Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

Löscher, Wolfgang; Stafstrom, Carl E.

doi:10.1111/epi.17433

Cited by 8 publications

(7 citation statements)

References 237 publications

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“…33,34 Animal models suggest multiple contributions to learning difficulties involving structural, network, and molecular abnormalities. 35 More evidence emerging in the past decade supports the long-recognized view that learning difficulties, along with other cognitive and mood disorders, are not merely epiphenomena of seizures, but develop in parallel and sometimes along different timelines. 1 In this study, we identified a subgroup of people without significant developmental delay, who nonetheless experienced learning difficulties in school, and later went on to develop focal epilepsy and were found to have reduced brain tissue volume to intracranial volume on MRI after controlling for other explanatory variables.…”

Section: Discussionmentioning

confidence: 88%

“…Previous studies have found that reduced cognitive function in epilepsy is related to less educational attainment, higher seizure frequency (generalized tonic–clonic seizures in particular), and longer disease duration 33,34 . Animal models suggest multiple contributions to learning difficulties involving structural, network, and molecular abnormalities 35 . More evidence emerging in the past decade supports the long‐recognized view that learning difficulties, along with other cognitive and mood disorders, are not merely epiphenomena of seizures, but develop in parallel and sometimes along different timelines 1 .…”

Section: Discussionmentioning

confidence: 99%

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Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

et al. 2023

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ObjectiveVisual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1.MethodsEnrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics.ResultsBrain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p = .0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = −.007 to −.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = −.014 to −.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities.SignificanceThis study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

et al. 2023

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“…Finally, although we focus here on disadvantage in human populations, an arguably relevant and important literature is that concerned with advantaged or enriched environments in animal populations. This longstanding highly developed literature has extended into epilepsy, demonstrating that antecedent exposure to enriched environments slows the development of epilepsy after an initial insult, and favorably modifies severity, course, and associated comorbidities, including animal models of TLE as reviewed by Löscher and Stafstrom 54 . The effects of environmental enrichment may affect the behavior of animals before, during, and after the induction of epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…This longstanding highly developed literature has extended into epilepsy, demonstrating that antecedent exposure to enriched environments slows the development of epilepsy after an initial insult, and favorably modifies severity, course, and associated comorbidities, including animal models of TLE as reviewed by Löscher and Stafstrom. 54 The effects of environmental enrichment may affect the behavior of animals before, during, and after the induction of epilepsy. These effects have been observed in a variety of experimental models, including chemoconvulsant-induced status epilepticus leading to chronic epilepsy, kindling, and mutant models.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Association of neighborhood deprivation with white matter connectome abnormalities in temporal lobe epilepsy

et al. 2023

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ObjectiveSocial determinants of health, including the effects of neighborhood disadvantage, impact epilepsy prevalence, treatment, and outcomes. This study characterized the association between aberrant white matter connectivity in temporal lobe epilepsy (TLE) and disadvantage using a US census‐based neighborhood disadvantage metric, the Area Deprivation Index (ADI), derived from measures of income, education, employment, and housing quality.MethodsParticipants including 74 TLE patients (47 male, mean age = 39.2 years) and 45 healthy controls (27 male, mean age = 31.9 years) from the Epilepsy Connectome Project were classified into ADI‐defined low and high disadvantage groups. Graph theoretic metrics were applied to multishell connectome diffusion‐weighted imaging (DWI) measurements to derive 162 × 162 structural connectivity matrices (SCMs). The SCMs were harmonized using neuroCombat to account for interscanner differences. Threshold‐free network‐based statistics were used for analysis, and findings were correlated with ADI quintile metrics. A decrease in cross‐sectional area (CSA) indicates reduced white matter integrity.ResultsSex‐ and age‐adjusted CSA in TLE groups was significantly reduced compared to controls regardless of disadvantage status, revealing discrete aberrant white matter tract connectivity abnormalities in addition to apparent differences in graph measures of connectivity and network‐based statistics. When comparing broadly defined disadvantaged TLE groups, differences were at trend level. Sensitivity analyses of ADI quintile extremes revealed significantly lower CSA in the most compared to least disadvantaged TLE group.SignificanceOur findings demonstrate (1) the general impact of TLE on DWI connectome status is larger than the association with neighborhood disadvantage; however, (2) neighborhood disadvantage, indexed by ADI, revealed modest relationships with white matter structure and integrity on sensitivity analysis in TLE. Further studies are needed to explore this relationship and determine whether the white matter relationship with ADI is driven by social drift or environmental influences on brain development. Understanding the etiology and course of the disadvantage–brain integrity relationship may serve to inform care, management, and policy for patients.

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“…104 Although rodent animal models may not identically mimic the heterogeneous semiology and EEG features of many of the human epilepsies, the strength of animal research comes from the information gained about the pathophysiological mechanisms and consequences of seizures. [120][121][122] Such information can often be extrapolated to the human condition. Although animal models will never parallel every nuance of the complex human condition, the fundamental physiological basis of seizures and their sequelae are conserved across species.…”

Section: Seizures Beget Seizuresmentioning

confidence: 99%

Do vaccines cause epilepsy? Review of cases in the National Vaccine Injury Compensation Program

Scott,

Moshé,

Holmes

2023

Epilepsia

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ObjectiveThe National Childhood Vaccine Injury Act of 1986 created the National Vaccine Injury Compensation Program (VICP), a no‐fault alternative to the traditional tort system. Since 1988, the total compensation paid exceeds $5 billion. While epilepsy is one of the leading reasons for filing a claim, there has been no review of the process and validity of the legal outcomes given current medical information. The objectives were to review the evolution of the VICP program in regard to vaccine‐related epilepsy and assess the rationale behind decisions made by the court.MethodsPublicly available cases involving epilepsy claims in the VICP were searched through Westlaw and the United States Court of Federal Claims websites. All published reports were reviewed for petitioner's theories supporting vaccine‐induced epilepsy, respondent's counterarguments, the final decision regarding compensation and the rationale underlying these decisions. The primary goal was to determine which factors went into decisions regarding whether vaccines caused epilepsy.ResultsSince the first epilepsy case in 1989, there have been many changes in the program including the removal of residual seizure disorder as a vaccine‐related injury, publication of the Althen prongs, release of the acellular form of pertussis, and recognition that in genetic conditions the underlying genetic abnormality rather than the immunization causes epilepsy. We identified 532 unique cases with epilepsy: 105 with infantile spasms and 427 with epilepsy without infantile spasms. The petitioners’ experts often espoused outdated, erroneous causation theories that lacked an acceptable medical or scientific foundation and were frequently criticized by the court.SignificanceDespite the lack of epidemiological or mechanistic evidence indicating that childhood vaccines covered by the VICP result in or aggravate epilepsy, these cases continue to be adjudicated. After 35 years of intense litigation, it is time to reconsider whether epilepsy should continue to be a compensable vaccine‐induced injury.

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Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

Cited by 8 publications

References 237 publications

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

Association of neighborhood deprivation with white matter connectome abnormalities in temporal lobe epilepsy

Do vaccines cause epilepsy? Review of cases in the National Vaccine Injury Compensation Program

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