Weihua Yu

Efficacy and Safety of Adjunctive Zonisamide in Adult Patients with Refractory Partial-Onset Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Trial

AbstractBackground and Objective: Clinical studies have reported that zonisamide is effective for a wide range of seizure types, including refractory partial-onset seizures. However, there have been no reported studies of the efficacy of zonisamide in the Chinese population to date. The aim of the present study was to evaluate the efficacy and safety of zonisamide in the treatment of adult Chinese patients with refractory partial-onset epilepsy. Methods: This was a randomized, double-blind, placebo-controlled trial conducted over a 16-week period. 104 patients with refractory partial-onset epilepsy were enrolled. Participants were randomly assigned to receive addon zonisamide or placebo. Zonisamide was titrated to a target dosage of 300 or 400 mg/day. Seizure frequency and adverse effects were documented. Results: 102 patients completed the trial. Zonisamide showed significantly greater efficacy compared with placebo (responder rate 55.8% vs 36.0%, p < 0.05), including 55.2% (16 of 29 patients) in the zonisamide 300 mg/day arm and 56.5% (13 of 23 patients) in the zonisamide 400 mg/day arm. Zonisamide 300 and 400 mg/day showed similar efficacy (p > 0.05). Moreover, similar efficacy of zonisamide was found in the control of complex partial seizures, simple partial seizures and secondary generalized seizures. There was no difference in the incidence of adverse effects between zonisamide and placebo. Reported adverse effects in the zonisamide group involved the digestive system (32.5% of total adverse effects in the group) [including transient increases in liver enzymes (27.8%)], weight changes (30.2%), the haematological system (15.1%), neurological/psychiatric effects (10.3%), the urinary system (7.9%) and the cardiovascular system (4.0%). Only digestive system adverse effects constituted a significantly higher proportion of adverse effects in the zonisamide group than in the placebo group (32.5% vs 30.2%, p < 0.05). Conclusion: Zonisamide 300–400 mg/day is effective and well tolerated as an adjunctive drug in adult Chinese patients with refractory partial-onset epilepsy.

Efficacy of Topiramate in Adult Patients with Symptomatic Epilepsy : An Open-Label, Long-Term, Retrospective Observation

AbstractBackground: Topiramate is a newer generation antiepileptic drug with a wide range of antiepileptic efficacy as monotherapy or as adjunctive therapy, and which has shown positive activity in intractable epilepsy and newly diagnosed epilepsy. Topiramate has also been shown to exert good seizure control with a low incidence of adverse effects in brain tumour-associated epilepsy. However, there have been few reports on the efficacy of topiramate in the treatment of symptomatic epilepsy of varying aetiologies Objective: The aim of the present study was to evaluate the efficacy of topiramate in the treatment of adult patients with symptomatic epilepsy of various aetiologies. Methods: This was an open-label, long-term, retrospective observation. 227 patients with symptomatic epilepsy (110 male, 117 female) were enrolled into this study. The underlying aetiologies included low-grade brain tumour, head trauma, cerebrovascular diseases, infection, diabetes mellitus, hydrocephalus and parasitosis. Topiramate was titrated up to a target dosage of 200 mg/day and maintained for at least 1 year. Response to topiramate was defined as ≥50% reduction in seizure frequency compared with baseline. Seizure free was defined as no seizure occurring during 1 year of topiramate therapy. Results: 157 (69.2%) patients were responders and 124 (54.6%) patients were seizure free with topiramate administration. Responders by subgroup included 40 patients (74.0%) with low-grade brain tumour, 32 (55.2%) with trauma, 30 (90.9%) with cerebrovascular disease, 21 (55.3%) with infection, 18 (81.8%) with diabetes, 12 (85.7%) with parasitosis and 4 (50.0%) with hydrocephalus. The percentage of seizure-free patients by subgroup was 61.0% with brain tumours, 31.0% with trauma, 78.8% with cerebrovascular disease, 44.7% with infection, 59.0% with diabetes, 85.7% with parasitosis and 50.0% with hydrocephalus. The incidence of adverse effects was 36.1%. The most commonly reported adverse effects were weight loss, memory impairments, paraesthesia, headache and dizziness; most were mild to moderate in severity and transient. Sixty-eight (30.0%) patients withdrew from topiramate treatment in this study: topiramate was discontinued in 56 patients because of lack of efficacy and in 12 patients because of adverse effects. At the end of the study, 109 patients received topiramate monotherapy, including 52 newly diagnosed patients and 57 subjects who transferred to topiramate monotherapy successfully; another 118 patients received add-on topiramate therapy. The percentage of patients responding to topiramate was 85.3% in the monotherapy group and 54.2% in the topiramate add-on therapy group; the percentage of seizure-free patients was 68.8% in the topiramate monotherapy group and 41.5% in the topiramate add-on therapy group. Conclusion: When administered either as a single drug or as an add-on drug, topiramate is effective and well tolerated in adult patients with symptomatic epilepsy of various aetiologies.

