Late but not early seizures impact negatively early post stroke recovery: A case-control study.

BACKGROUND: Seizures are a frequent complication of strokes. The initial severity of the stroke is a risk factor for both seizure occurrence and poor functional recovery. AIM: To determine whether epilepsy has a negative impact on functional recovery or is just a proxy for the initial severity of the stroke. PATIENTS AND METHODS: We conducted a monocentric retrospective case-control study in 408 consecutive patients hospitalized in the neurological rehabilitation department of the Pitié-Salpêtrière Hospital for rehabilitation of a recent stroke between 1999 and 2019. We matched 1:1 stroke patients with and without seizures according to numerous variables that may influence the outcome: type of stroke (ischemic vs hemorrhagic (ICH)), type of endovascular treatment performed (thrombolysis, thrombectomy), exact location of the stroke (arterial territory for ischemic strokes, lobar territory for ICH), extent of the stroke, side of the stroke, and age at the time of stroke. Two criteria were used to judge the impact on neurological recovery: the change in modified Rankin score between entry and the discharge from the rehabilitation department, and the length of stay. Seizures were divided into early (within 7 days of stroke) and late (after 7 days) seizures. RESULTS: We accurately matched 110 stroke patients with and without seizures. Compared to seizure-free matched stroke patients, stroke patients with late seizures had a poorer neurological functional recovery in terms of Rankin score evolution (p = 0.011*) and length of stay (p = 0.004*). The occurrence of early seizures had no significant impact on functional recovery criteria. CONCLUSION: Late seizures, that is, stroke-related epilepsy, have a negative impact on early rehabilitation, whereas early symptomatic seizures do not negatively impact functional recovery. These results reinforce the recommendation not to treat early seizures.

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Partial epilepsy: A pictorial review of 3 TESLA magnetic resonance imaging features.

Epilepsy is a disease with serious consequences for patients and society. In many cases seizures are sufficiently disabling to justify surgical evaluation. In this context, Magnetic Resonance Imaging (MRI) is one of the most valuable tools for the preoperative localization of epileptogenic foci. Because these lesions show a large variety of presentations (including subtle imaging characteristics), their analysis requires careful and systematic interpretation of MRI data. Several studies have shown that 3 Tesla (T) MRI provides a better image quality than 1.5 T MRI regarding the detection and characterization of structural lesions, indicating that high-field-strength imaging should be considered for patients with intractable epilepsy who might benefit from surgery. Likewise, advanced MRI postprocessing and quantitative analysis techniques such as thickness and volume measurements of cortical gray matter have emerged and in the near future, these techniques will routinely enable more precise evaluations of such patients. Finally, the familiarity with radiologic findings of the potential epileptogenic substrates in association with combined use of higher field strengths (3 T, 7 T, and greater) and new quantitative analytical post-processing techniques will lead to improvements regarding the clinical imaging of these patients. We present a pictorial review of the major pathologies related to partial epilepsy, highlighting the key findings of 3 T MRI.

Partial epilepsy: A pictorial review of 3 TESLA magnetic resonance imaging features

Epilepsy is a disease with serious consequences for patients and society. In many cases seizures are sufficiently disabling to justify surgical evaluation. In this context, Magnetic Resonance Imaging (MRI) is one of the most valuable tools for the preoperative localization of epileptogenic foci. Because these lesions show a large variety of presentations (including subtle imaging characteristics), their analysis requires careful and systematic interpretation of MRI data. Several studies have shown that 3 Tesla (T) MRI provides a better image quality than 1.5 T MRI regarding the detection and characterization of structural lesions, indicating that high-field-strength imaging should be considered for patients with intractable epilepsy who might benefit from surgery. Likewise, advanced MRI postprocessing and quantitative analysis techniques such as thickness and volume measurements of cortical gray matter have emerged and in the near future, these techniques will routinely enable more precise evaluations of such patients. Finally, the familiarity with radiologic findings of the potential epileptogenic substrates in association with combined use of higher field strengths (3 T, 7 T, and greater) and new quantitative analytical post-processing techniques will lead to improvements regarding the clinical imaging of these patients. We present a pictorial review of the major pathologies related to partial epilepsy, highlighting the key findings of 3 T MRI.

Hippocampal-thalamic wiring in medial temporal lobe epilepsy: Enhanced connectivity per hippocampal voxel.

OBJECTIVE: Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis is often accompanied by widespread changes in ipsilateral and contralateral white matter connectivity. Recent studies have proposed that patients may show pathologically enhanced wiring of the limbic circuits. To better address this issue, we specifically probed connection patterns between hippocampus and thalamus and examined their impact on cognitive function. METHODS: A group of 44 patients with TLE (22 with right and 22 with left hippocampal sclerosis) and 24 healthy control participants were examined with high-resolution T1 imaging, memory functional magnetic resonance imaging (fMRI) and probabilistic diffusion tractography. Thirty-four patients had further extensive neuropsychological testing. After whole brain segmentation with FreeSurfer, tractography streamline samples were drawn with hippocampus as the seed and thalamus as the target region. Two tractography strategies were applied: The first targeted the anatomic thalamic volume segmented in FreeSurfer and the second a functional region of interest in the mediodorsal thalamus derived from the activation during delayed recognition memory. RESULTS: We found a pronounced enhancement of connectivity between the sclerotic hippocampus and the ipsilateral thalamus both in the right and left TLE as compared to healthy control participants. This finding held for both the anatomically and the functionally defined thalamic target. Although differences were apparent in the number of absolute fibers, they were most pronounced when correcting for hippocampal volume. In terms of cognitive function, the number of hippocampal-thalamic connections was negatively correlated with performance in a variety of executive tasks, notably in the Trail Making Test, thus suggesting that the pathologic wiring did not compensate cognitive curtailing. SIGNIFICANCE: We suggest that TLE is accompanied by an abnormal and dysfunctional enhancement of connectivity between the hippocampus and the thalamus, which is maximal on the side of the sclerosis. This pathologic pattern of limbic wiring might reflect structural remodeling along common pathways of seizure propagation.

Structural connectivity differences in left and right temporal lobe epilepsy.

Our knowledge on temporal lobe epilepsy (TLE) with hippocampal sclerosis has evolved towards the view that this syndrome affects widespread brain networks. Diffusion weighted imaging studies have shown alterations of large white matter tracts, most notably in left temporal lobe epilepsy, but the degree of altered connections between cortical and subcortical structures remains to be clarified. We performed a whole brain connectome analysis in 39 patients with refractory temporal lobe epilepsy and unilateral hippocampal sclerosis (20 right and 19 left) and 28 healthy subjects. We performed whole-brain probabilistic fiber tracking using MRtrix and segmented 164 cortical and subcortical structures with Freesurfer. Individual structural connectivity graphs based on these 164 nodes were computed by mapping the mean fractional anisotropy (FA) onto each tract. Connectomes were then compared using two complementary methods: permutation tests for pair-wise connections and Network Based Statistics to probe for differences in large network components. Comparison of pair-wise connections revealed a marked reduction of connectivity between left TLE patients and controls, which was strongly lateralized to the ipsilateral temporal lobe. Specifically, infero-lateral cortex and temporal pole were strongly affected, and so was the perisylvian cortex. In contrast, for right TLE, focal connectivity loss was much less pronounced and restricted to bilateral limbic structures and right temporal cortex. Analysis of large network components revealed furthermore that both left and right hippocampal sclerosis affected diffuse global and interhemispheric connectivity. Thus, left temporal lobe epilepsy was associated with a much more pronounced pattern of reduced FA, that included major landmarks of perisylvian language circuitry. These distinct patterns of connectivity associated with unilateral hippocampal sclerosis show how a focal pathology influences global network architecture, and how left or right-sided lesions may have differential and specific impacts on cerebral connectivity.

Diffusion tensor imaging can localize the epileptogenic zone in nonlesional extra-temporal refractory epilepsies when [(18)F]FDG-PET is not contributive.

