Voltage-gated potassium channels (VGKCs) represent a group of tetrameric signaling proteins with several functions, including modulation of neuronal excitability and neurotransmitter release. Moreover, VGKCs give a key contribution to the generation of the action potential. VGKCs are complexed with other neuronal proteins, and it is now widely known that serum autoantibodies directed against VGKCs are actually directed against the potassium channel subunits only in a minority of patients. By contrast, these autoantibodies more commonly target three proteins that are complexed with alpha-dendrotoxin-labeled potassium channels in brain extracts. These three proteins are contactin-associated protein-2 (Caspr-2), leucine-rich, glioma inactivated 1 (LGI-1)-protein and the protein Tag-1/contactin-2. Neoplasms are detected only in a minority of seropositive patients for VGKC complex-IgG and do not significantly associate with Caspr-2 or LGI-1. Among all the cancers described in association with VGKC complex-IgG, lung carcinoma, thymoma, and hematologic malignancies are the most commonly detected. We will review all the major neurological conditions associated with VGKC complex-IgG. These include Isaacs’ syndrome, Morvan syndrome, limbic encephalitis, facio-brachial dystonic seizures, chorea and other movement disorders, epilepsy, psychosis, gastrointestinal neuromuscular diseases, a subacute encephalopathy that mimics Creutzfeldt-Jakob prion disease both clinically and radiologically and autoimmune chronic pain. The vast majority of these conditions are reversible by immunotherapy, and it is becoming increasingly recognized that early diagnosis and detection of VGKC complex-IgG is critical in order to rapidly start the treatment. As a result, VGKC complex-IgG are now part of the investigation of patients with unexplained subacute onset of epilepsy, memory or cognitive problems, or peripheral nerve hyperexcitability syndromes.

Fabry disease (FD) is a rare, progressive, multisystem and highly debilitating disease. FD is an X-linked lysosome storage disorder that results in α-galactosidase A deficiency. The subsequent accumulation of glycosphingolipids is more evident in vascular endothelium and smooth-muscle cells. The resulting effect of the deposition is generalized inflammation and vasculopathy, which can also affect the central and peripheral nervous system. FD progresses with kidney dysfunction, angiokeratoma of the skin, cardiomyopathy, cerebrovascular events and neurological disorders. In the present review, the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy, cochlear nerve dysfunction, psychiatric and cognitive symptoms, autonomic dysfunction and peripheral neuropathy. Enzyme replacement therapy is also discussed in the light of its more prominent effects when administered early in life, which make it essential to diagnose FD as soon as possible.

Cryptococcal meningitis (CM) is a central nervous system infectious disease caused by Cryptococcus. It is the most common fungal infection in the central nervous system, accounting for about 48% of fungal infection. The disease occurs mainly in acquired immunodeficiency syndrome (AIDS) patients and concentrates in the immunocompromised people without AIDS. There are nearly one million new cases of CM each year, and about 70% of them died. In China, CM occurs mainly in people without AIDS and there is an increasing trend in recent years. Early diagnosis and treatment is the key to reducing morbidity and mortality associated with CM. The diagnosis mainly depends on laboratory examination such as morphological examination, fungal culture and antigen detection. History, clinical manifestation and imaging examination are the important parts of auxiliary examination. The initial combined antifungal treatment is emphasized, and the principle of fractional treatment including induction, consolidation and maintenance therapy should be followed. The high intracranial pressure must be reduced actively at the same time. In addition, it is proved that the novel immunotherapy combined with antifungal agents can improve the curative effect and limit the chance of antimicrobial resistance. Large-scale clinical trials are needed for further study.

Rupture of intracranial aneurysms is the most common cause of nontraumatic subarachnoid hemorrhage, but the intricate neuroinflammatory processes which contribute to aneurysm pathophysiology are not well-understood. Mounting evidence has implicated the complement cascade in the progression of aneurysms from their formation to rupture. In this article, we identify and review studies that have sought to determine the role of the complement system in the aneurysm pathogenesis. The studies were generally conducted by immunhistological analyses on aneurysm tissue collected intraoperatively, and multiple components of the complement cascade and its modulators were identified in specific regions of the aneurysm wall. The results of the studies suggest that the complement cascade is locally upregulated and disinhibited in the perianeurysmal environment, and that it contributes to chronic as well as acute immunological damage to the aneurysm wall. In the future, understanding the mechanisms at work in complement-mediated damage is necessary to leading the development of novel therapies.

