Effect of Training on Visual Identification of High Frequency Oscillations-A Delphi-Style Intervention.

OBJECTIVE: We examined the effect of a simple Delphi-method feedback on visual identification of high frequency oscillations (HFOs) in the ripple (80-250 Hz) band, and assessed the impact of this training intervention on the interrater reliability and generalizability of HFO evaluations. METHODS: We employed a morphology detector to identify potential HFOs at two thresholds and presented them to visual reviewers to assess the probability of each epoch containing an HFO. We recruited 19 board-certified epileptologists with various levels of experience to complete a series of HFO evaluations during three sessions. A Delphi-style intervention was used to provide feedback on the performance of each reviewer relative to their peers. A delayed-intervention paradigm was used, in which reviewers received feedback either before or after the second session. ANOVAs were used to assess the effect of the intervention on the reviewers' evaluations. Generalizability theory was used to assess the interrater reliability before and after the intervention. RESULTS: The intervention, regardless of when it occurred, resulted in a significant reduction in the variability between reviewers in both groups (p GroupDI = 0.037, p GroupEI = 0.003). Prior to the delayed-intervention, the group receiving the early intervention showed a significant reduction in variability (p GroupEI = 0.041), but the delayed-intervention group did not (p GroupDI = 0.414). Following the intervention, the projected number of reviewers required to achieve strong generalizability decreased from 35 to 16. SIGNIFICANCE: This study shows a robust effect of a Delphi-style intervention on the interrater variability, reliability, and generalizability of HFO evaluations. The observed decreases in HFO marking discrepancies across 14 of the 15 reviewers are encouraging: they are necessarily associated with an increase in interrater reliability, and therefore with a corresponding decrease in the number of reviewers required to achieve strong generalizability. Indeed, the reliability of all reviewers following the intervention was similar to that of experienced reviewers prior to intervention. Therefore, a Delphi-style intervention could be implemented either to sufficiently train any reviewer, or to further refine the interrater reliability of experienced reviewers. In either case, a Delphi-style intervention would help facilitate the standardization of HFO evaluations and its implementation in clinical care.

Hippocampal subfield measurement and ILAE hippocampal sclerosis subtype classification with in vivo 4.7 tesla MRI.

OBJECTIVE: Neuropathological studies indicate that hippocampal sclerosis (HS) consists of three subtypes (ILAE types 1-3 HS). However, HS subtypes currently can only be diagnosed by pathological analysis of hippocampal tissue resected during epilepsy surgery or at autopsy. In vivo diagnosis of HS subtypes holds potential to improve our understanding of these variants in the ipsilateral as well as contralateral hippocampus. In this study, we aimed to: i) evaluate the reliability of our histology-derived segmentation protocol when applied to in vivo MRI; and ii) characterize variability of HS subtypes along the hippocampal long axis in patients with epilepsy. METHODS: Eleven subjects with unilateral HS were compared with ten healthy controls. We used 4.7 T MRI to acquire high resolution MR Images of the hippocampus in each subject. In vivo MRI-based diagnoses of HS subtypes were then determined in each patient by two methods: i) hippocampal subfield volumetry of the entire hippocampal body; and ii) subfield area analysis at multiple thin slices throughout the hippocampal body. RESULTS: Hippocampal body subfield segmentation demonstrated excellent reliability and volumetry of the symptomatic hippocampus revealed abnormalities in all eleven patients. Six subjects demonstrated findings consistent with type 1 HS while five subjects had volumetry-defined atypical HS (two with type 2 HS & three with type 3 HS) in the symptomatic hippocampus, while five subjects were found to have type 3 HS in the contralateral hippocampus. Subfield area analyses demonstrated remarkable variability of HS subtypes along the hippocampal long axis, both ipsilateral and contralateral to the seizure focus. SIGNIFICANCE: Our results provide preliminary evidence that determining HS Subtype using in vivo MRI may allow preoperative diagnosis of ILAE HS subtypes. Further studies are essential to determine the pathological correlates of these neuroimaging findings. The heterogeneity of abnormalities observed along the long axis of the hippocampus is consistent with previous autopsy studies and highlights the necessity of studying the entire hippocampus both ipsilateral and contralateral to the seizure focus in these future studies.

Curved multiplanar reformatting provides improved visualization of hippocampal anatomy.