Clinical value of decreased superoxide dismutase 1 in patients with epilepsy

PURPOSE Our previous study using proteomic analysis showed that superoxide dismutase 1 (SOD1) was significantly decreased in cerebrospinal fluid (CSF) of patients with epilepsy. However, the relevance of CSF-SOD1 alterations for the pathophysiology of epilepsy is currently unknown. The present study was intended to add to our understanding of this issue by measuring SOD1 levels in the CSF of patients with resistant epilepsy and non-resistant epilepsy. METHODS A total of 52 patients with epilepsy were recruited. 29 were non-resistant, 23 drug-resistant. 20 individuals with no evidence of any neurological diseases were used as control. The concentration of CSF and serum SOD1 was measured by enzyme-linked immunosorbent assay. RESULTS The concentration of CSF-SOD1 was decreased in both the drug-resistant (0.13 ± 0.12 ng/ml) and the non-resistant epilepsy subgroups (0.29 ± 0.23 ng/ml) compared to the control group (0.40 ± 0.35 ng/ml). SOD1 was significantly lower in the drug-resistant than the non-resistant epilepsy subgroup (P<0.05). CONCLUSION SOD1 levels are decreased in the CSF of patients with epilepsy, especially of patients with intractable epilepsy. Low CSF-SOD1 levels may be a predictor of antiepileptic drug resistance in patients with epilepsy.

Expression pattern of sorting nexin 25 in temporal lobe epilepsy: A study on patients and pilocarpine-induced rats

PURPOSE The transforming growth factor β (TGF-β) signaling pathway is involved in the epileptogenesis. Sorting Nexin 25 (SNX25) has been recently proposed to modulate TGF-β signaling through endosomal sorting of TGF-β receptors for lysosomal degradation. The aim of the present study was to determine the expression pattern of SNX25 in brains of epilepsy patients and in animal model of epilepsy. METHODS We investigated the expression of SNX25 in the brain tissues of patients with temporal lobe epilepsy (TLE) and in the pilocarpine-induced rat model of epilepsy using western blotting, real-time quantitative RT-PCR, and double-label immunofluorescence. RESULTS The expression of SNX25 was significantly increased in TLE patients in comparison to controls (0.21±0.07 vs. 0.11±0.03, P<0.05). In the lithium-pilocarpine induced epileptic rats, significant elevation of SNX25 levels was detected in the chronic phase, while no SNX25 alteration occurred in the acute and latent phases. Moreover, SNX25 localized to astrocytes and neurons, in both human samples and animal models. CONCLUSION Our results indicate that upregulation of SNX25 might be involved in the development of temporal lobe epilepsy.

Long-term retention rate of topiramate as initial monotherapy in Chinese patients with newly diagnosed epilepsy: a prospective, observational study.

