Faculty Bibliography

Developmental brain plasticity in association with focal brain injury is dependent on a number of factors, including age of the individual at the time of injury, size and topography of the brain lesion, maturational state of the brain system injured, integrity of brain areas surrounding and contralateral to the lesion, presence and duration of epilepsy, and medication effects. Recently developed functional neuroimaging tools now make it possible to study non-invasively several aspects of human brain functional reorganization in response to injury. Clinical models which are suitable for the study of developmental brain plasticity include patients who have undergone cortical resections for the alleviation of intractable epilepsy, patients who have sustained unilateral cerebrovascular insults at various periods of development, patients with chronic progressive unilateral brain injury such as in the Sturge-Weber syndrome, and patients with early sensory deprivation such as blind or deaf subjects. Although evidence of functional brain reorganization can be demonstrated in these models, it is emphasized that the neurobiological rules that govern intrahemispheric versus interhemispheric reorganization of function in the brain are, at present, poorly understood.

This prospective case study examined social communication (i.e., formal thought disorder, cohesion), language, positron emission tomography glucose utilization, and neuropathology in four children with Rasmussen encephalitis who achieved seizure control following right hemispherectomy. Prior to hemispherectomy, all four children had illogical thinking, loose associations, cohesive deficits, and impaired performance on formal language tests. Their postoperative improvement in social communication and language appeared to be related to age of onset, duration of illness, and postsurgical reversibility of hypometabolism in the nonresected prefrontal cortex. These changes were not associated with increase in IQ scores. The variability in the type and extent of pathologic change across subjects reflected the severity and duration of the illness. The study's findings imply that early surgical intervention might have mitigated certain aspects of the social communication and linguistic deficits found in these children.

Alpha-[11C]methyl-L-tryptophan (AMT) has been synthesized by stereoselective methylation with [11C]methyl iodide of the lithium-enolate generated by treating dimethyl 2(S), 3a(R), 8a(S)-(+)-hexahydro-8(phenylsulfonyl)pyrrolo [2, 3-b]indole-1,2-dicarboxylate (2) with lithium diisopropyl amide (LDA) at -55 degrees C, followed by ring opening using trifluoroacetic acid and alkaline hydrolysis of the protecting groups. The crude product was purified by a simple reverse-phase C-18 Sep-Pak procedure. The purified product was isolated with an average radiochemical yield of 53 +/- 12% (decay corrected) in 30-35 min from [11C]methyl iodide. At end of synthesis (EOS), 138 +/- 35 mCi (n = 24) of product was collected with a specific activity of ca. 1-1.3 Ci/mumol (EOS) (4-5 Ci/mumol @ EOB) starting from 1.5 Ci (EOB) of [11C]CO2.

Fifty-eight children who underwent anatomical, functional, or modified anatomical hemispherectomy for intractable seizures from 1986 to 1995 were evaluated for seizure control, motor function, and complications. Age at surgery ranged from 0.3 to 17.3 years (median 2.8 years). Twenty-seven anatomical, 27 functional, and 4 modified anatomical hemispherectomies were performed. Seizure control and motor function in the 50 patients with more than 1 year follow-up revealed a 90% or better reduction in seizure frequency in 44/50 (88%) overall: 19/22 (86%) anatomical, 23/26 (89%) functional, and 2/2 modified anatomical. Motor function of the preoperatively hemiparetic extremities was improved or unchanged postoperatively in 38/50 (76%) of the patients. Complications included one intraoperative death, one late death from shunt obstruction managed elsewhere, late postoperative seizure breakthrough requiring reoperation and further disconnection in 5/27 functional hemispherectomy patients, mild cerebrospinal fluid infections in 3/27 anatomical hemispherectomy patients, and hydrocephalus requiring shunting in 3/27 functional hemispherectomy patients. A review of the literature and comparison of techniques is presented.

