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

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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.

ABBREVIATIONSEEG = 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.

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.

Mutations in the sodium channel alpha 1 subunit gene (SCN1A), encoding the alpha subunit of the neuronal voltage gated sodium channel, Nav1.1, have been linked to several epilepsy phenotypes. These include severe phenotypes such as Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI), severe infantile multifocal epilepsy, and intractable childhood epilepsy with generalized tonic-clonic seizures. Generally, Dravet syndrome is characterized by onset of febrile or afebrile clonic and tonic-clonic, generalized, and hemiclonic seizures in the 1st year of life.9 As the child grows, multiple seizure types along with developmental delays and behavioral disorders appear. Mutations in SCN1A have also been identified in more benign phenotypes, including generalized epilepsy with febrile seizures plus (GEFS+) and isolated febrile seizures.6,10,12,21,25 These syndromes likely represent a spectrum of the same disorder, as the same SCN1A mutations and deletions can cause SMEI in some children and GEFS+, intractable childhood epilepsy with generalized tonic-clonic seizures, idiopathic epilepsy, or febrile seizures alone in others.10,17 The lack of a precise genotype-phenotype relationship suggests that other genetic and/or environmental influences are involved.

Findings on structural neuroimaging studies (CT and MRI) in patients with Dravet syndrome are usually normal or show slight diffuse atrophy, although focal imaging findings have been documented.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 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.

Methods

The 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.24 SCN1A 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 on PolyPhen software, location, function, and conservation of amino acid change) and found either de novo or with appropriate family history.

Surgical pathology specimens were reviewed, separately, by 2 board-certified neuropathologists independent of, and blinded to, the original pathological reports. All tissue had been prepared by the clinical pathology laboratory for the original pathological examinations. Sections reviewed were all sectioned at 4 μM and stained with H & E. Immunohistochemical analysis had been performed for glial fibrillary acid protein (GFAP), NeuN (a neuronal marker), and neurofilament light chain (NFl) antibodies. The pathology was classified using the Palmini criteria from Blümcke et al.4

Results

Clinical Findings

Seizure History

Six patients who underwent resective surgery and were later found to have SCN1A mutations were identified. A summary of all the clinical and genetic data are presented in Tables 13. In all cases seizure onset occurred within the 1st year of life. Three patients presented with partial seizures at onset. All eventually developed partial motor seizures (hemiconvulsions with or without secondary generalization) and/or complex partial seizures. All patients experienced generalized seizure types as well, including myoclonic seizures, atonic/head drops, and absence seizures. Exacerbation of seizures by fever or overheating was seen in 4 of the 6 patients, and 5 of the 6 patients had a history of status epilepticus. The clinical phenotype of the majority of patients was consistent with Dravet syndrome (Table 1). However, the patient in Case 5 had a phenotype most consistent with GEFS+. This was the one patient operated on with a known change in SCN1A. He had been found to carry a sequence variant of unknown significance, but his mother had a history of epilepsy and died as a consequence of epilepsy. His history was complicated by previous closed head injury resulting in hemorrhagic contusions in the left anterior frontal lobe and scattered subdural and subarachnoid hemorrhages. After the trauma he began having multiple daily seizures that localized to the region of injury, and he underwent a focal resection of the area of encephalomalacia. He had a brief seizure-free period following surgery, but the seizures later recurred.

TABLE 1.

Clinical characteristics of 6 SCN1A mutation-positive children

Case No.Age at Seizure Onset (in mos)Family History of SeizuresInitial Seizure TypePrecipitating/Associated FactorsOther Seizure TypesStatus EpilepticusPsychomotor StatusClinical DiagnosisSCN1A MutationMutation InterpretationAtaxia
15YesFocal motor w/ unresponsivenessSeizures common w/ fevers, overheating, illnessMyoclonic, atonic, focal sensory or motor seizures w/ & and w/o secondary generalizationYesNormal prior to seizure onset, later mild to moderate MRDravet syndromec.2927del; p.M976fsPredicted SMEI phenotypeNo
23NoFocal myoclonus, focal motorOnset shortly after DPT immunizationGTCsYesModerate MR w/ autistic featuresDravet syndromeDeletion at exons 17–20Previously reported SMEI phenotypeYes
34NoGTCsUnknownMyoclonic, atonic, tonic, absence, complex partialYesMR, autism, ADHDDravet syndromec.5434T>G; p.W1812GPreviously reported SMEI phenotypeNo
44YesFocal motorSeizures common w/ fevers, overheatingGTCs, myoclonus, head drops, apnea, focal motor seizuresYesNormal prior to seizure onset, later moderate MR, ADHD, OCDDravet syndromec.4587del; p.K1529fsXPredicted SMEI phenotypeYes
512YesGTCs w/feverSeizures initially only w/ fever≥1 complex partial seizureNoNormal milestones, borderline IQ, ADHDGEFS+c.5018T>G; p.I1673TPresumed pathogenicNo
611NoRefractory febrile status epilepticusFeversGTCs, atonic & myoclonic seizures, complex partial seizures w/ 2 distinct semiologiesYes (both febrile & afebrile)Normal prior to seizure onset, later mild MRDravet syndromec.1661A>G; p.E554RPredicted SMEI phenotypeNo