Surgical outcome in patients with nonlesional refractory partial epilepsies could be improved by a more precise definition of the epileptogenic zone (EZ). The value of interictal FDG-PET hypometabolism, voxel-based-morphometry (VBM) and diffusion tensor imaging (DTI) is still debated. We compared the sensitivity and specificity of these noninvasive techniques in localizing the EZ with stereo-electroencephalography (SEEG) results. Twenty patients with nonlesional partial epilepsy (13 temporal lobe epilepsy (TLE) and 7 extra-temporal (extra-TLE)) underwent structural MRI, DTI and FDG-PET. FDG-PET was analyzed visually (vPET) blinded and unblinded and by statistical parametric mapping (SPM) (sPET). Individual modifications of grey matter volume and mean diffusivity increase were compared to a control group with SPM. The best sensitivity was provided by vPET unblinded (75%) and the best specificity (60%) by DTI. The sensitivity of vPET blinded (55%) was lower and those of sPET (40%) and VBM (35%) were still lower. In TLE, vPET analyzed either blinded or unblinded, performed the best and additional use of the other tools improved slightly the sensitivity. For extra-TLE, combining vPET and DTI results increased the number of pertinent abnormalities detected especially for circumscribed changes in frontal lobe epilepsy (FLE). Combining vPET and DTI was the more efficient strategy for extra-TLE, allowing the detection of pertinent abnormalities in FLE when FDG-PET alone was not contributive. Combining sPET or VBM with vPET was less useful.

Postoperative recovery of hippocampal contralateral diffusivity in medial temporal lobe epilepsy correlates with memory functions.

This study aimed at determining if the recovery of mean diffusivity (MD) in the contralateral non sclerotic hippocampus is correlated with a change in memory outcome after surgery in patients with medial temporal lobe epilepsy (MTLE). Verbal and non-verbal memory scores and MD were assessed in 23 patients with MTLE before and after surgical treatment of epilepsy. The recovery of MD in the left hippocampus was correlated with the performance on verbal memory tests, and the recovery of MD in all patients was correlated with the performance on non-verbal memory tests. This finding strengthens the hypothesis that reversible diffusion abnormalities in the contralateral hippocampus in MTLE are linked to the active epileptic process that seems to interfere with memory abilities.

Visualization of disconnection syndromes in humans.

Knowledge of the relationship between structure and function is essential to the exploration of the architecture of cognition. Cognitive processes require the coordinated activity of large-scale brain networks consisting of distant cortical regions, connected by long-range white matter tracts. Despite decades of connectional tracing studies in monkeys, the backwardness of human anatomy makes it difficult to draw conclusions from lesion studies and functional neuroimaging when brain connectivity is at issue. We propose an approach to clinico-anatomical correlation, based on a standardized atlas of white matter tracts derived from diffusion tensor imaging tractography. Using OVER-TRACK, a method based on tracking and overlapping white matter tracts, we mapped the course of three rostro-caudal association pathways in the Montreal Neurological Institute space. For each voxel we defined the probability of finding fibers belonging to individual tracts. This method is defined to localize in the white matter the overlapping lesion derived from a group of patients with brain damage. Our study provides a general approach for establishing anatomo-functional correlations by estimating the cortical areas connected in normal subjects, or disconnected by white matter lesions. This method will help researchers and clinicians to identify the neural bases of cognitive abilities and the behavioral consequences of brain lesions.

Diffusion tensor imaging and voxel based morphometry study in amyotrophic lateral sclerosis: relationships with motor disability.

The aim of this study was to investigate the extent of cortical and subcortical lesions in amyotrophic lateral sclerosis (ALS) using, in combination, voxel based diffusion tensor imaging (DTI) and voxel based morphometry (VBM). We included 15 patients with definite or probable ALS and 25 healthy volunteers. Patients were assessed using the revised ALS Functional Rating Scale (ALSFRS-R). In patients, reduced fractional anisotropy was found in bilateral corticospinal tracts, the left insula/ventrolateral premotor cortex, the right parietal cortex and the thalamus, which correlated with the ALSFRS-R. Increased mean diffusivity (MD) was found bilaterally in the motor cortex, the ventrolateral premotor cortex/insula, the hippocampal formations and the right superior temporal gyrus, which did not correlate with the ALSFRS-R. VBM analysis showed no changes in white matter but widespread volume decreases in grey matter in several regions exhibiting MD abnormalities. In ALS patients, our results show that subcortical lesions extend beyond the corticospinal tract and are clinically relevant.

Postoperative recovery of hippocampal contralateral diffusivity in medial temporal lobe epilepsy.

