Faculty Bibliography

Early global deprivation of institutionalized children may result in persistent specific cognitive and behavioral deficits. In order to examine brain dysfunction underlying these deficits, we have applied positron emission tomography using 2-deoxy-2-[(18)F]fluoro-D-glucose in 10 children (6 males, 4 females, mean age 8.8 years) adopted from Romanian orphanages. Using statistical parametric mapping (SPM), the pattern of brain glucose metabolism in the orphans was compared to the patterns obtained from two control groups: (i) a group of 17 normal adults (9 males, 8 females, mean age 27.6 years) and (ii) a group of 7 children (5 males and 2 females, mean age 10.7 years) with medically refractory focal epilepsy, but normal glucose metabolism pattern in the contralateral hemisphere. Consistent with previous studies of children adopted from Romanian orphanages, neuropsychological assessment of Romanian orphans in the present study showed mild neurocognitive impairment, impulsivity, and attention and social deficits. Comparing the normalized glucose metabolic rates to those of normal adults, the Romanian orphans showed significantly decreased metabolism bilaterally in the orbital frontal gyrus, the infralimbic prefrontal cortex, the medial temporal structures (amygdala and head of hippocampus), the lateral temporal cortex, and the brain stem. These findings were confirmed using a region-of-interest approach. SPM analysis showed significantly decreased glucose metabolism in the same brain regions comparing the orphans to the nonepileptic hemisphere of the childhood epilepsy controls. Dysfunction of these brain regions may result from the stress of early global deprivation and may be involved in the long-term cognitive and behavioral deficits displayed by some Romanian orphans.

Rasmussen's syndrome is a chronic encephalitis characterized by intractable focal epilepsy and progressive neurologic deterioration with lateralized brain destruction. In the early stages of the disease, the diagnosis can be difficult to make, and brain biopsy is often performed. We evaluated the patterns of cerebral glucose metabolism using 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography (PET) in 15 children (age range 2.9-15.4 years, mean age 8.7 +/- 4.3 years) with Rasmussen's syndrome. In 6 patients evaluated early (< or = 1 year of onset of seizures), the PET scan showed areas of abnormal metabolism restricted mostly to the frontal and temporal regions, whereas the posterior cortex was preserved. Pathologic changes seen in the resected cortex were more pronounced in cortical areas of abnormal metabolism than in regions showing normal metabolism. In 9 patients evaluated later (>1 year after onset of seizures), the PET scan showed more diffuse hemispheric metabolic abnormalities including the occipital cortex, but the abnormalities remained highly lateralized. These patterns of glucose metabolic abnormalities in the early and late stages of the disease may facilitate the diagnosis of Rasmussen's syndrome and assist guidance of biopsy in early cases, when structural neuroimaging is still normal.

The discovery of focal or multifocal cortical lesions using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning in the majority of infants with West syndrome has led to a surgical approach in the treatment of some patients with intractable infantile spasms. The locations of these lesions should be concordant with localization of focal ictal and/or interictal electroencephalographic (EEG) abnormalities prior to proceeding with cortical resection. When a single lesion is present on the MRI or PET, and there is good correlation with EEG localization, surgical treatment is generally quite favorable in terms of both seizure control and cognitive development. Interictal glucose metabolism PET scans in children with intractable cryptogenic infantile spasms show unifocal cortical hypometabolism in about 20% of cases. In the majority, however, multifocal asymmetric hypometabolism is suggestive of multifocal underlying lesions, possibly multifocal cortical dysplasia. When the pattern of glucose hypometabolism is symmetric, a lesional etiology is less likely, thus neurometabolic or neurogenetic disorders should be considered. Therefore, the pattern of glucose hypometabolism on PET in infants with intractable cryptogenic spasms is a useful guide to decide whether a medical or surgical approach should be undertaken. In order to achieve the best cognitive outcome with surgery, it is important to resect the entire 'nociferous' area rather than just the seizure focus. Our research with new PET imaging probes has attempted to provide a comprehensive evaluation of the epileptogenic zone including the 'nociferous' cortex. We have used [(11)C]flumazenil (FMZ), which labels gamma aminobutyric acid(A) (GABA(A)) receptors, and have found this to be particularly useful in showing: (i) decreased receptor binding with medial temporal involvement thus indicating resection of medial temporal structures, (ii) the peri-lesional epileptogenic zone surrounding MRI lesions, (iii) the seizure onset zone in MRI-negative cases, and (iv) potential secondary epileptic foci. Another recently developed PET probe, alpha[(11)C]methyl-L-tryptophan (AMT) which is a precursor for the serotonin and the kynurenine metabolism pathways, is capable of differentiating between epileptogenic and non-epileptogenic tubers in patients with tuberous sclerosis complex and intractable epilepsy (including infantile spasms). Subsequently, we have applied AMT PET in patients with multifocal cortical dysplasia to determine the predominant seizure focus, and the results have been promising with regard to seizure control but not cognitive development. Thus, the introduction of newer more specific PET probes for epilepsy has led to improved and more accurate localization of seizure foci that should ultimately improve outcome of epilepsy surgery in West syndrome.

