Yi Li, MD, PhD

All Publications

• How does foetal exposure to valproate produce adverse neurodevelopmental outcomes? Brain : a journal of neurology Meador, K. J., Li, Y. 2022

  View details for DOI 10.1093/brain/awac374

  View details for PubMedID 36220973

• Epilepsy and Pregnancy. Continuum (Minneapolis, Minn.) Li, Y., Meador, K. J. 2022; 28 (1): 34-54

  Abstract

  Seizure disorders are the most frequent major neurologic complication in pregnancy, affecting 0.3% to 0.8% of all gestations. Women of childbearing age with epilepsy require special care related to pregnancy. This article provides up-to-date information to guide practitioners in the management of epilepsy in pregnancy.Ongoing multicenter pregnancy registries and studies continue to provide important information on issues related to pregnancy in women with epilepsy. Valproate poses a special risk for malformations and cognitive/behavioral impairments. A few antiseizure medications pose low risks (eg, lamotrigine, levetiracetam), but the risks for many antiseizure medications remain uncertain. Although pregnancy rates differ, a prospective study found no difference in fertility rates between women with epilepsy who were attempting to get pregnant and healthy controls. During pregnancy, folic acid supplementation is important, and a dose greater than 400 mcg/d during early pregnancy (ie, first 12 weeks) is associated with better neurodevelopmental outcome in children of women with epilepsy. Breastfeeding is not harmful and should be encouraged in women with epilepsy even when they are on antiseizure medication treatment.Women with epilepsy should be counseled early and regularly about reproductive health. Practitioners should discuss the risks of various obstetric complications; potential anatomic teratogenicity and neurodevelopmental dysfunction related to fetal antiseizure medication exposure; and a plan of care during pregnancy, delivery, and postpartum. Women with epilepsy should also be reassured that the majority of pregnancies are uneventful.

  View details for DOI 10.1212/CON.0000000000001056

  View details for PubMedID 35133310

  View details for PubMedCentralID PMC9642109

• Precision medicine in epilepsy. Progress in molecular biology and translational science McGinn, R. J., Von Stein, E. L., Summers Stromberg, J. E., Li, Y. 2022; 190 (1): 147-188

  Abstract

  Epilepsy is a common neurological disorder affecting over 50 million people worldwide. Although more than 20 new anti-seizure medications have been developed in the past three decades, about one-third of patients still experience recurrent seizures. The heterogeneity of epilepsy types and the highly variable inter-individual response to the therapies makes disease management challenging. A precision medicine approach of treatment for epilepsy patients that considers individual patient characteristics has long been advocated. With advances in DNA sequencing technology, it has been estimated than >30% of all epilepsy syndromes have genetic components. Here we summarize recent approaches in genetic testing and current personalized treatments that are already applicable in genetic epilepsy syndromes. We also discuss current precision therapy utilized in personalized pharmacogenomics, as well as tailored treatment with neuromodulation for epilepsy patients. In the near future, we envision precision medicine in epilepsy will be applicable on a large scale involving not only targeted therapies, but also diagnosis, prognosis, and comorbidity management.

  View details for DOI 10.1016/bs.pmbts.2022.04.001

  View details for PubMedID 36007998

• Precision medicine in women with epilepsy: The challenge, systematic review, and future direction. Epilepsy & behavior : E&B Li, Y. n., Zhang, S. n., Snyder, M. P., Meador, K. J. 2021; 118: 107928

  Abstract

  Epilepsy is one of the most prevalent neurologic conditions, affecting almost 70 million people worldwide. In the United States, 1.3 million women with epilepsy (WWE) are in their active reproductive years. Women with epilepsy (WWE) face gender-specific challenges such as pregnancy, seizure exacerbation with hormonal pattern fluctuations, contraception, fertility, and menopause. Precision medicine, which applies state-of-the art molecular profiling to diagnostic, prognostic, and therapeutic problems, has the potential to advance the care of WWE by precisely tailoring individualized management to each patient's needs. For example, antiseizure medications (ASMs) are among the most common teratogens prescribed to women of childbearing potential. Teratogens act in a dose-dependent manner on a susceptible genotype. However, the genotypes at risk for ASM-induced teratogenic deficits are unknown. Here we summarize current challenging issues for WWE, review the state-of-art tools for clinical precision medicine approaches, perform a systematic review of pharmacogenomic approaches in management for WWE, and discuss potential future directions in this field. We envision a future in which precision medicine enables a new practice style that puts focus on early detection, prediction, and targeted therapies for WWE.

  View details for DOI 10.1016/j.yebeh.2021.107928

  View details for PubMedID 33774354

• Pregnancy outcomes of refractory epilepsy patients treated with Brain-responsive neurostimulation. Epilepsy research Li, Y., Eliashiv, D., LaHue, S. C., Rao, V. R., Martini, M. L., Panov, F., Oster, J. M., Yoshii-Contreras, J., Skidmore, C. T., Kalayjian, L. A., Millett, D., Meador, K. J. 2020; 169: 106532

  Abstract

  OBJECTIVE: To study the pregnancy outcomes, including obstetric complications and fetal outcomes, in pregnant women with epilepsy (WWE) treated with direct brain-responsive neurostimulation (RNS System).METHODS: Retrospective review of obstetric outcomes and fetal outcomes in WWE treated with the RNS System at nine comprehensive epilepsy centers in the United States from 2014-2020. In addition, changes in seizure frequency, anti-seizure medications, and RNS System setting adjustments during pregnancy were investigated.RESULTS: A total of 10 subjects and 14 pregnancies were identified. The mean age at conception was 30.6 ± 4.3 years old. The mean age at implantation was 29.8 ± 4.4 years old. The mean stimulation charge densities ranged from 1.0 to 3.0 muC/cm2 during pregnancy. Obstetric complications included recurrent miscarriage (1 patient), cesarean section (3 patients) due to preeclampsia, non-reassuring fetal heart rate tracing or prolonged labor, preterm birth (1 patient), and preeclampsia (1 patient). No still birth, gestational hypertension, gestational diabetes, eclampsia, or maternal mortality were observed. No RNS System-exposed pregnancies had major congenital malformations. One offspring had a minor congenital anomaly of cryptorchidism in a pregnancy complicated with risk factors of advanced maternal age and bicornuate uterus.SIGNIFICANCE: The present study is the first report of RNS System-exposed pregnancies in WWE to date. No major congenital malformations were identified. All of the obstetric complications were within the expected range of those in WWE based on previously published data. The sample size of our study is small, so accumulation of additional cases will further help depict the safety profile of treatment with the RNS System during pregnancy.

