Cerebral glucose hypometabolism and hypoperfusion of cingulate gyrus: an imaging biomarker of autoimmune encephalitis with psychiatric symptoms.

BACKGROUND: About 60% of autoimmune encephalitis (AE) patients present psychiatric symptoms, but the underlying mechanism remains unknown. This study examined the role of the cingulate cortex in such patients to identify predictive poor psychiatric factors. METHODS: In this study, 49 AE patients and 39 healthy controls were enrolled. AE patients were further divided into two groups based on the presence/absence of psychiatric symptoms. The ratio of the standardized uptake value (SUVR) and relative cerebral blood flow (rCBF) in different regions of the cingulate cortex were calculated through positron emission tomography-computed tomography (PET/CT) and arterial spin labeling (ASL) MRI, and the results were compared among the three groups. In addition, we followed-up on the psychiatric outcomes and identified the risk factors for poor psychiatric prognosis, focusing on the cingulate cortex. RESULTS: More than half of the AE patients (27/49) exhibited psychiatric symptoms. Agitation and thought blocking were typical psychiatric phenotypes, except for anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, which mainly presented with catatonia and a depressed mood. AE patients with psychiatric symptoms experienced reduced metabolism and perfusion of the anterior cingulate cortex (ACC), midcingulate cortex (MCC), and posterior cingulate cortex (PCC). The SUVR of ACC can be used as an independent risk factor of poor psychiatric outcomes, which had an area under the ROC curve (AUC) of 0.865. CONCLUSION: Impaired cingulate cortex function in AE may be the potential mechanism of psychiatric symptoms. Hypometabolism of ACC is an independent prognostic factor predicting an unfavorable psychiatric prognosis in AE.

MRI characteristics due to gene mutations in a Chinese pedigree with Lafora disease.

BACKGROUND AND PURPOSE: Lafora disease (LD) is a very rare autosomal recessive disorder manifesting primarily as fatal, congenital, and neurodegenerative epilepsies. We aimed to describe the MRI characteristics due to gene mutations in a Chinese pedigree with LD. METHODS: Whole-exome sequencing, muscle biopsy, pedigree analysis, and MRI analysis were conducted. Five family members (two of whom were affected by LD) were whole-genome sequenced. Longitudinal changes in brain MRI volumes were analyzed by Freesurfer. RESULTS: We identified a new intron heterozygous mutation in the EMP2A gene c.71 (exon 1) G>A in a Chinese LD pedigree that was characterized by refractory seizures, progressive vision impairment, and declines in motor and cognitive functions. The patient suffered generalized tonic-clonic seizures since the age of 15 years and had severe forms of progressive myoclonic seizure. She eventually died after being admitted to the intensive care unit due to status epilepticus at the age of 24 years. Period acid Schiff staining showed positive polyglucosan particles in muscle biopsy specimens. Regions of atrophy in the whole brain, and especially in the hippocampus, were detected. CONCLUSIONS: We identified a new heterozygous mutation (c.71+1G>A) in a Chinese LD pedigree, which broadens the mutation spectrum of LD genes. We found that the patient exhibited brain volumetric atrophy along with rapidly worsening symptoms. These results contribute to our understanding of LD.

Clinical features and brain MRI volumetric changes in anti-mGluR5 encephalitis.

BACKGROUND: Anti-metabotropic glutamate receptor 5 (mGluR5) encephalitis is a rare and under-recognized autoimmune encephalitis. This study is conducted to characterize its clinical and neuroimaging features. METHODS: Twenty-nine patients with anti-mGluR5 encephalitis (15 new cases identified in this study and 14 previously reported cases) were included in this study and their clinical features were characterized. Brain MRI volumetric analysis using FreeSurfer software was performed in 9 new patients and compared with 25 healthy controls at both early (≤6 months of onset) and chronic (>1 year of onset) disease stages. RESULTS: The common clinical manifestations of anti-mGluR5 encephalitis included cognitive deficits (n = 21, 72.4%), behavioral and mood disturbances (n = 20, 69%), seizures (n = 16, 55.2%), and sleep disorder (n = 13, 44.8%). Tumors were observed in 7 patients. Brain MRI T2/FLAIR signal hyperintensities were observed predominantly in mesiotemporal and subcortical regions in 75.9% patients. MRI volumetric analysis demonstrated significant amygdala enlargement in both early and chronic disease stages compared to healthy controls (P < 0.001). Twenty-six patients had complete or partial recovery, one remained stable, one died and one was lost to follow-up. CONCLUSION: Our findings demonstrated that cognitive impairment, behavioral disturbance, seizures, and sleep disorder are the prominent clinical manifestations of anti-mGluR5 encephalitis. Most patients showed a good prognosis with full recovery, even in the paraneoplastic disease variants. The amygdala enlargement in the early and chronic disease stages is a distinct MRI feature, which exploratively offer a valuable perspective for the study of the disease processes.

