Electro-Clinical Features and Functional Connectivity Analysis in SYN1-Related Epilepsy.

OBJECTIVE: There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern. METHODS: In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls. RESULTS: The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions. INTERPRETATION: A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024.

Treatment of new onset refractory status epilepticus/febrile infection-related epilepsy syndrome with tocilizumab in a child and a young adult.

New onset refractory status epilepticus (NORSE) is a rare and devastating condition occurring in a previously healthy patient. It is called febrile infection-related epilepsy syndrome (FIRES) when preceded by a febrile infection. It often leads to intensive care treatment, including antiseizure drugs in combination with anesthetic agents, and sometimes ketogenic diet. The mortality rate is high, and severe epileptic and neuropsychiatric sequelae are usually observed. Based on the possible role of neuroinflammation, intravenous immunoglobulin, corticosteroids, and immunomodulatory treatment (anti-IL1, IL6) can be added. We describe here a child and a young adult with FIRES, both treated with tocilizumab. We observed a rapid positive response on the status epilepticus and good tolerance, but different neurological outcomes for our two patients. Further prospective studies may be necessary both to confirm the efficacy and the safety of this promising treatment and to optimize the immunomodulatory strategy in FIRES/NORSE.

Stratifying sudden death risk in adults with drug-resistant focal epilepsy: The SUDEP-CARE score.

BACKGROUND AND PURPOSE: A clinical risk score for sudden unexpected death in epilepsy (SUDEP) in patients with drug-resistant focal epilepsy could help improve prevention. METHODS: A case-control study was conducted including (i) definite or probable SUDEP cases collected by the French National Sentinel Mortality Epilepsy Network and (ii) control patients from the French national research database of epilepsy monitoring units. Patients with drug-resistant focal epilepsy were eligible. Multiple logistic regressions were performed. After sensitivity analysis and internal validation, a simplified risk score was developed from the selected variables. RESULTS: Sixty-two SUDEP cases and 620 controls were included. Of 21 potential predictors explored, seven were ultimately selected, including generalized seizure frequency (>1/month vs. <1/year: adjusted odds ratio [AOR] 2.6, 95% confidence interval [CI] 1.25-5.41), nocturnal or sleep-related seizures (AOR 4.49, 95% CI 2.68-7.53), current or past depression (AOR 2.0, 95% CI 1.19-3.34) or the ability to alert someone of an oncoming seizure (AOR 0.57, 95% CI 0.33-0.98). After internal validation, a clinically usable score ranging from -1 to 8 was developed, with high discrimination capabilities (area under the receiver operating curve 0.85, 95% CI 0.80-0.90). The threshold of 3 has good sensitivity (82.3%, 95% CI 72.7-91.8), whilst keeping a good specificity (82.7%, 95% CI 79.8-85.7). CONCLUSIONS: These results outline the importance of generalized and nocturnal seizures on the occurrence of SUDEP, and show a protective role in the ability to alert someone of an oncoming seizure. The SUDEP-CARE score is promising and will need external validation. Further work, including paraclinical explorations, could improve this risk score.

Case Studies in Neuroscience: Transcranial Doppler assessment of increased cerebral blood flow during iterative seizures.

This case study aimed at monitoring ictal vasodilation in a clinical setting to confirm the experimental data on enhanced cerebral perfusion during epileptic seizures. Clinical observation of a patient presenting relapsing seizures in the intensive care unit. Transcranial Doppler (TCD) was used to monitor both blood velocities and the arterial caliber in the B-flow mode as a proxy of blood flow of the middle cerebral artery (MCA). A 35-yr-old woman experienced partial epileptic seizures lasting for 1 min that recurred every 5 min. Seizures were monitored with continuous EEG and TCD. During the seizure, the MCA caliber increased whereas velocities remained stable, which doubled the MCA blood flow. Immediately after the seizure, the artery caliber returned to its initial value, and the velocities increased by one-third of the initial value. After intensification of antiepileptic treatment, clinical seizures ceased, and TCD findings returned to normal MCA caliber and velocities. Autoimmune encephalitis was identified by brain biopsy and the patient recovered with corticosteroids treatment. This is the first description of ictal vasodilatation assessed by TCD. Our current understanding holds that cerebral blood flow increases during a seizure, but our report demonstrates that arterial dilation preceded the acceleration of velocities. This case study in a clinical setting confirms the impact of seizures on cerebral blood flow. NEW & NOTEWORTHY The case study is a clinical demonstration of ictal vasodilation. By assessing arterial caliber and blood velocities with transcranial Doppler, we dissected the impact of seizures on blood flow of the middle cerebral artery in the following sequence: 1) vasodilation occurred, concomitant to the epileptic activity, whereas the blood velocities remained stable and 2) immediately after the seizure, the velocities increased and the artery caliber returned to its initial value. As per author, there was no protocol, but one patient gave consent to use data from her medical file.

