Impact of epilepsy duration, seizure control and EEG abnormalities on cognitive impairment in drug-resistant epilepsy patients

Gavrilović, Aleksandar; Toncev, Gordana; Matic, Tatjana Boskovic; Vesić, Katarina; Zivojinovic, J; Gavrilovic, Jagoda

doi:10.1007/s13760-019-01090-x

Cited by 29 publications

(22 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We therefore hypothesize that the expansion of CD4 T cells and their shift toward a proinflammatory phenotype could be associated with CNS infiltration and neuroaxonal injury in DRE. Recent studies report an association of DRE with progressive brain atrophy and cognitive deterioration over time in adults, suggesting that DRE could exhibit neurodegenerative features 34,35 . We report elevated concentration of sNfL in the serum of aging subjects suffering from DRE.…”

Section: Discussionmentioning

confidence: 45%

“…Proinflammatory Th17/Th1 CD4 T cells can exert cytotoxicity toward neurons, 15,17,33 whereas IL‐4 is considered neuroprotective 30 . Recent studies report a clinical deterioration in cognition over time in DRE subjects, especially in older individuals 4,34,35 . We therefore used ultrasensitive single molecule immunoassay to measure sNfL, a biomarker of neuronal injury validated in neuroinflammatory and neurodegenerative conditions 36 .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

et al. 2020

View full text Add to dashboard Cite

ObjectiveAdult drug‐resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well‐controlled epilepsy (WCE).MethodsPeripheral blood mononuclear cells and serum from >120 age‐ and sex‐matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array.ResultsUsing a data‐driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)‐17A, IL‐22, tumor necrosis factor, interferon‐γ, and granulocyte‐macrophage colony–stimulating factor, but not anti‐inflammatory cytokines IL‐10 and IL‐4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17‐related circulating proinflammatory cytokines are elevated, but Th2‐related cytokine IL‐4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals.SignificanceOur data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.

show abstract

Section: Discussionmentioning

confidence: 45%

Section: Resultsmentioning

confidence: 99%

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The present findings are consistent with literature showing relationships between reduced seizure frequency and cognitive improvement in people with epilepsy in general. For example, researchers have found that children with drug-sensitive epilepsies performed better on cognitive assessments than children with drug-resistant forms, and these cognitive improvements correlated with seizure control and duration of illness [50]. Additionally, longer seizure duration [51] and higher seizure frequency corresponded to diminished intellectual capacity [52].…”

Section: Discussionmentioning

confidence: 99%

Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome

Bishop

Isquith

Gioia

et al. 2021

Epilepsy & Behavior

View full text Add to dashboard Cite

Objective: Individuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use.Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year. Methods: This is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5-18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF Ò ) parent form, a questionnaire capturing parents'/caregivers' perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF Ò were mapped to the current edition, the BRIEF Ò 2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF Ò 2 T-scores from baseline in the core study to Year 1 of the OLE study was calculated. Spearman's rho correlation coefficients assessed associations between change in BRIEF Ò 2 indexes/composite T-scores and percentage change in MCSF. Children and young adults were divided into 2 groups based on percentage of MCSF reduction achieved from pre-randomization baseline in the core study to Year 1 of the OLE study: <50% and !50% MCSF reduction. Changes in the distribution of BRIEF Ò 2 indexes/composite T-scores were compared between MCSF reduction groups using Mann-Whitney U tests. The proportions of children and young adults in these groups who showed clinically meaningful improvement in everyday EF, defined as

show abstract

“…27 However, the cognitive effects of long-term refractory seizures have also been well described. 28,29 Careful consideration must be taken in weighing the potential side effects with the possible benefits nicotine therapy might have on refractory seizures and a child’s quality of life.…”

Section: Discussionmentioning

confidence: 99%

Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants

2020

View full text Add to dashboard Cite

Objective: Genetic variants of the neuronal nicotinic acetylcholine receptor (nAChR) cause autosomal dominant sleep-related hypermotor epilepsy. Approximately 30% of autosomal dominant sleep-related hypermotor epilepsy patients are medically intractable. In preclinical models, pathogenic nAChR variants cause a gain of function mutation with sensitivity to acetylcholine antagonists and agonists. Nicotine modifies the activity of nAChRs and can be used as targeted therapy. Methods: We reviewed next-generation sequencing epilepsy panels from a single laboratory (GeneDx) from patients at Children’s Medical Center Dallas between 2011 and 2015 and identified patients with nAChR variants. Retrospective review of records included variant details, medical history, neuroimaging findings, and treatment history. Results: Twenty-one patients were identified. Four patients were prescribed nicotine patches for intractable seizures. Three of 4 patients had a clinical response, with >50% seizure reduction. Conclusions: Treatment with a nicotine patch can be an effective therapy in epilepsy patients with nAChR gene variants. We propose consideration of transdermal nicotine treatment in intractable epilepsy with known nAChR variants as an experimental therapy. Further clinical trials are needed to fully define therapeutic effects.

show abstract

Impact of epilepsy duration, seizure control and EEG abnormalities on cognitive impairment in drug-resistant epilepsy patients

Cited by 29 publications

References 44 publications

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome

Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants

Contact Info

Product

Resources

About