There is a growing body of literature studying changes in hippocampal subfields in a variety of different neurological conditions, but this work has mainly focused on the hippocampal body given challenges in visualization of hippocampal anatomy in the head and tail when sectioned in the typical coronal image plane. Curved multiplanar reformatting (CMPR) is an image reconstruction method that can improve visualization of complex three-dimensional structures. The objective of this study was to determine whether CMPR could facilitate visualization of the human hippocampal anatomy along the entire caudal-rostral axis. CMPR was applied to high-resolution magnetic resonance imaging acquired ex vivo on four cadaveric hippocampal specimens at 4.7 T (T2-weighted, 0.2 × 0.2 × 0.5 mm3 ). CMPR provided clear visualization of the classic "interlocking C" appearance of the dentate gyrus and cornu ammonis along the entire caudal-rostral axis including the head and tail, which otherwise show complex anatomy on the standard coronal slices. CMPR facilitated visualization of hippocampal anatomy providing the impetus to develop simplified approaches to delineate subfields along the entire hippocampus including the usually neglected head and tail.

Regional hippocampal diffusion abnormalities associated with subfield-specific pathology in temporal lobe epilepsy.

OBJECTIVE: Hippocampal sclerosis (HS) is the most common pathology and best predictor of surgical outcome for medically refractory patients with temporal lobe epilepsy (TLE). Current clinical MRI methods can detect HS, but subfield pathology is poorly characterized, limiting accurate prediction of seizure-free outcomes after surgery. Diffusion tensor imaging (DTI) can probe regional microstructural changes associated with focal hippocampal pathology, but is typically limited by low-resolution whole-brain acquisitions. METHODS: High-resolution (1 × 1 × 1 mm3) DTI, T1, and quantitative T2 of the hippocampus was acquired in 18 preoperative TLE patients and 19 healthy controls. Diffusion images were qualitatively assessed for loss of internal architecture, and whole-hippocampus diffusion, volume, and quantitative T2 were compared across groups. Regional hippocampal diffusion abnormalities were examined in all subjects and compared to histology in four subjects who underwent anterior temporal lobectomy. RESULTS: High-resolution mean diffusion-weighted images enabled visualization of internal hippocampal architecture, used to visually identify HS with 86% specificity and 93% sensitivity. Mean diffusivity (MD) elevations were regionally heterogenous within the hippocampus and varied across TLE patients. The spatial location of diffusion abnormalities corresponded with the location of focal subfield neuron loss, gliosis, and reduced myelin staining abnormalities identified with postsurgical histology in four subjects who underwent anterior temporal lobectomy. Whole-hippocampus MD and T2 relaxation times were higher, and fractional anisotropy (FA) and volumes were lower in TLE patients relative to controls. Left hippocampus MD correlated with verbal memory in the TLE group. SIGNIFICANCE: Visualization of internal architecture and focal diffusion abnormalities on high-resolution diffusion imaging suggests potential clinical utility of diffusion imaging in TLE and may have significant implications for surgical planning and prediction of seizure-free outcomes in individual patients.

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Seizure outcome in pediatric medically refractory temporal lobe epilepsy surgery: selective amygdalohippocampectomy versus anterior temporal lobectomy.

OBJECTIVE The aim of this study was to investigate long-term seizure outcome, rate of reoperation, and postoperative neuropsychological performance following selective amygdalohippocampectomy (SelAH) or anterior temporal lobectomy (ATL) in pediatric patients with medically refractory temporal lobe epilepsy (TLE). METHODS The authors performed a retrospective review of cases of medically refractory pediatric TLE treated initially with either SelAH or ATL. Standardized pre- and postoperative evaluation included seizure charting, surface and long-term video-electroencephalography, 1.5-T MRI, and neuropsychological testing. RESULTS A total of 79 patients treated initially with SelAH (n = 18) or ATL (n = 61) were included in this study, with a mean follow-up of 5.3 ± 4 years (range 1-16 years). The patients' average age at initial surgery was 10.6 ± 5 years, with an average surgical delay of 5.7 ± 4 years between seizure onset and surgery. Seizure freedom (Engel I) following the initial operation was significantly more likely following ATL (47/61, 77%) than SelAH (8/18, 44%; p = 0.017, Fisher's exact test). There was no statistically significant difference in the proportion of patients with postoperative neuropsychological deficits following SelAH (8/18, 44%) or ATL (21/61, 34%). However, reoperation was significantly more likely following SelAH (8/18, 44%) than after ATL (7/61, 11%; p = 0.004) and was more likely to result in Engel I outcome for ATL after failed SelAH (7/8, 88%) than for posterior extension after failed ATL (1/7, 14%; p = 0.01). Reoperation was well tolerated without significant neuropsychological deterioration. Ultimately, including 15 reoperations, 58 of 79 (73%) patients were free from disabling seizures at the most recent follow-up. CONCLUSIONS SelAH among pediatric patients with medically refractory unilateral TLE yields significantly worse rates of seizure control compared with ATL. Reoperation is significantly more likely following SelAH, is not associated with incremental neuropsychological deterioration, and frequently results in freedom from disabling seizures. These results are significant in that they argue against using SelAH for pediatric TLE surgery.