Toll-like receptors (TLRs) are part of the innate immune system and can initiate an immune response upon exposure to harmful microorganisms. Neuronal TLRs are considered to be part of an established framework of interactions between the immune system and the nervous system, the major sensing systems in mammals. TLRs in the nervous system and neuronal TLRs are suspected to be important during inflammation and neurodegenerative diseases. The aim of this review is to offer an overview of the current knowledge about TLRs in neurodegenerative pathologies, with a focus on Parkinson’s disease. More research focusing on the role of TLRs in health and disease of the nervous system is needed and remains to be explored.

Cancer is one of the leading causes of death worldwide. Gliomas are among the most devastating tumor types, and current clinical therapies are unsatisfactory. Recent reports revealed the importance of glioma‑propagating cells in the malignancy of gliomas. These cells, also referred to as glioma stem cells (GSCs), share similarities with neural stem cells (NSCs). The Hedgehog (Hh) signaling pathway controls tissue polarity, patterning maintenance, and maintenance of NSCs during embryonic development. Aberrant activation of the Hh pathway resulting from mutation and deregulation has recently been recognized to cause tumorigenesis in a wide variety of tissues, including gliomas and GSCs. In this review, we explore the role of the Hh signaling pathway in GSCs and its potential as a therapeutic strategy.

Fabry disease (FD) is a rare, progressive, multisystem and highly debilitating disease. FD is an X-linked lysosome storage disorder that results in α-galactosidase A deficiency. The subsequent accumulation of glycosphingolipids is more evident in vascular endothelium and smooth-muscle cells. The resulting effect of the deposition is generalized inflammation and vasculopathy, which can also affect the central and peripheral nervous system. FD progresses with kidney dysfunction, angiokeratoma of the skin, cardiomyopathy, cerebrovascular events and neurological disorders. In the present review, the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy, cochlear nerve dysfunction, psychiatric and cognitive symptoms, autonomic dysfunction and peripheral neuropathy. Enzyme replacement therapy is also discussed in the light of its more prominent effects when administered early in life, which make it essential to diagnose FD as soon as possible.

Aim: The aim was to investigate the infectious conditions of Epstein-Barr virus (EBV) in patients with multiple sclerosis (MS).

Methods: Cerebrospinal fluid (CSF) of 20 patients with MS and 20 with other neurological diseases (OND) were tested with indirect immunofluorescence for anti-EBV capsid antigen (EBV-CA) immunoglobulin G (IgG), IgG affinity for anti-EBV-CA, anti-EBV-CA immunoglobulin M (IgM), anti-EBV early antigen (EBV-EA) IgG and anti-EBV nuclear antigen (EBNA) IgG. According to the pattern of antibodies in CSF, infection rates of acute, chronic, primary, recurrent, and past infections were analyzed in the two groups of patients.

Results: There were no significant differences in anti-EBV-CA, anti-EBC-EA, and anti-EBNA antigen IgG in CSF between MS and OND patients (P > 0.05). The positive rate of low affinity for anti-EBV-CA IgG in MS patients was significantly higher than that for OND patients (75% vs. 40%, P < 0.05). Furthermore, significant differences in the positive rate of anti-EBV-CA IgM were found between MS and OND patients (70% vs. 25%, P < 0.05). Of the MS patients, 75% were in an EBV acute infection state compared with 40% of OND patients (P < 0.05).

Conclusion: Acute infection of EBV closely correlates with the occurrence of MS.

Acquired isolated palatal palsy is a rare disease. It is commonly seen in children. It usually presents with acute onset nasal regurgitation of fluids, rhinolalia, and palatal asymmetry. Many causes of this disease, such as infections, trauma, tumor, and brainstem lesions, etc., have been reported. However, the most plausible explanation is immunological/ischemic damage to the affected nerve. After ruling out major potential causes of this disease, the damage is often considered to be idiopathic in nature. This disease has a benign self-limiting course with excellent recovery. In accordance with a hypothesized immunological basis for this condition, treatment with steroids results in significant improvement in its clinical features.