Anti-amphiphysin encephalitis: Expanding the clinical spectrum.

Objective: An analysis of the clinical features of autoimmune encephalitis accompanied by anti-amphiphysin antibodies. Methods: The data of encephalitis patients with anti-amphiphysin antibodies were retrospectively evaluated, including demographics, neurological and laboratory findings, imaging, treatment, and prognostic predictions. Results: Ten patients aged between 29 and 78 years (median age 52 years) were included. The male: female ratio was 4:6. Limbic encephalitis was found in nine patients while epileptic seizures were present in seven patients. All patients showed anti-amphiphysin antibody positivity in sera while one ninth was positive for CSF antibody. The EEG findings were abnormal, including reductions in background activity, and the presence of diffuse slow waves, sharp waves, and spikes and waves. Five patients showed signs of increased T2 signals in the medial temporal lobe on MRI while PET showed either hyper- or hypo-metabolic changes in several brain regions, including the temporal lobe, hippocampus, basal ganglia, frontal and parietal cortices. Nine of ten patients were treated with immunotherapy, with improvements of varying degrees. There was a significant reduction in seizure frequency, and all patients were seizure-free at last follow-up. Conclusion: Autoimmune encephalitis with anti-amphiphysin antibodies has a variety of clinical manifestations. The most common symptom is limbic encephalitis. Although relief from seizures can be achieved relatively easily, many patients suffer psychiatric, cognitive, and sleep sequelae. The disease was found to be associated with a lower incidence of cancer than has been previously reported for paraneoplastic neurologic syndromes.

Metabolic phenotyping of pilomotor seizures in autoimmune encephalitis.

OBJECTIVES: Ictal piloerection (IP) is an uncommon symptom in focal epilepsy and is associated with autoimmune encephalitis (AE). However, the networks involved in AE-associated IP are still unclear. To have a better understanding of IP underlying mechanisms, the current study investigated whole-brain metabolic networks for the analysis of AE-associated IP. METHODS: Patients with AE and IP diagnosed at our Institute between 2018 and 2022 were selected. We then investigated the brain regions associated with AE-associated IP using positron emission tomography (PET). Anatomometabolic changes (interictal 18 F fluorodeoxyglucose PET) in AE patients with IP were compared with those of AE patients of similar age without IP (p-voxel <0.001, uncorrected). RESULTS: Sixteen patients showed significant IP. The overall IP prevalence was 4.09% of patients with AE and 12.9% of patients with limbic encephalitis. The most common autoantibodies were against LGI1 (68.8%) followed by GAD65 (6.3%), NMDA (6.3%), GABAb (6.3%), CASPR2 (6.3%), and antibodies recognizing both GAD65 and mGLUR5 (6.3%). Most patients responded well to immunotherapy. Analysis of the imaging results at the voxel level showed that patients with IP had hypermetabolic changes in the right inferior temporal gyrus, suggesting involvement of this brain region in IP. CONCLUSIONS: Our findings indicate that IP as an uncommon AE-associated manifestations should be recognized. We observed that the metabolic pattern of IP was conspicuous in the right inferior temporal gyrus.

The prognosis of late-onset anti-N-methyl-D-aspartate receptor encephalitis in China.

