Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): contemporary advances and current controversies.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome with characteristic clinical, radiological, and pathological features, and can be effectively treated with corticosteroid-based immunotherapies. The exact pathogenesis of CLIPPERS remains unclear, and specific diagnostic biomarkers are not available. According to the 2017 diagnostic criteria, probable CLIPPERS should be considered in middle-aged patients with subacute onset of pontocerebellar symptoms and typical punctuate and curvilinear gadolinium enhancement lesions ("salt-and-pepper" appearance) located in the hindbrain (especially pons) on magnetic resonance imaging. In addition, CLIPPERS-mimics, such as central nervous system (CNS) lymphoma, and several antibody-associated autoimmune CNS diseases (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune glial fibrillary acidic protein astrocytopathy, and anti-N-methyl-D-aspartate receptor encephalitis), should be extensively excluded. The prerequisite for definite CLIPPERS is the perivascular T-cell-predominant inflammatory infiltration observed on pathological analysis. A biopsy is strongly suggested when clinical/radiological red flags are present. Most patients with CLIPPERS respond well to corticosteroids and have a good prognosis. Long-term low-dose corticosteroid maintenance therapy or corticosteroids coupled with immunosuppressants are recommended to prevent the recurrence of the syndrome. The potential progression of CLIPPERS to lymphoma has been suggested in some cases; therefore, at least 2-year clinical and radiological follow-up is essential. Here, we critically review the recent developments and provided an update on the clinical characteristics, diagnostic criteria, differential diagnoses, and therapeutic management of CLIPPERS. We also discuss the current controversies in this context that can be resolved in future research studies.

Myelin oligodendrocyte glycoprotein antibody and N-methyl-d-aspartate receptor antibody overlapping syndrome: insights from the recent case reports.

The overlapping of two or more types of neural autoantibodies in one patient has increasingly been documented in recent years. The coexistence of myelin oligodendrocyte glycoprotein (MOG) and N-methyl-d-aspartate receptor (NMDAR) antibodies is most common, which leads to a unique condition known as the MOG antibody and NMDAR antibody overlapping syndrome (MNOS). Here, we have reviewed the pathogenesis, clinical manifestations, paraclinical features, and treatment of MNOS. Forty-nine patients with MNOS were included in this study. They were young males with a median onset age of 23 years. No tumors were observed in the patients, and 24 of them reported prodromal symptoms. The most common clinical presentations were psychiatric symptoms (35/49) and seizures (25/49). Abnormalities on magnetic resonance imaging involved the brainstem (11/49), cerebellum (9/49), and parietal lobe (9/49). Most patients mostly responded to immunotherapy and had a good long-term prognosis. However, the overall recurrence rate of MNOS was higher than that of mono antibody-positive diseases. The existence of concurrent NMDAR antibodies should be suspected in patients with MOG antibody-associated disease having psychiatric symptoms, seizures, movement disorders, or autonomic dysfunction. Similarly, serum MOG antibody testing should be performed when patients with anti-NMDAR encephalitis present with atypical clinical manifestations, such as visual impairment and limb weakness, and neuroradiological findings, such as optic nerve, spinal cord, or infratentorial involvement or meningeal enhancement. Early detection of the syndrome and prompt treatment can be beneficial for these patients, and maintenance immunosuppressive therapy is recommended due to the high overall recurrence rate of the syndrome.

Anti-adenylate kinase 5 encephalitis: Clinical characteristics, diagnosis, and management of this rare entity.