Neuroimaging studies with magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning have contributed significantly to our understanding of West syndrome. Cortical dysplastic lesions are the most common abnormalities seen with MRI in infants with spasms, but other structural lesions are also detected occasionally. An underlying cortical dysplasia may not be apparent until myelination has advanced in the brain and poor gray-white matter differentiation becomes observable. Many cortical dysplastic lesions can only be detected using PET scanning of glucose metabolism or gamma-aminobutyric acid(A) (GABA(A)) receptor binding. The MRI and PET findings, together with neurophysiological observations, strongly suggest that infantile spasms are initiated as cortical epileptic discharges that, during a 'critical' developmental period, may undergo secondary generalization in an age-dependent mechanism to emerge as spasms. The onset of spasms often coincides with the functional maturation of cerebral cortex. Based on data from glucose metabolism PET scanning as well as electrophysiological and neurochemical findings on infants with spasms, we have postulated that the offending lesion is a focal or diffuse cortical abnormality which, at a critical stage of maturation, causes abnormal functional interactions with brainstem raphe nuclei which project widely throughout the brain. Raphe-cortical projections could mediate the hypsarrhythmic changes seen on EEG. The prominent serotonergic raphe-striatal pathway and descending spinal pathways may be responsible for secondary generalization of the cortical discharges to result in the relatively symmetric spasms. It is likely that additional factors (e.g. genetic) play a role in the manifestation of the age-specific electroclinical features of West syndrome. Recently developed PET tracers can be used to detect epileptogenic brain regions and also to investigate developmental abnormalities of serotonergic (using the tracer alpha[(11)C]methyl-L-tryptophan) and GABAergic (using [(11)C]flumazenil) neurotransmitter systems. These systems are implicated in epileptogenesis, and their involvement in the pathophysiology of West syndrome can be further addressed by future functional neuroimaging studies.

OBJECTIVE:To examine the relationship between autism and epilepsy in relation to structural and functional brain abnormalities in children with tuberous sclerosis complex (TSC). METHODS:Children with TSC and intractable epilepsy underwent MRI as well as PET scans with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and alpha-[(11)C]methyl-L-tryptophan (AMT). Based on the results of Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and overall adaptive behavioral composite (OABC) from Vineland Adaptive Behavior Scale, subjects were divided into three groups: autistic (OABC < 70; n = 9), mentally-retarded nonautistic (OABC < 70; n = 9), and relatively normal intelligence (OABC > or = 70; n = 8). RESULTS:PET studies showed that the autistic group had decreased glucose metabolism in the lateral temporal gyri bilaterally, increased glucose metabolism in the deep cerebellar nuclei bilaterally, and increased AMT uptake in the caudate nuclei bilaterally, compared to the mentally-retarded nonautistic group. In addition, a history of infantile spasms and glucose hypometabolism in the lateral temporal gyri were both significantly associated with communication disturbance. Glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nuclei were both related to stereotypical behaviors and impaired social interaction, as well as communication disturbance. CONCLUSIONS:These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.

