Edaravone administration and its potential association with a new clinical syndrome in cerebral infarction patients: Three case reports.

BACKGROUND: Edaravone is a widely used treatment for patients with cerebral infarction and, in most cases, edaravone-induced side effects are mild. However, edaravone-related adverse reactions have been receiving increasing attention. CASE SUMMARY: We treated three patients with acute cerebral infarction who died following treatment with edaravone. Edaravone is a widely used treatment for patients with cerebral infarction and, in most cases, edaravone-induced side effects are mild. However, edaravone-related adverse reactions have been receiving increasing attention. CONCLUSION: Our cases highlight the importance of educating clinicians regarding the new edaravone-induced clinical syndromes of cerebral infarction as potentially fatal adverse drug reactions. Considering that no laboratory or confirmatory test exists to diagnose edaravone-induced death from cerebral infarction, clinicians' knowledge is the key element in recognizing this phenomenon.

Analysis of urgent inpatient neurologic consultations in a large tertiary hospital center: Follow-up on the effect of standardized training of residents.

BACKGROUND: Clinical neurology is difficult for young residents. To familiarize with neurological emergencies as soon as possible for young doctors, the urgent inpatient neurologic consultations were analyzed. METHODS: A retrospective study was conducted on the urgent inpatient neurologic consultations in a large tertiary hospital for 4 consecutive years. RESULTS: A total of 1437 cases were included, and the annual consultation cases gradually decreased from 573 to 257, involving 29 clinical departments. The disorders of urgent inpatient neurologic consultations were divided into three categories: neurological disorders (77.8%), non-neurological disorders (10.4%), and undiagnosed disorders (11.8%), common causes in consultation were disturbance of consciousness (36.0%), convulsions/stiffness (13.6%), limb weakness (8%), and mental disorder (5.6%). Common neurological disorders included acute cerebrovascular disease (33.6%), epilepsy/status epilepticus (15.8%), and metabolic or infectious toxic encephalopathy (14.9%). CONCLUSION: Urgent inpatient neurologic consultations involve multidisciplinary critical diseases, mainly neurological diseases. The standardized training of residents may help to rapidly improve the comprehensive diagnosis and treatment ability of young residents and is suitable for use in hospitals at all levels.

The Efficacy and Safety of Intravenous Thrombolysis in Older Chinese Patients with Acute Ischemic Stroke.

To study the efficacy and safety of intravenous thrombolysis for the older acute ischemic stroke patients, clinical data were prospectively analyzed from 168 patients with acute ischemic stroke including 42 older adult patients (ET group), 66 younger patients (NET group) treated with rt-PA, and 60 older adult patients treated without rt-PA (ENT group). Stroke severity was assessed with an NIHSS score at baseline, 1-day and 14-day after treatment. Functional outcomes were evaluated by the modified Rankin scale and a Barthel index. Adverse effects were observed during the treatment. The rate of "good" prognosis was higher in the ET group than that in the ENT group at 90 days post-stroke. In older patients with stroke, thrombolytic therapy was found to be of greater benefit to patients with lower NIHSS scores at baseline, or patients classified as posterior circulation infarction, than for patients with higher NIHSS scores or infarctions located in other brain regions. Thrombolytic therapy may exhibit long-term efficacy by improving the future quality of life for older stroke patients with fewer bleeding risk factors and lower baseline NIHSS scores.

