonance imaging (MRI) scans were normal in 15, showed nonspecific changes in 8, and suggested malformations of cortical development (MCDs) in nine children. Asymmetry indices (AIs) were calculated to determine increased AMT uptake. KEY FINDINGS/RESULTS:Histopathology revealed MCDs in 16 (53%) children, including 12 with cortical dysplasia (CD) [mild MCD = 3; CD type IA = 2; CD type IIA = 2 and CD type IIB (severe CD with balloon cells) = 5]. Polymicrogyria and heterotopias (P&Hs) were seen in three cases and subependymal heterotopias (SEHs) in one child. The remaining 14 cases showed normal histopathology with varying degrees of gliosis. Increased AMT uptake was found in all five with CD type IIB, and all three with P&H, but in none with mild MCD and types IA-IIA CD or SEH. Whereas all five children with CD IIB and two with P&H had excellent surgical outcome (class I); children with milder CD or SEH had variable surgical outcome. The 14 patients with normal histopathology included seven patients with focally increased and seven with normal AMT uptake. Although patients with normal pathology and normal AMT-PET had better surgical outcome (class I = 5; II = 2), those with normal pathology, normal MRI, but abnormal AMT-PET had poor surgical outcome (class III = 4; IV = 3). SIGNIFICANCE/CONCLUSIONS:Increased AMT uptake in children with CD may predict type IIB dysplasia (with balloon cells) and good surgical outcome. Histopathologic similarities between CD type IIB and epileptogenic cortical tubers may imply a common role of the inflammatory kynurenine pathway of tryptophan metabolism in these lesions. In children with normal histopathology, there is a subgroup with increased AMT uptake and poor surgical outcome.

Approximately 15% of patients with Sturge-Weber syndrome demonstrate bilateral intracranial involvement, and the prognosis of these patients is considered particularly unfavorable. We reviewed the clinical and neuroimaging features of patients with Sturge-Weber syndrome and bilateral intracranial involvement. Seizure variables, the presence of hemiparesis, and the degree of developmental impairment at most recent follow-up were compared with imaging abnormalities. Of 110 Sturge-Weber syndrome patients, 14 demonstrated bilateral brain involvement, with an asymmetric pattern on glucose metabolism positron emission tomography. Although most patients manifested frequent seizures initially, associated with frontal hypometabolism on positron emission tomography, six (43%) had achieved good seizure control during follow-up. Bilateral frontal hypometabolism was associated with severe developmental impairment. Two children with bitemporal hypometabolism exhibited autistic features. Hemiparesis was associated with superior frontal (motor cortex) hypometabolism. Three patients underwent resective surgery, resulting in improved seizure control and developmental outcomes. The severity of neurologic complications and clinical course depend on the extent of cortical dysfunction in bilateral Sturge-Weber syndrome. Bilateral frontal and temporal hypometabolism is associated with poor developmental outcomes. Good seizure control and only mild/moderate developmental impairment can be achieved in about 50% of patients with bilateral Sturge-Weber syndrome, with or without resective surgery.

BACKGROUND AND PURPOSE/OBJECTIVE:Because we had previously observed geometric changes of frontal lobe association pathways in children with ASD, in the present study we analyzed the curvature of these white matter pathways by using an objective TBM analysis. MATERIALS AND METHODS/METHODS:Diffusion tensor imaging was performed in 32 children with ASD and 14 children with typical development. Curvature, FA, AD, and RD of bilateral AF, UF, and gCC were investigated by using the TBM group analysis assessed by P(FDR) for multiple comparisons. RESULTS:Significantly higher curvatures were found in children with ASD, especially at the parietotemporal junction for AF (left, P(FDR) < .001; right, P(FDR) < .01), at the frontotemporal junction for UF (left, P(FDR) < .005; right, P(FDR) < .03), and at the midline of the gCC (P(FDR) < .0001). RD was significantly higher in children with ASD at the same bending regions of AF (left, P(FDR) < .03, right, P(FDR) < .02), UF (left, P(FDR) < .04), and gCC (P(FDR) < .01). CONCLUSIONS:Higher curvature and curvature-dependent RD changes in children with ASD may be the result of higher attenuation of thinner axons in these frontal lobe tracts.

