Jh Cross

Psychopathology in children with epilepsy before and after temporal lobe resection

The aim of this study was to establish the rate and spectrum of psychiatric disorder among children before and after temporal lobe surgery for epilepsy. Data were examined for associations between psychopathology and seizure outcome following surgery, or association between psychopathology and other variables, such as laterality of lesion, sex, cognitive level, and underlying pathology. Participants were 60 children (35 males, 25 females) who had focal seizures of temporal lobe origin and who had undergone temporal lobe resection between 1992 and 1998; mean age at time of operation 10 y 7 mo, (SD 4 y 11 mo) range 7 mo to 17 y 11 mo. Mean length of follow-up was 5.1 years (SD 2.3, range 2 to 10 y). Twenty-eight (47%) children had undergone right temporal lobectomy. Diagnosis of a psychiatric disorder was present in 50/60 (83%) children at some point, with high rates of psychiatric comorbidity. Common childhood psychiatric disorders of attention-deficit-hyperactivity disorder, oppositional defiant disorder/conduct disorder, and emotional disorders were present in about 25% of children. Disorders rarely seen in the general child population were over-represented: disruptive behaviour disorder--not otherwise specified (30/60 [50%]), and pervasive developmental disorder (autistic spectrum disorder; 23/60 [38%]). there was no significant relationship between pathology, sex, seizure frequency, or postoperative seizure outcome and psychiatric disorder, other than for pervasive developmental disorder. The same proportion of children had psychiatric diagnoses pre- and postoperatively (43/60 [72%] and 41/57 [72%] respectively). Although mental health problems are common in children undergoing temporal lobe resection, there are few predictors of psychiatric outcome following epilepsy surgery. Parents require counselling on these issues in the preoperative work-up.

Cortical neuronal densities and lamination in focal cortical dysplasia

Focal cortical dysplasia (FCD) is considered to represent a malformation due to abnormal cortical development (MCD) and is an important cause of focal epilepsy. The histopathological features include abnormal laminar architecture, the presence of hypertrophic and dysmorphic neurones in FCD type IIA and additional balloon cells in FCD type IIB. The events causing these sporadic lesions are unknown, but abnormal progenitor cell proliferation occurring late in corticogenesis has been proposed. FCD-like lesions have, however, also been described following a cerebral injury early in life. We carried out a stereological assessment on 15 cases of FCD on NeuN- and Nissl-stained sections from patients with a wide age range, and identified a significant reduction in the neuronal density in all cases in the region of dysplasia compared to the adjacent unaffected cortex (mean neuronal densities 19.2×103/mm3 in the region of dysplasia; 42.8×103/mm3 in the adjacent cortex). Relative differences in neuronal density and size in FCD cases between the superficial (layer I and II) and deep cortical laminae (layer V and VI) were similar to that observed in other pathologies including mild MCD, temporal neocortex adjacent to hippocampal sclerosis as well as in a non-epilepsy surgical control group. The lower overall neuronal densities observed in FCD may reflect neuropil expansion, a local failure of neuronal migration, proliferation or secondary neuronal loss. The preservation of relative differences in neuronal densities between cortical layers and laminar patterns of neurofilament staining in FCD would support the view that the temporal sequence of lamination is not affected.

Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES)

Fever‐induced refractory epileptic encephalopathy in school‐age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4‐year‐old boy that was associated with elevated voltage‐gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody‐associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word‐finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low‐dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications.

Pathological tau tangles localize to focal cortical dysplasia in older patients.

Summary:  Purpose: Reactivation of neurodevelopmental processes may contribute to neurodegeneration. For example, the proteins cyclin dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta (GSK3β), which are essential to normal cortical development, can hyperphosphorylate tau and might contribute to the pathogenesis of Alzheimers disease. Focal cortical dysplasia (FCD) is an important neurodevelopmental cause of refractory human epilepsy within which dysplastic neurons exhibit increased immunoreactivity for cdk5 and GSK3β as well as neurofilamentous accumulations. We therefore hypothesized that the developmentally abnormal cortex of FCD might be more susceptible to tau‐mediated neurodegeneration than adjacent histologically normal cortex.

CHILDREN WITH INTRACTABLE FOCAL EPILEPSY: ICTAL AND INTERICTAL 99TcVi HMPAO SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY

Fourteen children with intractable complex partial seizures underwent ictal and interictal 99TCM HMPAO single photon emission computed tomography (SPECT) scans. Abnormalities concordant with clinical and/or FEG localisation were present in 13 of 14 ictal and/or interictal scans. Focal hyperpertusion was seen at the seizure focus on ictal scans and focal hypoperfusion was seen on interictal scans. The timing of the injection in relation to the start of the seizure was crucial for reliable localisation. While recognisable patterns of regional cerebral blood flow (rCBF) were seen on either interictal or ictal scans, marked changes in the patterns of rCBF between the ictal study and interictal study provided the most reliable information about seizure localisation. Using both ictal and interictal studies, 99rcM HMPAO SPF.CT may provide data about both the seizure origin and its relationship to structurally abnormal regions of the brain.

