Epileptic monocular nystagmus and ictal diplopia as cortical and subcortical dysfunction

AbstractWe present the case of a patient with ictal monocular nystagmus and ictal diplopia who became seizure-free after resection of a right frontal focal cortical dysplasia (FCD), type 2B. Interictal neuroophthalmological examination showed several beats of a monocular nystagmus and a spasm of the contralateral eye. An exclusively ictal monocular epileptic nystagmus could be an argument for an exclusively cortical involvement in monocular eye movement control. The interictal findings in our patient, however, argue for an irregular ictal activation of both the cortical frontal eye field and the brainstem

Quantifying the Confidence in fMRI-Based Language Lateralisation Through Laterality Index Deconstruction

Wegrzyn M, Mertens M, Bien C, Woermann FG, Labudda K. Quantifying the Confidence in fMRI-Based Language Lateralisation Through Laterality Index Deconstruction. Frontiers in Neurology. 2019;10: 655.In epilepsy patients, language lateralisation is an important part of the presurgical diagnostic process. Using task-based fMRI, language lateralisation can be determined by visual inspection of activity patterns or by quantifying the difference in left- and right-hemisphere activity using variations of a basic formula [(L-R)/(L+R)]. However, the values of this laterality index (LI) depend on the choice of activity thresholds and regions of interest. The diagnostic utility of the U also depends on how its continuous values are translated into categorical decisions about a patient's language lateralisation. Here, we analysed fMRI data from 712 epilepsy patients who performed a verbal fluency task. Each fMRI data set was evaluated by a trained human rater as depicting left-sided, right-sided, or bilateral lateralisation or as being inconclusive. We used data-driven methods to define the activity thresholds and regions of interest used for LI computation and to define a classification scheme that allowed us to translate the U values into categorical decisions. By deconstructing the LI into measures of laterality (L-R) and strength (L+R), we also modelled the relationship between activation strength and conclusiveness of a data set. In a held-out data set, predictions reached 91% correct when using only conclusive data and 82% when inconclusive data were included. Although only trained on human evaluations of fMRIs, the approach generalised to the prediction of language Wada test results, allowing for significant above-chance accuracies. Compared against different existing methods of U-computation, our approach improved the identification and exclusion of inconclusive cases and ensured that decisions for the remaining data could be made with consistently high accuracies. We discuss how this approach can support clinicians in assessing fMRI data on a single-case level, deciding whether lateralisation can be determined with sufficient certainty or whether additional information is needed

The hidden identity of faces. A case of lifelong prosopagnosia

Wegrzyn M, Garlichs A, Heß RWK, Woermann FG, Labudda K. The hidden identity of faces. A case of lifelong prosopagnosia. BMC Psychology. 2019;7(1): 4.Background Not being able to recognize a person’s face is a highly debilitating condition from which people with developmental prosopagnosia (DP) suffer their entire life. Here we describe the case of J, a 30 year old woman who reports being unable to recognize her parents, her husband, or herself in the mirror. Case presentation We set out to assess the severity of J’s prosopagnosia using tests with unfamiliar as well as familiar faces and investigated whether impaired configural processing explains her deficit. To assess the specificity of the impairment, we tested J’s performance when evaluating emotions, intentions, and the attractiveness and likability of faces. Detailed testing revealed typical brain activity patterns for faces and normal object recognition skills, and no evidence of any brain injury. However, compared to a group of matched controls, J showed severe deficits in learning new faces, and in recognizing familiar faces when only inner features were available. Her recognition of uncropped faces with blurred features was within the normal range, indicating preserved configural processing when peripheral features are available. J was also unimpaired when evaluating intentions and emotions in faces. In line with healthy controls, J rated more average faces as more attractive. However, she was the only one to rate them as less likable, indicating a preference for more distinctive and easier to recognize faces. Conclusions Taken together, the results illustrate both the severity and the specificity of DP in a single case. While DP is a heterogeneous disorder, an inability to integrate the inner features of the face into a whole might be the best explanation for the difficulties many individuals with prosopagnosia experience

Clinical characteristics and postoperative seizure outcome in patients with mild malformation of cortical development and oligodendroglial hyperplasia

Abstract Objective We describe for the first time clinical characteristics in a series of 20 pre‐surgically investigated patients with mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) who were operated on in our epilepsy center. We aimed to better diagnose this entity and help surgical planning. Methods Data on 20 patients with histologically confirmed MOGHE were retrospectively evaluated as to age at epilepsy onset and operation, seizure semiology, magnetic resonance imaging (MRI) localization, electroencephalography (EEG) patterns, extent of the operative resection, and postoperative seizure outcome. Results Epilepsy began mainly in early childhood; however, symptoms did not manifest until adolescence or adulthood in 30% of patients. All patients had pathologic MRI findings. In 45% of patients the lesion was initially overlooked. Most commonly, the lesion was seen in the frontal lobe. Seizure semiology was characterized as follows: (1) epileptic spasms at epilepsy onset were common and (2) nocturnal hyperkinetic seizures during the course of the disease were rare. EEG always showed frequent interictal epileptic discharges. Two peculiar patterns were observed: (1) during sleep stage I‐II, sub‐continuous repetitive (0.5–1.5/s) unilateral plump spike/polyspike slow waves were seen and (2) during wakefulness, unilateral paroxysms of 2–2.5/s spike‐wave complexes occurred. In total, 60% of patients were seizure‐free 1 year postoperatively. Postoperative seizure outcome was positively correlated with the extent of resection, age at epilepsy onset, and age at operation. Postoperative long‐term outcomes remained stable in patients undergoing larger operations. Significance MRI, EEG, and semiology already contribute to the diagnosis of probable MOGHE preoperatively. Because postoperative seizure outcomes depend on the extent of the resection, prior knowledge of a probable MOGHE helps to plan the resection and balance the risks and benefits of such an intervention. In patients undergoing larger operations, epilepsy surgery achieved good postoperative results; the first long‐term outcome data were stable in these patients

