Background: Abnormal expanded GGC repeats within theNOTCH2HLCgene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features ofNOTCH2NLC-related NIID in China.Methods: Patients withNOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.Results: In the 247 patients withNOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=−0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.Conclusions: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum ofNOTCH2NLC-related NIID.

Background: An increasing number of observational studies have revealed an association among the gut microbiota, gut metabolites, and epilepsy. However, this association is easily influenced by confounders such as diet, and the causality of this association remains obscure.Methods: Aiming to explore the causal relationship and ascertain specific gut microbe taxa for epilepsy, we conducted a bi-directional Mendelian randomization (MR) study based on the genome-wide association study (GWAS) data of epilepsy from the International League Against Epilepsy, with the gut microbiota GWAS results from MiBioGen, and summary-level GWAS data of gut microbiota-dependent metabolites trimethylamine N-oxide and its predecessors.Results: Nine phyla, 15 classes, 19 orders, 30 families, and 96 genera were analyzed. A suggestive association of host-genetic-driven increase in family Veillonellaceae with a higher risk of childhood absence epilepsy (odds ratio [OR]: 1.033, confidential interval [CI]: 1.015–1.051, P_IVW = 0.0003), class Melainabacteria with a lower risk of generalized epilepsy with tonic-clonic seizures (OR = 0.986, CI = 0.979–0.994, P_IVW = 0.0002), class Betaproteobacteria (OR = 0.958, CI = 0.937–0.979, P_IVW = 0.0001), and order Burkholderiales (OR = 0.960, CI = 0.937–0.984, P_IVW = 0.0010) with a lower risk of juvenile myoclonic epilepsy were identified after multiple-testing correction. Our sensitivity analysis revealed no evidence of pleiotropy, reverse causality, weak instrument bias, or heterogeneity.Conclusion: This is the first MR analysis to explore the potential causal relationship among the gut microbiota, metabolites, and epilepsy. Four gut microbiota features (two class levels, one order level, and one family level) were identified as potential interventional targets for patients with childhood absence epilepsy, generalized epilepsy with tonic-clonic seizures, and juvenile myoclonic epilepsy. Previous associations in numerous observational studies may had been interfered by confounders. More rigorous studies were needed to ascertain the relationship among the gut microbiota, metabolites, and epilepsy.

Objective: Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME.Methods: This prospective cross‐sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks.Results: During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure‐free patients. Receiver‐operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient‐sibling group against controls, respectively;P < .005).Significance: Motor system hyperactivation represents a cognitive, domain‐independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.

Mesial temporal lobe epilepsy (mTLE) is generally associated with focal brain atrophy, but little knowledge exists on possible disease-related hypertrophy of brain structures. We hypothesized that repeated seizures or adaptive plasticity may lead to focal brain hypertrophy and aimed to investigate associated clinical correlates. In this cohort study, we included patients with mTLE undergoing detailed epilepsy evaluations and matched healthy volunteers (HVs) from 2 tertiary centers (discovery and validation cohorts). We assessed areas of brain hypertrophy and their clinical correlates using whole-brain voxel-based or surface-based morphometry (VBM, SBM), subcortical volumetry, and shape analysis of T1-weighted MRI data by fitting linear models. We evaluated the functional implications of the findings on memory encoding using fMRI. We included 135 patients with mTLE with neuropathology-confirmed hippocampal sclerosis (77 left, 58 right; 82 women; mean age 37 ± 11 years) and 47 HVs (29 women, mean age 36 ± 11 years) in the discovery cohort. VBM detected increased gray matter volume of the contralateral amygdala in patients with both left (t = 8.7, p < 0.001) and right (t = 7.9, p < 0.001) mTLE. We confirmed the larger volume of the contralateral amygdala using volumetry (left mTLE 1.74 ± 0.16 mL vs HVs 1.64 ± 0.11, p < 0.001; right mTLE 1.79 ± 0.18 mL vs HVs 1.70 ± 0.11, p = 0.002) and shape analysis (left mTLE p ≤ 0.005; right mTLE p = 0.006). We validated the hypertrophy of the contralateral amygdala in the validation cohort (mTLE, n = 18, 1.91 ± 0.20 mL; HVs, n = 18, 1.75 ± 0.13; p = 0.009). In left mTLE, contralateral amygdala hypertrophy was associated with poorer verbal memory and, in right mTLE, with more frequent focal-to-bilateral tonic-clonic seizures. A larger volume of the contralateral amygdala correlated with increased functional activation of the right parietal memory encoding network in a subgroup (44/135 patients with mTLE, 26/47 HVs) receiving fMRI. Unilateral mTLE due to hippocampal sclerosis is associated with hypertrophy of the contralateral amygdala. This may represent plasticity to compensate for verbal memory deficits or may be the consequence of seizure spread to the contralateral hemisphere.

Aims: This study aimed to comprehensively explore the cerebellar structural and functional changes in temporal lobe epilepsy (TLE) and its association with clinical information.Methods: The SUIT toolbox was utilized to perform cerebellar volume and diffusion analysis. In addition, we extracted the average diffusion values of cerebellar peduncle tracts to investigate microstructure alterations. Seed-based whole-brain analysis was used to investigate cerebellar–cerebral functional connectivity (FC). Subgroup analyses were performed to identify the cerebellar participation in TLE with/without hippocampal sclerosis (HS)/focal-to-bilateral tonic–clonic seizure (FBTCS) and TLE with different lateralization.Results: TLE showed widespread gray matter atrophy in bilateral crusII, VIIb, VIIIb, left crusI, and left VIIIa. Both voxel and tract analysis observed diffusion abnormalities in cerebellar afferent peduncles. Reduced FC between the right crus II and the left parahippocampal cortex was found in TLE. Additionally, TLE showed increased FCs between left lobules VI–VIII and cortical nodes of the dorsal attention and visual networks. Across all patients, decreased FC was associated with poorer cognitive function, while increased FCs appeared to reflect compensatory effects. The cerebellar structural changes were mainly observed in HS and FBTCS subgroups and were regardless of seizure lateralization, while cerebellar–cerebral FC alterations were similar in all subgroups.Conclusion: TLE exhibited microstructural changes in the cerebellum, mainly related to HS and FBTCS. In addition, altered cerebellar–cerebral functional connectivity is associated with common cognitive alterations in TLE.