The new approach to classification of focal epilepsies: Epileptic discharge and disconnectivity in relation to cognition.

The new classification of epilepsy stratifies the disease into an acute level, based on seizures, and an overarching chronic level of epileptic syndromes (Berg et al., 2010). In this new approach, seizures are considered either to originate and evolve in unilateral networks or to rapidly encompass both hemispheres. This concept extends the former vision of focal and generalized epilepsies to a genuine pathology of underlying networks. These key aspects of the new classification can be linked to the concept of cognitive curtailing in focal epilepsy. The present review will discuss the conceptual implications for acute and chronic cognitive deficits with special emphasis on transient and structural disconnectivity. Acute transient disruption of brain function is the hallmark of focal seizures. Beyond seizures, however, interictal epileptic discharges (IEDs) are increasingly recognized to interfere with physiological brain circuitry. Both concomitant EEG and high-precision neuropsychological testing are necessary to detect these subtle effects, which may concern task-specific or default-mode networks. More recent data suggest that longstanding IEDs may affect brain maturation and eventually be considered as a biomarker of pathological wiring. This brings us to the overarching level of chronic cognitive and behavioral comorbidity. We will discuss alterations in structural connectivity measured with diffusion-weighted imaging and tractography. Among focal epilepsies, much of our current insights are derived from temporal lobe epilepsy and its impact on neuropsychological and psychiatric functioning. Structural disconnectivity is maximal in the temporal lobe but also concerns widespread language circuitry. Eventually, pathological wiring may contribute to the clinical picture of cognitive dysfunction. We conclude with the extrapolation of these concepts to current research topics and to the necessity of establishing individual patient profiles of network pathology with EEG, high-precision neuropsychological testing, and state-of-the-art neuroimaging. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy".

Interictal epileptic discharge correlates with global and frontal cognitive dysfunction in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) with hippocampal sclerosis has widespread effects on structural and functional connectivity and often entails cognitive dysfunction. EEG is mandatory to disentangle interactions in epileptic and physiological networks which underlie these cognitive comorbidities. Here, we examined how interictal epileptic discharges (IEDs) affect cognitive performance. METHODS: Thirty-four patients (right TLE=17, left TLE=17) were examined with 24-hour video-EEG and a battery of neuropsychological tests to measure intelligence quotient and separate frontal and temporal lobe functions. Hippocampal segmentation of high-resolution T1-weighted imaging was performed with FreeSurfer. Partial correlations were used to compare the number and distribution of clinical interictal spikes and sharp waves with data from imagery and psychological tests. RESULTS: The number of IEDs was negatively correlated with executive functions, including verbal fluency and intelligence quotient (IQ). Interictal epileptic discharge affected cognitive function in patients with left and right TLE differentially, with verbal fluency strongly related to temporofrontal spiking. In contrast, IEDs had no clear effects on memory functions after corrections with partial correlations for age, age at disease onset, disease duration, and hippocampal volume. CONCLUSION: In patients with TLE of long duration, IED occurrence was strongly related to cognitive deficits, most pronounced for frontal lobe function. These data suggest that IEDs reflect dysfunctional brain circuitry and may serve as an independent biomarker for cognitive comorbidity.

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.

Characterization of seizure-induced syncopes: EEG, ECG, and clinical features.

