Faculty Bibliography

PURPOSE/OBJECTIVE:To determine the electroclinical significance and histopathological correlates of cortical gamma-aminobutyric acid(A)(GABA(A)) receptor abnormalities detected in and remote from human neocortical epileptic foci. METHODS:Cortical areas with decreased(11)C-flumazenil (FMZ) binding were objectively identified on positron emission tomography (PET) images and correlated to intracranial electroencephalography (EEG) findings, clinical seizure variables, histology findings, and surgical outcome in 20 patients (mean age, 9.9 years) with intractable partial epilepsy of neocortical origin and nonlocalizing magnetic resonance imaging (MRI). RESULTS:Focal decrease of cortical FMZ binding was detected in the lobe of seizure onset in 17 (85%) patients. Eleven patients (55%) had 17 remote cortical areas with decreased FMZ binding outside the lobe of seizure onset. Thirteen of those 16 (81%) of the 17 remote cortical regions that were covered by subdural EEG were around cortex showing rapid seizure spread on intracranial EEG. Remote FMZ PET abnormalities were associated with high seizure frequency and, when resected, showed gliosis in all six cases where material was available. Higher number of unresected cortical regions with decreased FMZ binding was associated with poorer surgical outcome. CONCLUSIONS:Focal decreases of cortical GABA(A) receptor binding on PET may include cortical regions remote from the primary focus, particularly in patients with high seizure frequency, and these regions are commonly involved in rapid seizure propagation. Although these regions may not always need to be resected to achieve seizure freedom, a careful evaluation of cortex with decreased GABA(A) receptor binding prior to resection using intracranial EEG may facilitate optimal surgical outcome in patients with intractable neocortical epilepsy.

We applied diffusion-tensor MRI (DT-MRI) to investigate directly the water diffusivity within subcortical gray matter structures comprising the fronto-striato-thalamic (FST) circuit, which is implicated in the pathophysiology of Tourette syndrome (TS). We investigated the structural integrity of basal ganglia and thalamus in 23 children with TS and 35 age-matched healthy controls (NC), and examined the association of DT-MRI measures to tic severity and comorbid symptoms. We measured parallel (lambda(1)) and perpendicular (lambda(23)) diffusivity, mean diffusivity (MD), and fractional anisotropy (FA) in both hemispheres. Compared with NC, the TS group showed a significant increase in lambda(1) (P = 0.003) and MD (P = 0.027) in the bilateral putamen, an increase in lambda(23) in right thalamus (P = 0.008), and a reversed asymmetry of FA (P = 0.03) in the thalamus. There was a significant positive correlation between lambda(23) in right thalamus and tic severity. TS patients showed significantly lower left caudate volume (P = 0.011) and bilateral thalamic volumes (left, P = 0.035, right P = 0.006) compared with NC. These findings support the notion that microstructural dysfunction measured by DT-MRI in component regions of the FST circuit contribute to the pathophysiology in TS.

OBJECT/OBJECTIVE:Fever is a common occurrence after cerebral hemispherectomy in children and prolongs the hospital stay. The authors determined whether an external ventriculostomy might reduce the incidence of fever following a hemispherectomy. METHODS:The postoperative courses of 27 patients who had undergone cerebral hemispherectomy for intractable seizures were retrospectively analyzed. RESULTS:Thirteen children underwent an external ventriculostomy, and only 1 had an elevated axillary body temperature of > or = 39 degrees C during the postoperative period. Among 14 patients who did not undergo an external ventriculostomy, 7 had a posthemispherectomy fever of > or = 39 degrees C. Patients who underwent an external ventriculostomy had a lower risk of postoperative fever compared with those who did not undergo the procedure (8 vs 50%, respectively; p = 0.03, Fisher exact test). None of the patients had an infection accounting for the cause of the fever. The hospital stay for patients who had undergone postoperative external ventriculostomy was significantly shorter than for those who had not (7.2 +/- 2 vs 11.3 +/- 5 days, respectively; p = 0.01, Student t-test). CONCLUSIONS:The use of external ventriculostomy following hemispherectomy for intractable epilepsy in children reduces the incidence of postoperative fever due to infection.

To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 +/- 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 +/- 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.

