Faculty Bibliography

We performed positron emission tomographic (PET) studies with 2-deoxy-2[18F]fluoro-D-glucose in 8 children with hemimegalencephaly (HME). HME is a developmental brain malformation associated with epilepsy, hemianopsia, and varying degrees of developmental delay. We hypothesized that the relatively poor overall developmental outcome of surgically hemispherectomized HME patients as a group, compared to children undergoing hemispherectomy for Sturge-Weber syndrome or chronic focal encephalitis, is related to dysfunction of the structurally "normal" non-HME side and that PET would be helpful in the pre-surgical evaluation of HME patients with intractable epilepsy. Visual analysis of the non-HME side on PET clearly revealed evidence of cortical hypometabolism in 4 patients compared to controls. Seven children underwent epilepsy surgery. One child had a glucose metabolic pattern suggesting a cortical lamination defect in the non-HME hemisphere, bilateral independent seizure onset, and was not considered to be a surgical candidate. We found a general correlation between the pattern of glucose utilization in the less affected hemisphere and prognosis. Although the follow-up periods are short, it is recommended that HME children with intractable epilepsy undergo hemispherectomy in the first year of life in order to allow maximal brain plasticity to occur; however, preoperative evaluation should also include an assessment of the integrity of the non-HME hemisphere.

Recent developments in neuroimaging have advanced our capability to diagnose and perform presurgical evaluations in a large proportion of children without recourse to invasive monitoring techniques. Functional imaging is also providing us with novel insights into the mechanism of certain childhood epileptic syndromes. The role of anatomic (computed tomography, magnetic resonance imaging) and functional (single photon emission computed tomography, positron emission tomography) imaging modalities in the diagnosis and therapeutic decision making in major epileptic syndromes of childhood is reviewed.

Decreased glucose utilization in the epileptogenic zone is typically observed interictally on positron emission tomography (PET), whereas ictal PET studies reveal complex patterns of increased and decreased metabolism. PET findings of 7 children, ages 2 months to 16 years, are described and demonstrate small focal regions of hypermetabolism in the absence of clinical or electrographic seizure during the 2-deoxy-2[18F]fluoro-D-glucose (FDG) uptake period. Magnetic resonance imaging scans were nonlocalizing in 5 of 7 children. In 4 children, seizures had not occurred for at least several hours prior to PET. Electroencephalography during PET disclosed active spike-and-wave activity on the side of interictal hypermetabolism in these 4 children. The remaining 3 children had seizures within 15 min prior to FDG injection and were considered postictal; their PET images revealed focal hypermetabolism. Results indicated the need for electroencephalographic monitoring during functional neuroimaging studies of all epileptic patients. The biochemical basis of interictal hypermetabolism is probably related to increased energy consumption by an active epileptogenic focus, whereas postictal hypermetabolism is likely due to energy expenditure for the restoration of resting membrane potentials and chemical homeostasis following an epileptic event.

Positron emission tomography (PET) is an imaging technique that allows local chemical and physiologic functions in various body organs to be measured. Studies of local cerebral glucose metabolism in infants and children using PET have provided important information on human brain functional development and plasticity. In the neonate, PET studies have provided important clues into the pathophysiology of hypoxic-ischemic injury. Patterns of cerebral glucose utilization in various clinical subtypes of cerebral palsy associated with perinatal brain injury are discussed and contrasted to metabolic patterns seen in cerebral palsy without clear etiology. Expanding PET technology provides a new approach that holds great promise in the diagnosis and management of brain disorders affecting the neonate.

Using in vitro autoradiography, mu receptor binding in rat brain was characterized at different amygdala kindling stages and in amygdaloid kindled animals pretreated chronically with naloxone. Male Sprague-Dawley rats implanted with bipolar electrodes in the right amygdala received one of the following pretreatments s.c. for 14 days via osmotic minipumps: normal saline solution, 0.5 microliters/h, or naloxone HCl, 75 micrograms/h. Two days after treatments were accomplished animals were stimulated daily. Our data showed different patterns of mu receptor binding during the normal kindling process: during stage II-III, pronounced binding increase was detected in cingulate, temporal and entorhinal cortices, anterior amygdala, caudate putamen, thalamic nuclei, ventrolateral and dorsolateral portions of central gray, substantia nigra pars compacta and pars reticulata. Twenty-four hours after the last stage V kindled seizure, enhanced binding was observed in cingulate and frontoparietal cortices, anterior amygdala, caudate putamen and ventromedial thalamic nucleus. Twenty-eight days after the last stage V kindled seizure, binding augmentation was noticed in cingulate and frontoparietal cortices, whereas decreased binding was detected in amygdala complex, substantia nigra pars reticulata, piriform, perirhinal, parietal, temporal and entorhinal cortices. Mu receptor binding in kindled rats chronically pretreated with naloxone was significantly higher in several structures when compared with control and normal kindled groups. Our data indicate different regional selective patterns of mu receptor binding during amygdala kindling which may depend on epileptogenesis and long-term changes induced by this process. In addition, even higher mu receptor binding results from chronic naloxone administration prior to kindling.

The effects of chronic administration of naloxone, morphine and met-enkephalin on benzodiazepine (BDZ) receptor binding in rat brain were determined 2 and 50 days after treatments were accomplished. Two days after naloxone treatment (75 micrograms/h s.c. for 14 days), enhanced BDZ receptor binding was observed in cingulate, frontal, piriform, entorhinal and sensorimotor cortices; amygdala complex, hippocampus, substantia nigra and central gray. Two days after morphine treatment (20 mg/kg i.p. daily for 6 days), increased BDZ receptor binding was detected in cingulate, frontal, piriform, entorhinal and sensorimotor cortices; amygdala complex, hippocampus and substantia nigra. Two days after met-enkephalin treatment (10 micrograms/h i.c.v. for 6 days) enhanced BDZ receptor binding was shown only in sensorimotor cortex. No significant changes were observed 50 days after the treatments were completed. These data indicate an important interaction between GABAergic and opioid peptide systems.

Twenty-three infants and children underwent cortical resection (n = 15) or hemispherectomy (n = 8) for intractable infantile spasms. Infantile spasms were present at the time of surgery in 17 of the 23 patients; in six, spasms had evolved to other seizure types during surgical evaluation. Children with a remote history of infantile spasms were excluded from this study. Focal or hemispheric lesions were identified by magnetic resonance imaging in seven children; an additional two showed focal atrophy without a discrete lesion. Positron emission tomography (PET) showed lateralized or localized abnormalities of cerebral glucose utilization in all patients; in 14, PET was the only neuroimaging modality to identify the epileptogenic cortex. When this occurred, neuropathological examination of resected brain tissue typically showed malformative and dysplastic cortical lesions. Focal interictal and/or ictal electrographic abnormalities were present in all patients, and corresponded well with localization from neuroimaging. None of the patients were subjected to chronic invasive electrographic monitoring with intracranial electrodes. At follow-up (range 4-67 months; mean 28.3 months), 15 children were seizure-free, three had 90% seizure control, one had 75% seizure control, and four failed to benefit from surgery with respect to seizure frequency.