OBJECTIVE: Ictal bradycardia and ictal asystole (IA) are rare but severe complications of epileptic seizures. They are difficult to recognize within a seizure and their consequences remain unclear. Herein we aimed to extend the description of electrical and clinical features of seizures with IA and/or syncope. METHODS: Among 828 patients with epilepsy who were admitted for presurgical video-electroencephalogram (EEG) monitoring evaluation between 2003 and 2012, we selected those presenting IA and/or syncope. We studied the electroclinical sequence of these manifestations and their correlation with electrocardiogram (ECG), and we compared seizures with or without IA among the same patients. RESULTS: Nine (1.08%) of 828 patients (four men, mean age 43 ± 6 years) showed IA. Six patients had temporal lobe epilepsy and the others had frontal, temporooccipital, or occipital epilepsy, demonstrated by intracranial EEG in two. In these patients, 59 of 103 recorded seizures induced a reduction of heart rate (HR), leading to IA in 26. IAs were mostly (80%) symptomatic, whereas ictal HR decreases alone were not. In seizures with IA, we identified usual ictal symptoms, and then symptoms related primarily to cerebral hypoperfusion (pallor, atonia, early myoclonic jerks, loss of consciousness, hypertonia, and fall) and secondarily to cerebral reperfusion (skin flushing, late myoclonic jerks). At 32 ± 18 s after the onset of the seizure, the HR decreased progressively during 11 ± 6 s, reaching a sinusal pause for 13 ± 7 s. The duration of the IA was strongly correlated with electroclinical consequences. IA was longer in patients with atonia (14.8 ± 7 vs. 5.7 ± 3 s), late myoclonic jerks (15.8 ± 7 vs. 8 ± 6 s), hypertonia (19 ± 4.5 vs. 8.3 ± 5 s), and EEG hypoperfusion changes (16 ± 5.6 vs. 6.9 ± 5.5 s). IA may induce a fall during atonia or hypertonia. Surface and intracerebral EEG recordings showed that ictal HR decrease and IA often occurred when seizure activity became bilateral. Finally, we identified one patient with ictal syncopes but without IA, presumably related to vasoplegia. SIGNIFICANCE: We provide a more complete description of the electroclinical features of seizures with IA, of the mechanism of falls, and distinguish between hypoperfusion and reperfusion symptoms of syncope. Identification of the mechanisms of syncope may improve management of patients with epilepsy. A pacemaker can be proposed, when parasympathetic activation provokes a negative chronotropic effect that leads to asystole. It is less likely to be useful when vasoplegic effects predominate.

Memory functioning after hippocampal removal: Does side matter?

To address the memory functioning after medial temporal lobe (MTL) surgery for refractory epilepsy and relationships with the side of the hippocampal removal, 22 patients with pharmaco-resistant epilepsy who had undergone MTL resection (10 right/12 left) at the Salpêtrière Hospital were compared with 21 matched healthy controls. We designed a specific neuropsychological binding memory test that specifically addressed hippocampal cortex functioning, and left-right material-specific lateralization. Our results showed that both left and right mesial temporal lobe removal cause a severe memory impairment, for both verbal and visual material. The removal of left medial temporal lobe causes worse memory impairment than the right removal regardless of the stimuli type (verbal or visual) questioning the theory of the hippocampal material-specific lateralization. The present study provided new evidence for the role of both hippocampus and surrounding cortices in memory-binding whatever the material type and also suggested that a left MTL removal is more deleterious for both verbal and visual episodic memory in comparison with right MTL removal.

Genetic generalized epilepsy and generalized onset seizures with focal evolution (GOFE).

"Generalized Onset with Focal Evolution" (GOFE) is an underrecognized seizure type defined by an evolution from generalized onset to focal activity during the same ictal event. We aimed to discuss electroclinical aspects of GOFE and to emphasize its link with Genetic Generalized Epilepsy (GGE). Patients were identified retrospectively over 10 years, using the video-EEG data base from the Epilepsy Unit of Strasbourg University Hospital. GOFE was defined, as previously reported, from an EEG point of view with an evolution from generalized onset to focal activity during the same ictal event. Three male patients with GOFE were identified among 51 patients with recorded tonic-clonic seizures. Ages at onset of seizures were 13, 20 and 22 years. Focal clinical features (motor asymmetric phenomenology) could be identified. EEG showed generalized interictal discharges with focal evolution of various localization. Four seizures were recorded characterized by 2-3 s of generalized abnormalities followed by focal (parieto-occipital or frontal) discharges. There were initially uncontrolled seizures with lamotrigine, but all patients reported a good outcome with valproate monotherapy. We emphasize that GOFE presents many similarities with GGE. Recognition of the GOFE entity could bring a therapeutic interest avoiding misdiagnosis of focal epilepsy and consequently inappropriate use of narrow spectrum anti-seizure medicine.

Face Processing in Developmental Prosopagnosia: Altered Neural Representations in the Fusiform Face Area.

