Harry T. Chugani

Sturge-weber syndrome: A study of cerebral glucose utilization with positron emission tomography

We measured local cerebral metabolic rate for glucose (ICMRGIc) using positron emission tomography (PET) in six children with Sturge-Weber syndrome (SWS) and in six neurologically asymptomatic children with facial capillary hemangioma suggestive of SWS. Children with advanced SWS showed markedly depressed ICMRGIc in the anatomically affected cerebral hemisphere in a distribution that extended beyond the abnormalities depicted on computed tomography scan. In two infants with SWS and recent seizure onset, interictal PET revealed a paradoxical pattern of increased ICMRGIc in the cerebral cortex of the anatomically affected hemisphere. In one of these infants, ICMRGIc was also increased in the contralateral cerebellum, suggesting activation of the cortico-ponto-cerebellar circuitry. Subsequent PET (28 months later) in this child revealed the typical ICMRGIc pattern seen in advanced SWS. Further study of this transient ICMRGIc increase may be important in disclosing the pathogenesis of unilateral cerebral degeneration in SWS. In neurologically asymptomatic children with the facial stigmata of SWS and in children with early SWS, PET provides a sensitive measure of the extent and degree of cerebral metabolic impairment. Serial PET studies in children with SWS can be used to assess disease progression and, together with computed tomography or magnetic resonance imaging, may be useful in the selection of suitable candidates for cerebral hemispherectomy or focal cortical resection.

Surgical treatment of intractable neonatal‐onset seizures The role of positron emission tomography

We have performed positron emission tomography (PET) with 2-deoxy-2[18F]fluoro-D-glucose (FDG) in eight infants and children (aged 18 days to 5 years) with medically refractory epilepsy of neonatal onset. It was hypothesized that in at least some of these infants a surgical approach (focal resection, cerebral hemispherectomy) might be of benefit in achieving seizure control, and that PET might assist in surgical selection. In three of the eight subjects, interictal PET revealed unilateral diffuse hypometabolism; following cerebral hemispherectomy in these three patients, all seizures ceased and there were no adverse effects. In one child, ictal PET showed hypermetabolism in the left frontal cortex, left striatum, and right cerebellum; a partial left cerebral hemispherectomy guided by intraoperative electrocorticography was performed, following which all seizures ceased. One infant had relative hypermetabolism in the right temporal and occipital lobes, right thalamus, and left frontal lobe on ictal PET, and EEG telemetry revealed a right occipitotemporal epileptic focus; this infant died from anesthetic complications following right occipitotemporal cortical resection. Of the three unoperated patients, one is a potential candidate for right frontal lobectomy, but the other two were not considered to be surgical candidates due to bilateral epileptogenicity. Neuropathologic correlation in our series revealed that PET is a sensitive test capable of detecting cytoarchitectural disturbances whereas CT and MRI failed in this regard. In addition, PET provides a very unique and important assessment of the functional integrity of brain regions outside the area of potential resection.

Interictal and postictal focal hypermetabolism on positron emission tomography

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.

ELECTROCORTICOGRAPHIC CONFIRMATION OF FOCAL POSITRON EMISSION TOMOGRAPHIC ABNORMALITIES IN CHILDREN WITH INTRACTABLE EPILEPSY

Summary: The relationship between focal disturbances of glucose utilization demonstrated by positron emission tomography (PET) and electrophysiologic abnormalities defined by intraoperative electrocorticography (ECoG) was studied in eight children (aged 13 months to 12 years) who underwent cortical resection because of intractable seizures. None of the children had pure temporal lobe epilepsy. Computed tomography (CT) and/or magnetic resonance imaging (MRI) were normal in four of the eight children. The scalp electroencephalogram (EEG) showed lateralized interictal epileptiform abnormalities in all eight and lateralized ictal onset in five of eight. In seven children, interictal PET showed focal hypometabolism; the eighth child had focal, ictal hypermetabolism. ECoG at the time of surgery showed epileptiform spiking, slowing, and/or suppression of normal background activity that in every case corresponded to the focus on PET scan. The ECoG findings support the notion that in children with epilepsy focal metabolic abnormalities on PET correspond to electrophysiologically abnormal areas of cortex, which are presumably also the epileptogenic regions. Such areas can appear normal on anatomic imaging studies (CT and MRI). When ictal scalp EEG data are ambiguous or contradictory, PET provides a less invasive means than chronic grid or depth electrode recording for evaluating whether a localized epileptogenic area exists.

Temporal and Extended Temporal Resections for the Treatment of Intractable Seizures in Early Childhood

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.

Functional Brain Imaging in Pediatrics

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.

Cerebral hemidecortication alters expression of transforming growth factor alpha mRNA in the neostriatum of developing rats

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)

Neurosurgical Treatment of Refractory Status Epilepticus

Summary: 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 > 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.

Cerebral Metabolism Following Neonatal or Adult Hemineodecortication in Cats: I. Effects on Glucose Metabolism Using [14C]2-Deoxy-D-Glucose Autoradiography

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; μmol 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 μmol 100 g-1 min-1) than NH (ranging from 49 to 81 μmol 100g-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 μmol 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 μmol 100 g-1 min-1, which were significantly lower (p < 0.05) than in NH cats (range 47–72 μmol 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 μmol 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.

Maturation of Cerebral Oxidative Metabolism in the Cat: A Cytochrome Oxidase Histochemistry Study

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 neuro-behavioral studies.