This is a large-sample, prospective, long-term observational study to assess the retention rate of topiramate as initial monotherapy in Chinese patients with newly diagnosed epilepsy. The retention rate was calculated by Kaplan-Meier method using intention-to-treatment analysis. Cox proportional hazard models were used to analyze the risk factors for retention rate. A total of 229 patients were enrolled into this study. The retention rate was 75.5% at 1 year, 47% at 6 years. Three risk factors for treatment failure were female gender, rural residence, and frequent seizures before treatment. Four predominant causes leading to treatment failure were: lack of efficacy (7.4%), adverse effects (10.9%), follow-up loss (15.7%), and subjective misunderstanding (8.3%). Adverse effects occurred in 129 (56.3%) patients, with 7 (3.1%) patients suffered from renal calculus. This study suggests the long-term retention rate of topiramate as initial monotherapy is high in Chinese patients. Lower initial dose, lower target dose and slower titration contribute to better tolerability. Frequent abdominal ultrasound for detecting renal calculus is necessary. Rural patients and patients with poor education level should be paid more attention by physicians to ensure continued therapy.

Chitinase1 contributed to a potential protection via microglia polarization and Aβ oligomer reduction in D-galactose and aluminum-induced rat model with cognitive impairments

Chitinase activity is increased in Alzheimers disease (AD). However, the role of chitinase1 in AD is unknown. We investigated the effects of chitinase1 on Alzheimers pathology and microglia function. Artificial chitinase1 and chitinase inhibitor (chitinase-IN-2) were used to determine the effects of chitinase1 on inflammatory factors and β-amyloid (Aβ) oligomers deposition in D-galactose/AlCl3-induced rat model with cognitive impairments. Aβ-treated N9 microglia cells were analyzed to further verify whether the changes in inflammatory factors following chitinase1 treatment were associated with microglia alternative activation. Our data displayed that the activity of chitinase1 was both improved in D-galactose/AlCl3-injected rats and Aβ-pretreated microglia. Moreover, there was an improvement in cognitive function in chitinase1-treated AD rats. Furthermore, anti-inflammation factors (Arginase 1, Arg-1, mannose receptor type C 1, MRC1/CD206) were increased and pro-inflammation factors (tumor necrosis factor alpha, TNFα, interleukin 1 beta, IL-1β) were decreased in D-galactose/AlCl3-induced AD rats with chitinase1 treatment. A higher level of M2 markers (Arg-1, MRC1/CD206) and a lower level of classic M1 markers (TNFa, IL-1β) were obtained in Aβ-pretreated N9 cells with chitinase1, suggesting that chitinase1 polarized the microglia into an anti-AD M2 phenotype. We also detected that chitnase1 could weaken the deposition of Aβ oligomers in the brain of D-galactose/ AlCl3-induced AD rats. In conclusion, Chitinase1 might exert protective effects against AD by polarizing microglia to an M2 phenotype and resisting Aβ oligomer deposition.

Time-Dependent Decrease of Clusterin as a Potential Cerebrospinal Fluid Biomarker for Drug-Resistant Epilepsy

Our previous study on proteomic analysis has shown that clusterin (CLU) is significantly decreased in the cerebrospinal fluid (CSF) of patients with epilepsy. Therefore, the present study aimed to confirm CLU concentration reduction in the CSF of patients with drug-resistant epilepsy and drug-responsive epilepsy. Fifty-two patients with epilepsy (23 drug resistance and 29 drug effectivity) and 20 control individuals were recruited. The concentrations of CSF and serum CLU were detected. Moreover, alteration of CLU was detected in the rat hippocampus over time after pilocarpine-induced status epilepticus (SE). Our results showed that human CSF-CLU levels were decreased in patients with both drug-resistant epilepsy and drug-responsive epilepsy compared to controls, and concentration of CSF-CLU was obviously lower in drug-resistant epilepsy than in drug-responsive epilepsy. In the pilocarpine-induced seizure rats, expression of neuronal CLU was gradually decreased in a time-dependent manner from acute phase to chronic phase after the onset of SE. In conclusion, CLU level is decreased in the CSF of human epilepsy and the similar alteration is confirmed in a rat model with epilepsy. Therefore, CLU might contribute to the development of epilepsy and be a potential CSF biomarker for resistant epilepsy.

