Faculty Bibliography

The authors evaluated postsurgical reorganization of the arcuate fasciculus longitudinally using diffusion tensor imaging in 10 children with intractable epilepsy, whose resections included the left arcuate fasciculus. Evaluation of fractional anisotropy before and after surgery (mean follow-up: 7.5 months) showed a significant increase (P = .002) in the right arcuate fasciculus during follow-up. There was marked enlargement of the right arcuate fasciculus postsurgically in 8 patients. The change in right arcuate fasciculus fractional anisotropy values showed a positive correlation with interval between resection and postsurgical magnetic resonance imaging (MRI) (P = .044). Comparison of 10 age-matched controls to patients pre- and postsurgery showed significantly reduced presurgery fractional anisotropy in the left (P = .018) and right (P = .036) arcuate fasciculus and no difference in postsurgery fractional anisotropy in the right arcuate fasciculus (P = .399) in patients. These findings suggest a compensatory reorganization in the right arcuate fasciculus in children with intractable epilepsy following left arcuate fasciculus resection.

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.

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.

Previous studies of epileptic spasms reported that ictal events were associated with high-frequency oscillations (HFOs) or delta waves involving widespread regions. We determined whether ictal HFOs at 80-200 Hz were coupled with a phase of slow-wave, whether ictal slow-waves were diffusely or locally synchronous signals, and whether the mode of coupling between HFOs and slow-wave phases differed between ictal and interictal states. We studied 11 children who underwent extraoperative electrocorticography (ECoG) recording. The phases and amplitudes of slow-waves were measured at the peak of ictal and interictal HFOs in the seizure-onset sites. Ictal HFOs were locked tightly to the phase of slow-wave at ≤1 Hz. Ictal slow-waves propagated from the seizure-onset site to other regions. In contrast, interictal HFOs in the seizure-onset site were loosely locked to the phase of slow-wave at ≤1 Hz but tightly to that of ≥3-Hz. Ictal slow-waves coupled with HFOs can be explained as near-field and locally synchronized potentials generated by the neocortex rather than far-field potentials generated by subcortical structures. Ictal slow-waves in epileptic spasms may be generated by a mechanism different from what generates interictal HFOs-slow-wave complexes.

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.

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.

PURPOSE/OBJECTIVE:To investigate clinical correlates and longitudinal course of interictal focal cortical glucose hypermetabolism in children with Sturge-Weber syndrome (SWS). METHODS:Fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 60 children (age range 3 months to 15.2 years) with Sturge-Weber syndrome and epilepsy were assessed prospectively and serially for focal hypo- or hypermetabolism. Thirty-two patients had two or more consecutive PET scans. Age, seizure variables, and the occurrence of epilepsy surgery were compared between patients with and without focal hypermetabolism. The severity of focal hypermetabolism was also assessed and correlated with seizure variables. KEY FINDINGS/RESULTS:Interictal cortical glucose hypermetabolism, ipsilateral to the angioma, was seen in nine patients, with the most common location in the frontal lobe. Age was lower in patients with hypermetabolism than in those without (p=0.022). In addition, time difference between the onset of first seizure and the first PET scan was much shorter in children with increased glucose metabolism than in those without (mean: 1.0 vs. 3.6 years; p=0.019). Increased metabolism was transient and switched to hypometabolism in all five children where follow-up scans were available. Focal glucose hypermetabolism occurred in 28% of children younger than the age of 2 years. Children with transient hypermetabolism had a higher rate of subsequent epilepsy surgery as compared to those without hypermetabolism (p=0.039). SIGNIFICANCE/CONCLUSIONS:Interictal glucose hypermetabolism in young children with SWS is most often seen within a short time before or after the onset of first clinical seizures, that is, the presumed period of epileptogenesis. Increased glucose metabolism detected by PET predicts future demise of the affected cortex based on a progressive loss of metabolism and may be an imaging marker of the most malignant cases of intractable epilepsy requiring surgery in SWS.

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.

Angelman syndrome is a genetic disorder characterized by pervasive developmental disability with failure to develop speech. We examined the basis for severe language delay in patients with Angelman syndrome by diffusion tensor imaging. Magnetic resonance imaging/diffusion tensor imaging was performed in 7 children with genetically confirmed Angelman syndrome (age 70 ± 26 months, 5 boys) and 4 age-matched control children to investigate the microstructural integrity of arcuate fasciculus and other major association tracts. Six of 7 children with Angelman syndrome had unidentifiable left arcuate fasciculus, while all control children had identifiable arcuate fasciculus. The right arcuate fasciculus was absent in 6 of 7 children with Angelman syndrome and 1 of 4 control children. Diffusion tensor imaging color mapping suggested aberrant morphology of the arcuate fasciculus region. Other association tracts, including uncinate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and corticospinal tract, were identifiable but manifested decreased fractional anisotropy in children with Angelman syndrome. Increased apparent diffusion coefficient was seen in all tracts except uncinate fasciculus when compared to control children. Patients with Angelman syndrome have global impairment of white matter integrity in association tracts, particularly the arcuate fasciculus, which reveals severe morphologic changes. This finding could be the result of a potential problem with axon guidance during brain development, possibly due to loss of UBE3A gene expression.

Ten members of a 3-generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS-CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5' untranslated region of the OFCC1 gene was found in 2 TS-CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS.