Brain MRI Findings in Severe Myoclonic Epilepsy in Infancy and Genotype–Phenotype Correlations

Striano, Pasquale; Mancardi, Maria Margherita; Biancheri, Roberta; Madia, Francesca; Gennaro, Elena Di; Paravidino, Roberta; Beccaria, Francesca; Capovilla, Giuseppe; Bernardina, Bernardo Dalla; Darra, Francesca; Elia, Maurizio; Giordano, Lucio; Gobbi, Giuseppe; Granata, Tiziana; Ragona, Francesca; Guerrini, Renzo; Marini, Carla; Mei, Davide; Longaretti, Francesca; Romeo, Antonino; Siri, Laura; Specchio, Nicola; Vigevano, Federico; Striano, Salvatore; Tortora, Fabio; Rossi, Andrea; Minetti, Carlo; Dravet, Charlotte; Gaggero, R.; Zara, Federico

doi:10.1111/j.1528-1167.2007.01020.x

Cited by 82 publications

(68 citation statements)

References 18 publications

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“…In the whole-brain analysis, we found significantly smaller total brain volume, total cortical GM volume, subcortical GM volume, total cortical WM volume and cerebellar WM volume in the patient group compared to the control group. These volume changes are consistent with previous studies, suggesting non-specific neuroimaging findings, such as atrophic change on cerebral and cerebellar area (Brunklaus et al, 2012, Guerrini et al, 2011, Striano et al, 2007) and brain morphometry analysis in patients with Dravet syndrome (Perez et al, 2014). Although the potential mechanism responsible for the volume change is uncertain, functional changes in GABAergic inhibitory interneurons, which are important in normal brain development, can alter the neural network formation (Flores and Mendez, 2014).…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies were unable to find specific or consistent neuroimaging findings related to SCN1A mutation (Brunklaus et al, 2012, Guerrini et al, 2011, Striano et al, 2007, Moehring et al, 2013). Furthermore, the majority of patients with SCN1A mutation exhibited no gross structural brain abnormalities with the exception of a few minor findings, including cerebral or cerebellar atrophy, cortical dysplasia, or hippocampal sclerosis (Brunklaus et al, 2012, Guerrini et al, 2011, Striano et al, 2007). Therefore, quantitative neuroimaging approaches such as brain volumetry and cortical morphometry may be useful in assessing the structural changes which could not otherwise be seen by conventional brain magnetic resonance imaging (MRI), and in understanding the pathogenesis of SCN1A mutation.…”

Section: Introductionmentioning

confidence: 80%

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Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Lee

Yum

Kim

et al. 2017

NeuroImage: Clinical

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ObjectiveMutations in SCN1A gene encoding the alpha 1 subunit of the voltage gated sodium channel are associated with several epilepsy syndromes including genetic epilepsy with febrile seizures plus (GEFS +) and severe myoclonic epilepsy of infancy (SMEI). However, in most patients with SCN1A mutation, brain imaging has reported normal or non-specific findings including cerebral or cerebellar atrophy. The aim of this study was to investigate differences in brain morphometry in epileptic children with SCN1A mutation compared to healthy control subjects.MethodsWe obtained cortical morphology (thickness, and surface area) and brain volume (global, subcortical, and regional) measurements using FreeSurfer (version 5.3.0, https://surfer.nmr.mgh.harvard.edu) and compared measurements of children with epilepsy and SCN1A gene mutation (n = 21) with those of age and gender matched healthy controls (n = 42).ResultsCompared to the healthy control group, children with epilepsy and SCN1A gene mutation exhibited smaller total brain, total gray matter and white matter, cerebellar white matter, and subcortical volumes, as well as mean surface area and mean cortical thickness. A regional analysis revealed significantly reduced gray matter volume in the patient group in the bilateral inferior parietal, left lateral orbitofrontal, left precentral, right postcentral, right isthmus cingulate, right middle temporal area with smaller surface area and white matter volume in some of these areas. However, the regional cortical thickness was not significantly different in two groups.SignificanceThis study showed large-scale developmental brain changes in patients with epilepsy and SCN1A gene mutation, which may be associated with the core symptoms of the patients. Further longitudinal MRI studies with larger cohorts are required to confirm the effect of SCN1A gene mutation on structural brain development.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 80%

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Lee

Yum

Kim

et al. 2017

NeuroImage: Clinical

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“…16 Their population had a higher frequency of hippocampal, corpus callosum, and cerebellar dysgenesis in association with PVNH found in the trigonal and occipito-temporal horns. 18 In contrast to the EPGP cohort reported here (and ascertained as patients with epilepsy), only 62% of the patients reported by Pisano et al had epilepsy, and both unilateral and bilateral PVNH were included. A trend-level relationship between high heterotopia burden and cerebellar abnormality was seen in our FLNA -negative population with epilepsy.…”