  View details for DOI 10.1016/j.eplepsyres.2020.106532

  View details for PubMedID 33360540

• Impact of high-density EEG in presurgical evaluation for refractory epilepsy patients. Clinical neurology and neurosurgery Li, Y., Fogarty, A., Razavi, B., Ardestani, P. M., Falco-Walter, J., Werbaneth, K., Graber, K., Meador, K., Fisher, R. S. 2022; 219: 107336

  Abstract

  OBJECTIVE: Electrical source localization (ESI) can help to identify the seizure onset zone or propagation zone, but it is unclear how dipole localization techniques influence surgical planning.METHODS: Patients who received a high density (HD)-EEG from 7/2014-7/2019 at Stanford were included if they met the following inclusion criteria: (1) adequate epileptiform discharges were recorded for source localization analysis, (2) underwent surgical treatment, which was at least 6 months before the survey. Interictal ESI was performed with the LORETA method on age matched MRIs. Six neurophysiologists from the Stanford Epilepsy Program independently reviewed each case through an HIPPA-protected online survey. The same cases were presented again with additional data from the HD-EEG study. Ratings of how much the HD-EEG findings added value and in what way were recorded.RESULTS: Fifty out of 202 patients met the inclusion criteria, providing a total of 276h of HDEEG recordings. All patients had video EEG recordings and at least one brain MRI, 88 % had neuropsychological testing, 78 % had either a PET or SPECT scan. Additional HD-EEG information was rated as helpful in 83.8 %, not useful in 14.4 % and misleading in 1.8 % of cases. In 20.4 % of cases the HD-EEG information altered decision-making in a major way, such as choosing a different surgical procedure, avoidance of invasive recording or suggesting placement of invasive electrodes in a lobe not previously planned. In 21.5 % of cases, HD-EEG changed the plan in a minor way, e.g., extra invasive electrodes near the previously planned sites in the same sub-lobar region. In 42.3 % cases, HD-EEG did not change their plan but provided confirmation. In cases with normal MRI, additional HD-EEG information was more likely to change physicians' decision making during presurgical process when compared to the cases with MRI-visible lesions (53.3 % vs. 34.3 %, p=0.002). Among patients achieving Engel class I/II outcome, the concordance rate of HD-EEG and resection zone was 64.7 % versus 35.3 % with class III/IV (p=0.028).CONCLUSION: HD-EEG assists presurgical planning for refractory epilepsy patients, with a higher yield in patients with non-lesional MRIs. Concordance of HD-EEG dipole analysis localization and resection site is a favorable outcome indicator.

  View details for DOI 10.1016/j.clineuro.2022.107336

  View details for PubMedID 35716454

• Antibody Prevalence in Epilepsy before Surgery (APES) in drug-resistant focal epilepsy. Epilepsia Li, Y., Tymchuk, S., Barry, J., Muppidi, S., Le, S. 2021

  Abstract

  OBJECTIVE: There is a growing recognition of immune-mediated causes in patients with focal drug-resistant epilepsy (DRE); however, they are not systematically assessed in the pre-surgical diagnostic workup. Early diagnosis and initiation of immunotherapy is associated with a favorable outcome in immune-mediated seizures. Patients with refractory focal epilepsy with neuronal antibodies (Abs) tend to have a worse surgical prognosis when compared to other etiologies.METHODS: We studied the prevalence of serum Abs in patients ≥18years of age with DRE of unknown cause before surgery. We proposed and calculated a clinical APES (Antibody Prevalence in Epilepsy before Surgery) score for each subject, which was modified based on Dubey's previously published APE2 score. RESULTS`: A total of 335 patients were screened and 86 subjects were included in final analysis. The mean age at the time of recruitment was 44.84±14.86years, with age at seizure onset 30.89±19.88years. There were no significant differences among baseline clinical features between retrospective and prospective sub-cohorts. The prevalence of at least one positive Ab was 33.72%, and central nervous system (CNS)-specific Abs was 8.14%. APES score ≥4 showed slightly better overall prediction (area under the curve [AUC]: 0.84 vs 0.74) and higher sensitivity (100% vs 71.4%), with slightly lower but similar specificity (44.3% vs 49.4%), when compared to APE2 score ≥4. For subjects who had available positron emission tomography (PET) results and all components of APES score (n=60), the sensitivity of APES score ≥4 yielded a similar prediction potential with an AUC of 0.80.SIGNIFICANCE: Our findings provide persuasive evidence that a subset of patients with focal DRE have potentially immune-mediated causes. We propose an APES score to help identify patients who may benefit from a workup for immune etiologies during the pre-surgical evaluation for focal refractory epilepsy with unknown cause.

  View details for DOI 10.1111/epi.16820

  View details for PubMedID 33464599

• Ultrasound-guided lumbar puncture improves success rate and efficiency in overweight patients. Neurology. Clinical practice Li, Y., Carandang, R. A., Ade, S., Flahive, J., Daniello, K. 2020; 10 (4): 307–13

  Abstract

  Background: Approximately 400,000 diagnostic lumbar punctures (LPs) are performed by neurologists yearly in the United States. There has been a transition from neurologists performing >40% of LPs 2 decades ago to now <15% of the time. High body mass index (BMI) is one of the key obstacles of LP for neurology residents, and the success rates drop to 58% when BMI is >35 kg/m2.Methods: A prospective intervention study was conducted from March 2017 to March 2018 at an academic medical center. Patients were divided into ultrasound-guided LP or conventional LP. The primary outcome was the success rate of LP. The secondary outcome was the parameters regarding LP performance, the patients' feedback after procedures, and the residents' feedback about the learning modules.Results: Eighty-two patients were enrolled with inclusion criteria of age >18 years, BMI ≥25 kg/m2, and able to give written informed consent. The ultrasound-guided LP group showed higher success rate (92.7% vs 68.3%, p < 0.05) and less duration of time (17.02 vs 37.63 minutes, p < 0.05) compared with the conventional LP group. It also showed advantages of decreased trials of needle insertions and redirections and reduced pain levels perceived by patients.Conclusions: This study suggests that using ultrasound to localize before LP could increase the LP success rate and improve other related LP outcomes in the overweight populations. Our study also provides evidence that brief, targeted teaching modules are feasible and effective for ultrasound-guided LP training.Classification of evidence: This study provides Class III evidence that for patients with BMI ≥25 kg/m2 undergoing LP, ultrasound guidance increases the LP success rate.

