Cognitive impairment in REM-sleep behaviour disorder and individuals at risk of Parkinson's disease.

BACKGROUND: Mild cognitive impairment (MCI) is commonly present at the time of Parkinson's Disease (PD) diagnosis, but its prevalence amongst individuals at increased risk of PD is unclear. METHODS: Cognition was assessed using the Montreal Cognitive Assessment (MoCA) in 208 participants in the PREDICT-PD study, and 25 participants with REM-sleep behaviour disorder (RBD). Prevalence of MCI level I was determined in all participants, and level II MCI in the RBD sub-group. RESULTS: Total MoCA scores were worse in the higher risk than the lower risk group defined as those below the 15th percentile of risk (p = 0.009), and in the RBD group compared to all healthy participants (p < 0.001). The prevalence of MCI level I was 12.8% in the lower-risk, 21.9% in the higher-risk (within the highest 15th percentile) and 64% in RBD participants; 66% of RBD participants had MCI level II with multi-domain MCI, but particularly attention and memory deficits. CONCLUSIONS: Cognitive impairment is increased in different groups at higher risk of PD, particularly in the subgroup formally diagnosed with RBD.

National compliance with UK wide guidelines for usage of valproate in women of childbearing potential.

Valproate (VPA) is an effective treatment for epilepsy and also used in bipolar disorder. However, VPA is associated with a significant risk of birth defects and developmental disorders if used during pregnancy. This has led to the introduction of measures to reduce the use of valproate in women of childbearing potential such as the 'Prevent' pregnancy prevention program (PPP) and the completion of an annual risk acknowledgement form (ARAF). The aim of the current audit was to assess compliance with the guidance. An audit tool was made available to neurologists registered with the Association of British Neurologists (ABN) and to epilepsy nurse specialists via the Epilepsy Nurses Association (ESNA) in the UK. Data were collected between November 2020 and March 2021. The main indication for valproate was generalised epilepsy (55.8%), followed by focal (22.5%). For most, there was documentation that the woman had been informed about the risks associated with taking valproate during pregnancy (93.1%) and the need to be on highly effective contraception or that this was not deemed appropriate (92.2%). A signed ARAF was available in the notes for 81.2% although only 66% were <12 months old. Although information had been made available for most women, there were still individuals where this was not documented. Further work is needed to facilitate identification of women taking valproate and implementation of a digital ARAF. For clinicians, the audit highlights a need to carefully counsel women about the teratogenic risks of continuing to take valproate versus the risk of deteriorating seizure control if the drug is withdrawn. This is particularly true of women with focal epilepsy, where there may be safer, equally effective, alternative anti-seizure medication (ASM). The aim should be to create a partnership of trust between the patient and clinician in order to arrive at the best clinical decision for that individual.

Quantitative grey matter histological measures do not correlate with grey matter probability values from in vivo MRI in the temporal lobe.

Voxel-based morphometry (VBM) is commonly used to study systematic differences in brain morphology from patients with various disorders, usually by comparisons with control subjects. It has often been suggested, however, that VBM is also sensitive to variations in composition in grey matter. The nature of the grey matter changes identified with VBM is still poorly understood. The aim of the current study was to determine whether grey matter histopathological measurements of neuronal tissue or gliosis influenced grey matter probability values that are used for VBM analyses. Grey matter probability values (obtained using both SPM5 and FSL-FAST) were correlated with neuronal density, and field fraction of NeuN and GFAP immunopositivity in a grey matter region of interest in the middle temporal gyrus, in 19 patients undergoing temporal lobe resection for refractory epilepsy. There were no significant correlations between any quantitative neuropathological measure and grey matter probability values in normal-appearing grey matter using either segmentation program. The lack of correlation between grey matter probability values and the cortical neuropathological measures in normal-appearing grey matter suggests that intrinsic cortical changes of the type we have measured do not influence grey matter probability maps used for VBM analyses.

Correlation of quantitative MRI and neuropathology in epilepsy surgical resection specimens--T2 correlates with neuronal tissue in gray matter.

Newer MRI methods can detect cerebral abnormalities not identified on routine imaging in patients with focal epilepsy. Correlation of MRI with histopathology is necessary to understand the basis of MRI abnormalities and subsequently predict histopathology from in vivo MRI. The aim of this study was to determine if particular quantitative MR parameters were associated with particular histological features. Nine patients with temporal lobe epilepsy were imaged at 1.5 T using standard presurgical volumetric and quantifiable sequences: magnetization transfer and FFT2. The resected temporal lobe was registered with the volumetric MRI data according to our previously described method to permit correlation of the modalities. Stereologically measured neuronal densities and field fraction of GFAP, MAP2, synaptophysin and NeuN immunohistochemistry were obtained. Analyses were performed in the middle temporal gyrus and compared with quantitative MRI data from the equivalent regions. There was a significant Spearman Rho negative correlation between NeuN field fraction and the T2 value in gray matter (correlation coefficient -0.72, p=0.028). There were no significant correlations between any neuropathological and MR measures in white matter. These preliminary findings suggest that T2 in gray matter is sensitive to the proportion of neuronal tissue. Novel quantitative MRI measures acquired with higher field strength magnets, and so with superior signal to noise ratios, may generate data that correlate with histopathological measures. This will enable better identification and delineation of the structural causes of refractory focal epilepsy, and will be of particular benefit in patients in whom current optimal MRI does not identify a relevant abnormality.