BACKGROUND AND PURPOSE/OBJECTIVE:Thalamocortical connections play a crucial role in complex cognitive functioning, and several neuropsychiatric disorders may involve aberrant thalamocortical circuitry. Here, we quantified the cortical pattern and age-related changes of thalamocortical connections by using probabilistic tractography in children and adolescents. We hypothesized that detectable asymmetry (left>right) exists in thalamocortical fiber connections and the connectivity increases with age during maturation. MATERIALS AND METHODS/METHODS:Diffusion tensor imaging was acquired in 15 normally developing children (age range, 8.3-17.3 years; 11 males), and fiber tracking was initiated from the thalami. The cortical distribution of ipsilateral thalamocortical fibers was quantified by using a landmark-constrained conformal mapping technique. Furthermore, hemispheric asymmetries and potential age-related changes in regional thalamocortical connections were assessed. RESULTS:The left thalamus had significantly higher overall cortical connectivity than the right thalamus (P < .001). Left prefrontal cortical areas showed significantly higher thalamic connectivity compared with homotopic regions of the right hemisphere (P < .001), regardless of the applied parameters. There was an increase of overall thalamocortical connectivity with age, with the most pronounced age-related increases in bilateral prefrontal areas (P < .002). However, thalamic connectivity of some other cortical regions (right sensorimotor, left inferior temporal) showed a decrease with age. CONCLUSIONS:Our results indicate a region-specific left>right asymmetry and robust developmental changes in thalamocortical (particularly thalamo-prefrontal) connectivity during late childhood and adolescence. These data further add to our knowledge about structural lateralizations and their development in the maturing brain.

BACKGROUND AND PURPOSE/OBJECTIVE:One of the neurologic substrates of poor language in children with DD is the abnormal development of perisylvian language networks. We sought to determine whether this manifests as aberrant regional changes in diffusivity or geometry of the left AF. MATERIALS AND METHODS/METHODS:We performed DTI studies in 16 young (age, 55.4 ± 18.95 months) patients with DD and 11 age- and sex-matched TD children (age, 60.09 ± 21.27 months). All children were right-handed. To detect the malformation of left AF structure in native or standard space, we proposed new methodology consisting of 2 complementary approaches, principal fiber orientation quantification in color-coded anisotropic maps and tract-based morphometry analysis. RESULTS:Patients with DD did not show the typical pattern of age-related maturity of the AP and ML pathways passing through the left AF (R(2) of the AP pathway: DD versus TD = 0.002 versus 0.4542; R(2) of the ML pathway: DD versus TD = 0.002 versus 0.4154). In addition, the patients with DD showed significantly reduced FA in the temporal portion of the AF (mean FA of DD versus TD = 0.37 ± 0.11 versus 0.48 ± 0.06, P < .001), and the AF showed higher curvatures in the parietotemporal junction, resulting in sharper bends to the Wernicke area (mean curvature of DD versus TD = 0.12 ± 0.03 versus 0.06 ± 0.02, P < .001). CONCLUSIONS:The proposed methods successfully revealed regional abnormalities in the axonal integrity of the left AF in the patients with DD. These abnormalities support the notion that the perisylvian language network is malformed in children with DD.