  View details for DOI 10.1212/CPJ.0000000000000725

  View details for PubMedID 32983610

• Potential use of leukocytosis and anion gap elevation in differentiating psychogenic nonepileptic seizures from epileptic seizures. Epilepsia open Li, Y., Matzka, L., Flahive, J., Weber, D. 2019; 4 (1): 210–15

  Abstract

  Epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) can be difficult to differentiate from each other in the emergency department (ED) setting. We have previously shown that the anion gap (AG) can help differentiate between ES and PNES in the ED. In this study, we explored whether additionally considering leukocytosis can help better differentiate between ES and PNES. We screened a total of 1354 subjects seen in the ED of a tertiary care medical center; 27 PNES and 27 ES patients were identified based on clinical description and subsequent electroencephalography (EEG). Multivariable logistic regression analysis was used to model the association between ES, leukocytosis, and AG. Our results indicated that within 9hours after the index event, serum AG (adjusted odds ratio [aOR]2.07) and white blood cell (WBC) count (aOR1.61) were both independently associated with ES. We derived an equation to help differentiate between ES and PNES: 1.5*AG+WBC. A score >24.8 indicated a >90% likelihood of ES. A score <15.5 indicated a <10% likelihood of ES (ie, the alternate diagnosis of PNES should be considered). This study for the first time provides evidence to help differentiate PNES and ES utilizing acidosis and leukocytosis.

  View details for PubMedID 30868134

• Left Ventricular Ejection Fraction and Clinically Defined Heart Failure to Predict 90-Day Functional Outcome After Ischemic Stroke. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Li, Y., Fitzgibbons, T. P., McManus, D. D., Goddeau, R. P., Silver, B., Henninger, N. 2018

  Abstract

  BACKGROUND: Heart failure (HF) is a risk factor for atrial fibrillation (AF), stroke, and post-stroke disability. However, differing definitions and application of HF-criteria may impact model prediction. We compared the predictive ability of left ventricular ejection fraction (LVEF), a readily available objective echocardiographic index, with clinical HF definitions for functional disability and AF in stroke patients.METHODS: We retrospectively analyzed ischemic stroke patients evaluated between January 2013 and May 2015. Outcomes of interest were: (a) 90-day functional disability (modified Rankin score 3-6) and (b) AF. We compared: (1) LVEF (continuous variable), (2) left ventricular systolic dysfunction (LVSD)-categories (absent to severe), (3) clinical history of HF, and (4) HF/LVSD-categories: (i) HF absent without LVSD, (ii) HF absent with LVSD, (iii) HF with preserved ejection fraction (HFpEF), and (iv) HF with reduced ejection fraction (HFrEF). Multivariable logistic regression was used to determine the predictive ability for 90-day disability and AF, respectively.RESULTS: Six hundred eighty five consecutive patients (44.5% female) fulfilled the study criteria and were included. After adjustment, the LVEF was independently associated with 90-day disability (OR .98, 95% CI .96-.99, P = .011) with similar predictive ability (area under the curve [AUC] = .85) to models including the LVSD-categories (AUC = .85), clinically define HF (AUC = .86), and HF/LVSD-categories (AUC = .86). The LVEF, HF, LVSD-, and HF/LVSD-categories were independently associated with AF (P < .01, each) with similar predictive ability (AUC = .74, .74, .73, and .75, respectively).CONCLUSIONS: Compared to commonly defined HF definitions, the objectively determined LVEF possesses comparable predictive ability for 90-day disability and AF in stroke patients.

  View details for DOI 10.1016/j.jstrokecerebrovasdis.2018.10.002

  View details for PubMedID 30396839

• Ephrin‑b3 modulates hippocampal neurogenesis and the reelin signaling pathway in a pilocarpine‑induced model of epilepsy. International journal of molecular medicine Liu, T. T., Li, Y., Shu, Y., Xiao, B., Feng, L. 2018; 41 (6): 3457-3467

  Abstract

  Ephrin‑B3 is important in the regulation of cell proliferation, differentiation and migration via cell‑cell contact, and can activate the reelin pathway during brain development. However, the effect of ephrin‑B3 on hippocampal neurogenesis and the reelin pathway in epilepsy remains to be fully elucidated. In the present study, the expression of ephrin‑B3 in pilocarpine‑induced status epilepticus (SE) rats was investigated. SYBR Green‑based reverse transcription‑quantitative polymerase chain reaction analysis, immunohistochemical labeling and western blot analysis were used to detect the gene and protein expression levels of ephrin‑B3 and reelin pathway proteins. Immunofluorescence staining of doublecortin (DCX) was utilized to analyze hippocampal neurogenesis. The data revealed that the mRNA and protein expression levels of ephrin‑B3 in the hippocampus decreased during the spontaneous seizure period. Of note, the expression of reelin and its downstream phosphorylation disabled 1 (p‑Dab1) were also notably decreased during the spontaneous seizure period, which showed similar dynamic changes as in the expression of ephrin‑B3. In addition, it was found that the number of DCX‑labeled neuronal progenitor cells was increased in the hippocampus following pilocarpine‑induced SE. To further clarify the role of ephrin‑B3 in neurogenesis and the reelin pathway in epilepsy, an exogenous ephrin‑B3 clustering stimulator, EphB3‑Fc, was infused into the bilateral hippocampus of the rats post‑SE. Following EphB3‑Fc injection, it was found that the expression levels of reelin and p‑Dab1 were significantly increased in the epileptic rats following EphB3‑Fc injection. The number of DCX‑labeled neuronal progenitor cells was reduced in the hippocampus of the epileptic rats. Furthermore, the intensity and frequency of spontaneous recurrent seizures and electroencephalographic seizures were attenuated in the epileptic rats post‑injection. These results demonstrated the critical role of ephrin‑B3 in regulation of the reelin pathway and hippocampal neurogenesis in epilepsy, providing experimental evidence that ephrin‑B3 functions as a potential protective factor in epilepsy, at least in animals.

