C. Ákos Szabó

Neuropsychological Effect of Temporal Lobe Resection in Preadolescent Children with Epilepsy

Summary: Purpose: Numerous studies have demonstrated changes in cognitive, memory, and language functioning in adults and adolescents after temporal lobectomy, yet little information is available regarding neuropsychological outcome in preadolescent children.

Epilepsy surgery in children with pervasive developmental disorder

Pervasive developmental disorder (PDD) is occasionally associated with medically intractable complex partial seizures. The outcome of PDD was explored in three males and two females who underwent epilepsy surgery at 32 months to 8 years of age (mean = 4 years) after onset of epilepsy at 1 week to 21 months of age (mean = 11 months). Four children had temporal lobe resections (three right, one left; two for focal cortical dysplasia, and two for tumors), and one had a right temporoparieto-occipital resection (for focal cortical dysplasia). Each child underwent repeated evaluations by a pediatric neuropsychologist and psychiatrist. Fourteen to 47 months (mean = 23 months) after operation, one child with persistent seizures had moderate developmental and behavioral improvement, three children (two seizure free, one with rare staring spells) had mild developmental and behavioral improvement, and the remaining child (seizure free) experienced a worsening of her PDD. The four children with mild-to-moderate improvement in postoperative cognitive and behavioral development still demonstrated persistent delay. Cognitive gains were confirmed by neuropsychologic testing in the oldest patient but were not reflected in test results from the three younger children, who had more modest improvement. The child with worsening of her PDD had cognitive and emotional deterioration to babbling, echolalia, aggressiveness, decreased social interaction, and increased mouthing of objects beginning several months postoperatively. These results suggest that families should be counseled that PDD symptoms in children with focal epileptogenic lesions may or may not improve after epilepsy surgery, even if the surgery is successful with respect to seizure control.

Intracarotid amobarbital testing for language and memory dominance in children

The intracarotid amobarbital procedure (IAP) was attempted in 22 pediatric epilepsy surgery candidates, ages 5-12 years old. With extra pre-test teaching and emotional preparation, adjusted amobarbital dosage for younger patients, and simplified test items tailored to the childs abilities, language and memory testing were accomplished after at least one injection for 19 (86%) of patients. Language dominance was clarified in 11 children overall (50% of patients), in all of the children who had bilateral testing and at least borderline intelligence (IQ > 70), and in 57% of the children with mild or moderate mental retardation. Memory assessment was accomplished in 18 children after amobarbital injection of the hemisphere ipsilateral to the predominant epileptogenic zone. IAP retention scores tended to be lower in children than adults, especially in the setting of mental retardation. Retention scores after ipsilateral injection were > 60% in all 10 of the children with at least borderline intelligence, but < 60% (25-50%) in five of eight children with mental retardation. Retention scores after contralateral injection were > 60% in only four of 12 children. Our results suggested that a modified pediatric IAP protocol can clarify the hemisphere of language dominance in most verbal preadolescent children with at least borderline intelligence, and in many children with mental retardation. However, IAP memory retention scores tended to be lower in children than adults and should be interpreted with caution.

Mortality in captive baboons with seizures: a new model for SUDEP?

Because the baboon is a model of primary generalized epilepsy, we were interested in mortality of captive animals with a history of witnessed seizures. Causes of natural death were investigated in 46 seizure baboons (SZ) and 78 nonepileptic controls (CTL), all of which underwent a complete pathologic examination at the Southwest Foundation for Biomedical Research (SFBR) in San Antonio. SZ animals died at a younger age than the control baboons (p < 0.001). Almost all epileptic baboons that died suddenly without an apparent cause (SZ‐UKN), had pulmonary congestion or edema without evidence of trauma, systemic illness, or heart disease, compared to nine controls (12%) (p < 0.001), most of which demonstrated evidence of a concurrent illness. Serosanguineous bronchial secretions were found in 15 SZ‐UKN baboons (58%), but in only three controls (4%) (p < 0.001). Chronic multifocal fibrotic changes in myocardium were noted in only three (12%) of SZ‐UKN baboons and one control baboon. Based upon these results, untreated seizures appear to reduce the life expectancy of captive baboons. Sudden unexpected death in epilepsy (SUDEP) may be a common cause of natural death in epileptic baboons.