The effect and optimal parameters of repetitive transcranial magnetic stimulation on motor recovery in stroke patients: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The primary aim of this meta-analysis was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on limb movement recovery post-stroke and cortex excitability, to explore the optimal parameters of rTMS and suitable stroke population. Second, adverse events were also included. DATA SOURCES: The databases of PubMed, EBSCO, MEDLINE, the Cochrane Central Register of Controlled Trials, EBM Reviews-Cochrane Database, the Chinese National Knowledge Infrastructure, and the Chinese Science and Technology Journals Database were searched for randomized controlled trials exploring the effects of rTMS on limb motor function recovery post-stroke before December 2018. REVIEW METHODS: The effect sizes of rTMS on limb motor recovery, the effect size of rTMS stimulation parameters, and different stroke population were summarized by calculating the standardized mean difference (SMD) and the 95% confidence interval using fixed/random effect models as appropriate. RESULTS: For the motor function assessment, 42 eligible studies involving 1168 stroke patients were identified. The summary effect size indicated that rTMS had positive effects on limb motor recovery (SMD = 0.50, P < 0.00001) and activities of daily living (SMD = 0.82, P < 0.00001), and motor-evoked potentials of the stimulated hemisphere differed according to the stimulation frequency, that is, the high-frequency group (SMD = 0.57, P = 0.0006), except the low-frequency group (SMD = -0.27, P = 0.05). No significant differences were observed among the stimulation parameter subgroups except for the sessions subgroup ( P = 0.02). Only 10 included articles reported transient mild discomfort after rTMS. CONCLUSIONS: rTMS promoted the recovery of limb motor function and changed the cortex excitability. rTMS may be better for early and pure subcortical stroke patients. Regarding different stimulation parameters, the number of stimulation sessions has an impact on the effect of rTMS.

Clinical features, long-term clinical outcomes, and prognostic factors of tuberculous meningitis in West China: a multivariate analysis of 154 adults.

BACKGROUND: Tuberculosis is prevalent in China, which is the second greatest contributor to the global tuberculosis burden. Tuberculosis meningitis (TBM) is the most severe disease form but few reports describe long-term clinical outcomes and prognostic factors. Thus, we studied these features in Chinese TBM patients. METHODS: A retrospective follow-up study was used to collect clinical features and outcomes of adult TB meningitis at the First Affiliated Hospital of Chongqing Medical University from June 2012 to August 2015. Univariate analysis and multivariate analysis were used to identify predictive factors associated with outcomes at discharge and follow-up. RESULTS: TBM patients (N = 154) were a median age of 41 years (range: 16-82 years). Median time to follow-up was 26.4 months (range: 9.3-46.5 months) and 31% had poor outcomes at follow-up and limb weakness (p = 0.016), lower GCS scores (p < 0.001), cranial-nerve palsy (p = 0.024), and hydrocephalus (p = 0.009) were closely associated with these poor outcomes. Furthermore, a high neutrophil to lymphocytes ratio, high D-dimer, a low albumin to globulin ratio and slow background of EEG associated with poor outcomes as well. CONCLUSIONS: Mortality and disability associated with TBM are high in China. Limb weakness, GCS scores, cranial-nerve palsy and hydrocephalus were independent predictors of poor outcomes, and AGR, NLR, D-dimer, and EEG abnormalities may be prognostic factors of TBM.

Systemic Family Therapy of Comorbidity of Anxiety and Depression with Epilepsy in Adolescents.

OBJECTIVE: The aim of this study was to find if systemic family therapy (SFT) does work in anxiety and depression with epilepsy in adolescents (ADAE). METHODS: 104 adolescents with epilepsy, aged 13-20 years old, were included from December 2009 to December 2010, the enrolled patients were with anxiety [Hamilton Anxiety Scale (HAMA) score ≥14 points] or depression [Hamilton Depression Scale (HAMD) score ≥20 points]. The patients were randomly divided into the control group (n=52) treated with antiepileptic drugs (AED) and the intervention group (n=52) undergone Systemic Family Therapy (SFT) as well as AED. The AED improvements, anxiety and depression scores, Social Support Rating Scale (SSRS), Family Assessment Device (FAD) and scale of systemic family dynamics (SSFD) were observed after 3-month treatment. RESULTS: The frequencies of epileptic seizures in intervention group was decreased much more significantly than the control group (4.22±3.54 times/month vs. 6.20±5.86 times/month, p=0.04); and the scores of anxiety (9.52±6.28 points vs. 13.48±8.47 points, p=0.01) and depression (13.86±9.17 points vs. 18.89±8.73 points, p=0.02) were significantly decreased than the control group; meanwhile, the family dynamics and family functions were significantly improved, and the social support was also increased (p<0.05). CONCLUSION: SFT combined with AEDs had better efficacies than AEDs alone, not only the frequency of epileptic seizures was decreased, but also the patients' anxiety and depression were improved, and the family dynamics, family functions and social support were improved.

Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy.

Studies have shown that neurofibromin (NF1) restricts GABA release at inhibitory synapses and regulates dendritic spine formation, which may play an important role in temporal lobe epilepsy (TLE). NF1 expression was detected by double-label immunofluorescence, immunohistochemistry, and western blot analysis in the brains of pilocarpine-induced epilepsy model rats at 6 h, 24 h, 72 h, 7 days, 14 days, 30 days, and 60 days after kindling. NF1 was localized primarily in the nucleus and cytoplasm of neurons. NF1 protein levels significantly increased in the chronic phase (from 7 days until 60 days) in this epileptic rat model. After NF1 expression was knocked down by specific siRNA, the effects of kindling with pilocarpine were evaluated on the 7th day after kindling. The onset latencies of pilocarpine-induced seizures were elevated, and the seizure frequency and duration were reduced in these rats. Our study demonstrates that NF1 promoted seizure attacks in rats with pilocarpine-induced epilepsy.

The Brain Activity in Brodmann Area 17: A Potential Bio-Marker to Predict Patient Responses to Antiepileptic Drugs.

In this study, we aimed to predict newly diagnosed patient responses to antiepileptic drugs (AEDs) using resting-state functional magnetic resonance imaging tools to explore changes in spontaneous brain activity. We recruited 21 newly diagnosed epileptic patients, 8 drug-resistant (DR) patients, 11 well-healed (WH) patients, and 13 healthy controls. After a 12-month follow-up, 11 newly diagnosed epileptic patients who showed a poor response to AEDs were placed into the seizures uncontrolled (SUC) group, while 10 patients were enrolled in the seizure-controlled (SC) group. By calculating the amplitude of fractional low-frequency fluctuations (fALFF) of blood oxygen level-dependent signals to measure brain activity during rest, we found that the SUC patients showed increased activity in the bilateral occipital lobe, particularly in the cuneus and lingual gyrus compared with the SC group and healthy controls. Interestingly, DR patients also showed increased activity in the identical cuneus and lingual gyrus regions, which comprise Brodmann's area 17 (BA17), compared with the SUC patients; however, these abnormalities were not observed in SC and WH patients. The receiver operating characteristic (ROC) curves indicated that the fALFF value of BA17 could differentiate SUC patients from SC patients and healthy controls with sufficient sensitivity and specificity prior to the administration of medication. Functional connectivity analysis was subsequently performed to evaluate the difference in connectivity between BA17 and other brain regions in the SUC, SC and control groups. Regions nearby the cuneus and lingual gyrus were found positive connectivity increased changes or positive connectivity changes with BA17 in the SUC patients, while remarkably negative connectivity increased changes or positive connectivity decreased changes were found in the SC patients. Additionally, default mode network (DMN) regions showed negative connectivity increased changes or negative changes with BA17 in the SUC patients. The abnormal increased in BA17 activity may be a key point that plays a substantial role in facilitating seizure onset.

The inhibitory effects of Npas4 on seizures in pilocarpine-induced epileptic rats.