Methodological aspects of 3D and automated 2D analyses of white matter neuronal density in temporal lobe epilepsy.

White matter neuronal density has been correlated with clinical outcome after temporal lobectomy for refractory epilepsy. Both morphometric 2D (two-dimensional) and stereological 3D (three-dimensional) analyses of neuronal density have been performed. 3D analyses are thought to be more accurate than 2D counts, but more time-consuming. We compared 3D and automated 2D measurements in the same specimens. Adjacent 20-microm (for 3D analyses) and 5-microm (for 2D analyses) sections from 10 temporal lobectomies were stained for NeuN immunohistochemistry. Analysis of 100% of a region of interest (ROI) in deep white matter was performed using an image analysis system (Histometrix, Kinetic Imaging, UK). 3D analyses were undertaken using x 63 magnification (6 h/case). Automated 2D analyses were undertaken using automatic neuronal identification at x 10 magnification with three to four repeats (1.5 h/case). The range of neuronal densities for 3D measurements was 2120-4910 neurones/mm(3), and for automated 2D measurements 17.4-47.1 neurones/mm2. There was a linear correlation between the two methods with an r2 of 0.58. [corrected] Count-recount variability was 1.4-9.9% for the 3D and 5.1-36.6% for the automated 2D measurements. We found a wide range of white matter neuronal densities using either analysis. The low agreement between methods, and the high count-recount variability for the automated 2D analyses, indicate that despite being more time-consuming, rigorous 3D stereological analyses have to be performed to obtain reliable results. These findings have implications for studies requiring neuronal counts in normal and disease states.

Parenchymal lesions in pharmacoresistant temporal lobe epilepsy: dual and multiple pathology.

OBJECTIVES: Dual pathology is reported in 5-30% of temporal lobe resections performed in pharmacoresistant epilepsy. Dual pathology may be of importance for surgical planning and also for the understanding of the pathogenesis of epilepsy. We describe the frequency of dual or multiple pathology, i.e. more than one histopathological diagnosis, in adults with temporal lobe resections. MATERIAL AND METHODS: Surgical specimens from 33 consecutive patients with resections including mesial as well as neocortical temporal structures were reviewed. All histopathological findings were recorded. Post-mortem specimens from 11 control subjects were also reviewed. RESULTS: Dual or multiple pathology was found in almost half of the epilepsy patients (48%). Hippocampal sclerosis was found in 25 patients (76%), malformations of cortical development in 15 (46%), of which 12 (36%) were microdysgenesis, and low-grade tumours in seven (21%). Apart from mild gliosis, there were no histopathological changes in the control specimens. CONCLUSION: Dual or multiple pathology was a common finding in this group of adults with temporal lobe resections. In order to increase our understanding of how aetiological factors may combine in the development of seizures, we consider it relevant and important to report all histopathological findings in epilepsy surgery series.

Microdysgenesis in epilepsy.

Microdysgenesis is a microscopic malformation of cortical development characterized by heterotopic neurones and abnormal cortical architecture. It has been described in primary generalized and partial epilepsy. Its significance in epileptogenesis is controversial, partly due to lack of consensus of diagnostic criteria. Different terms have also been used for the malformation. Several quantitative studies have been performed of the histopathological aberrations associated with microdysgenesis. A majority of the studies have revealed an increased number of heterotopic neurones in specimens from epilepsy patients. However, the quantitative values given for abnormal numbers of white matter neurones vary greatly between studies and there is no consensus yet on quantitative criteria for microdysgenesis. There have also been conflicting results from studies correlating microdysgenesis with clinical data. Both favourable and worse outcome after epilepsy surgery have been reported in patients with increased numbers of white matter neurones and microdysgenesis. While some studies have shown earlier seizure onset and increased frequency of mental retardation in patients with microdysgenesis, others have not. Differences in inclusion criteria and definition might contribute to the contradictory results. There is some evidence that microdysgenesis could be important in epileptogenesis, but the mechanisms involved remain unknown and difficult to investigate. A consensus on what histopathological criteria to use for the diagnosis of microdysgenesis is needed to explore this further and enable comparisons between centres. There are advantages and disadvantages both with quantitative stereological and with qualitative assessments. It is necessary to evaluate these in the decision on diagnostic criteria, if possible taking both qualitative and quantitative aspects into account.

