Faculty Bibliography

The present study investigated a recently developed benzodiazepine, midazolam, as an intravenous adjuvant to ketamine in infant monkeys undergoing prolonged sedation during positron emission tomography of the brain and heart. Subjects were two rhesus macaque (Macaca mulatta) and ten vervet monkeys (Cercopithecus aethiops sabaeus) ranging in age from 26 to 260 days. Midazolam was an effective intravenous adjuvant to ketamine. This treatment regime resulted in complete immobilization of the animals. Ketamine infusion rates did not vary significantly with age for either species. Sensitivity to midazolam appeared to be age-dependent in vervets because significantly lower dose rates were sufficient to maintain anesthesia in older animals. For rhesus monkeys, midazolam dose rates decreased until approximately 4 months of age, and increased gradually thereafter. © 1993 Wiley-Liss, Inc.

The maturation of brain oxidative capacity was studied in kittens, using cytochrome oxidase histochemistry, at different ages throughout development. Optical densitometry values of reacted tissue were obtained for 50 different structures of the brain. In general, most structures reached adult levels of oxidative capacity by 30 days of age with some motor areas (e.g., cerebellum, red nucleus) exhibiting adult values as early as 7 days of age. Thereafter, some structures (e.g., basal ganglia, thalamus) exhibited levels of cytochrome oxidase activity that exceeded adult values for varying periods of time. These findings indicate regional heterogeneity in the maturation of cerebral oxidative capacity. Furthermore, these maturational patterns appear to correlate well with previous observations from anatomical, physiological and neurobehavioral studies.

Positron emission tomography (PET) of local cerebral glucose utilization is highly sensitive in detecting epileptogenic regions that correspond to electrographic localization in patients with epilepsy. In medically refractory temporal lobe epilepsy for which surgical resection of the epileptogenic zone is a therapeutic option, the application of PET enables more than 50% of adults and older children to be successfully operated on without the necessity for chronic intracranial electrographic monitoring. In infants with intractable infantile spasms and various types of partial epilepsy, PET has uncovered focal areas of cortical dysplasia and other anatomic abnormalities, which, after resection, have resulted in cessation of seizures and developmental improvement. The distribution of PET abnormality is in excellent agreement with the extent of the epileptogenic zone as determined by intraoperative electrocorticography, thus avoiding the necessity for chronic intracranial electrographic monitoring in 90% of these infants. As a result of PET, the preoperative evaluation of intractable epilepsy in both adults and children has become less invasive and less costly.

With the development of noninvasive tomographic imaging techniques, it is now possible to measure local chemical and physiologic functions in various body organs. Studies of local cerebral glucose metabolism in infants and children using positron emission tomography (PET) have provided important information on human brain functional development and plasticity. The clinical application of functional neuroimaging techniques in the management of pediatric neurologic disorders has yielded encouraging results. In children with intractable epilepsy being considered for surgical intervention, PET is highly sensitive in localizing focal areas of cortical dysplasia, heterotopias, and other migrational defects corresponding to surface electrographic localization of epileptogenic regions. Expanding PET technology provides a new approach that holds great promise in the diagnosis and management of brain disorders in children.

Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite aggressive treatment. A 9.8-year-old boy with a past history of daily left focal motor seizures was transferred to University of California at Los Angeles (UCLA) Hospital in pentobarbital coma after 4 days in RSE. The RSE was treated with very high doses of all appropriate antiepileptic drugs (AEDs), alone and in combination. The pentobarbital was titrated to burst suppression on EEG, but whenever pentobarbital was decreased, the seizures recurred. An ictal positron tomography scan of glucose metabolism demonstrated a right frontal area of hypermetabolism corresponding to an epileptic focus on EEG and magnetic resonance lesion. Eight days after the boy was admitted to UCLA, the right frontal focus was surgically removed, with immediate control of the status epilepticus. Whereas before onset of RSE, he had daily focal seizures, the boy has been seizure-free postoperatively for greater than 1 year. Operative treatment should be considered in patients with RSE in whom a focus of seizure onset can be demonstrated and who are reasonably considered surgical candidates.

Infantile spasms are generalized seizures specific to early infancy, and are believed to result from complex cortical-subcortical interactions during a critical period of development. We used positron emission tomography (PET) to determine local cerebral metabolic rates for glucose (1CMRG1c) in 44 infants with spasms, in an attempt to define the neuroanatomical substrates that mediate these seizures. All infants were studied in the awake state during continuous electroencephalographic monitoring. The most consistent abnormality on PET, seen in 32 infants, was the symmetrical increase in 1CMRG1c in the lenticular nuclei, compared to age-matched normal infants (p less than 0.05). In 21 infants, even though the brain stem appeared to be visually more prominent compared to normal infants, statistically significant differences could not be demonstrated. Relative hypermetabolism of the lenticular nuclei (1) occurred irrespective of whether the spasms were cryptogenic or symptomatic, (2) was associated with focal cortical hypometabolism in 22 and focal cortical hypermetabolism in 5 of the 44 infants, and (3) was not characterized by any specific electroencephalographic abnormality during PET. These findings suggest that the lenticular nuclei may contribute to the pathophysiological state that predisposes to infantile spasms, and is consistent with the observation that spasms are clinically symmetrical even when focal cortical lesions are present. A scheme describing the neuronal circuitry likely to be involved in the generation of infantile spasms is proposed.

In our series of 33 children who underwent temporal and extended temporal lobe resections because of seizures, the average age at surgery was 7 years, 11 months. Sixteen cases (48%) were diagnosed as having tumors: low-grade astrocytoma (6), hamartoma (5), and ganglioglioma/neuroma (5). Other pathologic diagnoses included one or more cytoarchitectural abnormalities and/or reactive changes. Due to a more aggressive and early radiologic and electrophysiologic investigation of children with seizures, a resectable focus, e.g. neoplasm or structural abnormality, was found in a much younger age group of patients than previously reported. In children who had intractable seizures but normal radiologic studies, positron emission tomography was of great value in localizing the seizure focus. In a group of children with infantile spasms, seizures were controlled following the identification and resection of a focal lesion. Prompt detection and precise localization of lesions in the temporal lobe in the pediatric population may lead to surgical management and seizure control.