  View details for DOI 10.3892/ijmm.2018.3543

  View details for PubMedID 29512697

  View details for PubMedCentralID PMC5881691

• Anion gap can differentiate between psychogenic and epileptic seizures in the emergency setting. Epilepsia Li, Y., Matzka, L., Maranda, L., Weber, D. 2017; 58 (9): e132-e135

  Abstract

  Differentiation between psychogenic nonepileptic seizures (PNES) and generalized convulsive epileptic seizures (ES) is important for appropriate triaging in the emergency department (ED). This can be difficult in the ED, as the event is often not witnessed by a medical professional. In the current study, we investigated whether anion gap (AG), bicarbonate, and the Denver Seizure Score (DSS) could differentiate between PNES and ES. Of a total of 1,354 subjects reviewed from a tertiary care medical center, 27 PNES and 27 ES patients were identified based on clinical description and subsequent electroencephalogram. Multivariate logistic regression analysis and receiver operating characteristic curves were used to determine whether there was an association between seizure type and AG, bicarbonate, or DSS (24-bicarbonate + 2 × [AG-12]) when samples were drawn within 24 h of the concerning event. The result showed that sensitivity and negative predictive value dropped markedly for all measures if samples were drawn >2 h after the event; the sensitivity was similar for AG and DSS and higher than for bicarbonate. We propose that AG > 10 (sensitivity of 81.8%, specificity of 100%) in the first 2 h after the event could be used as a potential tool in the ED to help differentiate between PNES and ES.

  View details for DOI 10.1111/epi.13840

  View details for PubMedID 28695610

• DISC1 Regulates the Proliferation and Migration of Mouse Neural Stem/Progenitor Cells through Pax5, Sox2, Dll1 and Neurog2 FRONTIERS IN CELLULAR NEUROSCIENCE Wu, Q., Tang, W., Luo, Z., Li, Y., Shu, Y., Yue, Z., Xiao, B., Feng, L. 2017; 11: 261

  Abstract

  Background: Disrupted-in-schizophrenia 1 (DISC1) regulates neurogenesis and is a genetic risk factor for major psychiatric disorders. However, how DISC1 dysfunction affects neurogenesis and cell cycle progression at the molecular level is still unknown. Here, we investigated the role of DISC1 in regulating proliferation, migration, cell cycle progression and apoptosis in mouse neural stem/progenitor cells (MNSPCs) in vitro. Methods: MNSPCs were isolated and cultured from mouse fetal hippocampi. Retroviral vectors or siRNAs were used to manipulate DISC1 expression in MNSPCs. Proliferation, migration, cell cycle progression and apoptosis of altered MNSPCs were analyzed in cell proliferation assays (MTS), transwell system and flow cytometry. A neurogenesis specific polymerase chain reaction (PCR) array was used to identify genes downstream of DISC1, and functional analysis was performed through transfection of expression plasmids and siRNAs. Results: Loss of DISC1 reduced proliferation and migration of MNSPCs, while an increase in DISC1 led to increased proliferation and migration. Meanwhile, an increase in the proportion of cells in G0/G1 phase was concomitant with reduced levels of DISC1, but significant changes were not observed in the number MNSPCs undergoing apoptosis. Paired box gene 5 (Pax5), sex determining region Y-box 2 (Sox2), delta-like1 (Dll1) and Neurogenin2 (Neurog2) emerged as candidate molecules downstream of DISC1, and rescue experiments demonstrated that increased or decreased expression of either molecule regulated proliferation and migration in DISC1-altered MNSPCs. Conclusion: These results suggest that Pax5, Sox2, Dll1 and Neurog2 mediate DISC1 activity in MNSPC proliferation and migration.

  View details for DOI 10.3389/fncel.2017.00261

  View details for Web of Science ID 000408934000001

  View details for PubMedID 28900388

  View details for PubMedCentralID PMC5581844

• EphA4 may contribute to microvessel remodeling in the hippocampal CA1 and CA3 areas in a mouse model of temporal lobe epilepsy. Molecular medicine reports Feng, L., Shu, Y., Wu, Q., Liu, T., Long, H., Yang, H., Li, Y., Xiao, B. 2017; 15 (1): 37-46

  Abstract

  Unclustered and pre-clustered ephrin-A5-Fc have identical anti-epileptic effects in the dentate gyrus of hippocampus in a mouse model of temporal lobe epilepsy (TLE), and act through alleviating ephrin receptor A4 (EphA4)‑mediated neurogenesis and angiogenesis. However, the effects of ephrin‑A5‑Fcs on EphA4 and angiogenesis in Cornu Ammonis (CA)1 and CA3 areas remain unclear. In the present study, male C57BL/6 mice underwent pilocarpine‑induced TLE. The expression of EphA4 and ephrin‑A5 proteins was analyzed by immunohistochemistry, and the mean density and diameter of platelet endothelial cell adhesion molecule‑1‑labeled microvessels in CA1 and CA3 were calculated in the absence or presence of two types of ephrin‑A5‑Fc intrahippocampal infusion. Microvessels perpendicular to the pyramidal cell layer decreased; however, microvessels that traversed the layer increased, and became distorted and fragmented. The mean densities and diameters of microvessels gradually increased and remained greater than those in the control group at 56 days post‑status epilepticus (SE). The upregulation of EphA4 and ephrin‑A5 proteins began at 7 days and was maintained until 28 days, subsequently decreasing slightly at 56 days post‑SE. Blockade of EphA4 by unclustered‑ephrin‑A5‑Fc effected a reduction in the mean density and mean diameter of microvessels in the CA1 and CA3 areas; conversely, activation of EphA4 by clustered‑ephrin‑A5‑Fc induced an increase in these values. Ephrin‑A5 ligand binding to EphA4 receptor may contribute to angiogenesis during epileptogenesis in the hippocampal CA1 and CA3 areas.