ADHD = attention deficit hyperactivity disorder; DPT = diphtheria, pertussis, and tetanus; GTC = generalized tonic-clonic seizure; MR = mental retardation; OCD = obsessive-compulsive disorder.

TABLE 2.

EEG and imaging characteristics

Case No.Initial EEGInterictal EEG AbnormalitiesExtra cranial Ictal EEGStructural ImagingFunctional Imaging
1NormalSlow, disorganized bkgd, irregularly generalized & independent bitemporal epileptiform dischargesAll seizures (including 6 w/ head version) w/ irregularly generalized onsetTiny focus of nonspecific hyperintensity in lt parietal periventricular white matterMEG showed predominant focus over lt frontal lobe, greatest over lt superior frontal gyrus, although sharp activity noted on rt
2UnknownSlow, disorganized bkgd, frequent bifrontal & irregularly generalized dischargesOne seizure w/ lt frontal onset, 5 nonlocalizingInitial MRI normal, repeat MRI atage19 yrs lt MTSSPECT showed possible lt temporal focus
3UnknownSlow, disorganized bkgd, irregularly generalized & multifocal dischargesLTM: rt frontal onsetLt MTS (present age 3 yrs)MEG showed rt posterior frontal/rt midtemporal sharp waves
4NormalSlow, disorganized bkgd, irregularly generalized & independent bifrontal discharges3 nonlocalized seizures, 1 seizure w/ lt parietal-parasagittal onsetSmall area of abnormal signal in lt posterior frontal parasagittal subcortical WMIctal SPECT showed radio-tracer activity increased in rt frontal lobe, decreased in lt frontal lobe
5NormalSlow, disorganized bkgd1 seizure w/ lt frontal onset, 1 nonlocalizingNormal prior to closed head injury, then lt frontal hem-orrhage/encephalomalaciaNot done
6NormalSlow, disorganized bkgd, multifocal sharp waves, generalized epileptiform patterns, continuous slowing over rt frontal & temporal regions during sleep9 seizures w/ rt temporal onset, 1 each arising from rt & lt parietal region, & 1 poorly localizedMultiple normal MRIsPET showed decreased uptake in lt posterior temporal lobe, MEG & SISCOM studies both suggested predominant focus in rt parietal region

Bkgd = EEG background; LTM = long-term inpatient video-EEG monitoring; MEG = magnitoencephalography; SISCOM = subtracted ictal SPECT co-registered on MRI; SPECT = single photon emission CT; WM = white matter.

TABLE 3.

Surgical and outcome data*

Case No.No. of Failed Medication TrialsLongest Seizure-Free PeriodAge at SurgeryIntracranial Ictal EEGArea ResectedInitial Response to SurgeryLong-Term Surgical Outcome (ILAE Class)Duration of Follow-Up (mos)
1>10 + VNS & ketogenic diet3 mos on topiramate8 yrs2 typical seizures w/ onset in lt frontal convexity & midlineLt frontal lobectomyDecreased seizure frequency after surgery, increased alertness538
291 yr on phenytoin20 yrsNot doneLt temporal lobectomy & lt inferior frontal gyrus resection6 wks seizure free530
310 + VNSNone significant11 yrs22 seizures w/ broad right frontal onsetRt frontal lobectomy & anterior 2/3 callosotomyIntermittent periods of seizure freedom up to 2 wks527
44 before surgery; 5 after + VNSNone significant18 mosNot doneLt parasagittal/posterior frontal/mesial parietal lesionDecreased seizure frequency & intensity after surgery571
582–3 yrs off all AEDs17 yrsNot doneLesionectomy of area of lt frontal encephalomalacia1 mo seizure free518
611 + VNS & ketogenic diet3 wks on clobazam, topiramate, & stiripentol (2 yrs after surgery)9 yrs5 seizures w/ right superior frontal & intrahemispheric onsetRt frontocentral resectionNo improvement443

AEDs = antiepileptic drugs; VNS = vagal nerve stimulator.