OBJECTIVES: Early-onset anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) differs from late-onset anti-NMDARE regarding clinical characteristics. Until recently, research focusing on prognosis of elder adults has been scarce and showed inconsistent results. This study aims to evaluate the prognosis of late-onset anti-NMDARE in China. MATERIALS & METHODS: One hundred and twelve adults diagnosed as anti-NMDARE in four hospitals in China were reviewed retrospectively. Outcome data were assessed using modified Rankin Scale (mRS) score in short term (3 months after discharge) and long term (≥12 months after discharge). The relapse rate was also computed. Multivariable logistic regression was used to evaluate whether there are substantial differences in functional outcomes and recurrence rate across two groups. RESULTS: Of the 112 patients with anti-NMDARE, 81 (72.3%) were early-onset disease and 31 (27.7%) were late-onset disease. Of these, all had short-term follow-up and 70 completed long-term follow-up. Late-onset anti-NMDARE group showed better short-term (OR 2.70, 95% CI 1.09-6.71) and long-term prognoses (OR 10.25, 95% CI 1.90-55.15). Recurrence rates were statistically different between the groups (OR 4.25, 95% CI 1.22-14.75). CONCLUSION: The prognosis for anti-NMDARE in China was poorer for older adults relative to younger adults. The relapse rates were higher in late-onset group compared to early-onset group.

Identification of Epileptogenic and Non-epileptogenic High-Frequency Oscillations Using a Multi-Feature Convolutional Neural Network Model.

Accurately identifying epileptogenic zone (EZ) using high-frequency oscillations (HFOs) is a challenge that must be mastered to transfer HFOs into clinical use. We analyzed the ability of a convolutional neural network (CNN) model to distinguish EZ and non-EZ HFOs. Nineteen medically intractable epilepsy patients with good surgical outcomes 2 years after surgery were studied. Five-minute interictal intracranial electroencephalogram epochs of slow-wave sleep were selected randomly. Then 5 s segments of ripples (80-200 Hz) and fast ripples (FRs, 200-500 Hz) were detected automatically. The EZs and non-EZs were identified using the surgery resection range. We innovatively converted all epochs into four types of images using two scales: original waveforms, filtered waveforms, wavelet spectrum images, and smoothed pseudo Wigner-Ville distribution (SPWVD) spectrum images. Two scales were fixed and fitted scales. We then used a CNN model to classify the HFOs into EZ and non-EZ categories. As a result, 7,000 epochs of ripples and 2,000 epochs of FRs were randomly selected from the EZ and non-EZ data for analysis. Our CNN model can distinguish EZ and non-EZ HFOs successfully. Except for original ripple waveforms, the results from CNN models that are trained using fixed-scale images are significantly better than those from models trained using fitted-scale images (p < 0.05). Of the four fixed-scale transformations, the CNN based on the adjusted SPWVD (ASPWVD) produced the best accuracies (80.89 ± 1.43% and 77.85 ± 1.61% for ripples and FRs, respectively, p < 0.05). The CNN using ASPWVD transformation images is an effective deep learning method that can be used to classify EZ and non-EZ HFOs.

A Validated Nomogram That Predicts Prognosis of Autoimmune Encephalitis: A Multicenter Study in China.

The aim of this retrospective study was to derive and validate a reliable nomogram for predicting prognosis of autoimmune encephalitis (AE). A multi-center retrospective study was conducted in four hospitals in China, using a random split-sample method to allocate 173 patients into either a training (n = 126) or validation (n = 47) dataset. Demographic, radiographic and therapeutic presentation, combined with clinical features were collected. A modified Rankin Scale (mRS) at discharge was the principal outcome variable. A backward-stepwise approach based on the Akaike information criterion was used to test predictors and construct the final, parsimonious model. Multivariable analysis was conducted using logistic regression to develop a prognosis model and validate a nomogram using an independent dataset. The performance of the model was assessed using receiver operating characteristic curves and a Hosmer-Lemeshow test. The final nomogram model considered age, viral prodrome, consciousness impairment, memory dysfunction and autonomic dysfunction as predictors. Model validations displayed a good level of discrimination in the validation set: area under the Receiver operator characteristic curve = 0.72 (95% Confidence Interval: 0.56-0.88), Hosmer-Lemeshow analysis suggesting good calibration (chi-square: 10.33; p = 0.41). The proposed nomogram demonstrated considerable potential for clinical utility in prediction of prognosis in autoimmune encephalitis.

