Neuromodulatory Focused Ultrasound for Epilepsy: Are Animal Models Useful?

Ultrasound neuromodulation is a potential alternative therapy for suppressing epileptic discharges. Recently, several human clinical trials have reported promising results from repeated focused ultrasound (FUS) treatments for temporal lobe epilepsy. In this Viewpoint, we highlight the valuable guidance of preclinical validation methods for choosing the optimal FUS parameters, thus ensuring consistency with the outcomes of clinical trials and leading human trials to the safest and most effective approaches.

Distributed source modeling of stereoencephalographic measurements of ictal activity.

OBJECTIVES: Stereoelectroencephalography (SEEG) can define the epileptogenic zone (EZ). However, SEEG is susceptible to the sampling bias, where no SEEG recording is taken within a circumscribed EZ. METHODS: Nine patients with medically refractory epilepsy underwent SEEG recording, and brain resection got positive outcomes. Ictal neuronal currents were estimated by distributed source modeling using the SEEG data and individual's anatomical magnetic resonance imaging. Using a retrospective leave-one-out data sub-sampling, we evaluated the sensitivity and specificity of the current estimates using MRI after surgical resection or radio-frequency ablation. RESULTS: The sensitivity and specificity in detecting the EZ were indistinguishable from either the data from all electrodes or the sub-sampled data (rank sum test: rank sum = 23719, p = 0.13) when at least one remaining electrode contact was no more than 20 mm away. CONCLUSIONS: The distributed neuronal current estimates of ictal SEEG data can mitigate the challenge of delineating the boundary of the EZ in cases of missing an electrode implanted within the EZ and a required second SEEG exploration. SIGNIFICANCE: Distributed source modeling can be a tool for clinicians to infer the EZ by allowing for more flexible planning of the electrode implantation route and minimizing the number of electrodes.

Glucose Metabolism of Hippocampal Subfields in Medial Temporal Lobe Epilepsy.

PURPOSE: Reduced glucose metabolism in the hippocampus is commonly observed in cases of medial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS). Glucose metabolism among the various hippocampal subfields has not been thoroughly investigated. PATIENTS AND METHODS: This study examined 29 patients (18 females; 15-58 years) diagnosed with HS who underwent surgery for drug-resistant epilepsy. FreeSurfer 7.1.1 was used in the processing of MRI data and 18 F-FDG PET scans to derive volumetric data and the FDG SUVr in the whole hippocampus and hippocampal subfields, including the CA1, CA2-4, granule cell and molecular layer of the dentate gyrus (GC-ML-DG), and subiculum. Asymmetries in the volume and SUVr between the 2 sides from the subfields of the hippocampus were defined in terms of an asymmetry index. Comparisons of the asymmetry index among these regions were performed. The correlations between asymmetry index values and postoperative outcomes and presurgical neuropsychological test results were also evaluated. RESULT: The CA1, CA2-4, subiculum, GC-ML-DG, and whole hippocampus presented reductions in volume and hypometabolism ipsilateral to MTLE. Asymmetries in volume and SUVr were significantly less pronounced in the CA1 and subiculum than in the CA2-4 or GC-ML-DG. Postoperative seizure outcomes were not correlated with the asymmetry index for volume or SUVr in any hippocampal subfield. In cases of left MTLE, scores of immediate logical memory and delayed logical memory were positively correlated with the asymmetry index for SUVr in the following subfields: CA1 ( R = 0.829, P = 0.021; R = 0.770, P = 0.043), CA2-4 ( R = 0.825, P = 0.022; R = 0.894, P = 0.007), subiculum ( R = 0.882, P = 0.009; R = 0.853, P = 0.015), GC-ML-DG ( R = 0.850, P = 0.015; R = 0.796, P = 0.032), and whole hippocampus ( R = 0.841, P = 0.018; R = 0.822, P = 0.023). In cases of right MTLE, the scores for delayed face memory were positively correlated with the asymmetry index for SUVr in the subiculum ( R = 0.935, P = 0.006). CONCLUSIONS: In cases of HS, changes in glucose metabolism levels varied among the hippocampal subfields. Asymmetries in glucose metabolism among the CA-1, CA2-4, subiculum, and GC-ML-DG subregions were correlated with scores for verbal memory among patients with left MTLE. Asymmetric glucose metabolism in the subiculum was also correlated with visual memory scores among patients with right MTLE.