The spectrum and understanding of antibody-positive autoimmune encephalitis (AE) have expanded over the past few decades. In 2007, a rare subtype of AE known as anti-adenylate kinase 5 (AK5) encephalitis, was first reported. This disease is more common in elderly males, with limbic encephalitis as the core phenotype (characterized by subacute anterograde amnesia, sometimes with psychiatric symptoms, and rarely with seizures). Brain magnetic resonance imaging typically demonstrated initial temporal lobe T2/fluid-attenuated inversion recovery hyperintensities, and subsequent atrophy. No concomitant tumors have been found yet. AK5 antibody, targeting the intracellular antigen, is a biomarker for a non-paraneoplastic T-cell autoimmunity response, and can be detected in serum and cerebrospinal fluid using tissue-based and cell-based assays. Cytotoxic T-cell-mediating neuronal injury and loss play a pivotal role in the immunopathogenesis of anti-AK5 encephalitis. Patients mostly show poor response to immunotherapy and thus a poor prognosis in the long run. Herein, we review the literature and provide updated knowledge of this less-known entity, focusing on clinical characteristics, paraclinical findings, diagnosis process, and therapeutic approaches.

Myelin oligodendrocyte glycoprotein antibody-associated disease preceding primary central nervous system lymphoma: causality or coincidence?

INTRODUCTION: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or eyes, in the absence of systemic diffusion. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a newly identified benign immune-mediated CNS inflammatory disorder with specific anti-MOG antibody seropositivity. These two seemingly unrelated nosological entities both have abundant clinical and radiological manifestations, and whether there is a potential link between them is unclear. CASE REPORT: We describe a 49-year-old man who presented progressive headache, dizziness, and unsteady gait with multifocal scattered T2 hyperintensities with contrast enhancement. The serum anti-MOG antibody test was positive, and a brain biopsy showed inflammatory infiltration. Initially, he was diagnosed with MOGAD and his condition improved after corticosteroid therapy. The patient relapsed with exacerbation of symptoms and neuroimaging showed new mass-forming lesions four months later. A second brain biopsy confirmed PCNSL. DISCUSSION: This is the first report of histologically confirmed successive MOGAD and PCNSL. Our case broadens the phenotypic spectrum of sentinel lesions in PCNSL. Though rare, PCNSL should be considered in patients diagnosed with benign CNS inflammatory disorder and responding well to steroid treatment when their clinical symptoms worsen and the imaging deteriorates. A timely biopsy is critical for accurate diagnosis and appropriate therapy.

Illuminating and Radiosensitizing Tumors with 2DG-Bound Gold-Based Nanomedicine for Targeted CT Imaging and Therapy.

Although radiotherapy is one of the most important curative treatments for cancer, its clinical application is associated with undesired therapeutic effects on normal or healthy tissues. The use of targeted agents that can simultaneously achieve therapeutic and imaging functions could constitute a potential solution. Herein, we developed 2-deoxy-d-glucose (2DG)-labeled poly(ethylene glycol) (PEG) gold nanodots (2DG-PEG-AuD) as a tumor-targeted computed tomography (CT) contrast agent and radiosensitizer. The key advantages of the design are its biocompatibility and targeted AuD with excellent sensitivity in tumor detection via avid glucose metabolism. As a consequence, CT imaging with enhanced sensitivity and remarkable radiotherapeutic efficacy could be attained. Our synthesized AuD displayed linear enhancement of CT contrast as a function of its concentration. In addition, 2DG-PEG-AuD successfully demonstrated significant augmentation of CT contrast in both in vitro cell studies and in vivo tumor-bearing mouse models. In tumor-bearing mice, 2DG-PEG-AuD showed excellent radiosensitizing functions after intravenous injection. Results from this work indicate that 2DG-PEG-AuD could greatly potentiate theranostic capabilities by providing high-resolution anatomical and functional images in a single CT scan and therapeutic capability.

An ultrasound-based radiomics model for survival prediction in patients with endometrial cancer.