The mechanism of altered glucose metabolism seen on positron emission tomography (PET) in focal epilepsy is not fully understood. We determined the association between interictal glucose metabolism and interictal neuronal activity, using PET and electrocorticography (ECoG) measures derived from 865 intracranial electrode sites in 11 children with focal epilepsy associated with tuberous sclerosis complex (TSC) (age: 0.5-16 years) undergoing epilepsy surgery. A multiple linear regression analysis was applied to each patient, to determine whether the glucose uptake at each electrode site on interictal PET was predicted by ECoG amplitude powers and interictal spike-frequency measured in the given electrode site. The regression slopes as well as R-square values (an indicator of fitness of the regression models) were finally averaged across the 11 patients. The mean regression slope for delta amplitude power was -0.0025 (95% CI: -0.0045 to -0.0004; P = 0.02 based on one-sample t-test) and that for spike frequency was -0.023 (95% CI: -0.042 to -0.0038; P = 0.02). On the other hand, the mean regression slopes for the remaining ECoG amplitude powers (theta, alpha, sigma, beta, and gamma activities) were not significantly different from zero. The mean R-square value was 0.39. These results suggest that increased delta-slowing and frequent spike activity were independently and additively associated with glucose hypometabolism in children with focal epilepsy associated with TSC. Association between frequent interictal spike activity and low glucose metabolism may be attributed to slow-wave components following spike discharges on ECoG recording, and a substantial proportion of the variance in regional glucose metabolism on PET could be explained by electrophysiological traits derived from conventional subdural ECoG recording.

Why do the epileptogenic foci appear hypometabolic on interictal glucose metabolism positron emission tomography (PET) in a substantial proportion of patients with focal epilepsy but appear normo- or even hyper-metabolic in others? Such observations on interictal PET have not been fully explained by the frequency of interictal spike discharges alone. In the present study using digital electrocorticography monitoring system with high-frequency sampling, we determined how well regression models using spectral ECoG measures and spike frequency derived from 651 intracranial electrode sites explained cortical glucose metabolic patterns in six children with nonlesional focal epilepsy. Univariate regression analysis demonstrated that spectral amplitudes at gamma ranges (32-64, 64-100, and 100-200 Hz) were tightly correlated with interictal glucose uptake in the given electrode site in all children. Spike frequency was negatively correlated with interictal glucose uptake in three patients, whose epileptogenic focus appeared hypometabolic and interictal epileptiform discharge often consisted of a spike followed by a subsequent delta-wave. Conversely, spike frequency was positively correlated with interictal glucose uptake in the other three patients, whose epileptogenic foci appeared more hypermetabolic compared to the surrounding regions and associated with frequent interictal spike bursts. The spatial pattern of interictal glucose metabolism in nonlesional focal epilepsy may be better explained by gamma-oscillations derived from epileptiform and physiological neuronal activities rather than the frequency of interictal epileptiform discharges alone.

This article discusses and reviews the role and contribution of PET in understanding the structural and functional changes that occur during brain development, and how these changes relate to behavioral and cognitive development in the infant and child. Data regarding various aspects of brain development, such as glucose metabolism, protein synthesis, and maturation and development of neurotransmitter systems will help in understanding the pathogenesis and neurologic basis of various developmental and neurologic disorders. This may help in following disease evolution and progression, planning and development of various therapeutic interventions, timing these interventions and monitoring their responses, and rendering long-term prognostication.

Postnatal deprivation is associated with neurocognitive delay/dysfunction. Although "catch up" in global cognition following adoption has been reported, this study examined the incidence of specific absolute impairment in adopted children with intact global cognitive functioning. Eighty-five children (38 males, mean age = 112.8, SD = 30.3 months; range 61-209 months) raised from birth in orphanages underwent comprehensive neuropsychological evaluation. Fifty-four were deemed globally intact (IQ > 85). Of those deemed globally intact, 46% evidenced absolute impairment in at least one domain of functioning. Duration of stay in the orphanage was directly associated with incidence of impairment and number of domains affected. A substantial proportion of participants evidenced persistent, absolute impairment in one or more domains of neurocognitive function despite integrity of basic intellectual functions.

Preliminary studies suggest that alpha[(11)C]methyl-l-tryptophan positron emission tomography can detect the epileptic focus within malformations of cortical development. We determined the sensitivity and specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying epileptic focus in children with intractable, neocortical epilepsy with and without malformations of cortical development. Seventy-three epileptic children were classified into lesional and nonlesional groups, and compared regarding focal increased alpha-[(11)C]methyl-l-tryptophan uptake. The sensitivity and specificity of focal increased alpha-[(11)C]methyl-l-tryptophan uptake, using intracranial electroencephalogram localization of seizure onset as the standard, were compared between lesional and nonlesional groups. The specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography for detecting seizure onset lobe was equally high in lesional (97%) and nonlesional groups (100%), whereas sensitivity was higher in the lesional than the nonlesional group (47% versus 29%; P = 0.047). The incidence of alpha-[(11)C]methyl-l-tryptophan uptake abnormality was higher in the lesional than the nonlesional group (P < 0.01). Alpha-[(11)C]methyl-l-tryptophan positron emission tomography localized and visualized epileptogenic regions in 25% of patients with nonlocalizing magnetic resonance imaging. Although overall sensitivity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying neocortical epileptic focus is modest, specificity is extremely high. When an alpha-[(11)C]methyl-l-tryptophan focus is detected, it likely represents the epileptogenic region to be resected.