Hypoxia-Up-Regulated Mitochondrial Movement Regulator Does Not Contribute to the APP/PS1 Double Transgenic Mouse Model of Alzheimer's Disease

Background/Aims: It has been demonstrated that mitochondrial dysfunction is associated with Alzheimers disease (AD); meanwhile, hypoxia-up-regulated mitochondrial movement regulator (HUMMR) plays an important role in regulating mitochondrial function. The present study aimed to confirm the association between HUMMR and mitochondrial function in AD. Methods: We detected the expression of HUMMR at transcriptional and translational levels in APP/PS1 double transgenic mice using real-time quantitative RT-PCR and Western blotting. Age- and gender-matched wild-type (WT) littermates were used as controls. Mitochondrial morphology was observed in the hippocampus and cortex of APP/PS1 double transgenic mice using transmission electron microscopy. Results: Damage to mitochondrial morphology in the hippocampus and cortex of APP/PS1 double transgenic mice was found, including swelling and cavitations. Our analysis showed no statistical differences in the expression of HUMMR between APP/PS1 double transgenic mice and WT littermates (p > 0.05). These results showed that there was no association between HUMMR and mitochondrial dysfunction in APP/PS1 transgenic mice. Conclusion: These results indicate that HUMMR does not play a key role in mitochondrial dysfunction in the APP/PS1 double transgenic AD mouse.

Increased ZAP70 Is Involved in Dry Skin Pruritus in Aged Mice

Dry skin pruritus is common in the elderly. Recent reports show that T-cell signal path is involved in dry skin pruritus. Zeta-chain-associated protein kinase 70 (ZAP70), as a T-cell receptor, may induce interleukin 2 (IL-2) secretion and promote nerve growth factor (NGF) secretion in skin. This study aimed to detect the alteration of ZAP70 in a mice model with dry skin pruritus. The C57BL mice with 5 months and 22 months were used as experimental animal. Following a 5-day period of treatment of back with a mixture of acetone-diethyl-ether-water (AEW), mice exhibited a significant increase in spontaneous scratching behavior directed to the treated back compared to control animals in which back was similarly treated with water only (W). After AEW process, spontaneous scratching in 22-month AEW mice was increased compared to 5-month AEW mice. Western blot and real-time quantitative PCR data analysis showed that ZAP70 expression was significantly increased in 22-month AEW mice compared with 5-month AEW mice. ELISA data showed that secretions of IL-2 and NGF in 22-month AEW mice were higher than 5-month AEW mice. Our results indicate that increased ZAP70 is involved in dry skin in elderly pruritus. Increased secretion of IL-2 and NGF may induce dry skin itch.

Synchronous alteration pattern between serine-threonine kinase receptor-associated protein and Smad7 in pilocarpine-induced rats of epilepsy.

Purpose: Recent studies have shown that transforming growth factor β (TGFβ) signaling participates in the epileptogenesis. Serine‐threonine kinase receptor‐associated protein (STRAP) and Smad7 synergize in the inhibition of the TGFβ signaling. The aim of the present study was to determine the expression pattern of STRAP and Smad7 in the hippocampus and temporal lobe cortex of pilocarpine‐induced rats models of epilepsy. Methods: Lithium chloride‐pilocarpine‐induced rats with status epilepticus (SE) were established. Total of 60 male Sprague‐Dawley rats was used as control (n = 10), 24 h (n = 10), 72 h (n = 10), 1 week (n = 10), 1 month (n = 10), and 2 months (n = 10) after pilocarpine‐induced SE, respectively. We detected the expression levels of STRAP and Smad7 in the hippocampus and temporal lobe cortex of rats at the aforementioned time points using western blotting and immunohistochemistry. Results: STRAP level was significantly decreased in 24 h, 72 h (acute stage), 1 week (latent stage), 1 month, 2 months (chronic stage), respectively, in the rat models compared with the control rats by using both western blotting and immunohistochemistry. Smad7 had similar reduced pattern as STRAP. Conclusions: Our results indicate that STRAP and Smad7 proteins might be involved in the development of temporal lobe epilepsy. Synapse 68:275–282, 2014.