PURPOSE: To establish a nomogram integrating radiomics features based on ultrasound images and clinical parameters for predicting the prognosis of patients with endometrial cancer (EC). MATERIALS AND METHODS: A total of 175 eligible patients with ECs were enrolled in our study between January 2011 and April 2018. They were divided into a training cohort (n = 122) and a validation cohort (n = 53). Least absolute shrinkage and selection operator (LASSO) regression were applied for selection of key features, and a radiomics score (rad-score) was calculated. Patients were stratified into high risk and low-risk groups according to the rad-score. Univariate and multivariable COX regression analysis was used to select independent clinical parameters for disease-free survival (DFS). A combined model based on radiomics features and clinical parameters was ultimately established, and the performance was quantified with respect to discrimination and calibration. RESULTS: Nine features were selected from 1130 features using LASSO regression in the training cohort, which yielded an area under the curve (AUC) of 0.823 and 0.792 to predict DFS in the training and validation cohorts, respectively. Patients with a higher rad-score were significantly associated with worse DFS. The combined nomogram, which was composed of clinically significant variables and radiomics features, showed a calibration and favorable performance for DFS prediction (AUC 0.893 and 0.885 in the training and validation cohorts, respectively). CONCLUSION: The combined nomogram could be used as a tool in predicting DFS and may assist individualized decision making and clinical treatment.

MS/MS molecular networking-guided in-depth profiling of triterpenoid saponins from the fruit of Eleutherococcus senticosus and their neuroprotectivity evaluation.

INTRODUCTION: Eleutherococcus senticosus fruit (ESF) is a natural health supplement resource that has been extensively applied as a tonic for the nervous system. The structures and neural bioactivities of triterpenoid saponins (TS), which are the major constituents of ESF, have not been comprehensively analyzed thus far. OBJECTIVE: We conducted a complete in-depth MS/MS molecular networking (MN)-based targeted analysis of TS from the crude extract of ESF and investigated its neuroprotective value. METHODS: An MS/MS MN-guided strategy was used to rapidly present a series of precursor ions (PIs) of TS in a compound cluster as TS-targeted information used in the discovery and characterization of TS. In addition, a prepared TS-rich fraction of ESF was assayed for its restraining effects on ß-amyloid-induced inhibition of neurite outgrowth. RESULTS: A total of 87 TS were discovered using a PI tracking strategy, 28 of which were characterized as potentially undescribed structures according to their high-resolution MS values. Furthermore, the TS-rich fraction can significantly reduce ß-amyloid-induced damage to neural networks by promoting the outgrowth of neurites and axons. CONCLUSION: Our findings reveal the richness of TS in ESF and will accelerate their application in the treatment of neurodegenerative diseases.

Phenotyping the late- and younger-onset neuronal surface antibody-mediated autoimmune encephalitis: a multicenter study.

Neuronal surface antibody-mediated autoimmune encephalitis (NSAE) occurs across a wide age range. However, few studies focused on the onset age and their related characteristics. We aimed to explore the age-dependent profile of NSAE. A total of 134 patients with a definite diagnosis of NSAE were retrospectively enrolled from 3 tertiary hospitals between July 2014 and August 2020. Demographic, clinical, therapeutic, and prognostic data were collected and compared between the late- (≥45) and younger-onset (<45) groups. The results showed that 56 (41.8%) patients were classified as late-onset NSAE, and 78 (58.2%) as younger-onset NSAE. There were more males, especially in the late-onset group (P = 0.036). Prodromal symptoms were more common in the younger-onset group (P = 0.004). Among the onset symptoms, more late-onset patients presented as seizures, while more younger-onset patients presented as psychiatric symptoms. Throughout the disease course, the late-onset patients were more likely to have memory dysfunction (P < 0.001), but less likely to have central hypoventilation (P = 0.045). The late-onset patients also had a significantly lower modified Rankin Scale score on admission (P = 0.042), required intensive care unit (ICU) admission less frequently during hospitalization (P = 0.042) and had a shorter hospital stay (P = 0.014). Our study revealed that the late- and younger-onset NSAE had a distinct spectrum of demographic features, presentations, and prognoses. More attention is needed for the younger-onset patients, given a higher disease severity on admission, more frequent requirement for ICU admission and longer length of stay.

