Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

OBJECTIVE: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. METHODS: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. RESULTS: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 = .05) and longer epilepsy duration ( η ρ max 2 = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SIGNIFICANCE: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.

ESR Essentials: advanced MR safety in vulnerable patients-practice recommendations by the European Society for Magnetic Resonance in Medicine and Biology.

For every patient, the MR safety evaluation should include the assessment of risks in three key areas, each corresponding to a specific hazard posed by the electromagnetic fields generated by the MR scanner: ferromagnetic attraction and displacement by the static field; stimulation, acoustic noise, and device interaction by the gradient fields; and bulk and focal heating by the radiofrequency field. MR safety guidelines and procedures are typically designed around the "average" patient: adult, responsive, and of typical habitus. For this type of patient, we can safely expect that a detailed history can identify metallic objects inside and outside the body, verbal contact during the scan can detect signs of discomfort from heating or acoustic noise, and safety calculations performed by the scanner can prevent hyperthermia. However, for some less common patient categories, these assumptions do not hold. For instance, patients with larger habitus, febrile patients, or pregnant people are more subject to bulk heating and require more conservative MR protocols, while at the same time presenting challenges during positioning and preparation. Other vulnerable categories are infants, children, and patients unable to communicate, who might require screening for ferromagnetic objects with other imaging modalities or dedicated equipment. This paper will provide guidance to implement appropriate safety margins in the workflow and scanning protocols in various vulnerable patient categories that are sometimes overlooked in basic MR safety guidance documents. CLINICAL RELEVANCE STATEMENT: Special care in the implementation of MR safety procedures is of paramount importance in the handling of patients. While most institutions have streamlined operations in place, some vulnerable patient categories require specific considerations to obtain images of optimal quality while minimizing the risks derived by exposure to the MR environment. KEY POINTS: Patients unable to effectively communicate need to be carefully screened for foreign objects. Core temperature management is important in specific patient categories. There are no hard quantitative criteria that make a patient fall into a specific vulnerable category. Protocols and procedures need to be adaptable.

Morphometry and network-based atrophy patterns in SCN1A-related Dravet syndrome.

Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = -0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.

Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

The impact of one-year COVID-19 containment measures in patients with mesial temporal lobe epilepsy: A longitudinal survey-based study.

BACKGROUND: We assessed levels of depression, anxiety, stress, anhedonia, somatization, psychological distress, sleep, and life quality in patients with mesial temporal lobe epilepsy (MTLE) after one year of containment measures started in Italy to stem the COVID-19 pandemic. METHODS: We consecutively enrolled 51 patients with MTLE, administering an online survey that compared the year before and after the COVID-19 propagation. We analyzed clinical data (e.g., seizure frequency, life quality) and neuropsychological assessment through Somatic Symptom Scale-8 (SSS-8), Beck Depression Inventory (BDI-2), State-Trait Anxiety Inventory (STAI-Y), Depression, Anxiety and Stress Scale (DASS-21), Pittsburgh Sleep Quality Index (PSQI), Snaith-Hamilton Pleasure Scale (SHAPS), Impact of Event Scale-Revised (IES-R). The BDI-2 and STAI-Y scores were compared to those acquired in the same patients before the COVID-19 outbreak. RESULTS: Comparing our population with MTLE before and after COVID-19 outbreak, we found a significant worsening in life quality (p = 0.03), SSS-8 (p = 0.001), BDI-2 (p = 0.032), and STAI-Y scores (p < 0.001). After one year of pandemic, 88.2% of patients obtained pathological scores at PSQI, 19.6% at SHAPS, 29.4% at IES-R. Reduction of life quality correlated with anxiety, depression, stress, and somatization. Higher levels of anhedonia correlated with stress, depression, and anxiety. Somatization correlated with depression, anxiety, and sleep quality. Distress levels correlated with anxiety, somatization, and depression. CONCLUSIONS: We demonstrated a significant worsening of depression, anxiety, life quality, and somatization in patients with MTLE after one year of COVID-19 beginning. Concomitantly, results suggest that the pandemic had a negative impact on sleep quality, psychological distress, and anhedonia, but not on epilepsy itself.

Microstructural changes in normal-appearing white matter in male sleep apnea patients are reversible after treatment: A pilot study.

Visually appreciable white matter (WM) changes have been described in obstructive sleep apnea (OSA). However, few data exist on the involvement of silent WM abnormalities. This prospective study investigated the microstructural integrity of normal-appearing white matter (NAWM) in male OSA patients before and after continuous positive airway pressure (CPAP) treatment, using a neuroimaging approach. Magnetic resonance imaging (MRI) was acquired from 32 participants (16 severe never-treated OSA and 16 controls). Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the microstructural NAWM changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). In order to evaluate the efficacy of the therapy, OSA patients underwent MRI evaluations at baseline and after 3 months of treatment (follow-up). CPAP treatment significantly increased the FA in NAWM of the brain stem, corpus callosum and bilateral internal capsule of OSA patients at follow-up compared to baseline (p < 0.05, TFCE-corrected). OSA patients also showed increases in AD in the corpus callosum, superior corona radiata, and internal capsule of the right hemisphere (p < 0.05, TFCE-corrected) after CPAP treatment. A significant negative correlation was found between the FA of the corona radiata, corpus callosum, internal capsule, limbic structures, and neuropsychological scores at follow-up evaluation. No significant differences were found in MD and RD of NAWM in our patients after treatment. Our results demonstrate that FA and AD of NAWM in major tracts such as the corpus callosum and the internal capsule increased significantly after CPAP treatment, as a potential beneficial effect of ventilatory therapy. The recovery of NAWM alterations might also be related to the improvement in the neurocognitive profile, suggesting that nonclearly visible WM alterations may contribute to the physiopathology of OSA-related cognitive impairment.