Intrinsic Brain Activity in Temporal Lobe Epilepsy With and Without Depression: Insights From EEG Microstates.

Background: Depression is the most common psychiatric comorbidity of temporal lobe epilepsy (TLE). In the recent years, studies have focused on the common pathogenesis of TLE and depression. However, few of the studies focused on the dynamic characteristics of TLE with depression. We tested the hypotheses that there exist abnormalities in microstates in patients with TLE with depression. Methods: Participants were classified into patients with TLE with depression (PDS) (n = 19) and patients with TLE without depression (nPDS) (n = 19) based upon the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). Microstate analysis was applied based on 256-channel electroencephalography (EEG) to detect the dynamic changes in whole brain. The coverage (proportion of time spent in each state), frequency of occurrence, and duration (average time of each state) were calculated. Results: Patients with PDS showed a shorter mean microstate duration with higher mean occurrence per second compared to patients with nPDS. There was no difference between the two groups in the coverage of microstate A-D. Conclusion: This is the first study to present the temporal fluctuations of EEG topography in comorbid depression in TLE using EEG microstate analysis. The temporal characteristics of the four canonical EEG microstates were significantly altered in patients with TLE suffer from comorbid depression.

CTLA4-Mediated Immunosuppression in Glioblastoma is Associated with the Infiltration of Macrophages in the Tumor Microenvironment.

PURPOSE: CTLA4, the immune checkpoint, has been widely reported to contribute to immune evasion in anti-tumor activity. The inhibitors of CTLA4 provide a novel strategy to improve the outcome of peripheral cancer, but their clinical effects are limited in glioblastoma (GBM), thus the comprehensive role of CTLA4 needs to be addressed. PATIENTS AND METHODS: A total of 471 GBM cases were enrolled in this study from 5 cohorts. In our works, the Cancer Genome Atlas (TCGA) cohort was divided into the training set, and the Chinese Glioma Genome Atlas (CGGA), REMBRANDT, and GSE84465 cohorts were divided into validation sets. Tissues from our cohort were collected for histopathologic validation. Then, the role of CTLA4 in the TME of GBM was comprehensively investigated. RESULTS: Significant differences exist in immunological characteristics between the low and high CTLA4 expression groups. Mutation analysis found different genomic patterns associated with CTLA4 expression. Next, network analysis found the module named c1-1562 including CTLA4 correlated with over survival (OS) in GBM. We also developed a predictive model to calculate the risk score for every GBM case and the risk score was independently related to OS. Furthermore, the expression of CTLA4 was positively related to the infiltration level and function of macrophage in GBM TME based on seven independent algorithms, single-cell RNA-seq data and immunohistochemistry. CONCLUSION: These findings implicate that CTLA4 could serve as a novel target for prognosis and therapy in GBM patients. CTLA4-mediated immune suppression may be attributed to the infiltration of macrophages in the tumor microenvironment.

Association Between Interictal High-Frequency Oscillations and Slow Wave in Refractory Focal Epilepsy With Good Surgical Outcome.

High-frequency oscillations (HFOs) have been proposed as a promising biomarker of the epileptogenic zone (EZ). But accurate delineation of EZ based on HFOs is still challenging. Our study compared HFOs from EZ and non-EZ on the basis of their associations with interictal slow waves, aiming at exploring a new way to localize EZ. Nineteen medically intractable epilepsy patients with good surgical outcome were included. Five minute interictal intracranial electroencephalography (EEG) epochs of slow-wave sleep were randomly selected; then ripples (80-200 Hz), fast ripples (FRs; 200-500 Hz), and slow waves (0.1-4 Hz) were automatically analyzed. The EZ and non-EZ were identified by resection range during the surgeries. We found that both ripples and FRs superimposed more frequently on slow waves in EZ than in non-EZ (P < 0.01). Although ripples preferred to occur on the down state of slow waves in both two groups, ripples in EZ tended to be closer to the down-state peak of slow wave than in non-EZ (-174 vs. -231 ms, P = 0.008). As for FR, no statistical difference was found between the two groups (P = 0.430). Additionally, slow wave-containing ripples in EZ had a steeper slope (1.7 vs. 1.5 µV/ms, P < 0.001) and wider distribution ratio (32.3 vs. 30.1%, P < 0.001) than those in the non-EZ. But for slow wave-containing FR, only a steeper slope (1.7 vs. 1.4 µV/ms, P < 0.001) was observed. Our study innovatively compared the different features of association between HFOs and slow wave in EZ and non-EZ from refractory focal epilepsy with good surgical outcome, proposing a new method to localize EZ and facilitating the surgical plan.