Clinical and EEG phenotypes of epilepsy in the baboon (Papio hamadryas spp.)

Spontaneous seizures have been reported in several baboon subspecies housed at the Southwest Foundation for Biomedical Research (SFBR), including Papio hamadryas anubis as well as cynocephalus/anubis and other hybrids. This study classified clinical and electroencephalographic (EEG) phenotypes in these subspecies based upon interictal and ictal findings, as well as photosensitivity, by scalp EEG. One hundred baboons underwent 1-h EEG studies with photic stimulation (PS), 49 with previously witnessed seizures and 51 without. The animals were classified according to these electroclinical phenotypes: presence or absence of interictal epileptic discharges (IEDs), seizures and photoparoxysmal or photoconvulsive responses. Effects of age, gender, and species on EEG phenotypes were also examined. Six discrete electroclinical phenotypes were identified. Generalized IEDs of 2-3, 4-6, and/or 6-7Hz were identified in 67 baboons. Epileptic seizures were recorded in 40 animals, including myoclonic and generalized tonic-clonic seizures. Thirty-three animals were photosensitive. Although the prevalence of IEDs and seizures were similar in seizure and asymptomatic animals, photosensitivity was more prevalent in the seizure animals (p=0.001). P.h. anubis/cynocephalus hybrids were more likely to be photosensitive than P.h. anubis (p=0.004). The reliable characterization of distinct epileptic phenotypes in this pedigreed colony is critical to the success of future genetic analyses to identify genetic factors underlying their epilepsy.

PET imaging in the photosensitive baboon : Case-controlled study

Summary:  Purpose: The baboon (Papio hamadryas spp) offers a natural primate animal model of photosensitive generalized epilepsy. This study compared changes in cerebral blood flow (CBF) during intermittent light stimulation (ILS) between photosensitive and asymptomatic baboons.

Epileptic baboons have lower numbers of neurons in specific areas of cortex

Significance We examined the variability of neuron packing densities across cortical regions and areas in two baboons with spontaneous, untreated epilepsy and two baboons without epilepsy. The two baboons without epilepsy had the distribution of neocortical neurons expected for Old World monkeys and baboons, whereas the baboons with untreated epilepsy had reduced numbers of cortical neurons overall, with the greatest reductions in motor and frontal areas of the cortex, and with little or no reduction in the primary visual cortex. The results suggest that neuron loss may follow untreated seizure activity, and this loss is greatest in areas of the cortex related to motor functions. Epilepsy is characterized by recurrent seizure activity that can induce pathological reorganization and alter normal function in neocortical networks. In the present study, we determined the numbers of cells and neurons across the complete extent of the cortex for two epileptic baboons with naturally occurring seizures and two baboons without epilepsy. Overall, the two epileptic baboons had a 37% average reduction in the number of cortical neurons compared with the two nonepileptic baboons. The loss of neurons was variable across cortical areas, with the most pronounced loss in the primary motor cortex, especially in lateral primary motor cortex, representing the hand and face. Less-pronounced reductions of neurons were found in other parts of the frontal cortex and in somatosensory cortex, but no reduction was apparent in the primary visual cortex and little in other visual areas. The results provide clear evidence that epilepsy in the baboon is associated with considerable reduction in the numbers of cortical neurons, especially in frontal areas of the cortex related to motor functions. Whether or not the reduction of neurons is a cause or an effect of seizures needs further investigation.

BOLD fMRI of visual and somatosensory-motor stimulations in baboons.