High resolution in-vivo diffusion imaging of the human hippocampus.

The human hippocampus is a key target of many imaging studies given its capacity for neurogenesis, role in long term potentiation and memory, and nearly ubiquitous involvement in neurological and psychiatric conditions. Diffusion tensor imaging (DTI) has detected microstructural abnormalities of the human hippocampus associated with various disorders, but acquisitions have typically been limited to low spatial resolution protocols designed for whole brain (e.g. > 2 mm isotropic, >8 mm3 voxels), limiting regional specificity and worsening partial volume effects. The purpose here was to develop a simple DTI protocol using readily available standard single-shot EPI at 3T, capable of yielding much higher spatial resolution images (1 x 1 x 1 mm3) of the human hippocampus in a 'clinically feasible' scan time of ~6 min. A thin slab of twenty 1 mm slices oriented along the long axis of the hippocampus enabled efficient coverage and a shorter repetition time, allowing more diffusion weighted images (DWIs) per slice per unit time. In combination with this strategy, a low b value of 500 s/mm2 was chosen to help overcome the very low SNR of a 1 x 1 x 1 mm3 EPI acquisition. 1 mm isotropic mean DWIs (averaged over 120-128 DWIs) showed excellent detail of the hippocampal architecture (e.g. morphology and digitations, sub-regions, stratum lacunosum moleculare - SLM) that was not readily visible on 2 mm isotropic diffusion images. Diffusion parameters within the hippocampus were consistent across subjects and fairly homogenous across sub-regions of the hippocampus (with the exception of the SLM and tail). However, it is expected that DTI parameters will be sensitive to microstructural changes associated with a number of clinical disorders (e.g. epilepsy, dementia) and that this practical, translatable approach for high resolution acquisition will facilitate localized detection of hippocampal pathology.

Development of a histologically validated segmentation protocol for the hippocampal body.

BACKGROUND: Recent findings have demonstrated that hippocampal subfields can be selectively affected in different disease states, which has led to efforts to segment the human hippocampus with in vivo magnetic resonance imaging (MRI). However, no studies have examined the histological accuracy of subfield segmentation protocols. The presence of MRI-visible anatomical landmarks with known correspondence to histology represents a fundamental prerequisite for in vivo hippocampal subfield segmentation. In the present study, we aimed to: 1) develop a novel method for hippocampal body segmentation, based on two MRI-visible anatomical landmarks (stratum lacunosum moleculare [SLM] & dentate gyrus [DG]), and assess its accuracy in comparison to the gold standard direct histological measurements; 2) quantify the accuracy of two published segmentation strategies in comparison to the histological gold standard; and 3) apply the novel method to ex vivo MRI and correlate the results with histology. METHODS: Ultra-high resolution ex vivo MRI was performed on six whole cadaveric hippocampal specimens, which were then divided into 22 blocks and histologically processed. The hippocampal bodies were segmented into subfields based on histological criteria and subfield boundaries and areas were directly measured. A novel method was developed using mean percentage of the total SLM distance to define subfield boundaries. Boundary distances and subfield areas on histology were then determined using the novel method and compared to the gold standard histological measurements. The novel method was then used to determine ex vivo MRI measures of subfield boundaries and areas, which were compared to histological measurements. RESULTS: For direct histological measurements, the mean percentages of total SLM distance were: Subiculum/CA1 = 9.7%, CA1/CA2 = 78.4%, CA2/CA3 = 97.5%. When applied to histology, the novel method provided accurate measures for CA1/CA2 (ICC = 0.93) and CA2/CA3 (ICC = 0.97) boundaries, but not for the Subiculum/CA1 (ICC = -0.04) boundary. Accuracy was poorer using previous techniques for CA1/CA2 (maximum ICC = 0.85) and CA2/CA3 (maximum ICC = 0.88), with the previously reported techniques also performing poorly in defining the Subiculum/CA1 boundary (maximum ICC = 0.00). Ex vivo MRI measurements using the novel method were linearly related to direct measurements of SLM length (r2 = 0.58), CA1/CA2 boundary (r2 = 0.39) and CA2/CA3 boundary (r2 = 0.47), but not for Subiculum/CA1 boundary (r2 = 0.01). Subfield areas measured with the novel method on histology and ex vivo MRI were linearly related to gold standard histological measures for CA1, CA2, and CA3/CA4/DG. CONCLUSIONS: In this initial proof of concept study, we used ex vivo MRI and histology of cadaveric hippocampi to develop a novel segmentation protocol for the hippocampal body. The novel method utilized two anatomical landmarks, SLM & DG, and provided accurate measurements of CA1, CA2, and CA3/CA4/DG subfields in comparison to the gold standard histological measurements. The relationships demonstrated between histology and ex vivo MRI supports the potential feasibility of applying this method to in vivo MRI studies.

