Deep brain stimulation improves central nervous system inflammation in Parkinson's disease: Evidence and perspectives.

BACKGROUND: In Parkinson's disease (PD), inflammation may lead to the degeneration of dopaminergic (DAergic) neurons. Previous studies showed that inflammatory mediators mainly contributed to this phenomenon. On the other hand, invasive neuromodulation methods such as deep brain stimulation (DBS) have better therapeutic effects for PD. One possibility is that DBS improves PD by influencing inflammation. Therefore, we further explored the mechanisms underlying inflammatory mediators and DBS in the pathogenesis of PD. METHODS: We measured serum levels of two inflammatory markers, namely RANTES (regulated on activation, normal T cell expressed and secreted) and tumor necrosis factor-alpha (TNF-α), using Luminex assays in 109 preoperative DBS PD patients, 49 postoperative DBS PD patients, and 113 age- and sex-matched controls. The plasma protein data of the different groups were then statistically analyzed. RESULTS: RANTES (p < 0.001) and TNF-α (p = 0.005) levels differed significantly between the three groups. A strong and significant correlation between RANTES levels and Hoehn-Yahr (H-Y) stage was observed in preoperative PD patients (rs  = 0.567, p < 0.001). Significant correlations between RANTES levels and Unified Parkinson's Disease Rating Scale III (UPDRS III) score (rs1  = 0.644, p = 0.033 and rs2  = 0.620, p = 0.042) were observed in matched patients. No correlation was observed for TNF-α levels. CONCLUSION: The results of this study indicate that PD patients have a persistent inflammatory profile, possibly via recruitment of activated monocytes, macrophages, and T lymphocytes to the central nervous system (CNS). DBS was shown to have a significant therapeutic effect on PD, which may arise by improving the inflammatory environment of the central nervous system.

Predictors and prognoses of epilepsy after anti-neuronal antibody-positive autoimmune encephalitis.

PURPOSE: This study aimed to investigate the incidence and predictors of epilepsy after anti-neuronal antibody-positive autoimmune encephalitis (AIE). The clinical outcomes of patients with epilepsy after AIE were also explored. METHODS: A total of 111 AIE patients were retrospectively evaluated. Post-AIE epilepsy (PAEE) was defined as at least one unprovoked seizure occurring six or more months after discharge from hospital. RESULTS: The incidence of acute symptomatic seizures was 80.2% (89/111) in our AIE patients. Furthermore, of the 89 AIE patients with seizures, 29 (32.6%) presented with seizures as the initial symptom. Overall, 44 out of 111 AIE patients (39.6%) had unprovoked seizures after six months, meeting our definition of PAEE. The independent risk factors for PAEE incidence included an initial presentation with new-onset refractory status epilepticus (NORSE), delayed immunotherapy treatment, the complication of a lung infection during admission, the requirement for mechanical ventilation during hospitalization, parietal lesions observed in magnetic resonance imaging (MRI), and focal slow waves on electroencephalographic (EEG) monitoring. CONCLUSIONS: Early initiation of immunotherapy and lung infection treatment may reduce the risk of conversion of symptomatic seizures to chronic epilepsy in the acute phase of AIE. In general, PAEE patients could have a good prognosis if treated properly and in a timely fashion.

Clinical characteristics and outcomes of autoimmune encephalitis patients associated with anti-glutamate decarboxylase antibody 65.

OBJECTIVE: This study was to investigate the clinical characteristics and prognosis of autoimmune encephalitis (AE) associated with anti-Glutamic Acid Decarboxylase 65 (GAD65). PATIENTS AND METHODS: From Jan 2016 to Aug 2018, three patients diagnosed as anti-GAD65 AE in our hospital were retrospectively analyzed for their general demographic characteristics, clinical presentation, cerebrospinal fluid (CSF) cytology, brain imaging, EEG, treatment and prognosis. RESULTS: We found that Anti-GAD65 AE may be more common in young and middle-aged women, with initial presentations of refractory status epilepticus or cognitive decline following the disease progresses, but with less psychiatric symptoms than other types of AEs. The abnormal signals of MRI may be obvious in bilateral frontal, temporal lobe and hippocampus. CONCLUSION: The production of anti-GAD65 may have a certain latency period, and it is usually negative at the onset stage. More studies need to be performed on larger populations and further understand the potential mechanisms underlying the above clinical features of anti-GAD65 AE.

