Towards in vivo focal cortical dysplasia phenotyping using quantitative MRI

Focal cortical dysplasias (FCDs) are a range of malformations of cortical development each with specific histopathological features. Conventional radiological assessment of standard structural MRI is useful for the localization of lesions but is unable to accurately predict the histopathological features. Quantitative MRI offers the possibility to probe tissue biophysical properties in vivo and may bridge the gap between radiological assessment and ex-vivo histology. This review will cover histological, genetic and radiological features of FCD following the ILAE classification and will explain how quantitative voxel- and surface-based techniques can characterise these features. We will provide an overview of the quantitative MRI measures available, their link with biophysical properties and finally the potential application of quantitative MRI to the problem of FCD subtyping. Future research linking quantitative MRI to FCD histological properties should improve clinical protocols, allow better characterisation of lesions in vivo and tailored surgical planning to the individual. Keywords: Focal cortical dysplasia, Biophysical tissue properties, Histology, Radiology, MRI, Quantitative mapping, qMRI, Quantitative MRI, Epilepsy surgery, Malformation of cortical developmen

GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity?

Background: Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. Methods: We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. Results: The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. Conclusion: The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients

Cognitive performance in distinct groups of children undergoing epilepsy surgery—a single-centre experience

Background We aimed first to describe trends in cognitive performance over time in a large patient cohort (n = 203) from a single tertiary centre for paediatric epilepsy surgery over the period of 16 years divided in two (developing—pre-2011 vs. established—post-2011). Secondly, we tried to identify subgroups of epilepsy surgery candidates with distinctive epilepsy-related characteristics that associate with their pre- and post-surgical cognitive performance. Thirdly, we analysed variables affecting pre-surgical and post-surgical IQ/DQ and their change (post- vs. pre-surgical). Methods We analysed IQ/DQ data obtained using standardized neuropsychological tests before epilepsy surgery and one year post-surgically, along with details of patient’s epilepsy, epilepsy surgery and outcomes in terms of freedom from seizures. Using regression analysis, we described the trend in post-operative IQ/DQ. Cognitive outcomes and the associated epilepsy- and epilepsy surgery-related variables were compared between periods before and after 2011. Using multivariate analysis we analysed the effect of individual variables on pre- and post-operative IQ/DQ and its change. Results Epilepsy surgery tends to improve post-surgical IQ/DQ, most significantly in patients with lower pre-surgical IQ/DQ, and post-surgical IQ/DQ strongly correlates with pre-surgical IQ/DQ (Rho = 0.888, p < 0.001). We found no significant difference in pre-, post-surgical IQ/DQ and IQ/DQ change between the periods of pre-2011 and post-2011 (p = 0.7, p = 0.469, p = 0.796, respectively). Patients with temporal or extratemporal epilepsy differed in their pre-surgical IQ/DQ (p = 0.001) and in IQ/DQ change (p = 0.002) from those with hemispheric epilepsy, with no significant difference in post-surgical IQ/DQ (p = 0.888). Groups of patients with different underlying histopathology showed significantly different pre- and post-surgical IQ/DQ (p < 0.001 and p < 0.001 respectively) but not IQ/DQ change (p = 0.345).Variables associated with severe epilepsy showed effect on cognitive performance in multivariate model. Discussion Post-surgical IQ/DQ strongly correlates with pre-surgical IQ/DQ and greatest IQ/DQ gain occurs in patients with lower pre-surgical IQ/DQ scores. Cognitive performance was not affected by changes in paediatric epilepsy surgery practice. Pre- and post-operative cognitive performances, as well as patients’ potential for cognitive recovery, are highly dependent on the underlying aetiology and epileptic syndrome

Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration

Background: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism. Material and methods: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients. Results: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal. Conclusion: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies. (c) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

Novel histopathological patterns in cortical tubers of epilepsy surgery patients with tuberous sclerosis complex

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC

Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes

Objective To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED-EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC).Methods Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy - Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED-EEG were studied in relation to clinical outcome. Epilepsy-related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]).Results Eighty-three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14-54). Seventy-nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23-111). Patients with a pathogenic TSC2 variant were significantly younger (P-value .009) at first ED-EEG and more frequently had multifocal IED (P-value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED-EEG was significantly associated with lower cognitive (P-value .010), language (P-value .001), and motor (P-value .013) developmental quotients at 24 months.In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED-EEG was predictive of earlier seizure onset (P-value .030). Earlier recording of epileptiform discharges (P-value .019), especially when multifocal (P-value .026) was associated with higher risk of drug-resistant epilepsy.In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED-EEG, preventive treatment delayed the onset of seizures significantly (P-value &lt;.001).Significance Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

Objective Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.Methods In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.Results In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p &lt; 0.001). No adverse events related to preventive treatment were noted.Interpretation Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 202

Association of early MRI characteristics with subsequent epilepsy and neurodevelopmental outcomes in children with tuberous sclerosis complex

Background and objectives: Multiple factors have been found to contribute to the high risk of epilepsy in infants with tuberous sclerosis complex (TSC), including evolution of EEG abnormalities, TSC gene variant, and MRI characteristics. The aim of this prospective multicenter study was to identify early MRI biomarkers of epilepsy in infants with TSC aged &lt;6 months and before seizure onset, and associate these MRI biomarkers with neurodevelopmental outcomes at 2 years of age. The study was part of the EPISTOP project. Methods: We evaluated brain MRIs performed in infants younger than 6 months with TSC. We used harmonized MRI protocols across centers and children were monitored closely with neuropsychological evaluation and serial video EEG. MRI characteristics, defined as tubers, radial migration lines, white matter abnormalities, cysts, calcifications, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA), were visually evaluated and lesions were detected semiautomatically. Lesion to brain volume ratios were calculated and associated with epilepsy and neurodevelopmental outcomes at 2 years. Results: Lesions were assessed on MRIs from 77 infants with TSC; 62 MRIs were sufficient for volume analysis. The presence of tubers and higher tuber-brain ratios were associated with the development of clinical seizures, independently of TSC gene variation and preventive treatment. Furthermore, higher tuber-brain ratios were associated with lower cognitive and motor development quotients at 2 years, independently of TSC gene variation and presence of epilepsy. Discussion: In infants with TSC, there is a significant association between characteristic TSC lesions detected on early brain MRI and development of clinical seizures, as well as neurodevelopmental outcomes in the first 2 years of life. According to our results, early brain MRI findings may guide clinical care for young children with TSC. Classification of evidence: This study provides Class I evidence that in infants with TSC, there is a significant association between characteristic TSC lesions on early brain MRI and the development of clinical seizures and neurodevelopmental outcomes in the first 2 years of life

Novel Histopathological Patterns in Cortical Tubers of Epilepsy Surgery Patients with Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC