Epilepsy as a Disease of White Matter

Hogan, Robert

doi:10.1177/1535759720975744

Cited by 2 publications

(6 citation statements)

References 9 publications

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“…25 White matter (myelin) damage is a common pathology in animal models of epilepsy and in patients with epilepsy and persons with demyelinating motor diseases (e.g., multiple sclerosis). 30,31,49 Further, the spheroidal D-MBP staining we observed in the DS mouse hippocampus is consistent with clinical studies in patients with DS showing elevated white matter damage throughout the brain by MRI 27,50 and upon autopsy. 29 It is unclear whether myelination protection/repair is a secondary consequence of reduced seizure activity by fenfluramine, whether fenfluramine acts through a direct mechanism that either protects or repairs myelin, or a combination of both.…”

Section: Fenfluramine Impact On Myelin Degradationsupporting

confidence: 88%

“…These findings support clinical evidence in DS, where white matter damage is evident on MRI 27 and in resected brain sections at autopsy 28,29 . White matter damage is increasingly recognized as a common epileptogenic pathology 30,31 . Conditional knockout and knockdown studies in DS models suggest that nonseizure comorbidities may occur as primary consequences of the Scn1a mutation in addition to secondary consequences of seizure burden, 32–40 confirming clinical reports 7 …”

Section: Introductionsupporting

confidence: 72%

“…28,29 White matter damage is increasingly recognized as a common epileptogenic pathology. 30,31 Conditional knockout and knockdown studies in DS models suggest that nonseizure comorbidities may occur as primary consequences of the Scn1a mutation in addition to secondary consequences of seizure burden, [32][33][34][35][36][37][38][39][40] confirming clinical reports. 7 The clinical data provide incontrovertible evidence that fenfluramine suppresses convulsive seizures in patients with DS.…”

Section: Key Pointsmentioning

confidence: 57%

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Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Cha,

Filatov,

Smith

et al. 2023

Epilepsia Open

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ObjectiveIn patients with Dravet syndrome (DS), fenfluramine reduced convulsive seizure frequency and provided clinical benefit in nonseizure endpoints (e.g., executive function, survival). In zebrafish mutant scn1 DS models, chronic fenfluramine treatment preserved neuronal cytoarchitecture prior to seizure onset and prevented gliosis; here, we extend these findings to a mammalian model of DS (Scn1a+/− mice) by evaluating the effects of fenfluramine on neuroinflammation (degenerated myelin, activated microglia) and survival.MethodsScn1a+/− DS mice were treated subcutaneously once daily with fenfluramine (15 mg/kg) or vehicle from postnatal day (PND) 7 until 35‐37. Sagittal brain sections were processed for immunohistochemistry using antibodies to degraded myelin basic protein (D‐MBP) for degenerated myelin, or CD11b for activated (inflammatory) microglia; sections were scored semi‐quantitatively. Apoptotic nuclei were quantified by TUNEL assay. Statistical significance was evaluated by 1‐way ANOVA with post‐hoc Dunnett's test (D‐MBP, CD11b, and TUNEL) or Logrank Mantel‐Cox (survival).ResultsQuantitation of D‐MBP immunostaining per 0.1 mm2 unit area of the parietal cortex and hippocampus CA3 yielded significantly higher spheroidal and punctate myelin debris counts in vehicle‐treated DS mice than in wild‐type mice. Fenfluramine treatment in DS mice significantly reduced these counts. Activated CD11b + microglia were more abundant in DS mouse corpus callosum and hippocampus than in wild‐type controls. Fenfluramine treatment of DS mice resulted in significantly fewer activated CD11b + microglia than vehicle‐treated DS mice in these brain regions. TUNEL staining in corpus callosum was increased in DS mice relative to wild‐type controls. Fenfluramine treatment in DS mice lowered TUNEL staining relative to vehicle‐treated DS mice. By PND 35‐37, 55% of control DS mice had died, compared with 24% of DS mice receiving fenfluramine treatment (P = 0.0291).SignificanceThis is the first report of anti‐neuroinflammation and pro‐survival after fenfluramine treatment in a mammalian DS model. These results corroborate prior data in humans and animal models and suggest important pharmacological activities for fenfluramine beyond seizure reduction.Plain Language SummaryDravet syndrome is a severe epilepsy disorder that impairs learning and causes premature death. Clinical studies in patients with Dravet syndrome show that fenfluramine reduces convulsive seizures. Additional studies suggest that fenfluramine may have benefits beyond seizures, including promoting survival and improving control over emotions and behavior. Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of fenfluramine. Results showed that fenfluramine treatment of Dravet mice reduced neuroinflammation significantly more than saline treatment. Fenfluramine‐treated Dravet mice also lived longer than saline‐treated mice. These results support clinical observations that fenfluramine may have benefits beyond seizures.

