Faculty Bibliography

Male Sprague-Dawley rats received either naloxone (75 micrograms/h) or saline (0.5 microliter/h) s.c. for 14 days delivered with osmotic minipumps. Two days after termination of either treatment, daily amygdala kindling stimulation was applied until the animals experienced stage V kindled seizures. Benzodiazepine (BDZ) binding sites were labeled with [3H]flunitrazepam (2 nM), and changes in specific brain areas were determined by in vitro quantitative autoradiography. Twenty-four hours after the last electrical stimulation, the saline pretreated fully kindled rats showed enhanced BDZ receptor binding in dentate gyrus, and decreased binding in cingulate cortex ipsilateral to the stimulation compared to saline controls. Twenty-eight days after the last stage V kindled seizure, the significant alterations were no longer evident. In agreement with a previous study, we found that naloxone pretreated amygdala kindled rats showed stage V kindled seizures followed by intervals of 3-5 days in which the same electrical stimulation failed to induce any behavioral and EEG alterations. In comparison with the saline pretreated kindled and saline control groups, the naloxone pretreated kindled rats had significantly higher BDZ binding in different cortical areas, amygdala complex, hippocampus, substantia nigra and periaqueductal gray, 24 h after the last electrical stimulation. The present study indicates that previous chronic exposure to naloxone increases BDZ receptor binding in kindled rats, and suggests that this effect may be associated with the enhanced seizure suppression observed in these animals.

To determine seizure propagation patterns, we analyzed ictal positron emission tomography (PET) studies of regional cerebral glucose utilization in 18 children (11 male and 7 female aged 2 weeks to 16 years) with epilepsy (excluding infantile spasms IS). Three major metabolic patterns were determined based on degree and type of subcortical involvement: Nine children had type I; asymmetric glucose metabolism of striatum and thalamus. Of these, the 7 oldest children showed unilateral cortical hypermetabolism (always including frontal cortex) and crossed cerebellar hypermetabolism. Two infants (aged < 1 year) had a similar ictal PET pattern but no cerebellar asymmetry, presumably owing to immaturity of corticopontocerebellar projections. Five children had type II, symmetric metabolic abnormalities of striatum and thalamus; this pattern was accompanied by hippocampal or insular cortex hypermetabolism, diffuse neocortical hypometabolism, and absence of any cerebellar abnormality. Four children had type III, hypermetabolism restricted to cerebral cortex. This classification can accommodate ictal PET and single photon emission computed tomography (SPECT) patterns described by other investigators. Future studies should be directed at the clinical relevance of this classification, particularly with regard to epilepsy surgery.