Widespread microdysgenesis in therapy-resistant epilepsy--a case report on post-mortem findings.

Microdysgenesis is a subtle malformation, which is often found in specimens from epilepsy surgery. It is, however, not clear whether the changes are focal or diffuse. A recent autopsy case offered an opportunity to investigate whether microdysgenesis found after temporal lobe surgery was focal or widespread in the brain. The entire brain of a 20-year-old patient who died suddenly and unexpectedly was examined histologically. Microdysgenesis had previously been diagnosed after a left temporal lobectomy performed because of therapy-resistant seizures. A light microscopic examination was performed on specimens stained with Luxol-fast blue-cresyl violet and polyclonal antibodies to glial fibrillary acidic protein. Widespread microdysgenesis with irregular nerve cell distribution in the cortex and an increased number of nerve cells in cortical layer I and in the white matter was found in the right temporal and parietal lobes and bilaterally in the frontal and occipital lobes. The post-mortem examination confirmed the previous diagnosis of microdysgenesis and showed that the changes were widespread in a patient who was operated on because of focal epilepsy.

Diffusion tensor imaging in patients with epilepsy and malformations of cortical development.

Malformations of cortical development (MCD) are a common cause of epilepsy. Studies of structural MRIs and PET data in patients with MCD have found widespread changes outside the visually identified lesions. The aim of this study was to investigate diffusion changes interictally in patients with MCD and to test the hypothesis that MCD would be associated with widespread abnormalities of diffusion. We used diffusion tensor imaging (DTI) and statistical parametric mapping (SPM) to compare objectively tissue organization in 22 patients with partial seizures and MCD, with 30 control subjects. Whole-brain DTI was acquired using echo planar imaging. Rotationally invariant anisotropy and diffusivity maps were calculated and, after normalization to Talairach space, each patient was compared with the group of control subjects using SPM. Areas of reduced anisotropy were found in 17 patients and areas of increased diffusivity in 10. Two patients had areas of increased anisotropy. There were no patients with reduced diffusivity. Areas of increased diffusivity were in general more extensive than areas of reduced anisotropy. Changes in tissue beyond the MCD, that appeared normal on conventional MRI, were found in six patients for anisotropy and nine patients for diffusivity. Both measurements showed widespread changes in tissue beyond the MCD, i.e. adding information to conventional MRI. Increased or abnormally located grey matter or pathological white matter with abnormal myelination or ectopic neurones could cause reduced anisotropy. Increased diffusivity could be caused by a defect of neurogenesis or cell loss resulting in increased extracellular space. The widespread nature of abnormalities should be considered if surgical treatment is contemplated.

Diffusion tensor imaging of cryptogenic and acquired partial epilepsies.

Current optimal MRI identifies a relevant structural abnormality in up to 80% of patients with refractory partial seizures. Identification of a structural lesion is fundamental to pre-surgical evaluation. We used diffusion tensor imaging (DTI) and statistical parametric mapping (SPM) to examine objectively the diffusion properties, and hence structural organization, of cerebral tissue in 10 patients with partial seizures and acquired lesions and 30 patients with partial seizures and normal MRI. Fractional anisotropy and mean diffusivity maps were calculated and, using SPM, individual patients were compared with a group of 30 control subjects. Diffusion tensor imaging and voxel-by-voxel statistical comparisons identified significant increases in diffusivity and significant reductions of anisotropy in all patients with acquired non-progressive cerebral lesions and partial seizures. In all of these patients, the areas of increased diffusivity, and in nine patients the areas of decreased anisotropy, concurred with abnormalities identified on visual inspection of conventional MRI. In addition, there were 10 areas which were normal on conventional imaging which exhibited abnormal anisotropy or diffusivity. Individual analyses of the 30 patients with partial seizures and normal optimal MRI identified a significant increase in diffusivity in eight of the subjects. In six of these, the areas of increased diffusivity concurred with the localization of epileptiform EEG abnormality. Analysis of anisotropy in the MRI-negative patients revealed significant differences in two patients, one of which concurred with electroclinical seizure localization. Group analysis of nine patients with normal conventional MRI and electroclinical seizure onset localizing to the left temporal region revealed a significant increase in diffusivity and a significant reduction in anisotropy within the white matter of the left temporal lobe. DTI analysed using SPM was sensitive in patients with acquired cerebral damage. Significant differences in the diffusion indices in individual MRI negative patients and the group effect in patients with left temporal lobe epilepsy suggest that minor structural disorganization exists in occult epileptogenic cerebral lesions. These techniques are promising, non-invasive imaging methods for identifying the cause of partial seizures, and can contribute to pre-surgical evaluation.