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

Although over 25 antiepileptic drugs (AEDs) have become currently available for clinical use, the incidence of epilepsy worldwide and the proportions of drug-resistant epilepsy among them are not significantly reduced during the past decades. Traditional screens for AEDs have been mainly focused on their anti-ictogenic roles, and their efficacies primarily depend on suppressing neuronal excitability or enhancing inhibitory neuronal activity, almost without the influence on the epileptogenesis or with inconsistent results from different studies. Epileptogenesis refers to the pathological process of a brain from its normal status to the alterations with the continuous prone of unprovoked spontaneous seizures after brain insults, such as stroke, traumatic brain injury, CNS infectious, and autoimmune disorders, and even some specific inherited conditions. Recently growing experimental and clinical studies have discovered the underlying mechanisms for epileptogenesis, which are multi-aspect and multistep. These findings provide us a number of interesting sites for antiepileptogenic drugs (AEGDs). AEGDs have been evidenced as significantly roles of postponing or completely blocking the development of epilepsy in experimental models. The present review will introduce potential novel candidate drug-targets for AEGDs based on the published studies.

Differential Diagnosis of Autoimmune Encephalitis from Infectious Lymphocytic Encephalitis by Analysing the Lymphocyte Subsets of Cerebrospinal Fluid.

This study is aimed at investigating the lymphocyte subsets of cerebrospinal fluid (CSF) to provide possible differential diagnostic values and better understand the pathophysiological mechanism underlying autoimmune encephalitis (AE) and infectious lymphocytic encephalitis. A series of CD markers, including CD3/4/8/20 representing different types and developmental stages of lymphocytes, were used to count the corresponding subpopulations of CSF from clinical and laboratory confirmed cases of anti-N-methyl-D-aspartate receptor AE (NMDAR-AE), herpes simplex virus encephalitis (HSVE), and tuberculous meningitis (TBM). The percentages of lymphocytes observed and the CD4 : CD8 ratios were compared between the three groups. There were no significant differences of the percentage of total lymphocytes, CD3 cells, and CD4 cells of CSF among each group. However, there were strongly statistical differences of the CD4 : CD8 ratio in CSF of each group with 0.6 : 1 in NMDAR-AE, 0.9 : 1 in HSVE, and 3.2 : 1 in TBM. The percentage of CD20 B lymphocytes in NMDAR-AE was statistically higher than that of other groups. The distinct percentages of lymphocyte subpopulations of CSF appeared to be characteristic and could potentially serve as diagnostic indicators. Further verification and research will be necessary to clarify the significance and nature of CD4 : CD8 ratios and B lymphocytes in CSF between AE and the infectious lymphocytic encephalitis.

Analysis of the reasons and costs of hospitalization for epilepsy patients in East China.

PURPOSE: This study aimed to assess the cause and cause-specific risks of hospitalization for epilepsy patients in East China. Further analysis was performed for inpatient hospitalization days, hospital mortality and costs. METHOD: This study was performed on epilepsy patients admitted to our hospital including 21 community health centers in East China from January 2011 to April 2017. Case records including patient data, length of hospitalization, reasons for admission, hospital mortality, and the costs incurred for hospitalization of epilepsy patients were reviewed. RESULTS: The three principal reasons for admission were: 1) cerebral vascular disease (CVD), 2) newly diagnosed epilepsy with unknown etiology; and 3) frequent seizures including status epilepticus. The median length of hospitalization was 13 days. The three major reasons regarding inpatient days were: 1) Parkinson's Disease (PD), 2) dementia, 3) trauma. The average hospital mortality was 14.81‰ (17/1148) with 1) lung infection (mainly pneumonia), 2) depression (deaths occurred by suicide) and 3) frequent seizures including status epilepticus being the three top reasons. The three major financial cost incurred for in-patients with epilepsy were: 1) PD, 2) arteriovenous malformation and 3) trauma. CONCLUSIONS: The most common hospitalized reasons for epilepsy patients were CVD, PD and dementia, which all were common diseases in the elderly. Consequently, the hospitalization days of these patients were longer and their financial burden was heavier. Epilepsy patients with comorbid depression should be closely monitored to prevent suicide from the onset of epilepsy.