The Association Between Age and Prognosis in Patients Under 45 Years of Age With Anti-NMDA Receptor Encephalitis.

This study aims to evaluate the association between age and prognosis in patients with anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) under the age of 45 years. A retrospective study was conducted in patients younger than 45 years diagnosed as anti-NMDARE in four hospitals in China. Age at admission was divided into four categories: <15, 15-24, 25-34, 35-45 years. Neurological prognosis was evaluated using modified Rankin Scale. Adjusted multivariable logistic regression was used to analyze the association. The multivariable-adjusted odds ratios (95% confidence interval) of prognosis in anti-NMDARE across the categories of age were as follows: in males, 1.00 (reference), 4.76 (0.39-58.76), 13.50 (0.79-230.40), and 8.81 (0.36-218.39) (P for trend = 0.171); in females, 1.00 (reference), 7.27 (0.36-146.19), 20.08 (1.09-370.39), and 54.41 (1.60-1,849.10) (P for trend = 0.01). We concluded that the increasing age was associated with a poorer prognosis of anti-NMDARE in females but not males.

Development and validation of the Chinese version of dry eye related quality of life scale.

BACKGROUND: To develop the Chinese version of quality of life scale for dry eye patients based on the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire and to assess the reliability and validity of the developed scale. METHODS: The original IDEEL was adapted cross-culturally to Chinese language and further developed following standard procedures. A total of 100 Chinese patients diagnosed with dry eye syndrome were included to investigate the psychometric properties of the Chinese version of scale. Psychometric tests included internal consistency (Cronbach's ɑ coefficients), construct validity (exploratory factor analysis), and known-groups validity (the analysis of variance). RESULTS: The Chinese version of Dry Eye Related Quality of Life (CDERQOL) Scale contains 45 items classified into 5 domains. Good to excellent internal consistency reliability was demonstrated for all 5 domains (Cronbach's ɑ coefficients range from 0.716 to 0.913). Construct validity assessment indicated a consistent factorial structure of the CDERQOL scale with hypothesized construct, with the exception of "Dry Eye Symptom-Bother" domain. All domain scores were detected with significant difference across three severity groups of dry eye patients (P < 0.05) except for "Satisfaction with Treatment" domain, indicating good known-groups validity. CONCLUSIONS: The results indicated that the CDERQOL scale is a reliable and valid instrument for patients with dry eye syndrome among Chinese population, and could be used as a supplementary diagnostic and treatment-effectiveness measure.

BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs.

Multiple abnormalities of bone morphogenetic protein (BMPs) signaling are implicated in the process of pulmonary arterial hypertension (PAH). BMP4 plays an important role during the process of pulmonary arterial remodeling and mutant of the principle BMP4 receptor, BMP receptors II (BMPRII), is found to associate with the development of PAH. However, the likely mechanism defining the contribution of BMPRII to BMP4 mediated signaling in pulmonary arterial smooth muscle cells (PASMCs) remains comprehensively unclear. We previously found that enhanced store operated calcium entry (SOCE) and basal intracellular calcium concentration [Ca2+]i were induced by BMP4 via upregulation of TRPC1, 4 and 6 expression in PASMCs, and that BMP4 modulated TRPC channel expression through activating p38MAPK and ERK1/2 signaling pathways. In this study, BMPRII siRNA was used to knockdown BMPRII expression to investigate whether BMP4 upregulates the expression of TRPC and activating Smad1/5/8, ERK1/2 and p38MAPK pathway via BMPRII in distal PASMCs. Our results showed that knockdown of BMPRII: 1) attenuated BMP4 induced activation of P-Smad1/5/8, without altering BMP4 induced P-p38MAPK and P-ERK1/2 activation in PASMCs; 2) did not attenuate the BMP4-induced TRPC1, 4 and 6 expression; 3) did not affect BMP4-enhanced SOCE and basal [Ca2+]i. Thus, we concluded that BMP4 activated Smad1/5/8 pathway is BMPRII-dependent, while the BMP4 - ERK/p-P38 - TRPC - SOCE signaling axis are likely mediated through other receptor rather than BMPRII.