Ultra-fast low-angle rapid acquisition and relaxation enhancement (UFLARE) in patients with epilepsy.

MRI is an important diagnostic tool in patients with epilepsy, but patient motion during long scans may result in image artefacts. We studied the utility of an ultra-fast MR sequence in patients with epilepsy. Ultra-fast low-angle rapid acquisition and relaxation enhancement (UFLARE) images were acquired for 100 consecutive patients and nine control subjects. Scans were compared with routine T2-weighted spin echo images for signal-to-noise ratio, contrast, and conspicuity, followed by a blind review of lesion detectability. UFLARE scans were also acquired for 15 patients who moved during conventional scans. All UFLARE scans had lower signal-to-noise ratios and lower contrast than the T2-weighted images. Compared with T1- and T2-weighted, PD and FLAIR images, 86% of hippocampal sclerosis (HS), 92% of large but only 24% of small white-matter lesions were detected on the blind review of the UFLARE images. Reduced motion artefacts were seen on the UFLARE images in all 15 patients who moved during the conventional scans, and in three patients UFLARE was the only sequence we were able to obtain. Despite the lower lesion detectability for smaller lesions, the use of an ultra-fast MRI sequence such as UFLARE may be very useful in patients who are not able to co-operate during conventional MRI examinations, if a general anaesthetic is to be avoided.

Persistent reelin-expressing Cajal-Retzius cells in polymicrogyria.

Cajal-Retzius (CR) cells are early-developing cells important in mammalian corticogenesis. Reelin, a protein secreted by CR cells, is essential for completion of neuronal migration and cortical lamination. Lack of reelin causes the 'reeler' phenotype in mice and autosomal recessive lissencephaly with cerebellar hypoplasia in man. Focal increases in reelin and CR cells are associated with thickening and local invaginations of the marginal zone and microgyria in animal studies. It has been suggested that abnormalities of reelin expression may be involved in human polymicrogyria. We have studied CR cells and reelin expression in pathological sections of human polymicrogyria to explore this possibility. Occurrence, distribution, morphology and reelin expression in CR cells were studied in 12 cases of human polymicrogyria, ranging from 21 gestational weeks to 10 years of age. Findings were compared with age-matched controls. Large, reelin-positive CR-like cells were more numerous in the majority of the polymicrogyria cases and persisted for longer than usual, up to 10 years of age. The CR-like cells tended to cluster and were most frequent in fused molecular layers in the polymicrogyria. Reelin-expressing CR-like cells were also found in bridges between the molecular layer and overlying leptomeningeal heterotopia and within the heterotopia itself. Clusters of CR-like cells were also found in adjacent non-polymicrogyric cortex. No clusters were seen in the control subjects. Increased numbers of CR-like cells were seen in both familial and acquired cases. In contrast to previous reports, the findings show that large CR-like cells persisted for longer than usual, up to 10 years of age, and that they may continue to express reelin. Their maximal aggregation in regions of polymicrogyria and overlying leptomeningeal heterotopia suggest an association between the presence of these cells and polymicrogyria, which we interpret in the light of recent findings concerning the roles of reelin and its downstream signalling pathway in neuronal and glial developmental dynamics and post-developmental function.

Magnetization transfer imaging in focal epilepsy.

OBJECTIVES: To test the hypothesis that magnetization transfer imaging (MTI), analyzed on a voxel-by-voxel basis, would identify areas of abnormal magnetization transfer ratio (MTR) in patients with focal epilepsy. METHODS: The authors used MTI maps and statistical parametric mapping (SPM) to objectively compare the cerebral structures of 15 patients with malformations of cortical development (MCD), 10 with partial seizures and acquired lesions, and 42 with partial seizures and normal conventional MRI with those of 30 control subjects. RESULTS: Significant reductions of MTR were identified in all 10 patients with acquired nonprogressive cerebral lesions and partial seizures. In all, the areas of decreased MTR concurred with abnormalities identified on visual inspection of conventional MRI. In 13 of the 15 patients with MCD, SPM detected regions of significantly reduced MTR, all of which corresponded to abnormalities identified on visual inspection of conventional MRI. In addition, in both groups, there were areas that were normal on conventional imaging that demonstrated abnormal MTR. There was a significant reduction of MTR in 15 of the 42 patients with cryptogenic focal epilepsy. In all of these, the areas of reduced MTR concurred with epileptiform EEG abnormality and clinical seizure semiology. CONCLUSIONS: Magnetization transfer imaging analyzed using statistical parametric mapping was sensitive in identifying malformations of cortical development and acquired cerebral lesions. Abnormalities of magnetization transfer ratio in individual MRI-negative patients suggest that minor structural disorganization exists in occult epileptogenic cerebral lesions.