To explore the effects of neuronal Per-Arnt-Sim domain protein 4 (Npas4) on seizures in pilocarpine-induced epileptic rats, Npas4 expression was detected by double-label immunofluorescence, immunohistochemistry, and Western blotting in the brains of pilocarpine-induced epileptic model rats at 6 h, 24 h, 72 h, 7 d, 14 d, 30 d, and 60 d after status epilepticus. Npas4 was localized primarily in the nucleus and in the cytoplasm of neurons. The Npas4 protein levels increased in the acute phase of seizures (between 6 h and 72 h) and decreased in the chronic phases (between 7 d and 60 d) in the rat model. Npas4 expression was knocked down by specific siRNA interference. Then, the animals were treated with pilocarpine, and the effects on seizures were evaluated on the 7th day. The onset latencies of pilocarpine-induced seizures were decreased, while the seizure frequency, duration and attack rate increased in these rats. Our study indicates that Npas4 inhibits seizure attacks in pilocarpine-induced epileptic rats.

QPEEG analysis of the effects of sodium valproate on adult Chinese patients with generalized tonic-clonic seizures.

Objectives EEG effects of the sustained-release form of sodium valproate (SR-VPA) are unknown, although it is widely used in Chinese patients with generalized tonicclonic seizures (GTCS). Methods Fourteen newly diagnosed, untreated GTCS patients were recruited and treated with SR-VPA. Waking EEG was recorded and analyzed by way of quantitative pharmaco-electroencephalogram (QPEEG) analysis during the three-month follow-up. Results There was a statistically significant decrease in the absolute power of the delta band (P < 0.05), theta band (P < 0.03) and partial alpha-1 band (p < 0.05) with treatment compared to before treatment, while there was no significantly different absolute power between one-month and three-months after treatment. There was a strong correlation between the decrease in absolute power and the degree of the initial abnormality in all frequency bands. Two of 14 patients experienced seizures during the second month after initiation of SR-VPA therapy. Conclusions SR-VPA selectively decreased the activity of the abnormal EEG synchronization in a use-dependent manner. The reduced theta, delta, and partial alpha-1 absolute power may reflect or confirm the efficacy of SR-VPA on patients with GTCS.

Generalized tonic-clonic seizures in adult patients following intravenous administration of desmopressin.

Desmopressin is a synthetic replacement for vasopressin, which is used to reduce perioperative blood loss. However, seizure attacks were observed in patients after administration of desmopressin. Here, we reported two cases of adult Chinese patients experienced generalized tonic-clonic seizures associated with severe hyponatremia caused by intravenously administered desmopressin after surgery. The patients' neurological conditions returned to baseline quickly and completely following discontinuation of desmopressin, control of the seizures, and fluid intake restriction. These cases illustrate the importance of periodic monitoring of electrolyte concentrations and fluid intake during use of desmopressin.

Outcomes of sustained-release formulation of valproate and topiramate monotherapy in patients with epilepsy: a multi-centre, cohort study.

BACKGROUND: New-generation antiepileptic drugs (AEDs) tend to replace traditional AEDs as the first-line choice for epilepsy. However, whether this change results in better outcome, especially in China, remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: Two broad spectrum AEDs, the traditional drug of sustained-release formulation of valproate (SRVPA) and the new-generation drug of topiramate, were compared in patients with epilepsy as monotherapy in this multi-centre, observational cohort study from 2000 to 2011. The primary outcome was time to treatment failure. The secondary outcomes included time to first seizure, time to 12-month remission, and time to 24-month remission. Drug tolerability was assessed. Cox proportional hazard models (95% confidence interval [CI]) were used to analyse the relative risks expressed as hazard ratios (HR). Of the 1008 recruited patients, 519 received SRVPA and 489 received topiramate. SRVPA was better than topiramate (28.3% vs. 41.5%; HR = 0.62, [95% CI 0.49-0.77]; p<0.0001) in primary outcome, and in time to first seizure (56.1% vs. 69.3%; HR = 0.73, [95% CI 0.62-0.86]; p = 0.0002). No significant difference was observed between two groups in time to 12-month remission (52.6% vs. 42.5%; HR = 1.01, [95% CI 0.84-1.23]; p = 0.88) and time to 24-month remission (34.7% vs. 25.2%; HR = 1.11, [95% CI 0.88-1.42]; p = 0.38). 36 patients (6.9%) in SRVPA group and 37 patients (7.6%) in topiramate group presented treatment failure associated with intolerable adverse events, there was no significant difference between the two groups (p = 0.70). CONCLUSIONS: The SRVPA is more suitable than topiramate for Chinese epileptic patients, and our results support the viewpoint that traditional AEDs should be the first-line choice for epilepsy rather than new-generation AEDs.

