Clinical and genetic features of GATOR1 complex-associated epilepsy.

OBJECTIVES: To analyse the prevalence of pathogenic variants in DEPDC5, NPRL2 and NPRL3 that encode the GATOR1 (GTPase-activating protein towards the Rags 1) complex, a modulator in the mammalian target of rapamycin (mTOR) pathway, and to define the characteristics of GATOR1-associated epilepsy. METHODS: Clinical details and whole-exome sequencing data of 170 novel probands with lesional or non-lesional epilepsy were retrieved. Candidate variants in GATOR1 genes were verified by Sanger sequencing, and cosegregate analysis was performed. The pathogenicity of variants and their effect on mTOR signalling were investigated. RESULTS: Two novel frameshift variants and one recurrent nonsense variant were detected in DEPDC5, with a prevalence of 1.8% (3 out of 170) in the whole cohort and 3.1% (3 out of 97) in focal epilepsies. These variants cosegregated in pedigrees with epilepsy, respectively. Rare missense variants in NPRL2 and NPRL3 did not segregate with epilepsy in families, respectively. Epileptic phenotypes of 21 patients with DEPDC5 variants showed focal seizures with non-lesional variable foci that were predominantly sleep-related, with a median onset age of 10 years (range 1-30). Seizure outcome was variable. About 24% of patients were drug-resistant, and seizure attacks were absent in 33% of variant carriers. Of 13 patients who experienced seizures, 54% tended to resolve spontaneously. Functional assessments showed that the three variants affected DEPDC5 expression. These loss-of-function (LoF) variants affected the DEPDC5-dependent inhibition of mTOR. CONCLUSIONS: Patients carrying DEPDC5-LoF variants might show a high prevalence of focal seizures with a dynamic phenotype, indicating reduced penetrance and self-resolving features. The associated epilepsy was caused by loss of inhibition of the mTOR pathway. The pathogenicity of missense variants in GATOR1 genes should be cautiously evaluated.

Progressive multifocal leukoencephalopathy and peripheral neuropathy in a patient with Good's syndrome.

Good's syndrome (GS) is an immunodeficiency characterized by thymoma, hypogammaglobulinemia, and impaired T-cell function. Progressive multifocal encephalopathy (PML), an infection caused by JC virus (JCV), usually occurs in patients infected with human immunodeficiency virus (HIV), or in patients on treatment with immunosuppressive or immunomodulatory drugs. There were few reports of PML due to GS, especially with the comorbidity of peripheral neuropathy. We describe a case of an uncommon presentation of PML and peripheral neuropathy in a male who presented with blurred vision, cognitive changes, limb weakness, and numbness over a 4-month period due to GS. To the best of our knowledge, this is the first report of PML and peripheral neuropathy due to GS. This case aims to highlight that it is necessary to consider the possibility of PML due to GS in patients with thymoma and intracranial lesions, and we should focus not only on opportunistic infections of the central nervous system, such as PML, but also on peripheral neuropathy.

Scalp-HFO indexes are biomarkers for the lateralization and localization of the epileptogenic zone in preoperative assessment.

During the noninvasive evaluation phase for refractory epilepsy, the localization of the epileptogenic zone (EZ) is essential for the surgical protocols. Confirmation of laterality is required when the preoperative evaluation limits the EZ to bilateral anterior temporal lobes or bilateral frontal lobes. High-frequency oscillations (HFOs) are considered to be promising biological markers for the EZ. However, a large number of studies on HFOs stem from intracranial research. There were few quantitative measures for scalp HFOs, so we proposed a new method to quantify and analyze scalp HFOs. This method was called the "scalp-HFO index" (HI) and calculated in both the EZ and non-EZ. The calculation was based on the numbers and spectral power of scalp HFOs automatically detected. We labeled the brain lobes involved in the EZ as regions of interest (ROIs). The HIs based on the ripple numbers (n-HI) and spectral power (s-HI) were significantly higher in the ROI than in the contra-ROI (P = 0.012, P = 0.003), indicating that HIs contributed to the lateralization of EZ. The sensitivity and specificity of n-HI for the localization of the EZ were 90% and 79.58%, respectively, suggesting that n-HI was valuable in localizing the EZ. HI may contribute to the implantation strategy of invasive electrodes. However, few scalp HFOs were recorded when the EZ was located in the medial cortex region.NEW & NOTEWORTHY We proposed the scalp-high-frequency oscillation (HFO) index (HI) as a quantitative assessment method for scalp HFOs to locate the epileptogenic zone (EZ). Our results showed that the HI in regions of interest (ROIs) was significantly higher than in contra-ROIs. Sensitivity and specificity of HI based on ripple rates (n-HI) for EZ localization were 90% and 79.58%, respectively. If the n-HI of the brain region was >1.35, it was more likely to be an epileptogenic region. Clinical application of HIs as an indicator may facilitate localization of the EZ.