Immune Cell Infiltrates in Hippocampal Sclerosis: Correlation With Neuronal Loss.

Immune mechanisms have been increasingly recognized in the pathogenesis of hippocampal sclerosis (HS), but infiltration of cytotoxic T-cells and its pathological significance in patients with HS has not been explored. We examined 30 cases of surgically resected hippocampi, including 16 International League Against Epilepsy (ILAE) type 1, 9 ILAE type 2, 1 ILAE type 3 HS, and 4 ILAE No-HS, as well as 6 autopsy No-HS hippocampi. The HS hippocampi showed sparse to scattered CD8-positive T-cells, rare CD4-positive T-cells, and a modest increase in CD68-positive microglia/macrophages, which were significantly more numerous than those in the No-HS controls. The infiltration of CD8-positive T-cells was significantly greater in the CA1 subfield than other subfields of type 1 and type 2 HS. The numbers of CD8-positive T-cells positively correlated with those of CD4-positive T-cells; there was a lower ratio of CD4/CD8-positive T-cells. There were positive correlations between these cells and scores of neuronal loss but no significant correlation between the infiltration of these cells and epilepsy disease duration or age of epilepsy onset. These findings suggest that an autoimmune process may be involved in the pathogenesis of HS and infiltration of immune cells, particularly CD8-positive cytotoxic T-cells, may contribute to neuronal loss in HS.

Neurological Nuance: Hodgkin lymphoma presenting with Guillain-BarrÉ syndrome.

INTRODUCTION: Hodgkin lymphoma (HL) is a common lymphoid malignancy rarely associated with Guillain-Barré syndrome (GBS). In most cases, GBS does not precede HL. METHODS: We describe a patient with acute inflammatory demyelinating polyneuropathy who fulfilled criteria for GBS that heralded undiagnosed HL. RESULTS: Cerebrospinal fluid (CSF) studies revealed albuminocytologic dissociation with significant protein elevation (250 mg/dl). The patient worsened during intravenous immunoglobulin (IVIg) therapy. Constitutional symptoms with elevated inflammatory markers prompted further investigation, and imaging revealed an anterior mediastinal mass confirmed on biopsy to be HL. Chemotherapy yielded early clinical improvement. CONCLUSIONS: GBS preceding HL is rare, and this case highlights the importance of considering HL in the setting of GBS. Marked elevations in CSF protein, ongoing deterioration despite administration of IVIg, and constitutional symptoms with elevated inflammatory markers may be clues to possible HL-induced GBS. Muscle Nerve 55: 601-604, 2017.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

National Institutes of Health Stroke Scale score is an unreliable predictor of perfusion deficits in acute stroke.

