Noriko Salamon

The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission†

Purpose:  Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities.

CT and MRI Early Vessel Signs Reflect Clot Composition in Acute Stroke

Background and Purpose— The purpose of this study was to provide the first correlative study of the hyperdense middle cerebral artery sign (HMCAS) and gradient-echo MRI blooming artifact (BA) with pathology of retrieved thrombi in acute ischemic stroke. Methods— Noncontrast CT and gradient-echo MRI studies before mechanical thrombectomy in 50 consecutive cases of acute middle cerebral artery ischemic stroke were reviewed blinded to clinical and pathology data. Occlusions retrieved by thrombectomy underwent histopathologic analysis, including automated quantitative and qualitative rating of proportion composed of red blood cells (RBCs), white blood cells, and fibrin on microscopy of sectioned thrombi. Results— Among 50 patients, mean age was 66 years and 48% were female. Mean (SD) proportion was 61% (±21) fibrin, 34% (±21) RBCs, and 4% (±2) white blood cells. Of retrieved clots, 22 (44%) were fibrin-dominant, 13 (26%) RBC-dominant, and 15 (30%) mixed. HMCAS was identified in 10 of 20 middle cerebral artery stroke cases with CT with mean Hounsfield Unit density of 61 (±8 SD). BA occurred in 17 of 32 with gradient-echo MRI. HMCAS was more commonly seen with RBC-dominant and mixed than fibrin-dominant clots (100% versus 67% versus 20%, P=0.016). Mean percent RBC composition was higher in clots associated with HMCAS (47% versus 22%, P=0.016). BA was more common in RBC-dominant and mixed clots compared with fibrin-dominant clots (100% versus 63% versus 25%, P=0.002). Mean percent RBC was greater with BA (42% versus 23%, P=0.011). Conclusions— CT HMCAS and gradient-echo MRI BA reflect pathology of occlusive thrombus. RBC content determines appearance of HMCAS and BA, whereas absence of HMCAS or BA may indicate fibrin-predominant occlusive thrombi.

FDG-PET/MRI coregistration improves detection of cortical dysplasia in patients with epilepsy.

Objective: Patients with cortical dysplasia (CD) are difficult to treat because the MRI abnormality may be undetectable. This study determined whether fluorodeoxyglucose (FDG)-PET/MRI coregistration enhanced the recognition of CD in epilepsy surgery patients. Methods: Patients from 2004–2007 in whom FDG-PET/MRI coregistration was a component of the presurgical evaluation were compared with patients from 2000–2003 without this technique. For the 2004–2007 cohort, neuroimaging and clinical variables were compared between patients with mild Palmini type I and severe Palmini type II CD. Results: Compared with the 2000–2003 cohort, from 2004–2007 more CD patients were detected, most had type I CD, and fewer cases required intracranial electrodes. From 2004–2007, 85% of type I CD cases had normal non–University of California, Los Angeles (UCLA) MRI scans. UCLA MRI identified CD in 78% of patients, and 37% of type I CD cases had normal UCLA scans. EEG and neuroimaging findings were concordant in 52% of type I CD patients, compared with 89% of type II CD patients. FDG-PET scans were positive in 71% of CD cases, and type I CD patients had less hypometabolism compared with type II CD patients. Postoperative seizure freedom occurred in 82% of patients, without differences between type I and type II CD cases. Conclusions: Incorporating fluorodeoxyglucose-PET/MRI coregistration into the multimodality presurgical evaluation enhanced the noninvasive identification and successful surgical treatment of patients with cortical dysplasia (CD), especially for the 33% of patients with nonconcordant findings and those with normal MRI scans from mild type I CD. GLOSSARY: AED = antiepileptic drug; CD = cortical dysplasia; FDG = fluorodeoxyglucose; mMCD = mild malformations of cortical development; TLE = temporal lobe epilepsy; UCLA = University of California, Los Angeles.

Epileptogenesis in pediatric cortical dysplasia: The dysmature cerebral developmental hypothesis

Cortical dysplasia (CD) is the most frequent pathology found in pediatric epilepsy surgery patients with a nearly 80% incidence in children younger than 3 years of age. Younger cases are more likely to have multilobar and severe forms of CD compared with older patients with focal and mild CD. Using clinico-pathologic techniques, we have initiated studies that unravel the timing of CD pathogenesis that in turn suggest mechanisms of epileptogenesis. Morphological comparisons provided the first clue when we observed that cytomegalic neurons have similarities with human subplate cells, and balloon cells have features analogous to radial glia. This suggested that failure of prenatal cell degeneration before birth could explain the presence of postnatal dysmorphic cells in CD tissue. Neuronal density and MRI volumes indicate that there were more neurons than expected in CD tissue, and they were probably produced in later neurogenesis cell cycles. Together these findings imply that there is partial failure in later phases of cortical development that might explain the distinctive histopathology of CD. If correct, epileptogenesis should be the consequence of incomplete cellular maturation in CD tissue. In vitro electrophysiological findings are consistent with this notion. They show that balloon cells have glial features, cytomegalic neurons and recently discovered cytomegalic interneurons reveal atypical hyperexcitable intrinsic membrane properties, there are more GABA than glutamate spontaneous synaptic inputs onto neurons, and in a subset of cells NMDA and GABA(A) receptor-mediated responses and subunit expression are similar to those of immature neurons. Our studies support the hypothesis that there are retained prenatal cells and neurons with immature cellular and synaptic properties in pediatric CD tissue. We propose that local interactions of dysmature cells with normal postnatal neurons produce seizures. This hypothesis will drive future studies aimed at elucidating mechanisms of epileptogenesis in pediatric CD tissue.