Frame-based versus robot-assisted stereo-electro-encephalography for drug-resistant epilepsy.

BACKGROUND: Stereoelectroencephalography (SEEG) is an effective presurgical invasive evaluation for drug-resistant epilepsies. The introduction of robotic devices provides a simplified, accurate, and safe alternative to the conventional SEEG technique. We report our institutional experience with robot-assisted SEEG and compare its in vivo accuracy, operation efficiency, and safety with the more traditional SEEG workflow. METHODS: All patients with medically refractory focal epilepsy who underwent SEEG depth electrode implantation between 2014 and 2022 were included in this study. Technical advancements of the robot-assisted technique are described. Analyses of patient demographics, electrode implantation accuracy, operation time, and procedure-related complications were performed. RESULTS: One hundred and sixty-six patients underwent 167 SEEG procedures. The first 141 procedures were performed using a conventional approach involving a Leksell stereotactic system, and the last 26 procedures were robot-assisted. Among the 1726 depth electrodes that were inserted, the median entry point localization error was as follows: conventional (1.0 mm; range, 0.1-33.5 mm) and robot-assisted (1.1 mm; range, 0-4.8 mm) (P = 0.17). The median target point localization error was as follows: conventional (2.8 mm; range, 0.1-49 mm) and robot-assisted (1.8 mm; range, 0-30.3 mm) (P < 0.001). The median operation time was significantly reduced with the robot-assisted workflow (90 min vs. 77.5 min; P < 0.01). Total complication rates were as follows: conventional (17.7%) and robot-assisted (11.5%) (P = 0.57). Major complication rates were 3.5% and 7.7% (P = 0.77), respectively. CONCLUSIONS: SEEG is a safe and highly accurate method that provides essential guidance for epilepsy surgery. Implementing SEEG in conjunction with multimodal planning systems and robotic devices can further increase safety margin, surgical efficiency, and accuracy.

Development and construction of the Multidimensional Self-Efficacy Scale for Epilepsy (MSESE) and its psychometric properties.

PURPOSE: It has become evident that patients with epilepsy require strong self-efficacy support in various domains, including work, social interaction, and academic performance, to ensure their complete social functioning. Nevertheless, previous studies have predominantly assessed the self-efficacy of individuals with epilepsy from a singular perspective of disease management. This study aimed to develop the Multidimensional Self-Efficacy Scale for Epilepsy (MSESE) to assess multiple dimensions and establish its psychometric properties. METHODS: We compiled a total of 25 questions for the initial version of the questionnaire based on a review of the literature and insights from experts, patients, and family members. The study included 180 adult patients with epilepsy who met the research criteria, with 126 of them serving as pre-test samples. All participants completed the MSESE, Brief Symptom Rating Scale-50 (BSRS-50), Rosenberg Self-Esteem Scale-Chinese version (RSES-C), and General Self-Efficacy Scale (GSES). RESULTS: The final scale consisted of 12 items across four dimensions, with item factor loadings ranging from .51 to .90. Most of the fit indices indicated a good fit. Construct validity was established through significant correlations with the BSRS-50, RSES-C, and GSES (r = -0.51 to 0.69, p < 0.01). Internal consistency coefficients for the MSESE were strong at .90, with individual dimensions ranging from 0.71 to 0.89. The MSESE also demonstrated a satisfactory test-retest reliability of 0.72. CONCLUSIONS: The MSESE is a convenient, multidimensional, and easy-to-use scale with good psychometric properties, making it suitable for both clinical assessments and research purposes.

Visual Stimuli Modulate Local Field Potentials But Drive No High-Frequency Activity in Human Auditory Cortex.