  View details for DOI 10.3892/mmr.2016.6017

  View details for PubMedID 27959424

  View details for PubMedCentralID PMC5355650

• Epilepsy with temporal encephalocele: Characteristics of electrocorticography and surgical outcome. Epilepsia Panov, F., Li, Y., Chang, E. F., Knowlton, R., Cornes, S. B. 2016; 57 (2): e33-8

  Abstract

  Temporal lobe encephaloceles (TEs) are increasingly identified in patients with epilepsy due to advances in neuroimaging. Select patients become seizure-free with lesionectomy. In practice, however, many of these patients will undergo standard anterior temporal lobectomy. Herein we report on the first series of patients with refractory temporal lobe epilepsy (TLE) with encephalocele to undergo chronic or intraoperative electrocorticography (ECoG) in order to characterize the putative epileptogenic nature of these lesions and help guide surgical planning. This retrospective study includes nine adult patients with magnetic resonance imaging/computed tomography (MRI/CT)-defined temporal encephalocele treated between 2007 and 2014 at University of California San Francisco (UCSF). Clinical features, ECoG, imaging, and surgical outcomes are reviewed. Six patients underwent resective epilepsy surgery. Each case demonstrated abnormal epileptiform discharges around the cortical area of the encephalocele. Two underwent tailored lesionectomy and four underwent lesionectomy plus anterior medial temporal resection. Postoperatively, five patients, including both with lesionectomy only, had Engel class Ia surgical outcome, and one had a class IIb surgical outcome. The role of TE in the pathogenesis of epilepsy is uncertain. ECoG can confirm the presence of interictal epileptiform discharges and seizures arising from these lesions. Patients overall had a very good surgical prognosis, even with selective surgical approaches.

  View details for DOI 10.1111/epi.13271

  View details for PubMedID 26682848

• The Ephrin-A5/EphA4 Interaction Modulates Neurogenesis and Angiogenesis by the p-Akt and p-ERK Pathways in a Mouse Model of TLE. Molecular neurobiology Shu, Y., Xiao, B., Wu, Q., Liu, T., Du, Y., Tang, H., Chen, S., Feng, L., Long, L., Li, Y. 2016; 53 (1): 561-576

  Abstract

  Studies have shown that neurogenesis and angiogenesis do exist in temporal lobe epilepsy (TLE). The ephrin ligands and Eph receptors are the largest members of receptor tyrosine kinases, and their interaction via cell-cell contact participates in cell proliferation, differentiation, migration, and tissue remodeling. However, there is little information about the function of the ephrin-A5/EphA4 complex in TLE. In the current study, we found that ephrin-A5 was expressed in astrocytes, while EphA4 existed in endothelial cells in the hippocampus in a mouse model of TLE. Furthermore, the messenger RNA (mRNA) and protein levels of both ephrin-A5 and EphA4 and the binding capacity of ephrin-A5/EphA4 showed gradual increase in spatiotemporal course. When ephrin-A5-Fc was injected into the hippocampus at 3 days post-status epilepticus (SE) for 7 days, the spontaneous recurrent seizure (SRS) frequency and intensity of the mice attenuated in the following 2 weeks. Furthermore, doublecortin-positive neuronal progenitor cells were reduced in the subgranular zone, and the density of microvessels decreased in the hilus. The molecular mechanism was attributed to ephrin-A5-Fc-induced inhibition of phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt), and also EphA4 and VEGF reduction. In summary, interaction between ephrin-A5 and EphA4 could mediate the ERK and Akt signaling pathways in pilocarpine-induced epilepsy, and intervention of the ephrin/Eph interaction may play an essential role in the suppression of newborn neuron generation, microvessel remodeling, and SRS in a mouse model of TLE. The ephrin-A5/EphA4 communication may provide a potential therapy for the treatment of TLE.

  View details for DOI 10.1007/s12035-014-9020-2

  View details for PubMedID 25502292

• Electroencephalography of Seizure-Like Movements During General Anesthesia with Propofol: Seizures or Nonepileptic Events? A & A case reports Li, Y., Flood, P., Cornes, S. 2015; 5 (11): 195-198

  Abstract

  Seizure-like behavior is an uncommon yet worrisome phenomenon during anesthesia with propofol. The current case report describes a 23-year-old man admitted for elective surgery who experienced several seizure-like episodes after induction with propofol and during a desflurane-based general anesthetic that were so severe it was not possible to complete the procedure. A second surgery was rescheduled 2 days later with simultaneous scalp electroencephalographic (EEG) recording and general anesthesia with propofol and fentanyl. During the second operation, he again experienced numerous episodes of generalized shaking movements. Simultaneous intraoperative EEG recording showed a background of diffuse beta and alpha frequencies interspersed with periods of pseudoperiodic delta activity; electrographic seizures were not apparent. With this information, muscle relaxants were given and the procedure was performed without difficulty. This is the first report of apparent seizure-like activity during anesthesia with propofol of an otherwise relatively healthy adult, in which concurrent EEG recording demonstrates the nonepileptic nature. The current case demonstrates that, at least in some instances, these concerning movements are not seizure related. Concurrent EEG monitoring may be helpful to evaluate the nature of the episodes in select cases.