A concordance study determining language dominance between navigated transcranial magnetic stimulation and the Wada test in patients with drug-resistant epilepsy.

OBJECTIVE: It remains unclear whether transcranial magnetic stimulation (TMS) can replace the Wada test to determine language hemisphere dominance (HD). Using the Wada test as the gold standard, this study aimed to investigate the accuracy of navigated TMS (nTMS) in determining language HD. METHODS: This study enrolled nine right-handed patients with drug-resistant epilepsy. We hypothesized that application of nTMS to language-related areas of the language-dominant hemisphere would induce positive manifestation of language dysfunction (LD). To test our hypothesis, the patients were instructed to perform a visual object-naming task while nTMS was applied to the anterior (e.g., Broca's area) and posterior (e.g., Wernicke's area) regions, which are closely related to language processing. The Wada test result was used as the gold standard, and the diagnostic value of nTMS was assessed using the Kappa consistency test. RESULTS: The nTMS-induced LD positive rate for the bilateral anterior language areas (85.7%) was higher than that for the posterior language areas (57.1%). There was high consistency between nTMS stimulation of the left anterior and posterior language areas and the Wada test results for determining language HD. In contrast, the consistency of stimulation of the right anterior and posterior transfer sites was moderate (Kappa value = 0.545, P = 0.171) and low, respectively. For the latter, no statistical calculation was performed because stimulation of the right posterior speech area was negative in all patients compared with the Wada test results. CONCLUSIONS: Our findings revealed that using nTMS to stimulate language-related left anterior and posterior areas could predict language HD with high accuracy. When the stimulation performance of these areas is positive, nTMS and the Wada test are equally accurate. Observing only negative performance may indicate that language HD has been transferred to the right side.

Posterior cingulate epilepsy: Seizure semiology and intracranial electrical stimulation using SEEG.

PURPOSE: This study aimed to explore seizure semiology and the effects of intracerebral electrical stimulation on the human posterior cingulate cortex (PCC) using Stereoelectroencephalography (SEEG) to deepen our comprehension of posterior cingulate epilepsy (PCE). METHODS: This study examined the characteristics of seizures through video documentation, by assessing the outcomes of intracranial electrical stimulation (iES) during SEEG. We further identified the connection between the observed semiology and precise anatomical locations within the PCC subregions where seizure onset zones (SOZ) were identified. RESULTS: Analysis was conducted on 59 seizures from 15 patients recorded via SEEG. Behavioural arrest emerged as the predominant manifestation across the PCC subregions. Where ictal activity extended to both the mesial and lateral temporal cortex, automatism was predominantly observed in seizures originating from the ventral PCC (vPCC). The retrosplenial cortex (RSC) is associated with complex motor behaviour, with seizure discharges spreading to the temporal lobe. Seizures originating from the PCC include axial tonic and autonomic seizures. Only one case of positive clinical seizures was documented. High frequencies of iES within the PCC induced various clinical responses, categorised as vestibular, visual, psychological, and autonomic, with vestibular reactions primarily occurring in the dorsal PCC (dPCC) and RSC, visual responses in the left RSC, and autonomic reactions in the vPCC and RSC. CONCLUSION: The manifestations of seizures in PCE vary according to the SOZ and the patterns of seizure propagation. The occurrence of seizures induced by iES is exceedingly rare, indicating that mapping of the PCC could pinpoint the primary sector of PCC.

Dynamic evolution of the anterior cingulate-insula network during seizures.