The classification of infantile spasms into symptomatic, cryptogenic, and idiopathic subgroups depends on clinical examination and available diagnostic technology. Positron emission tomography (PET) of glucose utilization is a powerful tool in detecting brain malformations (particularly cortical dysplasia) in infants with spasms. We analyzed etiologic data from 140 such infants, 78 girls and 62 boys, ages 2 months to 4 years 10 months (mean, 17 months). All had been evaluated extensively in one of two major medical centers. It should be emphasized that our referral population is biased toward infants with intractable spasms who fail to show a structural lesion. Seven patients had neurocutaneous syndromes, two had chromosomal abnormalities, two had inborn errors of metabolism, and one each had craniosynostosis or Menkes syndrome. Computed tomography and/or magnetic resonance imaging detected lesions in another 29 infants (20.7%) who did not have a specific disease or syndrome. Without the benefit of PET, the total number of symptomatic cases was 42 (30.0%). One infant, classified as idiopathic, had normal development and PET. In 97 cryptogenic cases, PET uncovered unifocal abnormalities in 30 and multifocal abnormalities in 62. Diffuse PET abnormalities, which did not provide specific etiologic information, were seen in three infants. Another two infants had normal PET scans. Thus, with the benefit of PET, the number of symptomatic cases rose dramatically from 42 (30.0%) to 134 (95.7%). The majority of unifocal and multifocal abnormalities on PET are believed to represent dysplastic lesions.

Positron emission tomography (PET) of brain glucose utilization is highly sensitive in detecting focal cortical abnormalities in patients with infantile spasms even when the computed tomographic (CT) and magnetic resonance imaging (MRI) scans are normal. Of 110 infants with spasms evaluated for potential surgical intervention during an 8-year period, we encountered 18 infants (7 males, 11 females; age range, 10 mo to 5 yr) with a common metabolic pattern on positron emission tomography (PET) consisting of bilateral hypometabolism in the temporal lobes. CT and MRI scans did not reveal any focal abnormalities in the 18 infants. Video-electroencephalographic monitoring indicated either bilateral or multifocal epileptogenicity, or failed to show any epileptic focus, so that none of the 18 infants were considered candidates for resective surgery. These patients were then enrolled in a prospective study aimed at determining long-term outcome in the presence of bilateral temporal PET hypometabolism. Analysis of outcome in 14 of the 18 subjects (follow-up period, 10 mo to 10 yr 5 mo; mean, 3 yr 11 mo +/- 2 yr 4 mo [SD]) revealed the following: (1) all had severe developmental delay and had failed to gain significant milestones; (2) language development had been minimal or absent; (3) 10 of the 14 met the DSM-IV criteria for autistic disorder. Our findings indicate that patients with infantile spasms and bitemporal glucose hypometabolism on PET comprise a relatively homogeneous group and are typically not candidates for cortical resection. The long-term outcome of these infants is particularly poor and the majority are autistic.

In the cat, cerebral hemispherectomy sustained neonatally results in a remarkable degree of recovery and/or sparing of function as compared with the effects of a similar lesion but sustained in adulthood. We have proposed that this effect is due to a combination of reduced neuronal loss within partially denervated structures and a lesion-induced reorganization of corticofugal projections arising from the remaining intact hemisphere in the neonatally lesioned animal. The current study was designed to assess the physiological consequences of these anatomical changes utilizing [14C]2-deoxy-D-glucose autoradiography. A total of 17 adult cats were studied. Seven animals served as intact controls, five received a left cerebral hemineodecortication as neonates (NH; mean age 11.4 days), and five sustained the same lesion in adulthood (AH). Histological analysis indicated that the lesion was very similar between the two age groups and essentially represented a unilateral hemineodecortication. Local CMRglc (LCMRglc; mumol 100 g-1 min-1) values were calculated for 50 structures bilaterally and indicated that in the remaining intact contralateral (right) cerebral cortex (including all areas measured), AH cats exhibited a significantly (p < 0.05) lower level of LCMRglc (ranging from 20 to 72 mumol 100 g-1 min-1) than NH (ranging from 49 to 81 mumol 100 g-1 min-1). In comparison, the rates of NH cats within the cerebral cortex were very similar to those seen in intact animals (ranging from 48 to 119 mumol 100 g-1 min-1). Ipsilateral to the lesion in AH cats, the structures spared by the resection, including the basal ganglia and thalamus, exhibited LCMRglc rates of between 23 and 69 mumol 100 g-1 min-1, which were significantly lower (p < 0.05) than in NH cats (range 47-72 mumol 100 g-1 min-1). Considering all structures, both age-at-lesion groups exhibited a lower level of metabolism compared with similar measurements for intact control animals (LCMRglc range 45-75 mumol 100 g-1 min-1). However, this depression of glucose metabolism was more pronounced in the AH cats (p < 0.05). These results indicate that following neonatal hemineodecortication, LCMRglc is maintained at a higher level in many regions of the brain than in animals that sustain the same resection in adulthood. This higher level of glucose metabolism in NH animals suggests that the lesion-induced anatomical reorganization of structures not directly injured by the lesion plays a functional role that is probably responsible for the greater degree of recovery and/or sparing of function in these early lesioned cats.