  View details for DOI 10.1213/XAA.0000000000000212

  View details for PubMedID 26588032

• NDEL1 was decreased in the CA3 region but increased in the hippocampal blood vessel network during the spontaneous seizure period after pilocarpine-induced status epilepticus. Neuroscience Wu, Q., Li, Y., Shu, Y., Feng, L., Zhou, L., Yue, Z. W., Luo, Z. H., Wu, Z. G., Xiao, B. 2014; 268: 276-83

  Abstract

  Nuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1). Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In present study, we first investigated the expression of NDEL1 and its binding protein DISC1 after pilocarpine-induced epilepsy in male C57BL/6 mice. Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole hippocampus increased during the spontaneous seizure period after status epilepticus (SE). Interestingly, however, the expression of NDEL1 was decreased in the cornu ammonis 3 (CA3) and dentate gyrus (DG) regions. Moreover, SE also increased the number of blood vessels that fed the CA3 and DG regions of the hippocampus and increased the incidence of abnormalities in capillary network formation where NDEL1 protein was expressed positively. Meanwhile, the expression of phosphorylated ERK (p-ERK) was also increased during the spontaneous seizure period, with a similar expression pattern as NDEL1 and DISC1. Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE.

  View details for DOI 10.1016/j.neuroscience.2014.03.030

  View details for PubMedID 24680936

• Altered expression of pannexin proteins in patients with temporal lobe epilepsy. Molecular medicine reports Jiang, T., Long, H., Ma, Y., Long, L., Li, Y., Li, F., Zhou, P., Yuan, C., Xiao, B. 2013; 8 (6): 1801-6

  Abstract

  The aim of the present study was to investigate the expression of the pannexin (Panx) proteins, Panx1 and Panx2, in the temporal lobe tissue of patients with temporal lobe epilepsy (TLE). Immunohistochemistry and western blotting methods were used to localize and quantify Panx1 and Panx2 in the surgically removed brain tissue of patients with TLE (n=37). The results were then compared with non-epileptogenic controls (n=9). Panx1 and Panx2 expression was detected in the temporal lobe cortex of patients with TLE and in the control tissues. Panx1 and Panx2 proteins were expressed in all layers of the epileptic cortex, but predominantly in layers II and III of the cortex in the control group. Panx1 protein expression was significantly higher in the temporal lobe cortex of the patients with TLE than in the controls (P<0.05; t-test); however, no significant differences were identified in the Panx2 expression levels between the patients and the controls (P>0.05; t-test). The expression of the two Panx proteins in the tissue layers of the epileptic cortex varied in the patients and controls. The results indicate that Panx channels may be involved in the pathogenesis of TLE.

  View details for DOI 10.3892/mmr.2013.1739

  View details for PubMedID 24146091

• DISC1-related signaling pathways in adult neurogenesis of the hippocampus. Gene Wu, Q., Li, Y., Xiao, B. 2013; 518 (2): 223-30

  Abstract

  Disrupted-in-schizophrenia 1 (DISC1) is a multifunctional scaffold protein which plays an important role in neurogenesis and neural development in the adult brain, especially in the dentate gyrus (DG) of the hippocampus. Accumulated research has unveiled the role of DISC1 in several aspects of neural development and neurogenesis, such as neuronal maturation, proliferation, migration, positioning, differentiation, dendritic growth, axonal outgrowth, and synaptic plasticity. Studies on the function of this protein have explored multiple facets, including variants and missense mutants in genetics, proteins interactivity and signaling pathways in molecular biology, and pathogenesis and treatment targets of major mental illness, and more. In this review, we present several signaling pathways discussed in recent research, such as the AKT signaling pathway, GABA signaling pathway, GSK3β signaling pathway, Wnt signaling pathway, and NMDA-R signaling pathway. DISC1 interacts, directly or indirectly, with these signaling pathways and they co-regulate the process of adult neurogenesis in the hippocampus.

  View details for DOI 10.1016/j.gene.2013.01.015

  View details for PubMedID 23353011

• The increased expression of CD21 on AchR specified B cells in patients with myasthenia gravis JOURNAL OF NEUROIMMUNOLOGY Yin, W., Allman, W., Ouyang, S., Li, Y., Li, J., Christadoss, P., Yang, H. 2013; 256 (1-2): 49–54

  Abstract

  CD21, a major complement receptor expressed on B cells, is associated with autoimmune disorders. In the present study, we investigated the role of CD21 in pathogenesis of myasthenia gravis (MG) in relationship to anti-acetylcholine receptor (AchR) IgG (anti-AchR IgG) secretion. We detected increased surface expression of CD21 on AchR specified B cells as well as decreased surface expression of CD21 on total B cells in peripheral blood of patients with generalized MG (gMG). In addition, the serum concentrations of soluble secreted CD21 (sCD21) were decreased in patients with gMG. We also found that the level of CD21(+) AchR specified B cells correlated positively with serum anti-AchR IgG level, while the serum concentration of soluble CD21 correlated negatively with serum anti-AchR IgG level. Our data suggests that CD21 might facilitate its function on AchR specified B cell activation, resulting in the secretion of anti-AchR IgG.

  View details for DOI 10.1016/j.jneuroim.2012.11.003

  View details for Web of Science ID 000316507100008

  View details for PubMedID 23266128

• Immature Dendritic Cell-Derived Exosomes: a Promise Subcellular Vaccine for Autoimmunity INFLAMMATION Yin, W., Ouyang, S., Li, Y., Xiao, B., Yang, H. 2013; 36 (1): 232–40

  Abstract

  Exosomes, 60-90-nm-sized vesicles, are produced by a large number of cell types, including tumor cells, neurons, astrocytes, hemocytes, intestinal epithelial cells, and so on. Dendritic cell (DC), the most potent professional antigen-presenting cell in the immune system, produces exosomes in the course of maturation. Mature DCs produce exosomes with the ability to elicit potent immunoactivation, resulting in tumor eradication and bacterial or virus elimination. Given the notion that exosomes are stable and easy to be modified artificially, autologous mature DC-derived exosomes have been vaccinated into patients with malignant diseases. In clinical trials utilizing exosomes as therapeutic approaches, researchers observed considerable curative effect with little side effect. However, immature or suppressive DC-derived exosomes harbor anti-inflammatory properties distinct from mature DC-derived exosomes. In murine models of autoimmune disease and transplantation, immature DC-derived exosomes reduced T cell-dependent immunoactivation, relieved clinical manifestation of autoimmune disease, and prolonged survival time of transplantation. Although the exact mechanism of how immature DC-derived exosomes function in vivo is still unclear, and there are no clinical trials regarding application of exosome vaccine into patients with autoimmune disease, we will analyze the promise of immature DC-derived exosomes as a subcellular vaccine in autoimmunity in this review.