Transforming growth factor alpha (TGF alpha) is a mitogenic polypeptide which acts at the epidermal growth factor receptor to produce its biologic effects. Recent studies have demonstrated that TGF alpha may act as a neurotrophic factor. Cerebral hemispherectomy (hemidecortication) is performed on some children with intractable epilepsy. Prior studies have demonstrated improved functional recovery in both children and animals when the surgery is performed at a very early age. In order to test whether TGF alpha may be involved in the functional recovery of the neostriatum following cerebral hemidecortication, we performed in situ hybridization for TGF alpha mRNA on brains of rats which underwent hemispherectomy at postnatal day (P) 6 or P12 or in adulthood, and sacrificed one, 7, or 30 days following surgery. Normal striatal expression in control animals was very high at P6 and then decreased throughout development. In animals undergoing lesion at earlier ages (P6 and P12), TGF alpha mRNA expression was first depressed in the ipsilateral neostriatum one day after surgery and then elevated to supranormal levels 7 and 30 days after surgery. Maximal decreases (40% below contralateral neostriatum) were seen in animals lesioned at P12 and sacrificed the next day. Maximal elevations (60% greater than opposite neostriatum) were seen in animals operated on at P6 and sacrificed 30 days post surgery. Expression in the adult animal was only mildly affected, with a 20% increase found in the ipsilateral caudate 7 days after the lesion, but no significant changes after one or 30 days survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Positron emission tomography (PET) with 2-deoxy-2[18F]fluoro-D-glucose (FDG) was used to study 9 children who demonstrated complete or partial agenesis of the corpus callosum (ACC) on magnetic resonance imaging (MRI). Of the 7 patients with epilepsy, FDG-PET clearly localized areas of cortical metabolic abnormality in 6 patients; in 5 of these, localization of the metabolic abnormalities on PET corresponded to electroencephalographic localization of epileptogenicity. MRI documented focal cortical abnormalities in only 2 of the 7 children with epilepsy. In 1 patient, the abnormality observed on MRI was confined to a frontal lobe, whereas the FDG-PET study revealed hypometabolism of the entire hemisphere. One patient with infantile spasms exhibited bilateral multifocal epileptiform discharges on electroencephalography, whereas both the PET and MRI revealed only left hemispheral cortical abnormalities. Another patient with infantile spasms had prominent brainstem glucose metabolic activity on FDG-PET in the absence of any MRI or PET cortical abnormality. Two children underwent surgery because of refractory seizures; the resected cortical tissue in both patients consisted of cortical microdysgenesis. Seizure control improved significantly in both patients. FDG-PET studies in the 2 highest functioning patients (i.e., only minor learning disabilities and no epilepsy) did not reveal any focal cortical hypometabolism; therefore, there appears to be an association between the presence of focal metabolic abnormalities on PET and the presence of seizures in ACC patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional brain imaging with positron emission tomography (PET) has led to significant advances in the diagnosis and management of various forms of childhood epilepsy. Interictal PET in temporal lobe epilepsy typically shows decreased glucose utilization (hypometabolism) in one or both temporal lobes. Children with early-onset refractory extratemporal lobe epilepsy who do not manifest structural abnormalities on magnetic resonance imaging often show single or multiple cortical foci of hypometabolism indicating underlying microdysgenesis that corresponds to the area of epileptogenicity. The findings of focal cortical metabolic lesions and metabolic activation of subcortical structures (brain stem and lenticular nuclei) in patients with infantile spasms have allowed many infants with intractable spasms to be treated surgically with cortical resection, and have altered our concepts regarding the pathophysiology of these seizures. New observations in Lennox-Gastaut syndrome, Sturge-Weber syndrome, tuberous sclerosis, hemimegalencephaly, Landau-Kleffner syndrome, and other pediatric epilepsy syndromes have been documented with PET and have improved our understanding of these disorders. Recent PET studies of several neurotransmitter receptors in adult epileptic patients suggest that this approach holds great promise in the study of childhood epilepsy. The current guidelines indicating which patients with epilepsy should be referred for a PET study are outlined.

We have studied seven patients with Spielmeyer-Vogt disease (SV), aged 11-29 years, using PET and 2-deoxy-2[18F]fluoro-D-glucose. Five patients showed a distinctive age-related progression with decreased metabolic activity starting in the calcarine area and spreading rostrally to the entire cortex, leaving normal uptake only in the basal ganglia and brainstem of the oldest patients. Calcarine hypometabolism was mild in the youngest patient. All patients, including the youngest when the study was repeated 2 years later, had significantly decreased calcarine metabolic activity (P = 0.002). Two patients had PET patterns markedly different from the five others, with significantly decreased metabolic activity in most brain areas. Both patients may represent a new SV variant. An adult pathological control with congenital amaurosis showed normal cerebral metabolic activity in all areas. Two patients had older sisters, one now deceased, the other not available for study, who presented a rapid regression associated with epilepsy. Phenytoin and carbamazepine probably caused increased seizure activity and faster regression. The younger siblings treated with phenobarbital monotherapy had few seizures and maintained motor functions 5-8 years longer compared with their respective sisters. While the clinical course made obvious that some areas, such as the macula, are damaged before others, the progression from the calcarine area to the more anterior regions (but sparing the basal ganglia) provides unexpected insights into selective vulnerability of neurons that will allow a more precise way of monitoring individual patients.