Neuroimaging studies suggest cross-sensory visual influences in human auditory cortices (ACs). Whether these influences reflect active visual processing in human ACs, which drives neuronal firing and concurrent broadband high-frequency activity (BHFA; >70 Hz), or whether they merely modulate sound processing is still debatable. Here, we presented auditory, visual, and audiovisual stimuli to 16 participants (7 women, 9 men) with stereo-EEG depth electrodes implanted near ACs for presurgical monitoring. Anatomically normalized group analyses were facilitated by inverse modeling of intracranial source currents. Analyses of intracranial event-related potentials (iERPs) suggested cross-sensory responses to visual stimuli in ACs, which lagged the earliest auditory responses by several tens of milliseconds. Visual stimuli also modulated the phase of intrinsic low-frequency oscillations and triggered 15-30 Hz event-related desynchronization in ACs. However, BHFA, a putative correlate of neuronal firing, was not significantly increased in ACs after visual stimuli, not even when they coincided with auditory stimuli. Intracranial recordings demonstrate cross-sensory modulations, but no indication of active visual processing in human ACs.

Electrophysiological population dynamics reveal context dependencies during decision making in human frontal cortex.

Evidence from monkeys and humans suggests that the orbitofrontal cortex (OFC) encodes the subjective value of options under consideration during choice. Data from non-human primates suggests that these value signals are context-dependent, representing subjective value in a way influenced by the decision makers' recent experience. Using electrodes distributed throughout cortical and subcortical structures, human epilepsy patients performed an auction task where they repeatedly reported the subjective values they placed on snack food items. High-gamma activity in many cortical and subcortical sites including the OFC positively correlated with subjective value. Other OFC sites showed signals contextually modulated by the subjective value of previously offered goods-a context dependency predicted by theory but not previously observed in humans. These results suggest that value and value-context signals are simultaneously present but separately represented in human frontal cortical activity.

Pulsed Focused Ultrasound Reduces Hippocampal Volume Loss and Improves Behavioral Performance in the Kainic Acid Rat Model of Epilepsy.

Focused ultrasound (FUS) has the potential to modulate regional brain excitability and possibly aid seizure control; however, effects on behavior of FUS used as a seizure therapy are unknown. This study explores behavioral effects and hippocampal restoration induced by pulsed FUS in a kainic acid (KA) animal model of temporal lobe epilepsy. Twenty-nine male Sprague-Dawley rats were observed for 20 weeks with anatomical magnetic resonance imaging (MRI) and behavioral performance evaluations, comprising measures of anxiety, limb usage, sociability, and memory. FUS targeted to the right hippocampus was given 9 and 14 weeks after KA was delivered to the right amygdala. Ultrasound pulsations were delivered with the acoustic settings of 0.25 of mechanical index, 0.5 W/cm2 of intensity spatial peak temporal average (ISPTA), 100 Hz of pulse repetition frequency, and 30% of duty cycle, during three consecutive pulse trains of 10 min separated by 5-min rests. Controls included normal animals with sham injections and KA-exposed animals without FUS exposure. Longitudinal MRI observations showed that FUS substantially protected hippocampal and striatal structures from KA-induced atrophy. KA alone increased anxiety, impaired contralateral limb usage, and reduced sociability and learning. Two courses of FUS sonications partially ameliorated these impairments by enhancing exploring and learning, balancing limb usage, and increasing social interaction. The histology results indicated that two sonications enhanced neuroprotection effect and decreased the inflammation markers induced by KA. This study supports existence of both neuroprotective and beneficial behavioral effects from low-intensity pulsed ultrasound in the KA animal model of epilepsy.

Telemedicine for Individuals with epilepsy: Recommendations from the International League Against Epilepsy Telemedicine Task Force.

Worldwide, People with Epilepsy (PWE) are confronted with several barriers to face-to-face consultations. These obstacles hamper appropriate clinical follow-up and also increase the treatment gap for Epilepsy. Telemedicine holds the potential to enhance management as follow-up visits for PWE are focused on more on clinical history and counselling rather than physical examination. Besides consultation, telemedicine can also be used for remote EEG diagnostics and tele-neuropsychology assessments. In this article, the Telemedicine Task Force of the International League Against Epilepsy (ILAE) outlines recommendations regarding optimal practice in utilizing in the management of individuals with epilepsy. We formulated recommendations for minimum technical requirements, preparing for the first tele-consultation and the specificities for follow-up consultations. Special considerations are necessary for specific populations, including paediatric patients, patients who are not conversant with tele-medicine and those with intellectual disability. Telemedicine for individuals with epilepsy should be vigorously promoted with the aim of improving the quality of care and ultimately reduce the wide clinician access related treatment gap across several regions of the globe.

