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ObjectiveTo determine hippocampal morphometric measures, including granule cell dispersion and features of malrotation, as potential biomarkers for sudden unexpected death in epilepsy (SUDEP) from an archival postmortem series.MethodsIn a retrospective study of 187 archival postmortems from 3 groups, SUDEP (68; 14 with hippocampal sclerosis [HS]), non-SUDEP epilepsy controls (EP-C = 66; 25 with HS), and nonepilepsy controls (NEC = 53), Nissl/hematoxylin & eosin–stained sections from left and right hippocampus from 5 coronal levels were digitized. Image analysis was carried out for granule cell layer (GCL) thickness and measurements of hippocampal dimensions (HD) for shape (width [HD1], height [HD2]) and medial hippocampal positioning in relation to the parahippocampal gyrus (PHG) length (HD3). A qualitative evaluation of hippocampal malrotational (HMAL) features, dentate gyrus invaginations (DGI), and subicular/CA1 folds (SCF) was also made.ResultsGCL thickness was increased in HS more than those without (p < 0.001). In non-HS cases, increased GCL thickness was noted in EP-C compared to NEC (p < 0.05) but not between SUDEP and NEC. There was no difference in the frequency of DGI, SCF, measurements of hippocampal shape (HD1, HD2, or ratio), or medial positioning among SUDEP, EP-C, and NEC groups, when factoring in HS, coronal level, and age at death. Comparison between left and right sides within cases showed greater PHG lengths (HD3) on the right side in the SUDEP group only (p = 0.018).ConclusionsNo hippocampal morphometric features were identified in support of either excessive granule cell dispersion or features of HMAL as definitive biomarkers for SUDEP. Asymmetries in PHG measurements in SUDEP warrant further investigation as they may indicate abnormal central autonomic networks.

Objective:To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP.Methods:Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen–antigen D related, glial fibrillary acid protein, hypoxia-inducible factor-1α [HIF-1α], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers.Results:Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivity for inflammatory reaction, BBB leakage, and HIF-1α in SUDEP cases was not different from that seen in control groups.Conclusions:This study represents a starting point to explore by immunohistochemistry the mechanisms underlying SUDEP in human brain tissue. Our approach highlights the potential and importance of considering immunohistochemical analysis to help identify biomarkers of SUDEP. Our results suggest that with the markers used, there is no clear immunohistochemical signature of SUDEP in human brain.

Objective To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. Methods Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death. Results Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. Conclusions We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Hippocampal malformations in patients with epilepsy usually are reported in the context of widespread cortical malformations. Isolated hippocampal malformations are more rarely identified in MRI studies with little documentation of their pathologic appearance. Postmortem examination revealed abnormal position and complex convolutional malformations isolated to the hippocampal formation in an adult with temporal lobe epilepsy in whom MRI demonstrated bilateral hippocampal abnormalities.

Objective: To characterize abnormalities in neocortical central benzodiazepine receptor (cBZR) binding in patients with mesial temporal lobe epilepsy (mTLE) with unilateral hippocampal sclerosis (HS) using [11C]-flumazenil-(FMZ) PET and complementary voxel-based and quantitative volume-of-interest (VOI) methods.Methods: The authors studied 13 control subjects and 15 patients with refractory mTLE and unilateral HS with [11C]-FMZ PET. Data were corrected for partial volume effect in the interactively outlined hippocampus and in 28 cortical VOI using an individualized template. A voxel-based analysis was also performed using statistical parametric mapping (SPM).Results: Fourteen patients with mTLE had reduced [11C]-FMZ volume distribution (Vd) in the hippocampus ipsilateral to the EEG focus, extending into the amygdala in four. Five patients showed additional significant neocortical abnormalities of [11C]-FMZ binding: temporal neocortical increases (1), extratemporal decreases (2), extratemporal increases only (1), and temporal and extratemporal neocortical increases (1). Group VOI analysis revealed significant reductions only in the ipsilateral hippocampus. SPM showed decreased [11C]-FMZ-Vd in the ipsilateral hippocampus in 13 of 15 patients, extending into the amygdala in eight. Five patients showed additional neocortical abnormalities: temporal neocortical increases only (3), extratemporal decreases (1), or both temporal neocortical and extratemporal decreases (1). Group analysis showed significant reductions in the ipsilateral hippocampus only.Conclusions: A combination of VOI- and voxel-based analysis of [11C]-FMZ PET detected extrahippocampal changes of cBZR binding in eight of 15 patients with mTLE due to HS. The finding of abnormalities in patients who were thought to have unilateral HS only based on MRI suggests that more widespread abnormalities are present in HS.

A 25-year-old man with a long history of temporal lobe epilepsy developed right occipital lobe seizures and a progressive right homonymous hemianopia. MRI showed diffuse enhancement of the left temporoparieto-occipital white matter and cortical thickening of the left medial temporal lobe. The resected temporal lobe revealed cortical dysplasia and angiodysplasia with foci of more recent ischemic necrosis and chronic inflammation as an explanation for the clinical deterioration.

A previously healthy 10-year-old boy presented with right-sided headache and focal motor seizures characterized by left facial twitching. Examination revealed a left hemiparesis. CT scan demonstrated a large, right frontoparietal mass containing calcification. Biopsy showed changes consistent with cerebral vasculitis involving the cortex, white matter, and leptomeningeal vessels. Despite treatment with dexamethasone 3 mg/day for 6 weeks, the patient’s condition deteriorated, with increasing left-sided weakness and a new left hemianopia. On re-investigation, inflammatory markers, autoantibody profile, and neurotropic virus screen were negative. CSF examination revealed intrathecal synthesis of oligoclonal bands but was otherwise normal. A cerebral angiogram showed the right middle cerebral artery and its branches to be of smaller caliber than the left. In view of the re-activation of the cerebral vasculitis, treatment with 2 mg/kg/day prednisolone was given for 3 months. His condition stabilized, and azathioprine was introduced as a steroid-sparing immunosuppressive therapy. Despite occasional focal seizures, he remained stable for the next decade, at which time the azathioprine therapy was withdrawn. Serial MRI was …

Objective: To determine whether clinical differences between the sexes seen in periventricular nodular heterotopia (PNH) have structural correlates on imaging. Background: PNH is the most common dysgenesis associated with hippocampal sclerosis (HS). Women with PNH have normal intellect; men may have mental retardation and other changes. Familial PNH, seen in women, is linked to Xq28—a region also abnormal in a sporadic male infant with PNH and retardation—suggesting sexual differences in gene expression. Epilepsy associated with PNH may be refractory to drugs, and surgery for associated HS does not stop seizures, suggesting intrinsic epileptogenicity of PNH. Methods: Quantitative MRI analysis was performed using established techniques for detecting subtle structural changes in 13 female patients (11 sporadic and two familial) and four male patients (sporadic). Results: There is structural heterogeneity in PNH, even in patients with bilateral PNH. On MRI, men have more cerebral abnormalities beyond PNH than control subjects or female patients (p Conclusions: The findings support the concept of intrinsic epileptogenicity of PNH. There may be additional structural abnormalities relevant to seizure generation, especially in men. Structural heterogeneity, and widespread abnormalities, may need consideration when patients are referred for surgical treatment or when additional studies of patients with PNH are conducted.