Of note, surgery was performed before genetic testing,

Complicated by poor adherence to prescribed regimen.

Seizure frequency remained unchanged until 2 years after surgery when stiripentol was added to medication regimen.

Developmental History

All patients exhibited varying degrees of developmental cognitive impairments ranging from borderline IQ with learning disabilities to moderate mental retardation with autistic features (Table 1). Three of the patients had normal development prior to seizure onset and one was delayed prior to seizure onset. The timing of cognitive impairment of the others is unknown. Two patients also developed ataxia.

Electrophysiology and Imaging

EEG and imaging features are summarized in Table 2. The initial EEG findings were normal in all children whose early data were available. Soon after, the EEG background became slow and poorly organized with irregularly generalized or multifocal sharps in all patients. Three of the 6 patients had normal MRI results originally, with 2 of these 3 having abnormal findings on follow-up studies. The patient in Case 5 had an area of encephalomalacia from previous head trauma and developed mesial temporal sclerosis (MTS). Of the 3 patients with abnormal findings on initial MRI, 2 had subtle, nonspecific findings and the third had MTS. Imaging results are described in Table 2.

Surgical History

Age at surgery ranged from 18 months to 20 years. Five of the 6 patients underwent either complete or partial frontal lobectomies (Table 3). One of these patients also underwent an anterior 2/3 corpus callosotomy, while another patient underwent a temporal lobectomy along with an inferior frontal resection. The sixth patient (Case 4) underwent a focal resection of a parasagittal posterior frontoparietal lesion. These operations were based on clinical and diagnostic findings indicating focal seizure onset and presumed focal pathology prior to the discovery of the SCN1A variant.

Patients were monitored for 18 months to almost 6 years following resection. Five of the 6 patients showed some clinical improvement immediately following surgery but soon returned to an intractable state. Five patients had ILAE Class 5 surgical outcomes with persistent frequent intractable seizures without significant benefit following surgery. The patient in Case 6 showed no improvement immediately following surgery but did show a greater than 50% improvement in seizure frequency approximately 2 years after the surgery, following the addition of stiripentol to her medication regimen.

Genetic Findings

Five of the 6 patients underwent epilepsy surgery before their SCN1A mutations were identified. The SCN1A mutations included 3 deletions (Cases 1, 2, and 4) and 3 missense mutations (Table 1). One deletion (in Case 2) was a previously reported mutation with known association with the severe SMEI phenotype. The other 2 deletions, both leading to frame shifts, were both predicted to result in the severe SMEI phenotype. Of the 3 missense mutations, 1 had been previously associated with the severe SMEI phenotype, while the other 2 (in Cases 5 and 6) were unknown variants. Parental testing demonstrated the latter patient’s (i.e., Case 6) mutation to be de novo. The patient in Case 5 underwent epilepsy surgery after SCN1A testing revealed a previously unidentified mutation that was of unclear significance at that time. His parents were not available for testing. His mutation, consisting of a T to G transition in nucleotide 5018 codon 1673, resulting in an amino acid change from isoleucine to threonine, however, is now predicted to be pathogenic in PolyPhen2 (Probably Damaging, Score 1.00)1 and is in a transmembrane region that is highly conserved in all species from fish to humans.

Histopathological Findings

There were no gross morphological abnormalities in the pathology specimens of any patient. On histological examination, the density of cell bodies seen with H & E staining appeared normal overall, and a clear 6-layered cortex was identified. Immunohistochemistry with Neurofilament antibody showed normal-appearing neurons with no dysmorphic, large, or balloon neurons. Staining directed against NeuN revealed a well-organized cortex with 6 layers and normal definition of the gray-white boundaries. However, the NeuN staining also revealed significantly increased numbers of cells in the molecular layer of the cortex and the white matter throughout the stained tissue in 4 of the 6 patients (Cases 1, 2, 3, and 5) (Fig. 1). The temporal lobe specimen in Case 2 showed gliosis consistent with MTS. The specimen from Case 5 also demonstrated a prominent region of gliosis extending from the pial surface into the white matter, consistent with his known history of traumatic brain injury. The pathological specimens from Cases 4 and 6 were quite limited, consisting of tiny, irregular bits of cortex and a minimal amount of white matter. Neither specimen demonstrated clear evidence of dysplasia or gliosis.