Mcm2 labelling of balloon cells in focal cortical dysplasia

Balloon cells (BC) are the prominent and defining cellular component of type IIB Focal Cortical Dysplasia (FCD), a common cause of focal epilepsy in patients undergoing surgical treatment. BC are considered immature cells of uncommitted cellular differentiation having immunophenotypical characteristics of both neurones and glia. They are often located in the lower cortical layers and white matter underlying the dysplastic cortex, suggesting migratory arrest during development. We investigated the proliferative potential of BC in 15 cases of FCD from patients with a wide range of ages using immunohistochemistry for Mcm2 (mini chromosome maintenance protein) and Ki67. In the majority of cases, BC showed Mcm2 nuclear positivity. In addition, cells with intermediate neuronal‐glial characteristics were labelled whilst the dysmorphic or hypertrophic pyramidal neuronal components of FCD were not. Ki67 labelled only occasional BC. These findings support the view that BC cells represent a pool of less differentiated glial cells with proliferative capacity which may have potential for delayed neuronal differentiation. Furthermore, as Mcm2 specifically identifies BC populations, this marker may be of diagnostic value in the subtyping of FCD lesions in patients with epilepsy.

Interictal 99Tcm HMPAO SPECT and 1H MRS in children with temporal lobe epilepsy

Summary: Purpose: To understand the pathological basis of focal hypoperfusion seen on interictal 99Tcm hexamethylpropyleneamine oxime (HMPAO) single‐photon‐emission computed tomography (SPECT) in intractable temporal lobe epilepsy, and to determine why the technique may be misleading in the localization and lateralization of the seizure focus in some cases.

An investigation of the expression of G1-phase cell cycle proteins in focal cortical dysplasia type IIB

Balloon cells (BCs) are the pathologic hallmark of focal cortical dysplasia type IIB, a common cause of pharmacoresistent epilepsy. Expression of markers of cell immaturity and of the proliferation marker minichromosome maintenance protein 2 (mcm2) have been previously shown in BCs, suggesting that these cells might represent a pool of less-differentiated cells licensed for replication. An alternative explanation is that these cells are the remnants of early cortical plate cells that have failed to differentiate or to be eliminated during development and are arrested in the cell cycle, a hypothesis that this study aims to explore. Using immunohistochemical methods and semiquantitative analysis in 19 cases of focal cortical dysplasia (ages 1-81 years), we studied the expression of cell cycle proteins important either in regulating progression through the G1 phase or inducing cell arrest and promoting premature senescence. Only a small fraction of BCs expressed geminin, suggesting that few BCs enter the S phase or complete the cell cycle. Variable expression of nonphosphorylated retinoblastoma protein (Rb), cdk4, and p53 was noted in BCs. Cyclin E, D1, cdk2, phosphorylated Rb (795 and 807/811), and checkpoint 2 expression levels were low in BCs. These findings suggest early rather than late G1 arrest. Cell senescence could be induced by an undefined cerebral insult during development or alternatively represent a physiologic replicative senescence. These findings also suggest that dysregulation of cell cycle pathways may occur in focal cortical dysplasia, which opens further areas for exploration as potential new treatment avenues.

Current standards of neuropsychological assessment in epilepsy surgery centers across Europe

We explored the current practice with respect to the neuropsychological assessment of surgical epilepsy patients in European epilepsy centers, with the aim of harmonizing and establishing common standards. Twenty‐six epilepsy centers and members of “E‐PILEPSY” (a European pilot network of reference centers in refractory epilepsy and epilepsy surgery), were asked to report the status of neuropsychological assessment in adults and children via two different surveys. There was a consensus among these centers regarding the role of neuropsychology in the presurgical workup. Strong agreement was found on indications (localization, epileptic dysfunctions, adverse drugs effects, and postoperative monitoring) and the domains to be evaluated (memory, attention, executive functions, language, visuospatial skills, intelligence, depression, anxiety, and quality of life). Although 186 different tests are in use throughout these European centers, a core group of tests reflecting a moderate level of agreement could be discerned. Variability exists with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. For the tests in use, little published evidence of clinical validity in epilepsy was provided. Participants in the survey reported a need for improvement concerning the validity of the tests, tools for the assessment of everyday functioning and accelerated forgetting, national norms, and test co‐normalization. Based on the present survey, we documented a consensus regarding the indications and principles of neuropsychological testing. Despite the variety of tests in use, the survey indicated that there may be a core set of tests chosen based on experience, as well as on published evidence. By combining these findings with the results of an ongoing systematic literature review, we aim for a battery that can be recommended for the use across epilepsy surgical centers in Europe.

Favourable response to ketogenic dietary therapies: undiagnosed glucose 1 transporter deficiency syndrome is only one factor

We aimed to determine whether response to ketogenic dietary therapies (KDT) was due to undiagnosed glucose transporter type 1 deficiency syndrome (GLUT1‐DS).