  View details for DOI 10.1007/s10753-012-9539-1

  View details for Web of Science ID 000313954300026

  View details for PubMedID 22956173

• MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus. BMC neuroscience Hu, K., Xie, Y. Y., Zhang, C., Ouyang, D. S., Long, H. Y., Sun, D. N., Long, L. L., Feng, L., Li, Y., Xiao, B. 2012; 13: 115

  Abstract

  The expression pattern and function of miRNAs in the rat model of temporal lobe epilepsy have not been well defined. Profiling miRNA expression in the rat model of temporal lobe epilepsy and investigating the function of specific miRNAs in epilepsy offers the prospect of a deeper understanding of the mechanisms of epilepsy.The lithium-pilocarpine-induced status epilepticus model and the temporal lobe epilepsy model were established in Sprague-Dawley rats. Samples were analysed to detect deregulated miRNAs in the hippocampal temporal lobe, and several of these deregulated miRNAs were confirmed by qPCR. The expression of the pro-apoptotic miR-34a was detected at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. The antagomir of miR-34a was then utilised. The expression of miR-34a after targeting and the expression change of activated caspase-3 protein were examined. The effects of altering the expression of miR-34a and activated caspase-3 protein on neuronal survival and neuronal death or apoptosis post-status epilepticus were assessed.The miRNA microarray detected 9 up-regulated miRNAs (miR-146a, -211, -203, -210, -152, -31, -23a, -34a, -27a) and 15 down-regulated miRNAs (miR-138*, -301a, -136, -153, -19a, -135b, -325-5p, -380, -190, -542-3p, -33, -144, -542-5p, -543, -296*). Some of the deregulated miRNAs (miR-146a, miR-210, miR-27a, miR-135b and miR-33) were confirmed using qPCR. Furthermore, an increase in expression of the pro-apoptotic miR-34a was demonstrated in the post-status epilepticus rat hippocampus. miR-34a was significantly up-regulated at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. Experiments with the miR-34a antagomir revealed that targeting miR-34a led to an inhibition of activated caspase-3 protein expression, which may contribute to increased neuronal survival and reduced neuronal death or apoptosis.Our study showed the expression profile of miRNAs in the hippocampus in a rat model of temporal lobe epilepsy and an increase in the expression of the pro-apoptotic miR-34a in post-status epilepticus rats. The results show that miR-34a is up-regulated during seizure-induced neuronal death or apoptosis, and targeting miR-34a is neuroprotective and is associated with an inhibition of an increase in activated caspase-3 protein.

  View details for DOI 10.1186/1471-2202-13-115

  View details for PubMedID 22998082

  View details for PubMedCentralID PMC3471047

• Rapamycin suppresses the recurrent excitatory circuits of dentate gyrus in a mouse model of temporal lobe epilepsy. Biochemical and biophysical research communications Tang, H., Long, H., Zeng, C., Li, Y., Bi, F., Wang, J., Qian, H., Xiao, B. 2012; 420 (1): 199-204

  Abstract

  Recurrent excitatory circuits and abnormal recurrent excitatory inputs are essential in epileptogenesis. Studies in temporal lobe epilepsy have shown that mossy fiber sprouting, which represents synaptic reorganization, renders the formation of abnormal recurrent excitatory circuits and inputs. The mammalian target of rapamycin (mTOR) pathway has recently been proved important in mossy fiber sprouting. In the present study, rapamycin, a mTOR inhibiter, was injected into the mouse of temporal lobe epilepsy. Electrophysiological and histological properties of the hippocampus were investigated by whole cell patch clamp, extracellular recording and Timm staining. Following the development of epilepsy, frequency of spontaneous excitatory postsynaptic currents (EPSCs) and amplitude of antidromically evoked EPSCs in granule cells were remarkably increased, as well as the epileptiform activity and mossy fiber sprouting were detected, which indicated the formation of abnormal recurrent excitatory circuits. By the use of rapamycin, frequency of spontaneous EPSCs, amplitude of antidromically evoked EPSCs, the epileptiform activity and mossy fiber sprouting were all remarkably suppressed. Our findings suggested an anti-epileptogenic role of rapamycin by suppressing the recurrent excitatory circuits of dentate gyrus.

  View details for DOI 10.1016/j.bbrc.2012.02.143

  View details for PubMedID 22414694

• [Neuronal synaptic reconstruction in hippocampus in chronic phase of pilocarpine-treated rats]. Zhonghua yi xue za zhi Yi, F., Abuhamed, M. M., Long, L. L., Li, Y., Li, S. Y., Wu, Z. G., Xiao, B. 2011; 91 (19): 1335-9

  Abstract

  To explore the aberrant formation of excitatory and inhibitory circuit rearrangements of hippocampus in temporal lobe epilepsy.Pilocarpine-induced animal model was established. At around Day 60 post-modeling, retrograde tracer fluorogold (FG) was injected in vivo into CA1 and CA3 areas of hippocampus by stereotaxic apparatus. Immunohistochemistry of FG was used to observe the aberrant excitatory circuit rearrangements. Double immunofluorescence with NPY (neuropeptide Y) and FG was performed to observe the aberrant inhibitory circuit rearrangements.After an injection of FG into CA1 area, the FG-labeled pyramidal cells could be observed distantly from the zone of dye spread in CA1 area, CA3 area and subiculm. And the FG-labeled non-principal neurons could be seen in stratum oriens of CA1 and hilus in experimental group. Double immunofluorescence revealed that the FG-labeled NPY interneurons were located distantly from the zone of dye spread in CA1 area, CA3 area and hilus in experimental rats. When injection was administered in CA3 area, the FG-labeled pyramidal cells were visible in the whole CA3 area and hilus in both groups. Some pyramidal cells were present in CA1 in experimental group. Also some FG-labeled non-principle cells were found in hilus and distantly from the zone of dye spread in CA1 area. And the FG-labeled NPY neurons could be seen in hilus in experimental rats.Aberrant excitatory and inhibitory synaptic reconstruction exist in hippocampus in chronic phase of temporal lobe epilepsy, including excitatory synaptic connections among pyramidal cells in CA1 area, pyramidal cells between CA1 and subiculum and pyramidal cells between CA1 and CA3, inhibitory synaptic connections among dendritic interneurons in CA1 area, CA3 to CA1, hilus to CA1 and hilus to CA3 area. These circuit arrangements may play an important role in the pathogenesis of epilepsy.