OBJECTIVES: In physiological situations, the anterior cingulate cortex (ACC) and anterior insular cortex (AIC) are prone to coactivation. The functional connectivity and interaction between ACC and AIC in the context of epilepsy remain unclear. This study aimed to investigate the dynamic coupling between these two brain regions during seizures. METHODS: Patients who underwent stereoelectroencephalography (SEEG) recording were included in this study. The SEEG data were visually inspected and quantitatively analyzed. The narrowband oscillations and aperiodic components at seizure onset were parameterized. The frequency-specific non-linear correlation analysis was applied to the functional connectivity. The excitation/inhibition ratio (E:I ratio) reflected by the aperiodic slope was performed to evaluate the excitability. RESULTS: Twenty patients were included in the study, with 10 diagnosed with anterior cingulate epilepsy and 10 with anterior insular epilepsy. In both types of epilepsy, the correlation coefficient (h2 ) between the ACC and AIC at seizure onset exhibited a significantly higher value than that during interictal and preictal periods (p < 0.05). The direction index (D) showed a significant increase at seizure onset, serving as an indicator for the direction of information flow between these two brain regions with up to 90% accuracy. The E:I ratio increased significantly at seizure onset, with the seizure-onset zone (SOZ) demonstrating a more pronounced increase compared to non-SOZ (p < 0.05). For seizures originating from AIC, the E:I ratio was significantly higher in the AIC than in the ACC (p = 0.0364). CONCLUSIONS: In the context of epilepsy, the ACC and AIC are dynamically coupled during seizures. The functional connectivity and excitability exhibit a significant increase at seizure onset. By analyzing connectivity and excitability, the SOZ in ACC and AIC can be identified. The direction index (D) serves as an indicator for the direction of information flow from SOZ to non-SOZ. Notably, the excitability of SOZ changes more significantly than that of non-SOZ.

The characteristics and alteration of peripheral immune function in patients with multiple system atrophy.

Objective: Multiple system atrophy (MSA) is a degenerative disease. Immune dysfunction found to play a crucial role in the pathogenesis of this disease in the literature, while the characteristics of peripheral immune function remain unclear. This study aimed to investigate the characteristics and alterations of peripheral immune function in patients with MSA. Methods: A case-control study was conducted between January 2021 to December 2022 at SanBo Brain Hospital, Capital Medical University, Beijing, China. A total of 74 participants were recruited, including 47 MSA patients and 27 non-MSA participants. Peripheral blood samples were collected from each participant. A total of 29 types of immune cells were measured using the flow cytometry analysis technology. Single-factor analysis and multiple-factor analysis (multiple linear regression models) were performed to determine the differences and risk factors in immune cells between the MSA and non-MSA groups. Results: Alterations of the count or percentage of CD19+ B lymphocytes and CD3-CD56+ B lymphocytes in MSA patients were found in this study. The reductions of the count and percentage of CD19+ B lymphocytes were still robust after adjusting for variables of age, gender, body mass index, albumin, and hemoglobin. Furthermore, the reductions in the count and percentage of CD19+ B lymphocytes in the MSA patients were more significant in women and individuals aged 60 years old or above than in the non-MSA participants. Conclusion: Our findings suggested that MSA patients may be influenced by B lymphocytes, particularly CD19+ cells. Therefore, the reductions in immune cells should be considered in the diagnosis and treatment of MSA. Further studies are warranted to confirm and expand upon these findings.

Occipital Lobe Epilepsy With Ictal Fear: Evidence From a Stereo-Electroencephalography (sEEG) Case.

Ictal fear-a relatively rare phenomenon-is a semiological characteristic of epilepsy. Most patients with epilepsy with ictal fear have an epileptic zone in the mesial temporal lobe, which is the classical brain area involved in emotion processing. Herein, we report a case of epilepsy with ictal fear as the first manifestation in a 10-year-old boy. All noninvasive evaluation including scalp video electroencephalography (EEG), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET-CT) suggested a possible lesion in the left posterior brain region. Stereo-electroencephalography (sEEG) results showed high frequency direct current shift in the left occipital lobe 1 s before the fear manifestation which preceded in 12 s the discharge in the amygdala. This case highlights the epileptic network hypothesis which suggested occipital cortex may play an important role in the early emotional network independently of amygdala activation.

Minimally Toxic Dose of Lipopolysaccharide and α-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation.