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex : A preliminary report

Summary:  Purpose: Patients with tuberous sclerosis complex (TSC) are potential surgical candidates if the epileptogenic region(s) can be accurately identified. This retrospective study determined whether FDG‐PET/MRI coregistration and diffusion‐tensor imaging (DTI) showed better accuracy in the localization of epileptogenic cortex than structural MRI in TSC patients.

Imaging of malformations of cortical development

Malformations of cortical development (MCD) include a broad range of disorders that result from disruption of the major steps of cortical development: cell proliferation in germinal zones, neuronal migration and cortical organization. With the improvement and increased utilization of modern imaging techniques, MCD have been increasingly recognized as a major cause of seizure disorders. The advent of Magnetic Resonance Imaging (MRI), in particular, has revolutionized the investigation and the treatment of patients with epilepsy. High-resolution MRI may elucidate the type, the extension and the localization of MCD; therefore, in a group of patients suffering from drug-resistant partial epilepsy (DRPE), MRI greatly contributes to the identification of subjects who are suitable for surgical treatment. In the recent past, many efforts were addressed to establish the MRI diagnostic criteria for a peculiar group of MCD, namely focal cortical dysplasias (FCD), histopathologically distinguished as types I and II. Some subtle FCD, which were previously cryptic to imaging investigation, can now be recognized by MRI, however their detection and specification remains challenging. This review will re-visit the neuroimaging findings, including structural MRI, PET, co-registered PET/MRI, MEG and diffusion tensor imaging (DTI) of FCD types I and II. Three major issues will be discussed: 1) the morphological MRI features of the FCDs, 2) the utility of PET and MEG and the use of co-registration methods and 3) diffusion tensor imaging (DTI) as a future modality of investigation, which may add additional informations regarding the microstructure of the grey matter (GM) and white matter (WM) in cortical dysplasia.

Early Neutrophilia Is Associated With Volume of Ischemic Tissue in Acute Stroke

Background and Purpose— Few data exist on the relationship between differential subpopulations of peripheral leukocytes and early cerebral infarct size in ischemic stroke. Using diffusion-weighted MR imaging (DWI), we assessed the relationship of early total and differential peripheral leukocyte counts and volume of ischemic tissue in acute stroke. Methods— All included patents had laboratory investigations and neuroimaging collected within 24 hours of stroke onset. Total peripheral leukocyte counts and differential counts were analyzed individually and by quartiles. DWI lesions were outlined using a semiautomated threshold technique. The relationship between leukocyte quartiles and DWI infarct volumes was examined using multivariate quartile regression. Results— 173 patients met study inclusion criteria. Median age was 73 years. Total leukocyte counts and DWI volumes showed a strong correlation (Spearman rho=0.371, P<000.1). Median DWI volumes (mL) for successive neutrophil quartiles were: 1.3, 1.3, 3.2, and 20.4 (P for trend <0.001). Median DWI volumes (mL) for successive lymphocyte quartiles were: 3.2, 8.1, 1.3, and 1.5 (P=0.004). After multivariate analysis, larger DWI volume remained strongly associated with higher total leukocyte and neutrophil counts (both probability values <0.001), but not with lymphocyte count (P=0.4971). Compared with the lowest quartiles, DWI volumes were 8.7 mL and 12.9 mL larger in the highest quartiles of leukocyte and neutrophil counts, respectively. Conclusions— Higher peripheral leukocyte and neutrophil counts, but not lymphocyte counts, are associated with larger infarct volumes in acute ischemic stroke. Attenuating neutrophilic response early after ischemic stroke may be a viable therapeutic strategy and warrants further study.

Improved outcomes in pediatric epilepsy surgery The UCLA experience, 1986–2008

Objective: Epilepsy neurosurgery is a treatment option for children with refractory epilepsy. Our aim was to determine if outcomes improved over time. Methods: Pediatric epilepsy surgery patients operated in the first 11 years (1986–1997; pre-1997) were compared with the second 11 years (1998–2008; post-1997) for differences in presurgical and postsurgical variables. Results: Despite similarities in seizure frequency, age at seizure onset, and age at surgery, the post-1997 series had more lobar/focal and fewer multilobar resections, and more patients with tuberous sclerosis complex and fewer cases of nonspecific gliosis compared with the pre-1997 group. Fewer cases had intracranial EEG studies in the post-1997 (0.8%) compared with the pre-1997 group (9%). Compared with the pre-1997 group, the post-1997 series had more seizure-free patients at 0.5 (83%, +16%), 1 (81%, +18%), 2 (77%, +19%), and 5 (74%, +29%) years, and more seizure-free patients were on medications at 0.5 (97%, +6%), 1 (88%, +9%), and 2 (76%, +29%), but not 5 (64%, +8%) years after surgery. There were fewer complications and reoperations in the post-1997 series compared with the pre-1997 group. Logistic regression identified post-1997 series and less aggressive medication withdrawal as the main predictors of becoming seizure-free 2 years after surgery. Conclusions: Improved technology and surgical procedures along with changes in clinical practice were likely factors linked with enhanced and sustained seizure-free outcomes in the post-1997 series. These findings support the general concept that clearer identification of lesions and complete resection are linked with better outcomes in pediatric epilepsy surgery patients.

Prediction of hemorrhagic transformation after recanalization therapy using T2*-permeability magnetic resonance imaging

Predicting hemorrhagic transformation (HT) is critical in the setting of recanalization therapy for acute stroke. Dedicated magnetic resonance imaging (MRI) sequences for detection of increased blood–brain barrier (BBB) permeability recently have been developed. We evaluated the ability of a novel MRI permeability technique to detect baseline derangements predictive of various forms of HT after recanalization therapy.