PURPOSE: To search for a recovery after surgery of mean diffusivity (MD) values in the contralateral nonsclerotic hippocampus of patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS). METHODS: Twenty-four MTLE patients (12 right-sided and 12 left-sided MTLE) and 36 healthy volunteers were investigated using diffusion tensor imaging. A region-of-interest approach was used to measure pre- and postoperative interictal hippocampal MD values in patients. RESULTS: Diffusion abnormalities in contralateral nonsclerotic hippocampus recovered after surgery (p<0.0001). A subgroup of 14 patients exhibited a clear increase in MD values whereas the remaining 10 patients were stable. No significant difference was found between the two subgroups for each of the electroclinical data studied including early postoperative outcome, all patients being either seizure free or with rare persistent auras. CONCLUSIONS: This finding suggests that diffusion abnormalities in contralateral hippocampus may represent a functional mechanism linked to the active epileptic process.

Interictal diffusion MRI in partial epilepsies explored with intracerebral electrodes.

Patients with refractory partial seizures may benefit from epilepsy surgery. However, invasive investigations are often needed to define the precise location and limits of the epileptogenic zone (EZ). In this study, we asked whether diffusion tensor imaging (DTI) might provide a non-invasive alternative to locate the EZ or at least provide insights to help place intracerebral electrodes for stereo-electroencephalography (SEEG). Whole brain DTI and voxel-based analysis (SPM99) was used to assess diffusion properties objectively in 16 epilepsy patients investigated with SEEG. Epilepsy was symptomatic in two patients and cryptogenic in the 14 remaining patients. The suspected onset of seizures was temporal in 10 patients, frontal in 2 and occipital in 4. Individual maps of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were calculated and compared to a database of 40 healthy volunteers. Thirteen of 16 patients exhibited diffusion abnormalities. ADC abnormalities were better correlated with SEEG data than FA abnormalities which were usually located at a distance or in the white matter. A significant increase in ADC (P < 0.01) was found in 11 patients and was located in the regions explored with depth electrodes in 7 of them. Surgery outcome was available in 3 of these 7 patients (2 were seizure free and 1 not). DTI specificity was better in extratemporal lobe epilepsy (83%) than in temporal lobe epilepsy (20%). When abnormalities concurred with the SEEG data, the concordance was optimal between the localization of the diffusion abnormalities and the irritative zone defined by SEEG. These encouraging, preliminary results, suggest that DTI examinations may provide accurate spatial data on the location and extent of the epileptogenic network in extratemporal lobe epilepsies.

Diffusion tensor imaging in medial temporal lobe epilepsy with hippocampal sclerosis.

Interictal diffusion imaging studies in patients with medial temporal lobe epilepsy (MTLE) accompanied by hippocampal sclerosis (HS) have shown an increased diffusivity in the epileptogenic hippocampus. In this study, we wanted to explore the whole brain in order to determine if MTLE could have an impact on the organization and the architecture of a large cerebral network and to identify clinical factors that could mediate diffusion abnormalities. Diffusion tensor imaging (DTI) and statistical parametric mapping of the entire brain were performed in 35 well-defined MTLE patients and in 36 healthy volunteers. SPM analyses identified three abnormal areas: an increased diffusivity was detected in the epileptic hippocampus and the ipsilateral temporal structures associated with a decreased anisotropy along the temporal lobe, a decreased diffusivity was found in the contralateral non-sclerotic hippocampus, the amygdala, and the temporal pole, and finally, a decreased anisotropy was noted ipsilaterally in posterior extratemporal regions. Duration of epilepsy, age at onset, and the frequency of generalized tonic-clonic seizures or partial complex seizures did not correlate with the presence of diffusion abnormalities. Region of interest analysis in the hippocampus/parahippocampus demonstrated a correlation between lower ipsilateral diffusivity values and occurrence of epigastric aura and between higher anisotropy values in both hemispheres and history of febrile seizures. In conclusion, this study showed that diffusion abnormalities are not restricted to the pathologic hippocampus and involve a larger network. This pattern may indirectly reflect the epileptogenic network and may be interpreted as a cause or a consequence of epilepsy.

Productive and perceptive language reorganization in temporal lobe epilepsy.