Section: Discussionmentioning

confidence: 66%

Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy

Fallil

Pardoe

Bachman

et al. 2015

Epilepsy & Behavior

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Purpose Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls. We report the clinical characteristics of the largest case series of FLNA negative patients with seizures and bilateral periventricular heterotopia. Methods Participants were recruited through the Epilepsy Phenome/Genome Project (EPGP), a multicenter collaborative effort to collect detailed phenotypic data and DNA on a large number of individuals with epilepsy, including a cohort with symptomatic epilepsy related to PVNH. Included subjects had epilepsy and MRI confirmed bilateral PVNH. MRI studies were visually and quantitatively reviewed to investigate the topographic extent of PVNH, symmetry and laterality. Key Findings We analyze data on 71 patients with bilateral PVNH. The incidence of febrile seizures was 16.6%. There was at least one other family member with epilepsy in 36.9% of this population. Developmental delay was present in 21.8%. Focal onset seizures were the most common type of seizure presentation (79.3%). High heterotopia burden was strongly associated with female gender and trigonal nodular localization. There was no evidence for differences in brain volume between PVNH subjects and controls. No relationship was observed between heterotopic volume and gender, developmental delay, location of PVNH, ventricular or cerebellar abnormalities, laterality of seizure onset, age at seizure onset and duration of epilepsy. Significance A direct correlation was observed between high heterotopia burden, female gender and trigonal location in this large cohort of FLNA-negative bilateral PVNH patients with epilepsy. Quantitative MRI measurements indicate that this correlation is based on the diffuse nature of the heterotopic nodules rather than on the total volume of abnormal heterotopic tissue.

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“…11,19,20 Unilateral or bilateral hippocampal sclerosis is an increasingly recognized finding in patients with Dravet syndrome and/or SCN1A mutations and may develop after an initially normal MRI. 5,19,22 abbreviations EEG = electroencephalography; GEFS+ = generalized epilepsy with febrile seizures plus; ILAE = International League Against Epilepsy; MCD = malformation of cortical development; MTS = mesial temporal sclerosis; SMEI = severe myoclonic epilepsy of infancy.…”

mentioning

confidence: 99%

Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy

Skjei

Church

Harding

et al. 2015

PED

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obJect Mutations in the sodium channel alpha 1 subunit gene (SCN1A) have been associated with a wide range of epilepsy phenotypes including Dravet syndrome. There currently exist few histopathological and surgical outcome reports in patients with this disease. In this case series, the authors describe the clinical features, surgical pathology, and outcomes in 6 patients with SCN1A mutations and refractory epilepsy who underwent focal cortical resection prior to uncovering the genetic basis of their epilepsy. methods Medical records of SCN1A mutation-positive children with treatment-resistant epilepsy who had undergone resective epilepsy surgery were reviewed retrospectively. Surgical pathology specimens were reviewed. results All 6 patients identified carried diagnoses of intractable epilepsy with mixed seizure types. Age at surgery ranged from 18 months to 20 years. Seizures were refractory to surgery in every case. Surgical histopathology showed evidence of subtle cortical dysplasia in 4 of 6 patients, with more neurons in the molecular layer of the cortex and white matter. conclusions Cortical resection is unlikely to be beneficial in these children due to the genetic defect and the unexpected neuropathological finding of mild diffuse malformations of cortical development. Together, these findings suggest a diffuse pathophysiological mechanism of the patients' epilepsy which will not respond to focal resective surgery. However, other authors have hypothesized that SCN1A mutations may actually protect from hippocampal sclerosis.2 Few pathological cases of Dravet syndrome have been published to date. 3,5,13,15,18 Most were case reports of autopsy specimens, and many had not undergone SCN1A testing. In this study, we review the clinical features and surgical pathology in 6 patients with treatment-resistant epilepsy who underwent surgery for intractable focal seizures and were later found to have presumed pathogenic mutations in SCN1A. We also review their outcomes and seek to draw conclusions regarding surgical evaluation and management. methodsThe medical records of 6 children with SCN1A mutations who underwent epilepsy surgery for medically refractory epilepsy were reviewed retrospectively. Patients were identified at the Children's Hospital of Philadelphia by surveying the epilepsy group to identify patients who had undergone epilepsy surgery and were later found to have SCN1A mutations. An additional patient was identified at the Cincinnati Children's Hospital. Data extracted included age at seizure onset, initial seizure types, clinical course, and neuroimaging and electroencephalography (EEG) reports. Surgical outcomes were classified using the International League Against Epilepsy (ILAE) surgical outcome scale as of their last follow-up visit. 24SCN1A mutation testing was done at commercially available laboratories (Athena and Transgenomics). A mutation was considered pathogenic if it was previously described as such, was a truncation mutation, or was a novel mutation with predicted pathogenicity (based o...

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Brain MRI Findings in Severe Myoclonic Epilepsy in Infancy and Genotype–Phenotype Correlations

Cited by 82 publications

References 18 publications

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy

Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy

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