Koyle D. Knape

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.

Electroclinical phenotypes in a pedigreed baboon colony

This is the first large-scale epidemiological study evaluating the prevalence of interictal epileptic discharges (IEDs) and photosensitivity (PS) recorded by scalp EEG in a natural nonhuman-primate model of photosensitive, generalized epilepsy. Scalp EEG was used to characterize electroclinical phenotypes in a large baboon pedigree housed at the Southwest National Primate Research Center at the Texas Biomedical Research Institute (Texas Biomed) based upon IEDs and photosensitivity. Scalp EEG studies including intermittent light stimulation (ILS) were performed in 671 baboons. Clinical histories were available for 531 (79%) of the animals. The EEG studies lasted 53 (±11) min, during which the baboons were lightly sedated with intramuscular ketamine doses of 5.6 (±0.8) mg. The animals were further classified according to electroclinical phenotypes recorded by scalp EEG: presence or absence of IEDs, seizures and photoparoxysmal or photoconvulsive responses. Effects of age, gender, and species on EEG phenotypes were compared using (Chi-square, two-sided, α<0.05). Sensitivity and specificity of IEDs and photosensitivity to detect a history of seizures was calculated. Generalized IEDs and photosensitivity were identified in 324 (49%) and 156 (23%) pedigreed baboons, respectively. Only photosensitivity was associated with gender, significantly increased in males. Otherwise, while IEDs were marginally more prevalent among males, there were no other significant associations of IEDs or photosensitivity with age or subspecies. Photosensitivity was significantly associated with IEDs, with demonstrating a possible association with gender and subspecies. Of 531 baboons with histories of clinical events, 91 (17%) had witnessed seizures and 269 (51%) were asymptomatic. IEDs demonstrated sensitivity and specificity of 62% and 57%, and photosensitivity of 40% and 83%, for prediction of seizures, respectively. While these EEG findings mirror the high prevalence of seizures in the colony, the sensitivity and specificity of scalp EEG may have been affected by ketamines ability to lower the threshold for IEDs and seizures, particularly in animals predisposed to epilepsy. Photosensitivity provides a specific biological marker for epilepsy in future epidemiological, genetic, behavioral and histopathological studies.

Baboon model of generalized epilepsy: Continuous intracranial video-EEG monitoring with subdural electrodes

The baboon provides a natural non-human primate model for photosensitive, generalized epilepsy. This study describes an implantation procedure for the placement of subdural grid and strip electrodes for continuous video-EEG monitoring in the epileptic baboon to evaluate the generation and propagation of ictal and interictal epileptic discharges. Subdural grid, strip and depth electrodes were implanted in six baboons, targeting brain regions that were activated in functional neuroimaging studies during photoparoxysmal responses. The baboons were monitored with continuous video-EEG monitoring for 2-21 (mean 9) days. Although the animals were tethered, the EEG signal was transmitted wirelessly to optimize their mobility. Spontaneous seizures, interictal epileptic discharges (IEDs), and responses to intermittent light stimulation (ILS) were assessed. Due to cortical injuries related to the electrode implantation and their displacement, the procedure was modified. Habitual myoclonic and generalized tonic-clonic seizures were recorded in three baboons, all associated with a generalized ictal discharge, but were triggered multiregionally, in the frontal, parietal and occipital cortices. IEDs were similarly expressed multiregionally, and responsible for triggering most generalized spike-and-wave discharges. Generalized photoparoxysmal responses were activated only in one baboon, while driving responses recorded in all three photosensitive baboons were 2.5 times the stimulus rate. In contrast to previous intracranial investigations in this model, generalized ictal and interictal epileptic discharges were triggered by parietal and occipital, in addition to the frontocentral cortices. Furthermore, targeted visual areas responded differently to ILS in photosensitive than nonphotosensitive baboons, but further studies are required before mechanisms can be implicated for ILS-induced activation of the epileptic networks.

Cortical sulcal areas in baboons (Papio hamadryas spp.) with generalized interictal epileptic discharges on scalp EEG

Brain MRI studies in people with idiopathic generalized epilepsies demonstrate regional morphometric differences, though variable in magnitude and location. As the baboon provides an excellent electroclinical and neuroimaging model for photosensitive generalized epilepsy in humans, this study evaluated MRI volumetric and morphometric differences between baboons with interictal epileptic discharges (IEDs) on scalp EEG and baboons with normal EEG studies. Seventy-seven baboons underwent high-resolution brain MRI and scalp EEG studies. The scans were acquired using an 8-channel primate head coil (Siemens TRIO 3T scanner, Erlangen, Germany). After spatial normalization, sulcal measurements were obtained by object-based-morphology methods. One-hour scalp EEG studies were performed in animals sedated with ketamine. Thirty-eight (22F/16M) baboons had normal EEGs (IED-), while 39 (22F/17M) had generalized IEDs (IED+). The two groups were compared for age, total brain volume, and sulcal areas (Hotellings Trace) as well as between-subjects comparison of 11 individual sulcal areas (averaged between left and right hemispheres). There were no differences between IED- and IED+ groups with respect to age or total brain (gray or white matter) volume, and multivariate tests demonstrated a marginally significant decrease of sulcal areas in IED+ baboons (p=0.075). Tests of between-subjects effects showed statistically significant decreases in the intraparietal (p=0.002), central (p=0.03) and cingulate sulci (p=0.02), and marginal decreases involving the lunate (p=0.07) and superior temporal sulci (p=0.08). Differences in sulcal areas in IED+ baboons may reflect global developmental abnormalities, while decreases of areas of specific sulci reflect anatomical markers for potential generators or cortical nodes of the networks underlying spontaneous seizures and photosensitivity in the baboon.

The Baboon Model of Epilepsy: Current Applications in Biomedical Research

Epilepsy is a condition of recurrent, unprovoked seizures (Adams and Victor, 1993). Seizures are episodic changes in behavior associated with a synchronized electrical discharge from the populations of neurons in the cerebral cortex. To classify human epilepsies as focal or generalized, clinicians rely on a seizure description combined with electroencephalography (EEG) (Commission on the Classification and Terminology of the International League Against Epilepsy, 1981 and 1989). Because seizures are rarely recorded in brief EEG samples, clinicians rely on the the detection of interictal (between seizures) epileptic discharges, which serve as markers for the seizure type. Focal epilepsies begin with focal symptomatology and are associated with interictal epileptic discharges (IEDs) that are focal or lateralized to one cerebral hemisphere. Generalized epilepsies are associated with sudden unresponsiveness or bilateral motor symptoms at onset, and IEDs tend to involve both hemispheres simultaneously. While most focal epilepsies are symptomatic, related to a localized structural lesion, generalized epilepsies are predominantly idiopathic, and considered to be heritable. Some epilepsies, mainly idiopathic in characterization, include seizure types that are elicited by specific stimuli. Photosensitivity describes an enhanced cerebral excitation by exposure to intermittent light stimulation (ILS), such as a flickering light source. Photosensitivity is rare, occurring in about 5% of people with epilepsy, but is more frequently encountered in idiopathic or symptomatic generalized epilepsies (Janz and Durner, 1997). Most photosensitive patients have juvenile myoclonic epilepsy (JME), with a prevalence of 30–60% (Janz and Durner, 1997). EEG findings of photosensitivity include the activation of IEDs, or photoparoxysmal responses, and the activation of myoclonic or generalized tonicclonic seizures, or photoconvulsive responses. Because all of these responses are associated with cortical excitability and a predisposition to seizures, they may be referred to as photoepileptic responses. Because of the prevalence of