BACKGROUND: Perfusion-weighted magnetic resonance imaging is not routinely used to investigate stroke/transient ischemic attack. Many clinicians use perfusion-weighted magnetic resonance imaging selectively in patients with more severe neurological deficits, but optimal selection criteria have never been identified. AIMS AND/OR HYPOTHESIS: We tested the hypothesis that a National Institutes of Health Stroke Scale score threshold can be used to predict the presence of perfusion-weighted magnetic resonance imaging deficits in patients with acute ischemic stroke/transient ischemic attack. METHODS: National Institutes of Health Stroke Scale scores were prospectively assessed in 131 acute stroke/transient ischemic attack patients followed by magnetic resonance imaging, including perfusion-weighted magnetic resonance imaging within 72 h of symptom onset. Patients were dichotomized based on the presence or absence of perfusion deficits using a threshold of Tmax (time to peak maps after the impulse response) delay ≥four-seconds and a hypoperfused tissue volume of ≥1 ml. RESULTS: Patients with perfusion deficits (77/131, 59%) had higher median (interquartile range) National Institutes of Health Stroke Scale scores (8 [12]) than those without perfusion deficits (3 [4], P < 0.001). A receiver operator characteristic analysis indicated poor to moderate sensitivity of National Institutes of Health Stroke Scale scores for predicting perfusion deficits (area under the curve = 0.787). A National Institutes of Health Stroke Scale score of ≥6 was associated with specificity of 85%, but sensitivity of only 69%. No National Institutes of Health Stroke Scale score threshold identified all cases of perfusion-weighted magnetic resonance imaging deficits with sensitivity >94%. CONCLUSIONS: Although higher National Institutes of Health Stroke Scale scores are predictive of perfusion deficits, many patients with no clinically detectable signs have persisting cerebral blood flow changes. A National Institutes of Health Stroke Scale score threshold should therefore not be used to select patients for perfusion-weighted magnetic resonance imaging. Perfusion-weighted magnetic resonance imaging should be considered in all patients presenting with acute focal neurological deficits, even if these deficits are transient.

Quantification of subfield pathology in hippocampal sclerosis: a systematic review and meta-analysis.

BACKGROUND: The utility of MRI-based hippocampal subfield volumetry as a diagnostic test for hippocampal sclerosis (HS) is based on the hypothesis that specific hippocampal subfields are differentially affected in HS. While qualitative studies suggest selective involvement of certain hippocampal subfields in this condition, whether quantifiable differences exist remains unclear. Neuronal density measurement is the most widely used technique for measuring subfield pathological change in HS. Therefore, a systematic review and meta-analysis of studies reporting neuronal densities in temporal lobe epilepsy was performed in order to quantify subfield pathology in hippocampal sclerosis. METHODS: Studies were identified by searching the Medline and Embase databases using the search terms: cell count, hippocampus, and epilepsy. Of the 192 studies identified by the literature search, seven met all inclusion and exclusion criteria. Random effects meta-analyses were performed, comparing: (i) neuronal densities in control (n=121) versus HS (n=371) groups for subfields CA1-4; and (ii) amount of neuronal loss in HS between subfields CA1-4. RESULTS: Statistically significant neuronal loss was observed comparing HS to control groups in all subfields CA1-4 (p<0.001 for all comparisons). Significantly greater neuronal loss was demonstrated in HS comparing CA1 versus CA2 (p<0.001), CA3 (p=0.005), and CA4 (p=0.003). Greater pyramidal cell loss was also demonstrated in CA3 relative to the CA2 subfield (p=0.003). No significant differences were identified comparing CA2 and CA4 (p=0.39); or comparing CA3 and CA4 (p=0.64). CONCLUSIONS: HS is characterized by pathology in all hippocampal subfields. Quantifiable differences exist in the involvement of specific hippocampal subfields in HS. Neuronal loss is greatest in CA1, intermediate in CA3 and CA4, and least in CA2. Further studies are required to determine if this pattern can be detected using in vivo MRI.

Alcohol-responsive epilepsia partialis continua.

Epilepsia partialis continua is typically associated with lesions of the cerebral cortex. However, subcortical lesions can also cause this condition. We present a patient with epilepsia partialis continua who failed to respond to conventional anticonvulsant medications but experienced a dramatic transient response to alcohol and a subsequent response to primidone. This pattern of sensitivity, which is similar to that seen in essential tremor, has led to the hypothesis that the two disorders are associated with pathology within the same anatomical network. A new pathophysiological model is thus proposed for the occurrence of epilepsia partialis continua in both cortical and subcortical disease processes.