Baboon, with its large brain size and extensive cortical folding compared to other non-human primates, serves as a good model for neuroscience research. This study reports the implementation of a baboon model for blood oxygenation level-dependent (BOLD) fMRI studies (1.5 x 1.5 x 4 mm resolution) on a clinical 3T-MRI scanner. BOLD fMRI responses to hypercapnic (5% CO(2)) challenge, 10 Hz flicker visual, and vibrotactile somatosensory-motor stimulations were investigated in baboons anesthetized sequentially with isoflurane and ketamine. Hypercapnia evoked robust BOLD increases. Paralysis was determined to be necessary to achieve reproducible functional activations within and between subjects under our experimental conditions. With optimized anesthetic doses (0.8-1.0% isoflurane or 6-8 mg/kg/h ketamine) and adequate paralysis (vecuronium, 0.2 mg/kg), robust activations were detected in the visual (V), primary (S1) and secondary (S2) somatosensory, primary motor (M cortices), supplementary motor area (SMA), lateral geniculate nucleus (LGN) and thalamus (Th). Data were tabulated for 11 trials under isoflurane and 10 trials under ketamine on 5 baboons. S1, S2, M, and V activations were detected in essentially all trials (90-100% of the time, except 82% for S2 under isoflurane and 70% for M under ketamine). LGN activations were detected 64-70% of the time under both anesthetics. SMA and Th activations were detected 36-45% of the time under isoflurane and 60% of the time under ketamine. BOLD percent changes among different structures were slightly higher under ketamine than isoflurane (0.75% versus 0.58% averaging all structures), but none was statistically different (P>0.05). This baboon model offers an opportunity to non-invasively image brain functions and dysfunctions in large non-human primates.

Functional neuroimaging of the baboon during concurrent image-guided transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. However the underlying mechanisms of TMS-induced alterations in brain function are not well understood. As a result, treatment design parameters are determined ad hoc and not informed by any coherent theory or model. Once the mechanisms underlying TMSs modulatory effects on brain systems are better understood and modeled, TMSs potential as a therapeutic and/or investigative tool will be more readily explored and exploited. An animal model is better suited to study different TMS variables, therefore we developed a baboon model to facilitate testing of some of the current theoretical models of TMS interactions with brain regions. We have demonstrated the feasibility of this approach by successfully imaging cerebral blood flow (CBF) changes with H(2)(15)O positron emission tomography imaging during high-frequency, suprathreshold repetitive TMS in the primary motor cortex of five healthy, adult baboons.

Functional PET Evaluation of the Photosensitive Baboon.

The baboon provides a unique, natural model of epilepsy in nonhuman primates. Additionally, photosensitivity of the epileptic baboon provides an important window into the mechanism of human idiopathic generalized epilepsies. In order to better understand the networks underlying this model, our group utilized functional positron emission tomography (PET) to compare cerebral blood flow (CBF) changes occurring during intermittent light stimulation (ILS) and rest between baboons photosensitive, epileptic (PS) and asymptomatic, control (CTL) animals. Our studies utilized subtraction and covariance analyses to evaluate CBF changes occurring during ILS across activation and resting states, but also evaluated CBF correlations with ketamine doses and interictal epileptic discharge (IED) rate during the resting state. Furthermore, our group also assessed the CBF responses related to variation of ILS in PS and CTL animals. CBF changes in the subtraction and covariance analyses reveal the physiological response and visual connectivity in CTL animals and pathophysiological networks underlying responses associated with the activation of ictal and interictal epileptic discharges in PS animals. The correlation with ketamine dose is essential to understanding differences in CBF responses between both groups, and correlations with IED rate provides an insight into an epileptic network independent of visual activation. Finally, the ILS frequency dependent changes can help develop a framework to study not only spatial connectivity but also the temporal sequence of regional activations and deactivations related to ILS. The maps generated by the CBF analyses will be used to target specific nodes in the epileptic network for electrophysiological evaluation using intracranial electrodes.