Behavioral changes following a single episode of early-life seizures support the latent development of an autistic phenotype

Bernard, Paul B.; Castano, Anna; Beitzel, Christy S.; Carlson, Vivian B.; Benke, Tim A.

doi:10.1016/j.yebeh.2015.01.006

Cited by 28 publications

(25 citation statements)

References 62 publications

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“…However, it is necessary to interpret these findings cautiously when underlying etiological factors of seizures are not taken into account, control groups are lacking, or a selected cohort consists only of infants with very low birthweight . While some long‐term preclinical studies with animal models have suggested that seizures in immature brains may cause epileptogenesis and cognitive deficits, they also suffer from inherent limitations such as a selected pathology to increased seizure susceptibilities, variant postnatal age and different central nervous system ontogenic schedules between species, and various ways of inducing seizures in the laboratory . In contrast, we attempted to isolate the neurological sequelae attributable to neonatal seizures per se from those arising from underlying pathological conditions in a real‐world setting.…”

Section: Discussionmentioning

confidence: 99%

Independent role of neonatal seizures in subsequent neurological outcomes: a population‐based study

Thurman

Kim

2019

Develop Med Child Neuro

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Aim This population‐based study aimed to estimate the impact of neonatal seizures on subsequent neurological outcomes, regardless of underlying etiology. Method We performed a retrospective cohort study (1st January 2009–31st December 2014), using a USA nationwide claims database. Newborn infants enrolled in 2009 were followed for up to 6 years. Neonatal seizures were identified by combining the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of 779.0 (convulsions in newborn), procedure codes of electroencephalogram and brain imaging, and antiepileptic drugs claims. Cox regression models were built to estimate the independent impact of neonatal seizures on developing epilepsy, intellectual disability, psychiatric/behavioral disorders, and headache. Results Out of 490 071 newborn infants (251 850 males [51.4%], 238 221 females [48.6%]), 800 neonatal seizure cases were identified. After controlling for sex, birthweight, preterm birth status, and underlying etiology, neonates with seizures were more likely to have epilepsy (hazard ratio=32.7; 95% confidence interval [CI]=27.7−38.7; p<0.001), intellectual disability (hazard ratio=2.0; 95% CI=1.8−2.3; p<0.001), and headache (hazard ratio=1.6; 95% CI=1.1−2.2; p=0.013) than those without seizures. Interpretation Observed covariates being equal, seizures in neonates appeared to play a significant role in developing epilepsy, intellectual disability, and headache. The findings showed a detrimental impact of the event in the very early life on neurological outcomes in later life. What this paper adds Seizures had their own impact on the development of adverse neurological outcomes. The magnitude of impact was quite large in epilepsy.

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Section: Discussionmentioning

confidence: 99%

Independent role of neonatal seizures in subsequent neurological outcomes: a population‐based study

Thurman

Kim

2019

Develop Med Child Neuro

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“…Early life seizures can be modeled in rodents using convulsants, and there is compelling evidence for long‐term effects on cognition . In addition, early life seizures were also found to cause deficits in some, but not all, ASD‐like behaviors, largely revealed as deficits in social interactions …”

Section: Epilepsy and Autismmentioning

confidence: 99%

Neurobehavioral comorbidities of epilepsy: Role of inflammation

2017

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Epilepsy is associated with a high incidence of comorbid neurologic and psychiatric disorders. This review focuses on the association of epilepsy with autism spectrum disorder (ASD) and depression. There is high concordance of these behavioral pathologies with epilepsy. We review data that unambiguously reveal that epilepsy, ASD, and depression are associated with elevated brain inflammatory markers and that these may interact with serotoninergic pathways. Interference with inflammatory pathways or actions can reduce the severity of seizures, depression, and ASD-like behavior. Inflammation in the brain can be induced by seizure activity as well as by behavioral, environmental, and physiologic stressors. Furthermore, induction of inflammation at an early time point during gestation and in early neonatal life can precipitate both an ASD-like phenotype as well as a more excitable brain. It appears likely that priming of the brain due to early inflammation could provide a means by which subsequent inflammatory processes associated with epilepsy, ASD, and depression may lead to comorbidity.

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“…This result, in part, contrasted findings reported in adult rats that had undergone one prior episode of KAinduced status epilepticus initiated on P7. As adults, males spent less time in the zone with the animal trap but more time sniffing the stranger rat compared to controls [44].…”

Section: Social Behaviormentioning

confidence: 88%

Chronic Subconvulsive Activity during Early Postnatal Life Produces Autistic Behavior in the Absence of Neurotoxicity in the Juvenile Weanling Period

Friedman

Kahen

2019

Preprint

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The diagnosis of autism spectrum disorder (ASD) varies from very mild to severe social and cognitive impairments. We hypothesized that epigenetic subconvulsive activity in early postnatal life may contribute to the development of autistic behavior in a sexrelated manner. Low doses of kainic acid (KA) (25-100 µg) were administered to rat pups for 15 days beginning on postnatal (P) day 6 to chronically elevate neuronal activity. A battery of classical and novel behavioral tests was used, and sex differences were observed. Our novel open handling test revealed that ASD males nose poked more often and ASD females climbed and escaped more frequently with age. In the social interaction test, ASD males were less social than ASD females who were more anxious in handling and elevated plus maze (EPM) tasks. To evaluate group dynamics, sibling and non-sibling control and experimental animals explored 3 different shaped novel social environments. Control pups huddled quickly and more frequently in all environments whether they socialized with littermates or non-siblings compared to ASD groups. Non-sibling ASD pups were erratic and huddled in smaller groups. In the object recognition test, only ASD males spent less time with the novel object compared to control pups. Data suggest that chronic subconvulsive activity in early postnatal life leads to an ASD phenotype in the absence of cell death. Males were more susceptible to developing asocial behaviors and cognitive pathologies, whereas females were prone to higher levels of hyperactivity and anxiety, validating our postnatal ASD model apparent in the pre-juvenile period. Highlights• Chronic subconvulsive activity in early life leads to autism phenotypes.• Juvenile males were susceptible to asocial behaviors and cognitive pathologies.• Juvenile females were prone to hyperactivity and anxiety validating sex differences.• Non-siblings were erratic in groups irrespective of sex.• A postnatal epigenetic model may drug screen for milder forms of autism.

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Behavioral changes following a single episode of early-life seizures support the latent development of an autistic phenotype

Cited by 28 publications

References 62 publications

Independent role of neonatal seizures in subsequent neurological outcomes: a population‐based study

Independent role of neonatal seizures in subsequent neurological outcomes: a population‐based study

Neurobehavioral comorbidities of epilepsy: Role of inflammation

Chronic Subconvulsive Activity during Early Postnatal Life Produces Autistic Behavior in the Absence of Neurotoxicity in the Juvenile Weanling Period

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