Stereo-EEG for Epileptogenic Focus Localization in Schizencephaly: A Single-center Experience in Four Patients.

OBJECTIVE: Schizencephaly is a congenital cerebral malformation characterized by clefts in the hemispheres of the brain, where variations in semiology often make it difficult to localize epileptogenic focus. Here, we report on a series of patients who underwent stereo-encephalography (SEEG) for epileptogenic focus localization and subsequent SEEG-guided surgical intervention. METHODS: Four patients (ages 27, 33, 27, 25 years) with a mean seizure history of 16 years (range 8-22 years) were analyzed. Data pertaining to semiology, video encephalography (EEG), magnetic resonance imaging, positron emission tomography, and invasive EEG studies, surgical intervention and post-surgery outcome were collected and analyzed. RESULTS: All seizure onset zones were within the extent of schizencephaly; however, the limbic system (including the hippocampus, amygdala, cingulate gyrus, or insula) was involved in early spreading. Two patients underwent SEEG-guided radiofrequency thermo-ablation (RFTA) in the seizure onset zone, 1 patient underwent lesionectomy via craniotomy, and 1 underwent neither RFTA nor lesionectomy. At 2 years post-surgery, the outcomes were as follows: Engel grade Ia (n = 2), Ib (n = 1), and III (n = 1). CONCLUSIONS: This article reports on a precise approach to treating patients with schizencephaly dependent of seizure onset zone and functional cortex mapping. Subsequent SEEG-guided surgical interventions (radiofrequency thermo-ablation and lesionectomy) were shown to reduce seizure frequency, while preserving the neurologic functions in drug-resistant epilepsy patients with schizencephaly.

Cross-task specificity and within-task invariance of cognitive control processes.

Cognitive control involves flexibly combining multiple sensory inputs with task-dependent goals during decision making. Several tasks involving conflicting sensory inputs and motor outputs have been proposed to examine cognitive control, including the Stroop, Flanker, and multi-source interference task. Because these tasks have been studied independently, it remains unclear whether the neural signatures of cognitive control reflect abstract control mechanisms or specific combinations of sensory and behavioral aspects of each task. To address these questions, we record invasive neurophysiological signals from 16 patients with pharmacologically intractable epilepsy and compare neural responses within and between tasks. Neural signals differ between incongruent and congruent conditions, showing strong modulation by conflicting task demands. These neural signals are mostly specific to each task, generalizing within a task but not across tasks. These results highlight the complex interplay between sensory inputs, motor outputs, and task demands underlying cognitive control processes.

Strategic infarct location for post-stroke seizure.

Post-stroke seizure (PSS) can have a strong negative impact on functional recovery after stroke. Researchers have identified numerous risk factors of PSS; however, the relationship between infarction location and PSS remains unclear. We recruited patients who presented with an acute cerebral infarction between 2012 and 2017 and suffered from seizures within 1 year after stroke (PSS group). PSS group was subgrouped into early-PSS and late-PSS groups based on the interval between seizure and stroke. We also recruited an equal number of acute cerebral infarction patients without post-stroke seizures during the follow-up period (Non-PSS group). All brain MRIs from the two groups were processed, whereupon normalized infarct maps from the PSS and Non-PSS groups were compared via voxel- and volumetric-based analyses. A total of 132 subjects were enrolled in the study, including PSS (n = 66, consisting of 31 early-PSS and 35 late-PSS) and Non-PSS (n = 66) patients. No significant differences were observed between the two groups in terms of stroke lateralization or severity. Image analysis revealed that the volume of infarction was larger in the PSS group than in the Non-PSS group; however, the difference did not reach the level of significance. Unlike the Non-PSS group, the PSS group presented hot spots over the left central region, left superior parietal lobule, and right frontal operculum. We observed differences between the distribution of hot spots among patients with early-PSS and those with late-PSS. We found that some brain regions were significantly associated with the development of PSS after ischemic stroke, and these regions differed between cases of early and late PSS. It appears that the location of infarction could help clinicians assess the risk of PSS in specific post-stroke stages.