FIG. 1.
FIG. 1.

NeuN staining revealed increased numbers of cells in the molecular layer of the cortex and white matter in the majority of samples. Figure is available in color online only.

Discussion

We present 6 patients who underwent epilepsy surgery for intractable focal seizures and were later noted to have clinical histories consistent with the spectrum of SCN1A-related disorders. Although a genetic diagnosis was not made, and in some cases was not available, prior to undergoing surgery, all patients were eventually found to have pathogenic mutations in SCN1A. In this cohort, mild malformations of cortical development (MCDs) were discovered in 4 of 6 patients’ surgical specimens, with excessive numbers of cells in the white matter and molecular layer of the cortex in all 4.

The implications of our neuropathological findings are limited by poor clinical outcomes in these patients. Nevertheless, there are scant published data available on pathological findings in Dravet syndrome and/or patients with SCN1A mutations. Three pediatric case reports of autopsy tissue in patients with clinical diagnoses of Dravet syndrome and/or demonstrated SCN1A mutations were shown to have abnormal cortical histopathology that was similar to or more extensive than that seen in our series.13,15,18 Two of the 3 revealed excessive neurons in the white matter,13,18 similar to that described herein in addition to irregularities in the laminar structure of the cerebellum and cortex in one patient18 and polymicrogyria and hippocampal gliosis/calcification in the other.13 A third patient with an SCN1A duplication resulting in a frame shift revealed multifocal micronodular dysplasia of the left temporal cortex and bilateral hippocampal gliosis.15 Most recently, Barba et al. reported on 6 patients with SCN1A mutations with co-occurring MCDs.9 Two of these patients underwent epilepsy surgery, and they both had unfavorable seizure outcomes. In contrast to these reports, a study examining postmortem specimens of 8 adult and pediatric cases with clinical Dravet syndrome and/or documented SCN1A mutations failed to find any consistent pathological abnormalities.5

There are important differences between our cases and those described in previous studies. In our series all specimens were obtained in the process of epilepsy surgery. Therefore, we specifically examined areas identified as epileptogenic during presurgical evaluation. This may suggest that the mild cortical changes we observed are a reflection of the epileptogenicity of regions examined and techniques used. In contrast, Catarino et al. examined only one surgical specimen, so the epileptogenicity of the areas sampled in the postmortem studies is unknown.5 Because we were only able to review tissue deemed epileptogenic in the preoperative evaluation, the epileptogenicity of these histopathological findings cannot be proved. However, the diffuse nature of our findings, along with poor surgical success, point to the diffuse nature of this syndrome as would be expected in a genetic diagnosis. Immunohistochemical studies were only available in 4 of the 8 cases in the series by Catarino et al., and only 2 of these had documented SCN1A mutations. Moreover, there may be a discrepancy in conservativeness of the diagnosis of dysplasia. Indeed, the grading of mild MCD is still under debate and interrater reliability is somewhat variable.7,14 However, expert pathologists reviewed all data in both our series and the Catarino paper. In summary, our data along with the previous reports strongly argue that at least a subset of SCN1A/Dravet syndrome patients have some level of cortical disorganization.

It is unclear whether the pathological abnormalities described here and previously are reflective of disruption of neuronal migration or are secondary to the earlyonset seizures seen in this disorder.3,13,15,18 Early infantile seizures could theoretically affect the final stages of neuronal migration that extend after birth.8,16,23 If abnormal migration is a direct result of postnatal seizures, similar histopathological abnormalities would be expected to be found in all epilepsy syndromes associated with SCN1A mutations with seizure onset in infancy, but not those with later seizure onset. However, the 2 patients in our series with later seizure onset (11–12 months vs 3–5 months) both demonstrated mild MCD. Furthermore, the one patient in our study whose surgical specimen did not show clear evidence of mild MCD suffered early seizure onset at 4 months (Case 4).