Brain astrocytoma misdiagnosed as anti-NMDAR encephalitis: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, which is the most common type of autoimmune encephalitis, is caused by the production of autoantibodies against NMDA receptor. Anti-NMDAR encephalitis patients present with various non-specific symptoms, such as abnormal psychiatric or behaviour, speech dysfunction, cognitive dysfunction, seizures, movement disorders, decreased level of consciousness, and central hypoventilation or autonomic dysfunction. CASE PRESENTATION: A 67-year-old man presented with new-onset focal seizures. The brain magnetic resonance imaging (MRI) plain scan and enhanced scan showed abnormal signal on the proximal midline frontoparietal junction region. Anti-NMDAR antibody was detected in cerebrospinal fluid (CSF) and serum using a commercial kit (Euroimmune, Germany) by indirect immunofluorescence testing (IIFT) according to the manufacturer's instructions for twice. Both of the test results were positive in CSF and serum. The patient was diagnosed as anti-NMDAR encephalitis and then was treated repeatedly with large dose of intravenous corticosteroids and gamma globulin. Accordingly, the refractory nature of seizures in this case may be attributed to NMDAR autoantibodies. When the patient presented at the hospital for the third time, the brain MRI revealed an increase in the size of the frontal parietal lesion and one new lesion in the left basal ganglia. The patient underwent a surgical biopsy and astrocytoma was confirmed by histopathology. CONCLUSIONS: Although the sensitivity and specificity of anti-NMDAR-IgG antibodies in CSF to diagnose anti-NMDAR encephalitis are close to 100%, it is not absolute. Anti-NMDAR antibodies were positive, which might make the diagnosis more complex. The diagnosis of atypical presentation of anti-NMDAR encephalitis requires reasonable exclusion of other disorders.

Indirubin-3'-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation.

Indirubin-3'-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer's disease. Here, we found that indirubin-3'-monoxime improved the morphology and increased the survival rate of SH-SY5Y cells exposed to amyloid-beta 25-35 (Aß25-35), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3'-monoxime inhibited phosphorylation of glycogen synthase kinase-3ß (GSK-3ß). Our results suggest that indirubin-3'-monoxime reduced Aß25-35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3ß-mediated mechanism. Indirubin-3'-monoxime is a promising drug candidate for Alzheimer's disease.

Comparative study of CD4 and CD45RO T cells and CD20 B cells in cerebrospinal fluid of syphilitic meningitis and tuberculous meningitis patients.

This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p < 0.05). After medical therapy, there was a significantly decline trend of the CD4 T-cell proportion in both groups (p < 0.05). The proportion of CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p < 0.05). After medical therapy, the positive ratio of CD45RO T cells was increased in the CSF of both group patients (p < 0.05). The proportion of CD20B cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM.

A clinical survey of pain in Parkinson's disease in Eastern China.