PURPOSE/OBJECTIVE:To determine whether prolonged treatment with vigabatrin (VGB), an antiepileptic drug (AED) that acts by elevating brain gamma-aminobutyric acid (GABA) levels, interferes with age-related changes of in vivo GABA(A)-receptor binding in children with epilepsy. METHODS:Using [11C]flumazenil (FMZ)-positron emission tomography (PET) imaging, 15 children (aged 1-8 years) with medically intractable epilepsy were studied. Seven of these children were treated with VGB (1,000-2,500 mg/day) for > or =3 months before the FMZ-PET study. The remaining eight patients were medicated with other drugs that are known not to act directly on the GABAergic system. Absolute quantification of PET data was performed by using the volume of distribution (VD) of FMZ in brain tissue representing FMZ ligand binding. RESULTS:After controlling for age, hemispheric FMZ VD values were significantly lower in children treated with VGB as compared with the non-VGB group (p = 0.012). Regional FMZ VD values of the VGB-treated patients were significantly lower in all cortical regions and the cerebellum, whereas the difference was not significant in the thalamus and basal ganglia. No significant drug effect or drug-by-region interaction could be determined when the patients were separated according to treatment with carbamazepine (p = 0.97) or valproate (p = 0.55). CONCLUSIONS:VGB induces a decrease in GABA(A)-receptor binding in the cortex and cerebellum of the developing epileptic brain. A similar effect of other drugs and substances of abuse targeting the GABAergic system may be hypothesized. Because of the important role of the GABAergic system in developmental plasticity, the reversibility and functional consequences of this age-specific drug effect should be further studied.

PURPOSE/OBJECTIVE:To identify brain regions with abnormal function in children with intractable partial epilepsy and aggressive behavior by using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET). METHODS:Six children (mean age, 9.9 years) with intractable partial epilepsy and aggressive behavior underwent detailed psychodevelopmental assessment and FDG-PET scanning. The objective technique of statistical parametric mapping (SPM) was applied to define focal abnormalities of glucose metabolism, and compared those with those of a group of normal adult subjects (n = 17) as well as age-matched children with epilepsy with similar seizure characteristics but without aggression (n = 7). The findings were analyzed further by using a region-of-interest (ROI) approach. RESULTS:The aggressive children all showed developmental delay, and four of them also manifested autistic symptoms. SPM analysis demonstrated extensive glucose hypometabolism in the aggressive group bilaterally in the temporal and prefrontal cortex compared with that in normal adult controls. A focal area of medial prefrontal glucose hypometabolism was defined in the aggressive children as compared with the nonaggressive pediatric group with SPM, whereas ROI comparison of these groups confirmed prefrontal hypometabolism and also showed glucose hypometabolism of the temporal neocortex in the aggressive children. Severity of aggression correlated inversely with glucose metabolism of the left temporal as well as bilateral medial prefrontal cortex. CONCLUSIONS:Bilateral prefrontal and temporal neocortical brain glucose hypometabolism in children with epilepsy and aggressive behavior may indicate a widespread dysfunction of cortical regions, which normally exert an inhibitory effect on subcortical aggressive impulses. PET studies may be used to elucidate the neurobiologic basis of aggressive behavior in children.

OBJECTIVE:To determine whether the extent and degree of glucose hypometabolism defined by PET correlate with seizure characteristics, cognitive function, and interictal EEG abnormalities in children with unilateral cerebral involvement of Sturge-Weber syndrome (SWS). METHODS:2-Deoxy-2[18F]fluoro-D-glucose (FDG) PET was performed in 13 children (age range 0.7 to 15.1 years; five boys, eight girls) with unilateral SWS. Based on asymmetries between homologous cortical areas in FDG PET images, cortical areas of mildly (10% to 20% decrease), and severely (>20% decrease) asymmetric cortical metabolism were defined. These areas were normalized to the size of the ipsilateral hemisphere and correlated with clinical seizure characteristics, full-scale IQ, and interictal EEG abnormalities. RESULTS:Both seizure frequency (p = 0.027) and lifetime number of seizures (p = 0.017) showed a positive correlation with the area (expressed as the percentage of cortical area of ipsilateral hemisphere) of mildly asymmetric cortical metabolism. Patients with higher IQ had a shorter duration of epilepsy (p = 0.044) and a larger area of severely asymmetric cortical metabolism (p = 0.044). Patients with bilateral interictal EEG abnormalities had larger lifetime number of seizures (p = 0.042), lower IQ (p = 0.024), and smaller area of severely asymmetric cortical metabolism (p = 0.019) than those with only ipsilateral EEG abnormalities. CONCLUSIONS:Association of severely asymmetric cortical metabolism with relatively preserved cognitive function in SWS suggests that functional reorganization occurs more readily when cortex is severely rather than mildly damaged. Therefore, the area of mildly asymmetric cortical metabolism may exert a nociferous effect on the remaining of the brain. Thus, the extent and degree of glucose asymmetry detected by PET are sensitive markers of seizure severity and cognitive decline in SWS.