Validation of the Taiwanese version of the Epilepsy Surgery Satisfaction Questionnaire (Tw-ESSQ-19).

OBJECTIVE: Satisfaction with epilepsy surgery in Mandarin-speaking countries remains unknown. We aimed to validate in our Taiwanese patients an existing instrument to measure patient satisfaction with epilepsy surgery, the 19-item Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19). METHODS: Consecutive patients with epilepsy who received epilepsy surgery one year earlier in Taipei Veterans General Hospital were recruited and provided clinical and demographic data. The Mandarin version of the ESSQ-19 for the Taiwanese population and eight other questionnaires were completed to assess construct validity. To evaluate the validity and reliability of the tool, the data were analyzed by confirmatory factor analysis, Spearman's rank correlation, and internal consistency analysis. RESULTS: The study involved 120 patients (70 F/50 M, median age 35 years [IQR = 28-41]). The mean summary score (±SD) of the Tw-ESSQ-19 was 82.5 ±â€¯14.5. The mean scores of the four domains were 90.3 ±â€¯15.4 (surgical complications), 83.2 ±â€¯16.7 (seizure control), 80.1 ±â€¯17.3 (recovery from surgery), and 76.6 ±â€¯18.3 (psychosocial functioning). The questionnaire was shown to have good construct validity with satisfactory goodness-of-fit of the data (standardized root mean square residual = 0.0492; comparative fit index = 0.946). It also demonstrated good discriminant validity (being seizure free [AUC 0.78; 95% CI 0.68-0.89], endorsing depression [AUC 0.84; 95% CI 0.76-0.91], self-rating epilepsy as disabling [AUC 0.71; 95% CI 0.58-0.84], and self-rating epilepsy as severe [AUC 0.78; 95% CI 0.64-0.93]), high internal consistency in four domains (Cronbach's alpha = 0.83-0.96), and no significant floor/ceiling effects of the summary score. SIGNIFICANCE: The Mandarin version of the ESSQ-19 adapted for the Taiwanese population is a reliable and valid self-reported questionnaire for assessing patient satisfaction with epilepsy surgery.

Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model.

Focused ultrasound (FUS) has potential utility for modulating regional brain excitability and possibly aiding seizure control; however, the duration of any beneficial effect is unknown. This study explores the efficacy and time course of a short series of pulsed FUS in suppressing EEG epileptiform spikes/bursts in a kainic acid (KA) animal model of temporal lobe epilepsy. Forty-four male Sprague-Dawley rats were recorded for 14 weeks with EEG while software calculated EEG numbers of epileptiform spikes and bursts (≥ 3 spikes/s). Four regimens of FUS given in a single session at week 7 were evaluated, with mechanical index (MI) ranging from 0.25 to 0.75, intensity spatial peak temporal average (ISPTA) from 0.1 to 2.8 W per cm2, duty cycle from 1 to 30%, and three consecutive pulse trains for 5 or 10 min each. Controls included sham injections in four and KA without FUS in eleven animals. Histological analysis investigated tissue effects. All animals receiving KA evidenced EEG spikes, averaging 10,378 ± 1651 spikes per 8 h and 1255 ± 199 bursts per 8 h by weeks 6-7. The KA-only group showed a 30% of increase in spikes and bursts by week 14. Compared to the KA-only group, spike counts were reduced by about 25%, burst counts by about 33%, and burst durations by about 50% with FUS. Behavioral seizures were not analyzed, but electrographic seizures longer than 10 s declined up to 70% after some FUS regimens. Repeated-measure ANOVA showed a significant effect of higher intensity and longer sonication duration FUS treatment using 0.75-MI, ISPTA 2.8 W/cm2, 30% duty cycle for 10-min sonications (group effect, F (4, 15) = 6.321, p < 0.01; interaction effect, F (44, 165) = 1.726, p < 0.01), with the hippocampal protective effect lasting to week 14, accompanied by decreased inflammation and gliosis effect. In contrast, spike and burst suppression were achieved using an FUS regimen with 0.25-MI ISPTA 0.5 W/cm2, 30% duty cycle for 10-min sonications. This regimen reduced inflammation and gliosis at weeks 8-14 and protected hippocampal tissue. This study demonstrates that low-intensity pulsed ultrasound can modulate epileptiform activity for up to 7 weeks and, if replicated in the clinical setting, might be a practical treatment for epilepsy.