BACKGROUND: This is a case-control study to investigate the prevalence, characteristics, and risk factors of pain in patients with Parkinson's disease (PD). METHODS: A total of 200 PD patients from eastern China were enrolled in our study. Accordingly, 200 healthy elderly adults were recruited as controls. The characteristics of pain were collected by using the Visual Analog Scale, Brief Pain Inventory (BPI), SF-36 Bodily Pain Scale, Unified Parkinson's Disease Rating Scale, Hoehn-Yahr Scale (H-Y), Hamilton Depression Scale, and Leeds Assessment of Neuropathic Symptoms and Signs. RESULTS: Of the 200 PD patients, pain was complained by 106 patients (53%). According to the SF-36 Bodily Pain Scale, pain morbidity in PD patients was significantly higher than in the control group. The average pain during last 24 h measured by the BPI was 2.67. About 76% of PD patients were found to have one pain type, 21.7% were having two pain types, and 1.9% had three pain types. Further, 69.8% of these patients were presented with musculoskeletal pain, 4.7% with dystonic pain, 22.6% with radicular-neuropathic pain, 20.8% with central neuropathic pain, and 9.4% with akathisia pain. The onset age and depression were the most significant predictors of pain in PD patients (p < 0.05). However, there was no significant association between pain and gender, age, disease duration, or severity of the disease. Only 5.7% of PD patients with pain received treatment in this study. CONCLUSIONS: Pain is frequent and disabling, independent of demographic and clinical variables, and is significantly more common in PD patients.

MELAS and Kearns-Sayre overlap syndrome due to the mtDNA m. A3243G mutation and large-scale mtDNA deletions.

This paper reported an unusual manifestation of a 19-year-old Chinese male patient presented with a complex phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome and Kearns-Sayre syndrome (KSS). He was admitted to our hospital with the chief complaint of "acute fever, headache and slow reaction for 21 days". He was initially misdiagnosed as "viral encephalitis". This Chinese man with significant past medical history of intolerating fatigue presented paroxysmal neurobehavioral attacks that started about 10 years ago. During this span, 3 or 4 attack clusters were described during which several attacks occurred over a few days. The further examination found that the hallmark signs of this patient included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy and bifascicular heart block (Wolff-Parkinson-White syndrome). By young age the disease progression is characterized by the addition of migraine, vomiting, and stroke-like episodes, symptoms of MELAS expression, which indicated completion of the MELAS/KSS overlap syndrome. The m. A3243G mitochondrial DNA mutation and single large-scale mtDNA deletions were found in this patient. This mutation has been reported with MELAS, KSS, myopathy, deafness and mental disorder with cognitive impairment. This is the first description with a MELAS/KSS syndrome in Chinese.

Plasma resistin levels and single-nucleotide polymorphisms in resistin gene 5' flanking region in patients with stroke.

OBJECTIVE: To analyze the role of resistin in insulin resistance (IR) through investigating the variation of plasma resistin levels and single-nucleotide polymorphisms (SNPs) in resistin gene 5' flanking region in stroke patients. METHODS: In 103 atherothrombotic cerebral infarction (ACI) patients, 85 lacunar infarction (LI) patients, 70 intracerebral hemorrhage (ICH) patients, and 86 healthy controls, plasma resistin and insulin levels were measured by ELISA, SNPs in resistin gene 5' flanking region were detected by PCR and direct DNA sequencing. The subjects' body height and weight, the body mass index, quantitative insulin sensitivity check index (QUICKI), blood pressure, and the concentration of fasting plasma glucose, triglyceride, total cholesterol, creatinine, low-density lipoprotein, and high-density lipoprotein were also determined. RESULTS: QUICKI was significantly lower in the ACI and ICH patients (0.316 +/- 0.037 and 0.309 +/- 0.032, respectively) than that in the controls (0.342 +/- 0.043, P < 0.001), while plasma resistin level was significantly higher in the ACI and ICH patients (6.36 +/- 3.79 and 7.15 +/- 4.27 ng/mL, respectively) than that in the controls (5.28 +/- 2.56 ng/mL, P < 0.05), but such difference was not observed in the LI patients compared with controls. There was a statistically negative correlation between plasma resistin level with QUICKI (r = -0.228, P < 0.001). The distributions of allele and genotype frequencies of resistin gene - 420C > G and - 537A > C SNPs were not significantly different among the different groups, and those SNPs were not correlated with other clinical and biochemical parameters. CONCLUSIONS: Plasma resistin is associated with stroke by participating in the development of IR. The SNPs in resistin gene 5' flanking region has no impact on the plasma resistin level.