Orbito-frontal thinning together with a somatoform dissociation might be the fingerprint of PNES.

OBJECTIVE: To investigate neuroanatomical changes in patients with psychogenic nonepileptic seizures (PNES) compared to major depressive disorder (MDD) and healthy controls. METHODS: Forty-two drug-naïve PNES subjects and 25 patients with MDD, matched for demographic characteristics and level of depression (as measured by Beck Depression Inventory-II, BDI-II), were consecutively recruited. Patients performed an extensive neuropsychiatric assessment including: Hamilton Anxiety Rating Scale, Traumatic Experience Checklist, Dissociative Experiences Scale, Toronto Alexithymia Scale and Somatoform Dissociation Questionnaire (SDQ-20). All patients, together with 78 healthy matched controls, underwent 3T brain MRI followed by surface-based morphometry. RESULTS: Cortical thickness analysis revealed significant cortical thinning in bilateral medial orbitofrontal cortex (OFC) and left rostral anterior cingulate cortex (ACC) in patients with MDD compared to subjects with PNES and controls. Interestingly, increased thickness of the right pars triangularis was found in PNES subjects compared to controls. PNES showed higher scores in SDQ-20 (p < 0.001) compared to MDD, which was corroborated by neuroimaging data, where somatoform dissociation scores correlated with morphological changes in the left medial OFC. CONCLUSION: Our results show selective cortical thinning over the medial OFC in patients with PNES compared to wider regions of thinning in patients with MDD. Somatoform dissociation was the only psychopathological assessment significantly different in PNES and MDD.

Perampanel as first add-on choice on the treatment of mesial temporal lobe epilepsy: an observational real-life study.

PURPOSE: To evaluate the efficacy of perampanel (PER) in patients with a diagnosis of mesial temporal lobe epilepsy (MTLE) taking PER as first add-on option due to inefficacy of first antiepileptic drug (AED), rather than late add-on choice. METHODS: Thirty-seven MTLE patients aged ≥ 12 years were recruited consecutively with a minimum duration of follow-up of 1 year and intermediate follow-up of 3 months. Patients were divided into two groups: 20/37 taking PER as first add-on due to inefficacy of first AED (first group) and 17/37 taking PER as late add-on due to inefficacy of ≥ 2 AEDs (second group). Efficacy, retention rate, and safety were evaluated. RESULTS: At 3 months, the 70% of the first group had a reduction > 50% of seizure frequency, with six patients becoming also seizure free, while in the second group, only the 23.5% had a reduction > 50% of seizure frequency and none became seizure free (p = 0.005). Six patients of first group were also switched to a monotherapy of PER and five out of six remained seizure free at 12 months. At 1 year of follow-up, efficacy of PER was 70% for the first group, while only of 29.4% for the second group (p = 0.014). Retention rate of the first group at 3 months and 1 year was 85%, while for the second group was, respectively, 82.3% and 64.7%. CONCLUSION: PER was significantly successful and tolerated in MTLE patients when used as first add-on option rather than as late add-on.

Alteration of Iron Concentration in Alzheimer's Disease as a Possible Diagnostic Biomarker Unveiling Ferroptosis.

Proper functioning of all organs, including the brain, requires iron. It is present in different forms in biological fluids, and alterations in its distribution can induce oxidative stress and neurodegeneration. However, the clinical parameters normally used for monitoring iron concentration in biological fluids (i.e., serum and cerebrospinal fluid) can hardly detect the quantity of circulating iron, while indirect measurements, e.g., magnetic resonance imaging, require further validation. This review summarizes the mechanisms involved in brain iron metabolism, homeostasis, and iron imbalance caused by alterations detectable by standard and non-standard indicators of iron status. These indicators for iron transport, storage, and metabolism can help to understand which biomarkers can better detect iron imbalances responsible for neurodegenerative diseases.

Circulating microRNA: The Potential Novel Diagnostic Biomarkers to Predict Drug Resistance in Temporal Lobe Epilepsy, a Pilot Study.

MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as new potential epigenetic biomarkers. Here, we evaluate the efficacy of six circulating miRNA previously described in the literature as biomarkers for the diagnosis of temporal lobe epilepsy (TLE) and/or as predictive biomarkers to antiepileptic drug response. We measured the differences in serum miRNA levels by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in a cohort of 27 patients (14 women and 13 men; mean ± SD age: 43.65 ± 17.07) with TLE compared to 20 healthy controls (HC) matched for sex, age and ethnicity (11 women and 9 men; mean ± SD age: 47.5 ± 9.1). Additionally, patients were classified according to whether they had drug-responsive (n = 17) or drug-resistant (n = 10) TLE. We have investigated any correlations between miRNAs and several electroclinical parameters. Three miRNAs (miR-142, miR-146a, miR-223) were significantly upregulated in patients (expressed as average expression ± SD). In detail, miR-142 expression was 0.40 ± 0.29 versus 0.16 ± 0.10 in TLE patients compared to HC (t-test, p < 0.01), miR-146a expression was 0.15 ± 0.11 versus 0.07 ± 0.04 (t-test, p < 0.05), and miR-223 expression was 6.21 ± 3.65 versus 1.23 ± 0.84 (t-test, p < 0.001). Moreover, results obtained from a logistic regression model showed the good performance of miR-142 and miR-223 in distinguishing drug-sensitive vs. drug-resistant TLE. The results of this pilot study give evidence that miRNAs are suitable targets in TLE and offer the rationale for further confirmation studies in larger epilepsy cohorts.

The ENIGMA-Epilepsy working group: Mapping disease from large data sets.

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Looking for indicative magnetic resonance imaging signs of hippocampal developmental abnormalities in patients with mesial temporal lobe epilepsy and healthy controls.

OBJECTIVE: To evaluate the frequency of qualitative features for hippocampal developmental abnormalities (HiDeA) definition on magnetic resonance imaging (MRI) in mesial temporal lobe epilepsy (MTLE) patients and healthy controls, highlighting which were more sensitive and specific to the epileptic syndrome. METHODS: We enrolled 93 healthy controls and 187 MTLE patients. Among patients, 133 were MRI-negative and 54 had hippocampal sclerosis (HS). Two blinded, trained investigators defined HiDeA if three signs were present, including at least one of the following: (1) globular hippocampal shape (HCS), (2) verticalized collateral sulcus, and (3) medial positioning of hippocampus (HCP). After evaluating the prevalence of HiDeA in MTLE and controls, we assessed the frequency of each sign. Then, we classified differences in type or number of HiDeA diagnostic features, calculating their sensitivity and specificity. Fisher exact test was used to assess statistical significance. RESULTS: HiDeA was detected in 36 of 187 MTLE cases (19.25%) and in eight of 93 (8.6%) controls. In particular, HiDeA was present in 25 of 133 (18.8%) patients with MRI-negative MTLE. Among all visual criteria here considered, HCS showed higher sensitivity both in the MRI-negative MTLE group (88%) and in the HS-MTLE group (91%). HCP, thickened subiculum, and reduction of the upper horizontal portion of the parahippocampal gyrus (HCTH) signs demonstrated a 100% specificity in both groups. In healthy controls, HCS was confirmed to have the highest sensitivity (100%), whereas HCP showed the highest specificity (98.8%). All these criteria were statistically associated with HiDeA. Electroencephalographic focus was concordant with the HiDeA side in 52.2% of MTLE patients. An association was not found among signs of HiDeA and treatment responsiveness. SIGNIFICANCE: We identified characteristic signs of HiDeA, such as HCTH or HCP, differentiating HiDeA features between MTLE and healthy controls. The identification of sensitive and, more importantly, specific criteria of HiDeA could be helpful to make a more confident visual diagnosis.

Late drug-resistance in mild MTLE: Can it be influenced by preexisting white matter alterations?

OBJECTIVE: To identify early structural alterations preceding the development of drug-resistance in mild mesial temporal lobe epilepsy (mMTLE), a drug-responsive syndrome ideal for investigating epilepsy pathophysiology and potential prognostic markers of long-term clinical outcome, using magnetic resonance imaging (MRI) at baseline and after 12-year follow-up. METHODS: Since 2002, a total of 55 participants with a baseline diagnosis of mMTLE underwent three-dimensional (3D) T1 1.5T MRI. Based on long-term outcome (follow-up 12 ± 3 years), we identified 39 patients with stable mMTLE (smMTLE) and 16 patients who had developed drug-resistance overtime (refractory MTLE [rMTLE]). At follow-up, 21 smMTLE and 13 rMTLE patients underwent 3T-MRI including diffusion-weighted scans. Structural images were processed using longitudinal voxel-based morphometry and standard Freesurfer analysis. Statistical analyses were carried out accounting for age, age at onset, gender, hippocampal volume, and hippocampal sclerosis (Hs). RESULTS: Patients presented similar demographic, clinical, and Hs features. White matter volume of the arcuate fasciculi, corticospinal tracts, left retrosplenial cingulum, and left inferior longitudinal fasciculus was reduced only in rMTLE patients before the development of drug-resistance. At follow-up, rMTLE showed decreased fractional anisotropy in the corpus callosum, superior longitudinal fasciculi, and major bundles of the right hemisphere. SIGNIFICANCE: White matter temporal and extratemporal abnormalities are preexisting in patients with mild MTLE who will develop drug-resistance, independently from the presence of Hs. Thus, these changes might be due to an inherited genetic alteration rather than a subordinate worsening after repeated seizures, multiple antiepileptic drugs, or initial precipitating factors.

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.