Grey matter heterotopias, demonstrated by MRI, may present with a broad spectrum of clinical severity. We have studied 33 patients with periventricular nodular heterotopias (PNH); 19 (58%) had unilateral and 14 (42%) bilateral lesions. Thirteen of the 19 patients (68%) with unilateral subependymal nodules of grey matter had, in addition, unilateral focal subcortical heterotopias (SNH), comprising 39% of the entire group. Most had normal intellectual and motor function but some presented with mild mental retardation and neurological deficits. Recurrent seizures were described in 82%, mainly partial attacks with temporo-parieto-occipital auras. Nodular heterotopias led to unilateral or bilateral independent temporal epileptic discharges in 47% of epileptic patients with PNH alone and in 61% of those who had SNH in addition. Extratemporal or multilobar, unilateral or bilateral interictal spiking was present in 10 other patients (36%). Two first degree relatives of patients with seizures were affected but had no seizures, three were investigated for other apparently unrelated neurological symptoms: memory impairment, vertigo or transient ischaemic attacks in one person each. Contiguous ovoid nodules of grey matter, symmetrically lining both lateral ventricles, were described in nine patients. Seven of them were female, including four with familial incidence of PNH. Such lesions may explain the familial occurrence of epilepsy in some families. Seven patients underwent anterior temporal resection: two patients with unilateral subependymal and focal subcortical heterotopias were seizure free or significantly improved. Four patients, three with PNH alone and one with additional subcortical nodules, did not improve significantly after surgery. The remaining patient was followed for less than 6 months.

A 32-month-old child presented in status epilepticus (SE) involving the left side of the body. Fast spin-echo magnetic resonance imaging (FSE-MRI) with hippocampal volumetry performed < or = 24 h after the seizure showed increased T2 signal of the right hippocampus, but no atrophy. Complex partial seizures (CPS) appeared at age 33 months, and three more episodes of SE occurred between 33 and 37 months of age. Follow-up FSE-MRI at 34 and at 45 months of age demonstrated progressive hippocampal atrophy with resolution of the increased T2 signal. Her CPS became intractable and, at age 51 months, she underwent right temporal lobectomy. In the ensuing 5 months, she has had only one major motor seizure. This case demonstrates that acute increased hippocampal T2 signal intensity can occur soon after SE and hippocampal sclerosis (HS) may become evident within months in the setting of recurrent early childhood SE. This observation may support the hypothesis that early childhood SE can lead to HS. Furthermore, this case suggests that years of temporal lobe CPS may not be necessary for development of HS.

We analyzed the interictal [18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) findings of 17 epileptic patients with neuronal migration disorders (NMDs). Fifteen patients had abnormal PET findings, i.e., focal hypometabolism in 9 patients and displaced metabolic activity of normal gray matter in 6. All 15 patients had magnetic resonance imaging (MRI) abnormalities; however, PET abnormality assisted in the identification of NMDs on MRI in 3 patients. Two patients with negative MRI also had negative PET studies. PET hypometabolism appeared to correlate with severity of neuronal dysgenesis or temporal lobe involvement, or both. Displaced metabolic activity of gray matter is regarded as a unique interictal [18F]fluoro-2-deoxy-D-glucose-PET finding in NMD. This study demonstrates variable metabolic patterns in NMD and that PET may be a useful complement to MRI in the evaluation of NMD.

To assess the value of magnetic resonance imaging (MRI)-measured hippocampal volume in the detection of hippocampal sclerosis, we studied 28 patients undergoing anterior temporal lobectomy for medically intractable mesial temporal lobe epilepsy. Hippocampal volumetry and visual analysis of T2 signal change were performed using fast spin-echo T2-weighed MRI. Quantitative neuronal density measurements were performed in the resected hippocampal specimens. There was a significant correlation between MRI-measured absolute hippocampal volume (AHV) and neuronal density in CA1, CA2, and CA3 subfields (p < 0.0001, p < 0.01, and p < 0.05, respectively). Differential hippocampal volume (side-to-side volume difference) failed to detect bilateral atrophy in three patients, but the bilateral hippocampal atrophy was recognized by considering AHV in these patients. This study suggests that MRI-measured AHV can be of value in elevating patients with mesial temporal lobe epilepsy, especially when there is no side-to-side difference in hippocampal volumetry.

Summary:Purpose: This retrospective study reports the longterm surgical outcome of patients with medically refractory epilepsy and vascular malformations who were treated with lesionectomy. A detailed analysis of surgical failures had been performed in an attempt to define predictors of surgical success and failure.Methods: Fifteen patients with medically intractable epilepsy and angiographically occult vascular malformations (AOVMs) were treated surgically with lesionectomy at Duke University Medical Center. Lesionectomy consisted of removal of the AOVM and surrounding hemosiderin-stained brain only, without the use of electrocorticography (ECoG) to guide resection.Results: Eleven (73%) patients are seizure free after lesionectomy. Three showed no significant improvement, and one patient died, presumably after a seizure. Age of onset, duration of seizures, age at resection, and gender did not affect outcome. All patients with neocortical AOVMs in whom EEG findings correlated with the site of the lesion were seizure free after lesional resection. Treatment failures were associated with the presence of multiple intracranial lesions, poorly localized or diffuse EEG findings, discordant positron emission tomography (PET) imaging, or with a lesion in close proximity to the limbic system.Conclusions: Lesionectomy, with removal of surrounding hemosiderin-stained brain, can be considered the procedure of choice in carefully selected patients with epilepsy with occult vascular malformations.

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Rad18 is a key factor in double-strand break DNA damage response (DDR) pathways via its association with K63-linked polyubiquitylated chromatin proteins through its bipartite ubiquitin-binding domains UBZ and LRM with extra residues between them. Rad18 binds K63-linked polyubiquitin chains as well as K48-linked ones and monoubiquitin. However, the detailed molecular basis of polyubiquitin recognition by UBZ and LRM remains unclear. Here, we examined the interaction of Rad18(201-240), including UBZ and LRM, with linear polyubiquitin chains that are structurally similar to the K63-linked ones. Rad18(201-240) binds linear polyubiquitin chains (Ub2-Ub4) with affinity similar to that of a K63-linked one for diubiquitin. Ab initio modeling suggests that LRM and the extra residues at the C-terminus of UBZ (residues 227-237) likely form a continuous helix, termed the "extended LR motif" (ELRM). We obtained a molecular envelope for Rad18 UBZ-ELRM:linear Ub2 by small-angle X-ray scattering and derived a structural model for the complex. The Rad18:linear Ub2 model indicates that ELRM enhances the binding of Rad18 with linear polyubiquitin by contacting the proximal ubiquitin moiety. Consistent with the structural analysis, mutational studies showed that residues in ELRM affect binding with linear Ub2, not monoubiquitin. In cell data support the idea that ELRM is crucial in the localization of Rad18 to DNA damage sites. Specifically, E227 seems to be the most critical in polyubiquitin binding and localization to nuclear foci. Finally, we reveal that the ubiquitin-binding domains of Rad18 bind linear Ub2 more tightly than those of RAP80, providing a quantitative basis for blockage of RAP80 at DSB sites. Taken together, our data demonstrate that Rad18(201-240) forms continuous ubiquitin-binding domains, comprising UBZ and ELRM, and provides a structural framework for polyubiquitin recognition by Rad18 in the DDR pathway at a molecular level.

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