Reliability and validity of the traditional Chinese version of the GAD-7 in Taiwanese patients with epilepsy.

BACKGROUND: Generalized anxiety disorder (GAD) is the second most common psychiatric comorbidity of epilepsy. GAD has a negative impact on seizure control, and it is underrecognized. The Generalized Anxiety Disorder 7-item (GAD-7) questionnaire is useful for screening GAD in patients with epilepsy (PWE). This study aimed to validate the traditional Chinese version of the GAD-7 for Taiwanese patients by obtaining data on adult PWE from our hospital. METHOD: PWE were recruited from the Taipei Veterans General Hospital from April 2017 to January 2020. The mood disorder module of the Mini International Neuropsychiatric Interview (MINI) was used for the psychiatric assessment. The traditional Chinese version of the GAD-7 and the Beck Anxiety Inventory were included as self-rated psychiatric evaluation. To investigate the psychometric properties, internal consistency, external validation, and receiver operator characteristic (ROC) curve analysis were conducted to assess the utility of the Taiwanese version of the GAD-7. RESULTS: We recruited 109 patients in the present study. Seventeen patients (15.9%) had GAD according to the MINI. The mean GAD-7 score was 10.28 ± 10.68. All the GAD-7 items were significantly and positively associated with the corrected overall GAD-7 score (Cronbach's alpha = 0.928, p < 0.0001). The cut-off point for the GAD-7 in ROC curve analysis was 7. The patients with GAD were more likely to be female and single. CONCLUSION: The traditional Chinese version of the GAD-7 is a reliable and valid self-report questionnaire for detecting GAD in Taiwanese PWE.

Clinical characteristics and long-term outcome of cerebral cavernous malformations-related epilepsy.

OBJECTIVE: Cerebral cavernous malformations (CCMs) present variably, and epileptic seizures are the most common symptom. The factors contributing to cavernoma-related epilepsy (CRE) and drug resistance remain inconclusive. The outcomes of CRE after different treatment modalities have not yet been fully addressed. This study aimed to characterize the clinical features of patients with CRE and the long-term seizure outcomes of medical and surgical treatment strategies. METHODS: This was a retrospective cohort of 135 patients with CCM who were diagnosed in 2007-2011 and followed up for 93.6 months on average. The patients were divided into drug-resistant epilepsy (DRE; n = 29), non-DRE (n = 45), and no epilepsy (NE; n = 61). RESULTS: Temporal CCM was the factor most strongly associated with the development of both CRE and DRE. The majority of patients with single temporal CCMs had CRE (86.8%, n = 33), and 50% had DRE, whereas only 14.7% (n = 5) with a nontemporal supratentorial CCM had DRE (p < .05). The most common lesion site in the DRE group was the mesiotemporal lobe (50%). Multiple CCMs were more frequently observed in the CRE (29.2%) than the NE (11.5%) group (p < .05). In patients with CRE, multiple lesions were associated with a higher rebleeding rate (odds ratio = 11.1), particularly in those with DRE (odds ratio = 15.4). The majority of patients who underwent resective surgery for DRE (76.5%, n = 13) achieved International League Against Epilepsy Class I and II seizure outcomes even after a long disease course. SIGNIFICANCE: Temporal CCM not only predisposes to CRE but also is a major risk factor for drug resistance. The mesiotemporal lobe is the most epileptogenic zone. Multiple CCMs are another risk factor for CRE and increase the rebleeding risk in these patients. Surgical resection could provide beneficial long-term seizure outcomes in patients with DRE.

Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy.

Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, Southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and were diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsies from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patients presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%; 4/34) and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesions on diffusion weighted images were the best biomarkers for diagnosing NIID with high specificity (98.4%) and sensitivity (88.2%). However, this diffusion weighted imaging abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, the presence of white matter hyperintensity lesions either in the paravermis or middle cerebellar peduncles also favoured the diagnosis of NIID with a specificity of 85.3% and sensitivity of 76.5%. Among the MRI scans of 10 patients, performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical hyperintense lesions on diffusion weighted images and two revealed focal brain oedema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients developed encephalitis-like episodes with restricted diffusion in the cortical regions on diffusion weighted images at the acute stage. Corticomedullary junction hyperintense lesions, white matter hyperintensities in the paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnosing NIID.

Counseling about sudden unexpected death in epilepsy (SUDEP): A global survey of neurologists' opinions.

OBJECTIVE: To investigate the opinions and attitudes of neurologists on the counseling about sudden unexpected death in epilepsy (SUDEP) worldwide. METHODS: Practicing neurologists from around the world were invited to participate in an online survey. On February 18th, 2021, we emailed an invitation including a questionnaire (using Google-forms) to the lead neurologists from 50 countries. The survey anonymously collected the demographic data of the participants and answers to the questions about their opinions and attitudes toward counseling about SUDEP. RESULTS: In total, 1123 neurologists from 27 countries participated; 41.5% of the respondents reported they discuss the risk of SUDEP with patients and their care-givers only rarely. Specific subgroups of patients who should especially be told about this condition were considered to be those with poor antiseizure medication (ASM) adherence, frequent tonic-clonic seizures, or with drug-resistant epilepsy. The propensity to tell all patients with epilepsy (PWE) about SUDEP was higher among those with epilepsy fellowship. Having an epilepsy fellowship and working in an academic setting were factors associated with a comfortable discussion about SUDEP. There were significant differences between the world regions. CONCLUSION: Neurologists often do not discuss SUDEP with patients and their care-givers. While the results of this study may not be representative of practitioners in each country, it seems that there is a severe dissociation between the clinical significance of SUDEP and the amount of attention that is devoted to this matter in daily practice by many neurologists around the world.

Machine Learning Quantitative Analysis of FDG PET Images of Medial Temporal Lobe Epilepsy Patients.

PURPOSE: 18F-FDG PET is widely used in epilepsy surgery. We established a robust quantitative algorithm for the lateralization of epileptogenic foci and examined the value of machine learning of 18F-FDG PET data in medial temporal lobe epilepsy (MTLE) patients. PATIENTS AND METHODS: We retrospectively reviewed patients who underwent surgery for MTLE. Three clinicians identified the side of MTLE epileptogenesis by visual inspection. The surgical side was set as the epileptogenic side. Two parcellation paradigms and corresponding atlases (Automated Anatomical Labeling and FreeSurfer aparc + aseg) were used to extract the normalized PET uptake of the regions of interest (ROIs). The lateralization index of the MTLE-associated regions in either hemisphere was calculated. The lateralization indices of each ROI were subjected for machine learning to establish the model for classifying the side of MTLE epileptogenesis. RESULT: Ninety-three patients were enrolled for training and validation, and another 11 patients were used for testing. The hit rate of lateralization by visual analysis was 75.3%. Among the 23 patients whose MTLE side of epileptogenesis was incorrectly determined or for whom no conclusion was reached by visual analysis, the Automated Anatomical Labeling and aparc + aseg parcellated the associated ROIs on the correctly lateralized MTLE side in 100.0% and 82.6%. In the testing set, lateralization accuracy was 100% in the 2 paradigms. CONCLUSIONS: Visual analysis of 18F-FDG PET to lateralize MTLE epileptogenesis showed a lower hit rate compared with machine-assisted interpretation. While reviewing 18F-FDG PET images of MTLE patients, considering the regions associated with MTLE resulted in better performance than limiting analysis to hippocampal regions.