The importance of these findings for surgical decision making cannot be underestimated. All 6 patients described in this study, despite having focal seizure semiologies and focal findings on surgical evaluations, continued to have intractable seizures following resection of their predominant ictal onset zone. Both the genetic defect and the diffuse abnormalities in cortical cytoarchitecture as described herein could be contributing factors to the intractable nature of their epilepsy. Indeed, the functional change in the cellular physiology induced by alterations in SCN1A occurs diffusely and focal brain resection would not rectify the problem. A combination of these 2 mechanisms may be involved in a subset of patients like the group presented. Unfortunately, our data do not allow us to hypothesize further about the cause of the mild MCD seen in this patient cohort as well as in previous series.

Neurosurgeons and epileptologists should consider genetic testing in patients whose clinical presentation is consistent with Dravet syndrome before proceeding with surgery. Our experience indicates that these patients are unlikely to benefit from focal resection. This appears to be true even when the preoperative evaluation points to focal pathology and seizure onset. Up to this point, scant examples of Dravet syndrome histopathology in patients undergoing epilepsy surgery have been available. It is our hope that improved understanding of this syndrome will lead to better screening, diagnosis, and treatment, whether surgical or otherwise.

Conclusions

We have described patients with medically refractory epilepsy with mixed seizure types in whom resective surgery failed and who were later found to be positive for SCN1A mutations. The majority of pathological specimens demonstrated increased numbers of neurons in the molecular layer of the cortex and in the white matter. In all cases the patients continued to experience seizures despite surgery. Patients with histories consistent with SCN1A-related syndromes would benefit from genetic testing as part of the surgical evaluation, as cortical resection did not result in sustained improved outcome in this population.

Author Contributions

Conception and design: Marsh, Skjei, Church, Harding, Holland-Bouley, Clancy, Porter, Heuer. Acquisition of data: Skjei, Harding, Santi, Holland-Bouley, Clancy, Porter, Heuer. Analysis and interpretation of data: all authors. Drafting the article: Skjei, Church. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Marsh. Study supervision: Marsh, Heuer.

Supplemental Information

Current Affiliations

Dr. Skjei: Department of Neurology, University of Louisville, KY.

Dr. Porter: Department of Neurology, Stanford University, Stanford, CA.

References

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    Adzhubei IASchmidt SPeshkin LRamensky VEGerasimova ABork P: A method and server for predicting damaging missense mutations. Nat Methods 7:2482492010

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    Auvin SDulac OVallée L: Do SCN1A mutations protect from hippocampal sclerosis?. Epilepsia 49:110711082008

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    Barba CParrini ECoras RGaluppi ACraiu DKluger G: Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 55:100910192014

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    Blümcke IThom MAronica EArmstrong DDVinters HVPalmini A: The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52:1581742011

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    Catarino CBLiu JYLiagkouras IGibbons VSLabrum RWEllis R: Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 134:298230102011

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    Ceulemans BPClaes LRLagae LG: Clinical correlations of mutations in the SCN1A gene: from febrile seizures to severe myoclonic epilepsy in infancy. Pediatr Neurol 30:2362432004

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    Chamberlain WACohen MLGyure KAKleinschmidt-DeMasters BKPerry APowell SZ: Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 50:2593 25982009

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    Cuzon VCYeh PWCheng QYeh HH: Ambient GABA promotes cortical entry of tangentially migrating cells derived from the medial ganglionic eminence. Cereb Cortex 16:137713882006

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    Guerrini RStriano PCatarino CSisodiya SM: Neuroimaging and neuropathology of Dravet syndrome. Epilepsia 52:Suppl 230342011

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    Harkin LAMcMahon JMIona XDibbens LPelekanos JTZuberi SM: The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130:8438522007

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    Hayashi MSugai KKurihara ETamagawa K: An autopsy case of severe myoclonic epilepsy of infancy, who died of acute encephalopathy associated with influenza infection. Epilepsia 45:Suppl 8652004

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    Krsek PMaton BKorman BPacheco-Jacome EJayakar PDunoyer C: Different features of histopathological subtypes of pediatric focal cortical dysplasia. Ann Neurol 63:7587692008

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    Le Gal FKorff CMMonso-Hinard CMund MTMorris MMalafosse A: A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia 51:191519182010

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    LoTurco JJBlanton MGKriegstein AR: Initial expression and endogenous activation of NMDA channels in early neocortical development. J Neurosci 11:7927991991