Trends in epilepsy surgery: stable surgical numbers despite increasing presurgical volumes

Introduction Despite the success of epilepsy surgery, recent reports suggest a decline in surgical numbers. We tested these trends in our cohort to elucidate potential reasons. Patients and methods Presurgical, surgical and postsurgical data of all patients undergoing presurgical evaluation in between 1990 and 2013 were retrospectively analysed. Patients were grouped according to the underlying pathology. Results A total of 3060 patients were presurgically studied, and resective surgery was performed in 66.8% (n=2044) of them: medial temporal sclerosis (MTS): n=675, 33.0%; benign tumour (BT): n=408, 20.0%; and focal cortical dysplasia (FCD): n=284, 13.9%. Of these, 1929 patients (94.4%) had a follow-up of 2 years, and 50.8% were completely seizure free (Engel IA). Seizure freedom rate slightly improved over time. Presurgical evaluations continuously increased, whereas surgical interventions did not. Numbers for MTS, BT and temporal lobe resections decreased since 2009. The number of non-lesional patients and the need for intracranial recordings increased. More evaluated patients did not undergo surgery (more than 50% in 2010–2013) because patients were not suitable (mainly due to missing hypothesis: 4.5% in 1990–1993 up to 21.1% in 2010–2013, total 13.4%) or declined from surgery (maximum 21.0% in 2010–2013, total 10.9%). One potential reason may be that increasingly detailed information on chances and risks were given over time. Conclusions The increasing volume of the presurgical programme largely compensates for decreasing numbers of surgically remediable syndromes and a growing rate of informed choice against epilepsy surgery. Although comprehensive diagnostic evaluation is offered to a larger group of epilepsy patients, surgical numbers remain stable

Deep Histopathology Genotype-Phenotype Analysis of Focal Cortical Dysplasia Type II Differentiates Between the GATOR1-Altered Autophagocytic Subtype Iia and MTOR-Altered Migration Deficient Subtype Iib

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype–phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin–eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype–phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration

Carbamazepine reduces memory induced activation of mesial temporal lobe structures: a pharmacological fMRI-study

BACKGROUND AND PURPOSE: It is not known whether carbamazepine (CBZ; a drug widely used in neurology and psychiatry) influences the blood oxygenation level dependent (BOLD) contrast changes induced by neuronal activation and measured by functional MRI (fMRI). We aimed to investigate the influence of CBZ on memory induced activation of the mesial temporal lobes in patients with symptomatic temporal lobe epilepsy (TLE). MATERIAL AND METHODS: Twenty-one individual patients with refractory symptomatic TLE with different CBZ serum levels and 20 healthy controls were studied using BOLD fMRI. Mesial temporal lobe (MTL) activation was induced by a task that is based on the retrieval of individually familiar visuo-spatial knowledge. The extent of significant MTL fMRI activation was measured and correlated with the CBZ serum level. RESULTS: In TLE patients, the extent of significant fMRI activation over both MTL was negatively correlated to the CBZ serum level (Spearman r = -0.654, P < 0.001). Activation over the supposedly normal MTL, i.e. contralateral to the seizure onset of TLE patients, was smaller than the averaged MTL activation in healthy controls (P < 0.005). Age, duration of epilepsy, side of seizure onset, and intelligence were not correlated to the extent of the significant BOLD-response over both MTL in patients with TLE. CONCLUSIONS: In TLE patients, carbamazepine reduces the fMRI-detectable changes within the mesial temporal lobes as induced by effortful memory retrieval. FMRI appears to be suitable to study the effects of chronic drug treatment in patients with epilepsy

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Abstract Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here, we analyzed 26 PMG patients employing array-based DNA methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases, about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q

Thought experiment: Decoding cognitive processes from the fMRI data of one individual

Wegrzyn M, Aust J, Barnstorf L, et al. Thought experiment: Decoding cognitive processes from the fMRI data of one individual. PLOS ONE. 2018;13(9): e0204338.Cognitive processes, such as the generation of language, can be mapped onto the brain using fMRI. These maps can in turn be used for decoding the respective processes from the brain activation patterns. Given individual variations in brain anatomy and organization, analyzes on the level of the single person are important to improve our understanding of how cognitive processes correspond to patterns of brain activity. They also allow to advance clinical applications of fMRI, because in the clinical setting making diagnoses for single cases is imperative. In the present study, we used mental imagery tasks to investigate language production, motor functions, visuo-spatial memory, face processing, and resting-state activity in a single person. Analysis methods were based on similarity metrics, including correlations between training and test data, as well as correlations with maps from the NeuroSynth meta-analysis. The goal was to make accurate predictions regarding the cognitive domain (e.g. language) and the specific content (e.g. animal names) of single 30-second blocks. Four teams used the dataset, each blinded regarding the true labels of the test data. Results showed that the similarity metrics allowed to reach the highest degrees of accuracy when predicting the cognitive domain of a block. Overall, 23 of the 25 test blocks could be correctly predicted by three of the four teams. Excluding the unspecific rest condition, up to 10 out of 20 blocks could be successfully decoded regarding their specific content. The study shows how the information contained in a single fMRI session and in each of its single blocks can allow to draw inferences about the cognitive processes an individual engaged in. Simple methods like correlations between blocks of fMRI data can serve as highly reliable approaches for cognitive decoding. We discuss the implications of our results in the context of clinical fMRI applications, with a focus on how decoding can support functional localization

Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb

AbstractFocal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype–phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin–eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype–phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration.</jats:p