Altered expression of CX3CL1 in patients with epilepsy and in a rat model.

Chemokine C-X3-C motif ligand 1 (CX3CL1, alias fractalkine), is highly expressed in the central nervous system and participates in inflammatory responses. Recent studies indicated that inflammatory processes within the brain constitute a common and crucial mechanism in the pathophysiological characteristics of epilepsy. This study investigated the expression pattern of CX3CL1 in epilepsy and its relationship with neuronal loss. Double immunolabeling, IHC, and immunoblotting results showed that CX3CL1 expression was up-regulated in the temporal neocortex of patients with temporal lobe epilepsy. In a rat model of epilepsy, CX3CL1 up-regulation began 6 hours after epilepsy, with relatively high expression for 60 days. In addition, ELISA revealed that the concentrations of CX3CL1 in cerebrospinal fluid and serum were higher in epileptic patients than in patients with neurosis but lower than in patients with inflammatory neurological diseases. Moreover, H&E staining demonstrated significant neuronal loss in the brains of epileptic patients and in the rat model. Finally, the expression of tumor necrosis factor-related apoptosis-inducing ligand was significantly increased in both patients and the animal model, suggesting that tumor necrosis factor-related apoptosis-inducing ligand may play a role in CX3CL1-induced cell death. Thus, our results indicate that CX3CL1 may serve as a possible biomarker of brain inflammation in epileptic patients.

Down-regulation of CRMP-1 in patients with epilepsy and a rat model.

The Collapsin Response Mediator Protein-1 (CRMP-1) is a brain specific protein identified as a signaling molecule of Semaphorin-3A and act as axon repellent guidance factor in nervous system. Recent studies indicated that axon guidance molecules may play a role in synaptic reorganization in the adult brain and thereby promote epileptogenesis. This study aimed to investigate expression pattern of CRMP-1 in epileptogenesis. Using double immunofluorescence labeling, immunohistochemistry and western blot analysis, we looked into the CRMP-1 expression in temporal neocortex from patients with temporal lobe epilepsy (TLE) and histological normal temporal neocortex from the controls. We also studied the expression pattern of CRMP-1 in hippocampus and adjacent cortex of a TLE rat model on 6, 24, 72 h, 1, 2 weeks, 1 month, and 2 months post-seizure, and from control rats. CRMP-1 was mainly expressed in the neuronal cytoplasm in the temporal lobe of intractable TLE patients, which was co-expressed with -2. CRMP-1 expression was downregulated in temporal neocortical of TLE patients. In addition, in pilocarpine-induced animal model of epilepsy, CRMP-1 dynamically decreased in a range of 2 months. Thus, our results indicate that CRMP-1 may be involved in the development of TLE.

Increased placental growth factor in cerebrospinal fluid of patients with epilepsy.