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    Marini CScheffer IENabbout RSuls ADe Jonghe PZara F: The genetics of Dravet syndrome. Epilepsia 52:Suppl 224292011

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    Renier WORenkawek K: Clinical and neuropathologic findings in a case of severe myoclonic epilepsy of infancy. Epilepsia 31:2872911990

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    Siegler ZBarsi PNeuwirth MJerney JKassay MJanszky J: Hippocampal sclerosis in severe myoclonic epilepsy in infancy: a retrospective MRI study. Epilepsia 46:7047082005

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    Striano PMancardi MMBiancheri RMadia FGennaro EParavidino R: Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations. Epilepsia 48:109210962007

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    Sugawara TMazaki-Miyazaki EFukushima KShimomura JFujiwara THamano S: Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy. Neurology 58:1122 11242002

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    Van Poppel KPatay ZRoberts DClarke DFMcGregor APerkins FF: Mesial temporal sclerosis in a cohort of children with SCN1A gene mutation. J Child Neurol 27:8938972012

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    Weissman TARiquelme PAIvic LFlint ACKriegstein AR: Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex. Neuron 43:6476612004

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Article Information

Correspondence Eric D. Marsh, Children’s Hospital of Philadelphia, Department of Neurology, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. email: marshe@email.chop.edu.

INCLUDE WHEN CITING Published online September 4, 2015; DOI: 10.3171/2015.5.PEDS14551.

Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    NeuN staining revealed increased numbers of cells in the molecular layer of the cortex and white matter in the majority of samples. Figure is available in color online only.

References

  • 1

    Adzhubei IASchmidt SPeshkin LRamensky VEGerasimova ABork P: A method and server for predicting damaging missense mutations. Nat Methods 7:2482492010

  • 2

    Auvin SDulac OVallée L: Do SCN1A mutations protect from hippocampal sclerosis?. Epilepsia 49:110711082008

  • 3

    Barba CParrini ECoras RGaluppi ACraiu DKluger G: Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 55:100910192014

  • 4

    Blümcke IThom MAronica EArmstrong DDVinters HVPalmini A: The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52:1581742011

  • 5

    Catarino CBLiu JYLiagkouras IGibbons VSLabrum RWEllis R: Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 134:298230102011

  • 6

    Ceulemans BPClaes LRLagae LG: Clinical correlations of mutations in the SCN1A gene: from febrile seizures to severe myoclonic epilepsy in infancy. Pediatr Neurol 30:2362432004

  • 7

    Chamberlain WACohen MLGyure KAKleinschmidt-DeMasters BKPerry APowell SZ: Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 50:2593 25982009

  • 8

    Cuzon VCYeh PWCheng QYeh HH: Ambient GABA promotes cortical entry of tangentially migrating cells derived from the medial ganglionic eminence. Cereb Cortex 16:137713882006

  • 9

    Dravet C: The core Dravet syndrome phenotype. Epilepsia 52:Suppl 2392011

  • 10

    Fujiwara TSugawara TMazaki-Miyazaki ETakahashi YFukushima KWatanabe M: Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures. Brain 126:5315462003

  • 11

    Guerrini RStriano PCatarino CSisodiya SM: Neuroimaging and neuropathology of Dravet syndrome. Epilepsia 52:Suppl 230342011

  • 12

    Harkin LAMcMahon JMIona XDibbens LPelekanos JTZuberi SM: The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130:8438522007

  • 13

    Hayashi MSugai KKurihara ETamagawa K: An autopsy case of severe myoclonic epilepsy of infancy, who died of acute encephalopathy associated with influenza infection. Epilepsia 45:Suppl 8652004

  • 14

    Krsek PMaton BKorman BPacheco-Jacome EJayakar PDunoyer C: Different features of histopathological subtypes of pediatric focal cortical dysplasia. Ann Neurol 63:7587692008

  • 15

    Le Gal FKorff CMMonso-Hinard CMund MTMorris MMalafosse A: A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia 51:191519182010

  • 16

    LoTurco JJBlanton MGKriegstein AR: Initial expression and endogenous activation of NMDA channels in early neocortical development. J Neurosci 11:7927991991

  • 17

    Marini CScheffer IENabbout RSuls ADe Jonghe PZara F: The genetics of Dravet syndrome. Epilepsia 52:Suppl 224292011

  • 18

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