The aim of this study is to investigate the role and mechanism of microglial NOX2 activation in minimally toxic dose of LPS and Syn-elicited synergistic dopaminergic neurodegeneration. NOX2+/+ and NOX2-/- mice and multiple primary cultures were treated with LPS and/or Syn in vivo and in vitro. Neuronal function and morphology were evaluated by uptake of related neurotransmitter and immunostaining with specific antibody. Levels of superoxide, intracellular reactive oxygen species, mRNA and protein of relevant molecules, and dopamine were detected. LPS and Syn synergistically induce selective and progressive dopaminergic neurodegeneration. Microglia are functionally and morphologically activated, contributing to synergistic dopaminergic neurotoxicity elicited by LPS and Syn. NOX2-/- mice are more resistant to synergistic neurotoxicity than NOX2+/+mice in vivo and in vitro, and NOX2 inhibitor protects against synergistic neurotoxicity through decreasing microglial superoxide production, illustrating a critical role of microglial NOX2. Microglial NOX2 is activated by LPS and Syn as mRNA and protein levels of NOX2 subunits P47and gp91 are enhanced. Molecules relevant to microglial NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-КBP50 as their mRNA and protein levels are elevated after treatment with LPS and Syn. Combination of exogenous and endogenous environmental factors with minimally toxic dose synergistically propagates dopaminergic neurodegeneration through activating microglial NOX2 and relevant signaling molecules, casting a new light for PD pathogenesis.

Identification of the epileptogenic zone of temporal lobe epilepsy from stereo-electroencephalography signals: A phase transfer entropy and graph theory approach.

The aim of this research is to apply an approach based on phase transfer entropy (PTE) and graph theory to study the interactions between the stereo-electroencephalography (SEEG) activities recorded in multilobar origin, in order to evaluate their ability to detect the epileptogenic zone (EZ) of temporal lobe epilepsies (TLE). Forty-three patients were included in this retrospective study. Five to sixteen (median = 12) multilead electrodes were implanted per patient, and, for each patient, a sub-set of between 10 and 32 (median = 22) bipolar derivations was selected for analysis. The leads were classified into the onset leads (OLs), the early propagation leads (EPLs), and the rest of the leads (RLs). The results showed that a significantly different dynamic trend of the out/in ratio (more obvious in the gamma band) distinguishes the OLs from RLs in the 23 patients who were seizure-free not only during the ictal event (significant elevation), but also during the inter-,pre-, late-ictal periods, and especially in the post-ictal (sharp decline) state. However, in the 20 patients who were not-seizure-free, the differences between the OLs and RLs during the post-ictal period were not found in any frequency band. The dynamic trend was used to predict surgical outcome, and the results showed that the sensitivity was 91% and the specificity was 70%. In brief, this study indicates that our approach may add new and valuable information, providing efficient quantitative measures useful for localizing the EZ.

Role and mechanism of microglial activation in iron-induced selective and progressive dopaminergic neurodegeneration.

Parkinson's disease (PD) patients have excessive iron depositions in substantia nigra (SN). Neuroinflammation characterized by microglial activation is pivotal for dopaminergic neurodegeneration in PD. However, the role and mechanism of microglial activation in iron-induced dopaminergic neurodegeneration in SN remain unclear yet. This study aimed to investigate the role and mechanism of microglial ß-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) activation in iron-induced selective and progressive dopaminergic neurodegeneration. Multiple primary midbrain cultures from rat, NOX2+/+ and NOX2-/- mice were used. Dopaminergic neurons, total neurons, and microglia were visualized by immunostainings. Cell viability was measured by MTT assay. Superoxide (O2·-) and intracellular reactive oxygen species (iROS) were determined by measuring SOD-inhibitable reduction of tetrazolium salt WST-1 and DCFH-DA assay. mRNA and protein were detected by real-time PCR and Western blot. Iron induces selective and progressive dopaminergic neurotoxicity in rat neuron-microglia-astroglia cultures and microglial activation potentiates the neurotoxicity. Activated microglia produce a magnitude of O2·- and iROS, and display morphological alteration. NOX2 inhibitor diphenylene iodonium protects against iron-elicited dopaminergic neurotoxicity through decreasing microglial O2·- generation, and NOX2-/- mice are resistant to the neurotoxicity by reducing microglial O2·- production, indicating that iron-elicited dopaminergic neurotoxicity is dependent of NOX2, a O2·--generating enzyme. NOX2 activation is indicated by the increased mRNA and protein levels of subunits P47 and gp91. Molecules relevant to NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-КBP65 as their mRNA and protein levels are enhanced by NOX2 activation. Iron causes selective and progressive dopaminergic neurodegeneration, and microglial NOX2 activation potentiates the neurotoxicity. PKC-σ, P38, ERK1/2, JNK, and NF-КBP65 are the potential molecules relevant to microglial NOX2 activation.