Recent studies suggest that angiogenesis and vascular endothelial growth factor (VEGF) are involved in the pathophysiology of epilepsy. However, relatively little data are available linking placenta growth factor (PIGF) with epilepsy. In this study, we assessed concentrations of PIGF in cerebrospinal fluid (CSF) of 60 epileptic patients and 24 non-seizure subjects using sandwich enzyme-linked immunosorbent assays. Epileptic patients in general had higher concentration of CSF-PIGF than controls (7.95 ± 0.88 ng/l vs. 5.87 ± 0.79 ng/l, P < 0.01). CSF-PIGF level in secondary epileptic patients (8.59 ± 1.26 ng/l) was higher than that in idiopathic epileptic patients (7.62 ± 0.20 ng/l) (P < 0.05). In idiopathic epilepsy, CSF-PIGF level in patients with high seizure frequency was higher than those in patients with low seizure frequency and seizure-free in recent 3 years (7.78 ± 0.23 ng/l vs. 7.49 ± 0.09 ng/l and 7.59 ± 0.10 ng/l, P < 0.05). Concentration of CSF-PIGF in patients with a disease duration of > 5 years was higher than those in patients with durations of 1-5 years and <1 year (7.72 ± 0.20 ng/l vs. 7.52 ± 0.09 ng/l and 7.41 ± 0.07 ng/l, P < 0.05). These results indicate that preexisting brain damage, seizure frequency and disease duration are important factors contributing to elevated PIGF.

Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients.

OBJECTIVE: Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy. METHODS: The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic-clonic (n=110), partial and partial secondarily generalized (n=395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening. RESULTS: A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%--PHT, 61.5%--VPA, and 66.2%--LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n=7) discontinued the study due to rash. CONCLUSION: Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.

Epileptiform discharge upregulates p-ERK1/2, growth-associated protein 43 and synaptophysin in cultured rat hippocampal neurons.

Extracellular signal-regulated protein kinase, ERK1/2 is activated by phosphorylation (p-ERK1/2) during environmental stress such as epileptiform discharge. We investigated the role of ERK1/2 in abnormal axon growth and synapse reorganization in cultured neurons displaying epileptiform activity. The cultured neurons displaying epileptiform activity were treated with magnesium-free extracellular fluid for 3h and monitored epileptiform discharges using whole-cell patch clamp. Two study groups, neurons displaying epileptiform activity and the same neurons treated with ERK1/2 inhibitor U0126, were studied at six time points, 0 min, 30 min, 2h, 6h, 12h, and 24h following discharge. The expressions of p-ERK1/2, C-fos, growth-associated protein 43 (GAP-43) and synaptophysin (SYP), as markers of axon growth and synapse reorganization, were investigated by double-label immunofluorescence and western blotting. In the neurons displaying epileptiform activity, p-ERK1/2 was detected immediately following discharge, and expression peaked at 30 min. The expression of C-fos, GAP-43 and SYP followed the same pattern as p-ERK1/2. In the treated group, p-ERK1/2 was inhibited completely, and C-fos, GAP-43 and SYP were reduced. These findings indicate that epileptiform discharge activates ERK1/2 which regulates C-fos in cultured neurons displaying epileptiform activity, and this cascade may upregulate GAP-43 and SYP to contribute to axon growth and synapse reorganization to potentiate epileptic activities.

Enhanced synaptic vesicle traffic in hippocampus of phenytoin-resistant kindled rats.

AIM: Intractable epilepsy is characterized of seizure resistance to the anti-epileptic drugs. The underlying mechanisms are still elusive. Alterations of synaptic vesicle traffic may be one of the candidate mechanisms. METHODS: Phenytoin-resistant and phenytoin-non resistant epileptic rats were selected in the amygdala kindled adult male Wistar rats. Synaptotagmin-I and clathrin were determined by cDNA microarry analysis and Western blotting in the hippocampus of phenytoin-resistant and phenytoin-nonresistant kindled rats, which were associated with the exocytosis and endocytosis of the synaptic vesicle traffic. RESULTS: Microarry analysis showed both synaptotagmin-I and clathrin mRNA were up-regulated at least 3.06 fold accompanied with their correspondent proteins increased by 52.3 +/- 6.4 % and 76.7 +/- 12.4 % respectively in the hippocampus of phenytoin-resistant rats as compared with those in phenytoin-nonresistant rats. There were no significant differences in plasma phenytoin concentrations between the two groups. CONCLUSIONS: The increased expressions of synaptotagmin-I and clathrin in the hippocampus of phenytoin-resistant kindled rats play a role in the development of intractable epilepsy.