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Section: Fenfluramine Impact On Myelin Degradationsupporting

confidence: 88%

Section: Introductionsupporting

confidence: 72%

Section: Key Pointsmentioning

confidence: 57%

See 1 more Smart Citation

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Cha,

Filatov,

Smith

et al. 2023

Epilepsia Open

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“…Another plausible explanation would be the evolving concepts of the pathogenesis of epilepsy being not merely limited to the well-defined injury to the cortex but involvement of the subcortical circuits including the thalamocortical connections, brainstem, and white matter. 31 In the term-born children, functional independence and motor abilities were superior compared with the nonmotor neurodevelopmental deficits, where more than two-thirds of them were ambulatory and/or able to handle objects independently and semi-independently. On the contrary, language delay and nonverbal communication were prevalent (67.5%) in the term-born children with PVWMI in our study, which was disproportional to the prevalence of cognitive impairment (14.4%), auditory deficits (10.6%), and visual deficits (18.1%).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Risk Factors for Term-Born Periventricular White Matter Injury in Children With Cerebral Palsy

et al. 2022

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Objective:The aim of this study was to identify possible risk factors associated with term born children with cerebral palsy (CP) and periventricular white matter injury (PVWMI) on imaging.Methods:This is a case-controlled study restricted to term born children with CP with the cases extracted from the Canadian Cerebral Palsy Registry (CCPR) and controls from Alberta Pregnancy Outcomes and Nutrition (APrON) Study. A diagnosis of PVWMI was made based on expert categorization of MRI reports. Risk factor variables were selected a priori; these included pregnancy complications, antenatal toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity (i.e. neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia). We used multivariable analyses to calculate odds ratios (ORs) and their 95% confidence intervals (CIs).Results:A total of 160 cases (7.06% of the registry sample) were compared to 1950 controls. Of the term born PVWMI participants, 59.4% were males and 13.5 % were born to mothers of extreme maternal age. Multivariable analysis of each risk factor controlled for weight showed PVWMI is associated with pregnancy complications (OR=3.35; 95% CI=2.23-4.94), antenatal toxin exposure (OR=2.45; 95% CI=1.67-3.55), perinatal infection (OR=3.61; 95% CI=1.96-6.29) and perinatal adversity (OR=2.03; 95% CI=1.42-2.94). Term born males were not more likely to have PVWMI compared to females (OR=1.37; 95% CI=0.98-1.93). Multiple regression analyses suggested independent associations between PVWMI and pregnancy complications (OR=3.75; 95% CI 2.46-5.62), antenatal toxin exposure (OR=2.80; 95% CI 1.88-4.12), perinatal infection (OR=4.62; 95% CI 2.46-8.42) and perinatal adversity (OR=2.49; 95% CI= 1.71-3.69).Conclusions:Risk factors such as pregnancy complications, antenatal toxin exposure, perinatal infection as well as perinatal adversity are associated with PVWMI in term born children, suggesting perhaps variable interactions between antenatal and perinatal factors to yield this under-recognized CP phenotype.

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Epilepsy as a Disease of White Matter

Abstract: [Box: see text]

Cited by 2 publications

References 9 publications

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Risk Factors for Term-Born Periventricular White Matter Injury in Children With Cerebral Palsy

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