BACKGROUND:Cortical areas showing abnormal glucose metabolism and [(11)C]flumazenil (FMZ) binding are commonly seen on PET scans of patients with intractable partial epilepsy, but it is unclear whether these must be totally resected to achieve seizure control. OBJECTIVE:To analyze whether the extent of cortex showing 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) or FMZ PET abnormalities correlates with the outcome of resective epilepsy surgery. METHODS:Cortical FDG and FMZ PET abnormalities in 15 young patients (mean age, 12.2 +/- 7.0 years) with intractable partial epilepsy of neocortical origin were marked as regions with abnormal asymmetry using an objective semiautomated software package. These marked regions were then projected and measured on the brain surface reconstructed from the coregistered high-resolution MRI. Following cortical resection, the size of nonresected cortex with preoperative PET abnormalities was also measured (calculated separately for marked areas in the lobe of seizure onset as defined by long-term video EEG monitoring, and in remote cortical areas). Extent of preoperative PET abnormalities and postoperative nonresected cortex abnormalities on PET were correlated with outcome scores. RESULTS:Large preoperative FMZ PET abnormalities were associated with poor outcome (r = 0.57; p = 0.025). Larger areas of nonresected cortex with preoperative FMZ PET abnormalities in the lobe of seizure onset were also associated with worse outcome in the whole group (r = 0.66; p = 0.007) as well as in patients with extratemporal resection (r = 0.73; p = 0.007), and in those with no lesion on MRI (r = 0.60; p = 0.049). Patients with seizure-free outcome had significantly smaller nonresected cortex with preoperative FMZ PET abnormalities than those who continued to have seizures (p = 0.022). No significant correlations between nonresected FDG PET abnormalities and surgical outcome were found. CONCLUSIONS:Extensive cortical abnormalities on FMZ PET predict poor outcome in neocortical epilepsy surgery. Resection of FMZ abnormalities in the lobe of seizure onset is associated with excellent outcome even in the absence of a structural lesion. In contrast, although FDG PET abnormalities regionalized the epileptogenic area, their size was not related to the extent of epileptogenic tissue to be removed.

During brain development in nonhuman primates, there are large changes in GABAA receptor binding and subunit expression. An understanding of human GABAA receptor ontogeny is highly relevant in elucidating the pathophysiology of neurodevelopmental disorders in which GABAergic mechanisms play a role as well as in understanding differences that occur during development in the pharmacology of drugs acting on this system. We have measured age-related changes in the brain distribution of the GABAA receptor complex in vivo using positron emission tomography (PET) in epileptic children under evaluation for surgical treatment. PET imaging was performed using the tracer [11C]flumazenil (FMZ), a ligand that binds to alpha subunits of the GABAA receptor. FMZ binding was quantified using a two-compartment model yielding values for the volume of distribution (VD) of the tracer in tissue. All brain regions studied showed the highest value for FMZ VD at the youngest age measured (2 years), and the values then decreased exponentially with age. Medial temporal lobe structures, primary visual cortex, and thalamus showed larger differences between values for age 2 years and adults (approximately 50% decrease) than did basal ganglia, cerebellum, and other cortical regions (25-40% decreases). Furthermore, subcortical regions reached adult values earlier (14-17.5 years) than did cortical regions (18-22 years). The ontogeny data of FMZ VD from children may contribute to understanding regional differences in synaptic plasticity as well as improve rational therapeutic use of drugs acting at the GABAA receptor in the pediatric population.