Myasthenia gravis (MG) is an acquired autoimmune disease affecting synaptic transmission via the neuromuscular junction mainly due to the presence of auto-antibodies targeting acetylcholine receptors. Ocular or generalized MG is clinically diagnosed when the extra-ocular muscles or other muscle groups beyond the extra-ocular muscles are involved. MG occurs in both sexes at any ages from all races but shows a wide variability in incidence and prevalence. Differences in clinical phenotypes of MG patients between West and East countries have been observed. Herein, we review the current concept on epidemiology, classification, and generalized progression in MG, mainly focusing on the differential features from mainland China.

Over the past decade the discovery of novel forms of encephalitis associated with neuronal surface antibodies had changed the paradigms for diagnosing and treating disorders that were previously mischaracterized. Recognition of clinical syndromes, consistent methods of diagnosis, and early targeted immunotherapy can lead to a favorable outcome in diseases that may be associated with significant disability or death if left untreated. Here the conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of these disorders are suggested. Furthermore, a diagnostic algorithm to detect and characterize neuronal cell surface autoantibodies is suggested and some of the caveats of serum testing are outlined. Future directions will involve the identification of novel autoantibodies, the standardization of methods to detect and characterize them, as well as evaluation of the most efficacious therapeutic strategies in patients with established diagnosis of autoimmune encephalitis.

Aim: The aim was to validate a newly developed methodology of semi-automatic image analysis to analyze microglial morphology as marker for microglial activation in ionized calcium-binding adaptor protein-1 (IBA-1) stained brain sections.

Methods: The novel method was compared to currently used analysis methods, visual characterization of activation stage and optical density measurement, in brain sections of young and aged rats that had undergone surgery or remained naïve.

Results: The cell body to cell size ratio of microglia was strongly correlated to the visual characterization activation stage. In addition, we observed specific surgery and age-related changes in cell body size, size of the dendritic processes and cell body to cell size ratio.

Conclusion: The novel analysis method provides a sensitive marker for microglial activation in the rat brain, which is quick and easy to perform and provides additional information about microglial morphology.

Several million people with chronic liver diseases (cirrhosis, hepatitis) show neurological alterations, named hepatic encephalopathy (HE) with cognitive and motor alterations that impair quality of life and reduces life span. Inflammation acts synergistically with hyperammonemia to induce cognitive and motor alterations in patients with chronic liver disease and minimal hepatic encephalopathy (MHE). Previous studies in animal models have suggested that neuroinflammation is a major player in HE. This would also be the case in patients with liver cirrhosis or hepatitis C with HE. Rats with MHE show microglial activation and neuroinflammation that is associated with cognitive impairment and hypokinesia. The anti-inflammatory drug ibuprofen reduces microglial activation and neuroinflammation and restores cognitive and motor functions in rats with MHE. Chronic hyperammonemia per se induces neuroinflammation. Both peripheral inflammation and hyperammonemia would contribute to neuroinflammation in chronic liver failure. Therefore, neuroinflammation may be a key therapeutic target to improve the cognitive and motor alterations in MHE and overt HE. Identifying new targets to reduce neuroinflammation in MHE without inducing secondary effects would serve to develop new therapeutic tools to reverse the cognitive and motor alterations in patients with HE associated with chronic liver diseases

Aim: The pathogenesis of central nervous system infections (CNSI) has not been fully understood; some studies indicated that reactive oxygen species may induce brain damage. The aim of our study was to investigate serum antioxidant status in patients with CNSI.

Methods: The serum levels of uric acid (UA), bilirubin and albumin of 548 individuals were enrolled in our study, comprising of 114 healthy controls (HC) and 434 patients with five different kinds of CNSI, which including viral meningitis and/or meningoencephalitis, cysticercosis of brain, tuberculous meningitis and/or meningoencephalitis, cryptococcus meningitis and/or meningoencephalitis, and bacterial meningitis and/or meningoencephalitis.

Results: The data suggested that there were reducing levels of oxidation state (serum UA, bilirubin and albumin) in CNSI patients when compared with HC. Likewise, similar results were observed when cohorts were divided into male and female subgroups.

Conclusion: The authors demonstrated that serum antioxidant status in patients with CNSI was lower; the reason may be due to exhaustion of antioxidant capacity. Therefore, enhancing antioxidant power and keeping oxidative stress and antioxidants in balance may be beneficial to the patients with CNSI.