BACKGROUND AND PURPOSE/OBJECTIVE:Low brain tissue perfusion due to abnormal venous drainage is thought to be a central mechanism of brain damage in SWS. Here, HR-PWI was used to quantify WM perfusion abnormalities and to correlate these with brain atrophy and clinical variables. MATERIALS AND METHODS/METHODS:Fourteen children (age range, 0.8-10.0 years) with unilateral SWS underwent MR imaging examinations, including HR-PWI. rCBV, rCBF, and MTT in the affected WM and in contralateral homotopic WM were measured. AI for each perfusion parameter was correlated with age, brain atrophy, and motor and seizure variables as well as IQ. RESULTS:Increased perfusion was seen in the affected hemisphere in 5 children and decreased perfusion in 9 children. Brain atrophy was more severe in the low-perfusion group (P = .01) and was related to both CBF-AI and CBV-AI (r = -0.69, P = .007; r = -0.64, P = .014, respectively). Older children had lower CBV values on the affected side (r = -0.62, P = .02). Longer duration of epilepsy was related to lower CBF (more negative CBF-AI, r = -0.58, P = .03) and low CBV (r = -0.55, P = .04) on the affected side. Lower perfusion was associated with more frequent seizures (rCBF-AI: r = -0.56, P = .04; rCBV-AI: r = -0.63, P = .02). CONCLUSIONS:Increased perfusion in the affected cerebral WM may indicate an early stage of SWS without severe brain atrophy. Decreased perfusion is associated with frequent seizures, long duration of epilepsy, and brain atrophy.

Using diffusion tensor imaging tractography and color-coded anisotropy map quantification, we investigated asymmetry of the arcuate fasciculus to determine language laterality in children and compared it with the Wada test. Arcuate fasciculus volume and fractional anisotropy were measured after tractography. We also quantified the fiber orientation distribution in the arcuate fasciculus region, ie, the fraction of arcuate fasciculus fibers oriented in the anteroposterior and mediolateral directions. A Laterality Index was calculated for each of the measured parameters. Volumetric analysis of the arcuate fasciculus showed asymmetry favoring the language dominant hemisphere (P = .02), while fractional anisotropy showed no significant asymmetry (P = .07). The mean anteroposterior and mediolateral components on the language dominant side were significantly higher than on the nondominant side (P = .003 and .002, respectively). The Laterality Index values were concordant with the Wada test results except for 1 case. Fractional anisotropy also falsely lateralized language in 1 case.

The clinical manifestation and nuclear imaging findings in a 15-year-old boy with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis are described in this case report. The previously healthy patient presented with new onset hallucinations, seizure, and within a week, his mental status rapidly deteriorated to nonverbal with oro-lingual-facial dyskinesias. An extensive laboratory work-up for encephalopathy was negative. Repeated brain magnetic resonance imaging (MRI) studies were normal. On day 26 of admission, nuclear imaging using fluorodeoxyglucose positron emission tomography (FDG-PET) showed global hypometobolism with a prominent focally intense hypermetabolic lesion in the right cerebellar cortex. Diagnosis of anti-NMDAR encephalitis was confirmed with quantitative serology. The patient showed clinical signs of improvement after 2 courses of intravenous immunoglobulin therapy over 4 weeks. On day 46, repeat brain FDG-PET showed overall improvement but in contrast to the previous, the right cerebellar cortex showed focal hypometabolism. This is the first reported case of such findings using FDG-PET in anti-NMDAR encephalitis.

We tested the hypothesis that extent of severe hypometabolism measured by fluorodeoxyglucose PET has a U-shaped (nonlinear) relationship to IQ in children with unilateral Sturge-Weber syndrome. Thirty-five consecutive children (age range: 30-153 months) with Sturge-Weber syndrome and unilateral brain involvement were enrolled in the study. Participants underwent cognitive assessment and interictal fluorodeoxyglucose PET scans. Regression analyses tested whether a quadratic model best accounted for the relationship between extent of severe cortical hypometabolism and IQ, controlling for seizure variables. A significant quadratic relationship was found between IQ and extent of severe (but not total) hypometabolism. Seizure variables also contributed significant variance to cognitive functions. Results suggest that intermediate size of severe hemispheric hypometabolism is associated with the worst cognitive outcomes, and small or absent lesions, with the best cognitive outcomes. Children in whom a very large extent of the hemisphere is severely affected are likely to have relatively preserved cognitive function.

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.