Rationale: Face expertise is a pivotal social skill. Developmental prosopagnosia (DP), i.e., the inability to recognize faces without a history of brain damage, affects about 2% of the general population, and is a renowned model system of the face-processing network. Within this network, the right Fusiform Face Area (FFA), is particularly involved in face identity processing and may therefore be a key element in DP. Neural representations within the FFA have been examined with Representational Similarity Analysis (RSA), a data-analytical framework in which multi-unit measures of brain activity are assessed with correlation analysis. Objectives: Our study intended to scrutinize modifications of FFA-activation during face encoding and maintenance based on RSA. Methods: Thirteen participants with DP (23-70 years) and 12 healthy control subjects (19-62 years) participated in a functional MRI study, including morphological MRI, a functional FFA-localizer and a modified Sternberg paradigm probing face memory encoding and maintenance. Memory maintenance of one, two, or four faces represented low, medium, and high memory load. We examined conventional activation differences in response to working memory load and applied RSA to compute individual correlation-matrices on the voxel level. Group correlation-matrices were compared via Donsker's random walk analysis. Results: On the functional level, increased memory load entailed both a higher absolute FFA-activation level and a higher degree of correlation between activated voxels. Both aspects were deficient in DP. Interestingly, control participants showed a homogeneous degree of correlation for successful trials during the experiment. In DP-participants, correlation levels between FFA-voxels were significantly lower and were less sustained during the experiment. In behavioral terms, DP-participants performed poorer and had longer reaction times in relation to DP-severity. Furthermore, correlation levels were negatively correlated with reaction times for the most demanding high load condition. Conclusion: We suggest that participants with DP fail to generate robust and maintained neural representations in the FFA during face encoding and maintenance, in line with poorer task performance and prolonged reaction times. In DP, alterations of neural coding in the FFA might therefore explain curtailing in working memory and contribute to impaired long-term memory and mental imagery.

Herpes simplex encephalitis: A new type of "ICU-acquired infection"?

PURPOSE: Although it is a well-known disease, the occurrence of Herpes simplex encephalitis (HSE) during a hospital stay may render the diagnosis particularly challenging. The objective of this report is to alert clinicians about the diagnostic pitfalls arising from hospital-developed HSE. MATERIALS AND METHODS: Clinical observation of one patient. CASE REPORT: An 87-year-old male was admitted to the Intensive Care Unit (ICU) because of respiratory failure due to an exacerbation of myasthenia gravis. After corticoids and azathioprine treatment, his clinical condition improved, allowing weaning from mechanical ventilation. One month after admission, while still hospitalized in the ICU, the patient developed fever and confusion. In the context of confounding factors, HSE was not suspected before a convulsive status epilepticus occurred, resulting in a significant delay in treatment. Diagnosis was confirmed by PCR-analysis in the cerebrospinal fluid. Serological status confirmed reactivation of prior herpes simplex infection. The patient died one week after the onset of confusion. CONCLUSIONS: Hospital-"acquired" HSE must be suspected in case of new neurologic symptoms associated with fever, even in ICU-hospitalized patients. The diagnosis is made even more difficult by nonspecific symptoms due to previous diseases, leading to an even more severe prognosis in those vulnerable patients.

4h versus 1h-nap-video-EEG monitoring in an Epileptology Unit.

OBJECTIVE: To compare the performance of 4h-video EEG monitoring (VEEG) and 1h-nap-VEEG in an Epileptology Unit. METHODS: We examined short-term VEEG data from 196 patients admitted to characterize their: (i) clinical events; (ii) epileptic syndromes or (iii) state after status epilepticus or surgery. We compared the 4h-VEEG and 1h-nap-VEEG performances using three measures: (i) the capability to detect epileptic seizures (ES), psychogenic non-epileptic seizures (PNES), interictal epileptiform abnormalities (IEA) and sleep-related IEA; (ii) the usefulness to answer questions on referral; (iii) the sensitivity for the final diagnosis. RESULTS: The 4h-VEEG test recorded clinical events in 53.6% of 196 patients, IEA in 41.3%, sleep-related IEA in 34.7%, and was judged as useful in 66.8%. The 4h-VEEG was compared to the 1h-nap-VEEG in 129 patients. 4h-VEEG had a better capability to record clinical events (50.3% vs. 6.2%, p<0.001), a higher usefulness (63.5% vs. 37.2%, p<0.001), and a higher sensitivity for both ES (69.3% vs. 49.3%, p=0.0035) and PNES (61.3% vs. 15.4%, p=0.0014) than nap-EEG. CONCLUSIONS: This work found 4h-VEEG records were superior to the 1h-nap-VEEG test on the basis of three complementary measures, capability, usefulness and sensitivity. SIGNIFICANCE: 4h-VEEG is a useful alternative investigation tool in an Epileptology Unit.