Effects of chronic exposure to cigarette smoke on canonical transient receptor potential expression in rat pulmonary arterial smooth muscle.

To clarify the possible mechanism of cigarette smoke (CS)-induced pulmonary hypertension and furthermore provide effective targets for prevention and treatment, the effects of chronic CS on rat pulmonary arterial smooth muscle in vivo and nicotine treatment on rat pulmonary arterial smooth muscle cells (PASMCs) in vitro were investigated. In this study, we demonstrated that chronic CS exposure led to rat weight loss, right ventricular hypertrophy, and pulmonary arterial remodeling. A fluorescence microscope was used to measure intracellular calcium concentration ([Ca(2+)]i) in rat distal PASMCs. Results showed that basal [Ca(2+)]i and store-operated calcium entry (SOCE) levels in PASMCs from 3- and 6-mo CS-exposed rats were markedly higher than those in cells from the unexposed control animals (the increases in 6-mo CS group were more significant than that in 3-mo group), accompanied with increased canonical transient receptor potential 1 (TRPC1) and TRPC6 expression at both mRNA and protein levels in isolated distal PA. Simultaneously, in vitro study showed that nicotine treatment (10 nM) significantly increased basal [Ca(2+)]i and SOCE and upregulated TRPC1 and TRPC6 expression in cultured rat distal PASMCs. TRPC siRNA knockdown strategies revealed that the elevations of basal [Ca(2+)]i and SOCE induced by nicotine in PASMCs were TRPC1 and TRPC6 dependent. These results suggested that chronic CS-induced changes in vascular tone and structure in PA and the development of pulmonary hypertension might be largely due to upregulation of TRPC1 and TRPC6 expression in PASMCs, in which nicotine played an important role.

Sodium tanshinone IIA sulfonate inhibits canonical transient receptor potential expression in pulmonary arterial smooth muscle from pulmonary hypertensive rats.

Danshen, the dried root of Salvia miltiorrhiza, is widely used in clinics in China for treating various diseases, including cardiovascular diseases. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA isolated as the major active component from Danshen, was recently reported to be effective in attenuating the characteristic pulmonary vascular changes associated with chronically hypoxic pulmonary hypertension (CHPH); however, the underlying detailed mechanisms are poorly understood. In this study, we investigated the effects of STS on basal intracellular Ca(2+) concentration ([Ca(2+)](i)) and store-operated Ca(2+) entry (SOCE) in distal pulmonary arterial smooth muscle cells (PASMCs) exposed to prolonged hypoxia or isolated from CHPH rats. SOCE measured by Mn(2+) quenching of Fura-2 fluorescence in PASMCs from rats exposed to chronic hypoxia (10% O(2), 21 d) was increased by 59%, and basal [Ca(2+)](i) was increased by 119%; this effect was inhibited by intraperitoneal injection of STS. These inhibitory effects of STS on hypoxic increases of SOCE and basal [Ca(2+)](i) were associated with reduced expression of canonical transient receptor potential (TRPC)1 and TRPC6 in distal pulmonary arterial smooth muscle and decreases on right ventricular pressure, right ventricular hypertrophy, and peripheral pulmonary vessel thickening. In ex vivo cultured distal PASMCs from normoxic rats, STS (0-25 µM) dose-dependently inhibited hypoxia-induced cell proliferation and migration, paralleled with attenuation in increases of basal [Ca(2+)](i), SOCE, mRNA, and protein expression of TRPC1 and TRPC6. STS also relieved right ventricular systolic pressure, right ventricular hypertrophy, and TRPC1 and TRPC6 protein expression in distal pulmonary arteries in a monocrotaline-induced rat model of pulmonary arterial hypertension. These results indicate that STS prevents pulmonary arterial hypertension development likely by inhibiting TRPC1 and TRPC6 expression, resulting in normalized basal [Ca(2+)](i) and attenuated proliferation and migration of PASMCs.