The aim of this work was to determine whether productive and perceptive language functions are differentially affected in homogeneous groups of epilepsy patients with right and left temporal lobe epilepsy (TLE). Eighteen patients with left TLE, 18 with right TLE, and 17 healthy volunteers were studied using fMRI during performance of three tasks assessing the productive and perceptive aspects of language (covert semantic verbal fluency, covert sentence repetition, and story listening). Hemispheric dominance for language was calculated in the frontal and temporal regions using laterality indices (LI). Atypical lateralization was defined as a right-sided LI (LI<-0.20) in the frontal lobes during the verbal fluency task or in the temporal lobes during the story listening task. Control subjects and right TLE patients demonstrated a strong left lateralization for language in the frontal lobes during the fluency task, whereas activation was less lateralized to the left hemisphere in left TLE patients, although the difference did not reach significance. In the story listening and the repetition tasks, activation was significantly more right sided in the temporal lobes of patients with left TLE. Atypical language representation was found in 19% of TLE patients (five left and two right TLE). The shift toward the right hemisphere was significantly larger in the temporal than the frontal lobes in patients with atypical language lateralization compared to TLE patients with a typical language lateralization. Neuropsychological performances of patients with atypical language patterns were better than those of patients with typical patterns, suggesting that this reorganization may represent a compensatory mechanism.

Diffusion tensor fiber tracking shows distinct corticostriatal circuits in humans.

A landmark of corticostriatal connectivity in nonhuman primates is that cortical connections are organized into a set of discrete circuits. Each circuit is assumed to perform distinct behavioral functions. In animals, most connectivity studies are performed using invasive tracing methods, which are nonapplicable in humans. To test the proposal that corticostriatal connections are organized as multiple circuits in humans, we used diffusion tensor imaging axonal tracking, a new magnetic resonance technique that allows demonstration of fiber tracts in a noninvasive manner. Diffusion tensor imaging-based fiber tracking showed that the posterior (sensorimotor), anterior (associative), and ventral (limbic) compartments of the human striatum have specific connections with the cortex, and particularly the frontal lobes. These results provide the first direct demonstration of distinct corticostriatal connections in humans.

Temporal pole hypometabolism may be linked to a reduction of grey matter in temporal lobe epilepsy.

In order to gain further insight into the pathophysiology of temporal pole hypometabolism, we decided to perform a voxel-based automated analysis of structural MRI in epileptic patients with or without temporal pole hypometabolism. After fully automated segmentation of cerebral grey matter from structural T1-weighted MRI scans, we applied the automated technique of statistical parametric mapping (SPM) to the analysis of grey matter of nine control subjects, and 18 patients with right medial temporal lobe epilepsy with (n = 13) or without (n = 5) significant temporal pole hypometabolism. Group comparisons between subject controls and epileptic patients with temporal pole hypometabolism showed a reduction of grey matter located into the superior part of the right temporal pole, the right hippocampus and the left parahippocampal gyrus. Epileptic patients without temporal pole hypometabolism did not exhibit temporal pole grey matter abnormalities. These findings suggest that a reduction of temporal pole neocortical grey matter might contribute to temporal pole hypometabolism in temporal lobe epilepsy.

The neuroanatomical substrate of sound duration discrimination.

We investigated the neuroanatomical substrate of sound duration discrimination, using the same experimental design as in a previous study on sound intensity discrimination [J. Neurosci. 18 (16) (1998) 6388]. Seven normal subjects were trained to detect deviant sounds presented with a slightly longer duration than a 300 ms long standard harmonic sound, using a Go/No Go paradigm. Individual psychometric curves were assessed using a three-step psychoacoustic procedure. Subjects were then scanned while passively listening to the standard sound, and while discriminating changes in sound duration at four different performance levels (d'=1.5, 2.5, 3.5 and 4.5). Analysis of regional cerebral blood flow (rCBF) data outlined activation, during the discrimination conditions, of a right hemispheric fronto-parietal network very similar to the one previously observed for intensity discrimination, as well as additional activation in the right prefrontal cortex (Brodmann Area (BA) 10), bilateral basal ganglia and cerebellar hemispheres. These findings suggest that discrimination of sound duration, as for discrimination of sound intensity, involves two cerebral networks: a supramodal right fronto-parietal cortical network responsible for allocation of sensory attentional resources, and a network of regions such as the basal ganglia, cerebellum, and right prefrontal cortex, more specifically involved in the temporal aspects of the discrimination task.