Identification and localization of morphological feature-specific metabolites in Reynoutria multiflora roots.

Reynoutria multiflora roots are a classical herbal medicine with unique nourishing therapeutic effects. Anomalous vascular bundle (AVB) forming "cloudy brocade patterns" is a typical morphological feature of R. multiflora roots and has been empirically linked to its quality classification. However, scientific evidence, especially for AVB-specific specialised metabolites, has not been comprehensively revealed thus far. Herein, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) analysis was applied to carry out an in situ analysis of specialised metabolites distributed specifically at the AVB and cork of R. multiflora roots. To enlarge the scope of compounds by DESI detection, various solvent systems including acetone, acetonitrile, methanol, and water were used to assist in the discoveries of 40 specialised metabolites with determined localization. A series of bioactive constituents including stilbenes, flavonoids, anthraquinones, alkaloids, and naphthalenes were found specifically around the brocade patterns. Notably, phospholipids were detected from R. multiflora roots by in situ analysis for the first time and were found mainly in the phloem of AVB (PAB). This is the first study to use gradient solvent systems in DESI-MSI analysis to locate the specialised metabolites distribution. The discovery of feature-specific compounds will bridge the empirical identification to precision quality control of R. multiflora roots.

Management of epilepsy in pregnancy in eastern China: A survey from the Zhejiang association against epilepsy.

Objective: We aimed to evaluate the knowledge of the board members of the Zhejiang Association Against Epilepsy (ZAAE) regarding pregnancy of women with epilepsy (WWE), as well as their clinical practice and obstacles in the management of WWE. Methods: A cross-sectional survey was conducted among the board members of the ZAAE using a questionnaire based on the management guidelines for WWE during pregnancy in China. We recorded the demographic characteristics of the surveyed practitioners, the coincidence rate of each question, clinical practice, and the barriers encountered in managing WWE. Results: This survey showed that the average knowledge score of the surveyed practitioners was 71.02%, and the knowledge score of neurologists was higher than that of neurosurgeons. Knowledge regarding the following three aspects was relatively poor: whether WWE is associated with an increased risk of cesarean section and preterm delivery, the preferred analgesic drugs for WWE during delivery, and the time of postpartum blood concentration monitoring. After multiple linear regression analysis, the score of neurologists was correlated to the number of pregnant WWE treated each year. In addition, the biggest difficulty in the management of WWE during pregnancy is the lack of patient education and doctors training on pregnant epilepsy management. Conclusion: Our study revealed the ZAAE board members' knowledge and management status of pregnant WWE. In addition, our study identified the biggest obstacle to the management of WWE during pregnancy, and emphasized the importance of training and practice of epilepsy knowledge during pregnancy for practitioners and the significance of interdisciplinary communication.

Evaluation of CSF albumin quotient in neuronal surface antibody-associated autoimmune encephalitis.

BACKGROUND AND OBJECTIVES: Disruption of brain barriers is considered to be involved in the pathogenesis of neuronal surface antibody-associated autoimmune encephalitis (NSAE), but few studies have focused on their relationship. We aimed to explore the association between the integrity of brain barriers and clinical and paraclinical characteristics in patients with NSAE. METHODS: This retrospective study consecutively recruited patients with NSAE. The cerebrospinal fluid (CSF) / serum albumin quotient (Qalb) was used to evaluate the function of brain barriers. The data on demographic information, clinical manifestations, magnetic resonance imaging (MRI), CSF findings and prognosis were collected and analyzed. RESULTS: Of the 93 patients included, 33 (35.5%) patients were assigned to the elevated Qalb group and 60 (64.5%) patients to the normal Qalb group. Males and prodromal symptoms were more common in elevated Qalb group (both P < 0.05). The CSF white blood cell, protein, immunoglobulin G and albumin were significantly higher in elevated Qalb group (all P < 0.05). Patients with elevated Qalb were more likely to have brain lesions on MRI (60.6% versus 33.3%, P = 0.011). The modified Rankin Scale (mRS) scores at discharge and at last follow-up were significantly higher in patients with elevated Qalb than those with normal Qalb (both P < 0.05). After univariate and multivariate analyses, Qalb elevation (adjusted odds ratio = 3.96, 95% confidence interval = 1.15-13.59, P = 0.029) was demonstrated as the only independent risk factor for a poor prognosis. DISCUSSION: Males, prodromal symptoms, brain lesions on MRI, CSF pleocytosis, and elevated CSF protein were more common in NSAE patients with increased Qalb. Qalb elevation was an independent prognostic indicator for a poor prognosis in NSAE.