  View details for PubMedID 21756761

• Selective loss and axonal sprouting of GABAergic interneurons in the sclerotic hippocampus induced by LiCl-pilocarpine. The International journal of neuroscience Long, L., Xiao, B., Feng, L., Yi, F., Li, G., Li, S., Mutasem, M. A., Chen, S., Bi, F., Li, Y. 2011; 121 (2): 69-85

  Abstract

  In this study, we performed immunohistochemistry for somatostatin (SS), neuropeptide Y (NPY), and parvalbumin (PV) in LiCl-pilocarpine-treated rats to observe quantitative changes and axonal sprouting of GABAergic interneurons in the hippocampus, especially in the sclerotic hippocampus. Fluoro-Jade B (FJB) was performed to detect the specific degeneration of GABAergic interneurons. Compared with age-matched control rats, there were fewer SS/NPY/PV-immunoreactive (IR) interneurons in the hilus of the sclerotic hippocampus in pilocarpine-treated rats; hilar dentritic inhibitory interneurons were most vulnerable. FJB stain revealed degeneration was evident at 2 months after status epilepticus. Some SS-IR and NPY-IR interneurons were also stained for FJB, but there was no evidence of degeneration of PV-IR interneurons. Axonal sprouting of GABAergic interneurons was present in the hippocampus of epileptic rats, and a dramatic increase of SS-IR fibers was observed throughout all layers of CA1 region in the sclerotic hippocampus. These results confirm selective loss and degeneration of a specific subset of GABAergic interneurons in specific subfields of the hippocampus. Axonal sprouting of inhibitory GABAergic interneurons, especially numerous increase of SS-IR neutrophils within CA1 region of the sclerotic hippocampus, may constitute the aberrant inhibitory circum and play a significant role in the generation and compensation of temporal lobe epilepsy.

  View details for DOI 10.3109/00207454.2010.530007

  View details for PubMedID 21142829

• Expression profile of microRNAs in rat hippocampus following lithium-pilocarpine-induced status epilepticus. Neuroscience letters Hu, K., Zhang, C., Long, L., Long, X., Feng, L., Li, Y., Xiao, B. 2011; 488 (3): 252-7

  Abstract

  Although microRNAs are expressed extensively in the central nervous system in physiological and pathological conditions, their expression in neurological disorder of epilepsy has not been well characterized. Here we investigated microRNA expression pattern in post status epilepticus rats (24h after status). Rat MicroRNA array and differential analysis had detected 19 up-regulated microRNAs and 7 down-regulated microRNAs in rat hippocampus, and four randomly selected deregulated microRNAs (microRNA-34a, microRNA-22, microRNA-125a, microRNA-21) were confirmed by qRT-PCR, then their expression alterations in rat peripheral blood were analyzed. We found that these four deregulated microRNAs were also differentially expressed in rat peripheral blood, and trends for their blood expression alterations were just the same as their counterparts in rat hippocampus. Thus, our results have not only characterized the microRNA expression profile in post status epilepticus rat hippocampus but also demonstrated that some rat hippocampal microRNAs were probably associated with rat peripheral blood microRNAs. Moreover, targets of these deregulated microRNAs were analyzed using bioinformatics and the identified enriched MAPK pathway and long-term potentiation pathway might have been involved in molecular mechanisms concerning neuronal death, inflammation and epileptogenesis.

  View details for DOI 10.1016/j.neulet.2010.11.040

  View details for PubMedID 21094214

• Activation of ERK by spontaneous seizures in neural progenitors of the dentate gyrus in a mouse model of epilepsy EXPERIMENTAL NEUROLOGY Li, Y., Peng, Z., Xiao, B., Houser, C. R. 2010; 224 (1): 133-145

  Abstract

  Cellular changes that are associated with spontaneous seizures in temporal lobe epilepsy are not well understood but could influence ongoing epilepsy-related processes. In order to identify cell signaling events that could occur at the time of spontaneous seizures, the localization of phosphorylated extracellular signal-regulated kinase (pERK) was studied in a pilocarpine mouse model of epilepsy at very short intervals (1.5-2.5 min) after detection of a spontaneous seizure. Within the hippocampal formation, immunolabeling of pERK was evident in a subpopulation of cells in the subgranular zone (SGZ) of the dentate gyrus at these short intervals. Many of these cells had a long vertical process and resembled radial glia, while others had short processes and were oriented horizontally. Labeling with a series of developmental markers demonstrated that virtually all pERK-labeled cells were neural progenitor cells (NPCs). A high percentage ( approximately 80%) of the pERK-labeled cells was labeled with either glial fibrillary acidic protein or brain lipid binding protein, indicating that these cells were radial glia-like NPCs. A smaller percentage of labeled cells expressed NeuroD, suggesting that they were later-developing NPCs that were assuming a neuronal identity. Early expression of pERK was not detected in immature neurons. Double labeling with proliferation markers demonstrated that approximately 30% of pERK-labeled NPCs expressed Mcm2, indicating that they were actively proliferating. Furthermore, virtually all radial glia-like NPCs that were in the proliferative cycle expressed pERK. These findings suggest that spontaneous seizures and associated ERK activation could contribute to the proliferation of radial glia-like NPCs in this epilepsy model.

  View details for DOI 10.1016/j.expneurol.2010.03.003

  View details for Web of Science ID 000279128400016

  View details for PubMedID 20226181

  View details for PubMedCentralID PMC2893891