Aim: The herpes simplex virus (HSV), one of the most common viruses infecting humans, is featured by a high infection rate and usually causes complex disorders difficult to diagnose and treat. Disease progression is always combined with the specific interaction between organism and environment, but genetic factors play a decisive role in most pathogenic processes. Like most human disorders, individual difference has also been involved in the pathogenesis of HSV infection. The present study aimed to screen the potential gene loci that regulates human predisposition to HSV infection.

Methods: With reference to previous studies, inbred mouse lines with significantly distinct predisposition to HSV infection were chosen for gene loci screening. Gene sites on mouse chromosome 17 associated with susceptibility to HSV infection were then identified by correlation analysis and genome-wide scanning technique.

Results: Genes affecting the vulnerability of mice to HSV infection were mapped to three regions on the 17th mouse chromosome, D17MIT51.1, D17MIT39.1 and the region between D17MIT180.1 and D17MIT184.

Conclusion: The results suggest that the mouse genetic background plays an important role in its susceptibility to HSV-1 infection, which might be regulated by multiple predisposing quantitative trait loci.

Herpes simplex encephalitis (HSE) can cause permanent injury to the brain parenchyma. As such, it is usually treated as a medical emergency for which correct immediate diagnosis and introduction of specific therapies are critical for survival and prognosis. Here, the authors review the current status of diagnosis and treatments and discuss unsolved issues surrounding therapeutic interventions. The authors also highlight the current expectations for future management of HSE.

Aim: Myasthenia gravis (MG) is a rare and heterogeneous disease for which there is no generally accepted standard of care. Thus, it is critical that MG experts develop consensus guidelines based on their practice and disease management to assist clinicians and provide advice for insurance companies, health organizations and institutional review boards.

Methods: An international treatment guidance was developed based on national guidelines established in the US, Denmark, Norway, Germany, Japan, Netherlands, United Kingdom and Europe. The RAND/UCLA appropriateness method (RAM) was applied to reach consensus among 15 worldly renowned experts and experienced clinicians.

Results: This paper introduced the RAM procedure with its principles and applications and conducted a brief review of the resulting 2016 international consensus guidance for MG in comparison to clinical experience and management of Chinese MG patients.

Conclusion: The 2016 international consensus guidance is a major contribution to the treatment and management of MG, providing an up-to-date expert consensus to assist clinicians around the world, especially those with limited experience and/or practice in countries/regions that have limited resources to develop local treatment guidelines. It is also an important contribution showing how RAM can help to develop consensus guidance for treatment of rare diseases based on scientific findings and expert experience.

Creutzfeldt-Jakob disease (CJD), which is caused by prion scrapie protein, is a rare, chronic, transmissible and fatal disease. Clinical manifestations of CJD include rapidly progressive dementia, cerebellar ataxia, visual disturbance, as well as pyramidal and extrapyramidal tract signs. Four subtypes of CJD have been reported, including sporadic, familial or genetic, iatrogenic and variant. Given the infectiousness and high mortality of the disease, it is imperative that earlier and more accurate diagnostic methods are developed. In the past years, 14-3-3 protein testing and periodic sharp wave complexes in electroencephalogram have been widely used in CJD clinical diagnosis; and the abnormal hyper-intensity in diffusion weighted imaging has also been used. Recently, there has been a focus on the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography. New findings of potential biomarkers in cerebrospinal fluid and decreases in diffusion tensor imaging measures have emerged as having an association with CJD. Magnetic resonance spectroscopy has also drawn attention as an emerging method for diagnosis. In this review, the progress in auxiliary examinations of CJD is discussed and the potential, future diagnostic methods are introduced.

Meningeal carcinomatosis (MC) is a disease that malignant tumor cells cultivate in the cerebrospinal fluid or meninges. With the development of therapy methods and new techniques, survival time of patients with tumor is prolonged, and the incidence of MC is increasing. Diagnosis is based on the evaluation of clinical manifestations, cerebrospinal fluid and neuroimaging findings. Furthermore, in recent years, the diagnostic value of the tumor-derived cell-free DNA in the cerebrospinal fluid (CSF) is promising and may improve the diagnostic yield of CSF analysis. Traditional treatments of MC include surgery, radiation therapy, systemic therapy, and intrathecal therapy. Recently, molecular targeted therapy and immunotherapy have received more and more attention. The authors review the epidemiology, pathogenesis, clinical manifestation, diagnosis and treatment of MC in solid cancer, and discuss the diagnosis and treatment options currently available as well as those under investigation.