Detecting vulnerable carotid plaque and its component characteristics: Progress in related imaging techniques.

Carotid atherosclerotic plaque rupture and thrombosis are independent risk factors for acute ischemic cerebrovascular disease. Timely identification of vulnerable plaque can help prevent stroke and provide evidence for clinical treatment. Advanced invasive and non-invasive imaging modalities such as computed tomography, magnetic resonance imaging, intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy can be employed to image and classify carotid atherosclerotic plaques to provide clinically relevant predictors used for patient risk stratification. This study compares existing clinical imaging methods, and the advantages and limitations of different imaging techniques for identifying vulnerable carotid plaque are reviewed to effectively prevent and treat cerebrovascular diseases.

Inflammatory markers of hemogram parameters as predictive factors for disease severity in anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: This study aimed to investigate the utility of inflammatory markers of hemogram parameters as objective indicators of disease severity in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: A total of 98 patients were retrospectively reviewed. Inflammatory markers of hemogram parameters, including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio, were acquired within 24 h of admission. We then analyzed their utility as predictive factors for disease severity at different time points assessing with the modified Rankin Scale (mRS). RESULTS: There were 49 patients in the mild group (mRS ≤ 2) and 49 patients in the moderate-to-severe (mRS > 2) group at admission. The moderate-to-severe group presented more frequently with psychiatric symptoms and central hypoventilation, as well as a lower lymphocyte count, a higher neutrophil count, a higher NLR and a higher MLR (all p < 0.05) when compared with the mild group. NLR and MLR showed similar positive correlations with mRS scores (r = 0.40, r = 0.40, both p < 0.001). Further multivariate logistic regression analyses indicated that NLR > 4.232 was an independent risk factor for moderate-to-severe status at admission. Meanwhile, NLR and MLR were associated with disease severity at different stages of follow-up but showed no independent predictive value. CONCLUSION: Our findings suggested that NLR was an independent risk factor for moderate-to-severe status in the initial stage of anti-NMDAR encephalitis with a cut-off value of > 4.232.

First-line immunotherapy of neuronal surface antibody-mediated autoimmune encephalitis: Assessment of therapeutic effectiveness and cost-efficiency.

OBJECTIVE: To evaluate the therapeutic effectiveness and cost-efficiency of first-line immunotherapies on neuronal surface antibody-mediated autoimmune encephalitis (AE) based on a real-world observational study in China. METHODS: Our study retrospectively collected the clinical and paraclinical data of patients with definite neuronal surface antibody-mediated AE between July 2014 and July 2020. Regular follow-up was performed after administering standard regimens of first-line immunotherapies, including intravenous methylprednisolone (IVMP) and / or intravenous immunoglobulin (IVIG). Therapeutic effectiveness was reflected by modified Rankin Scale scores. The health resource utilization and direct medical costs were extracted to analyze the cost-efficiency. RESULTS: Among the 78 eligible patients, 48 (61.5%) were males with a median age of 40 years. More than half (56, 71.8%) were treated with combination therapy, with the rest receiving IVMP and IVIG monotherapy (both of 11, 14.1%). Related objective variables, i.e., sex, onset age, disease course, onset symptoms, antibody types, abnormal paraclinical results, disease severity, and the health insurance, showed insignificant differences on the selection of therapy. Each therapy showed similar short-term (4-week) and long-term (1-year) therapeutic effects. Yet the single or combination of IVIG had a slightly better effectiveness but higher cost than the monotherapy of IVMP. CONCLUSION: The combination of IVMP and IVIG was used more frequently than either alone, which may be associated with neurologist's personal experience and patient's wishes. Though with similar therapeutic effectiveness, the use of IVMP alone might be a better choice with a better cost-efficiency.

Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome: A state-of-the-art review.

The Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome (KLHL 11-PNS) was first identified in 2019. This novel antibody, targeting the intracellular KLHL 11 antigen, can be detected in serum and cerebrospinal fluid using tissue-based and cell-based assays. It is thought to be a biomarker for a T-cell autoimmunity response. The most likely immunopathogenesis of KLHL 11-PNS appears to be linked to cytotoxic T-cell-mediated neuronal injury and loss. Patients have adult-male predilection, rhombencephalitis (brainstem and / or cerebellar involvement), and a robust oncological correlation with testicular germ cell tumors (predominately seminoma). Brain magnetic resonance imaging demonstrated T2 / fluid-attenuated inversion recovery hyperintensities and atrophy of the temporal lobe, cerebellum, and brainstem. Most patients responded poorly to immunotherapy and oncotherapy and thus had a poor long-term prognosis. We review the literature and provide an update of current knowledge regarding KLHL 11-PNS, including epidemiology, underlying mechanism, clinical presentations, paraclinical and oncological findings, diagnostic workup, and treatment approaches.

Seizures and epilepsy in multiple sclerosis, aquaporin 4 antibody-positive neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease.

Seizure is one of the manifestations of central nervous system inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Acute symptomatic seizures secondary to MS/AQP4-NMOSD/MOGAD occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent nonprovoked seizures, mainly attributed to autoimmune-associated epilepsy, occur in the nonacute phase of the diseases. Seizures in MS/AQP4-NMOSD/MOGAD mostly have a focal onset. MS patients with concomitant systemic infections, earlier onset, and greater disease activity are more likely to have seizures, whereas factors such as greater MS severity, the presence of status epilepticus, and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis and acute disseminated encephalomyelitis (ADEM)-like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a greater seizure risk. Multiple relapses with ADEM-like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction, and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS/AQP4-NMOSD/MOGAD consists of immunotherapy along with antiseizure medications. This critical review discusses the most-updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS/AQP4-NMOSD/MOGAD. Treatment cautions including drug-drug interactions and the impact of treatments on the diseases are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions.

Case Report: Neuromyelitis Optica Spectrum Disorder With Progressive Elevation of Cerebrospinal Fluid Cell Count and Protein Level Mimicking Infectious Meningomyelitis: A Diagnostic Challenge.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated idiopathic inflammatory demyelinating disease with a typical clinical presentation of optic neuritis, acute myelitis, and area postrema syndrome. Most NMOSD patients are seropositive for disease-specific and pathogenic aquaporin-4 (AQP4) antibodies, which are key markers for the NMOSD diagnosis. Herein, we report an atypical case of a 41-year-old man who complained of intractable hiccups and vomiting at disease onset, followed by fever, headache, back pain, progressive paresthesia, and weakness of extremities later on. Magnetic resonance imaging revealed longitudinally extensive transverse myelitis. Cerebrospinal fluid analysis showed progressive increases in the white blood cell count and the protein level, which were accompanied by the deterioration of clinical manifestations. The patient was initially suspected of infectious meningomyelitis but was finally diagnosed with NMOSD. This case with distinct cerebrospinal fluid findings broadens the phenotypic spectrum of NMOSD. Furthermore, it also highlights the clinical value of AQP4 antibody test for early definitive diagnosis and proper treatment.