Mei-Hua Yang

Pediatric intractable epilepsy syndromes: Reason for early surgical intervention

Drug-resistance in several childhood epilepsy syndromes is common, and these patients may tolerate epilepsy surgery. In this study, the surgical outcomes of 24 pediatric patients with various intractable epilepsy syndromes and three patients with tuberous sclerosis were examined at Xinqiao hospital between 1997 and 2004. The study included nine cases of Lennox-Gastaut syndrome, two cases of Rasmussens syndrome, one case of Sturge-Weber syndrome, three cases of West syndrome, three cases of tuberous sclerosis and nine cases of mesial temporal lobe epilepsy syndrome. In each case, different surgical procedures were performed according to preoperative evaluation and ECoG. At an average of 4.5 years after surgery, 14 out of 27 patients (51.9%) had an Engel Class I outcome after surgery, and an additional eight patients (29.6%) had rare seizure (Engel ClassII). Three patients showed a significant decrease in seizure frequency (Engel Class III). The mean IQ increased from 61.4+/-12.2 to 75.0+/-11.0, and greater IQ increase was seen in patients with shorter seizure history and drug-resistance. Temporary complications were observed in four patients and there were no deaths. In conclusion, early surgical intervention in pediatric intractable epilepsy syndromes may results in a favorable outcome in a high percentage of cases and may provides an important opportunity to prevent irreversible decline in intelligence and disability.

Increased expression of matrix metalloproteinase 9 in cortical lesions from patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.

The malformative cortical lesions in the cerebral cortex that are characteristic of focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. Increasing evidence suggests that extracellular matrix molecules play important roles in epileptogenesis. Matrix metalloproteinase 9 (MMP9), a typical extracellular matrix proteolytic protease, has been shown to participate in the occurrence of seizures in experimental models. In the present study, we used immunoblotting to analyze the levels of MMP9 protein in FCDIIb lesions, TSC tubers and control samples, which included epileptic neocortices from temporal lobe epilepsy and non-epileptic normal cortices (CTX). The cellular distribution of MMP9 was further investigated by immunohistochemical methods. Our findings demonstrated the elevated levels of the inactive and active forms of MMP9 protein in FCDIIb and TSC lesions compared with CTX. Furthermore, the immunohistochemical results showed that MMP9 was characteristically expressed in the following misshapen cells: hypertrophic neurons, dysmorphic neurons, balloon cells and giant cells. Additionally, double immunofluorescent staining revealed that the reactive astrocytes, but not the microglia, expressed high levels of MMP9. Taken together, our findings suggest that the overexpression and spatial distribution patterns of MMP9 may be linked with the intractable epilepsy caused by FCDIIb and TSC.

Clinical outcomes and quality of life following surgical treatment for refractory epilepsy: a systematic review and meta-analysis.

AbstractSurgery for refractory epilepsy is widely used but the efficacy of this treatment for providing a seizure-free outcome and better quality of life remains unclear.This study aimed to update current evidence and to evaluate the effects of surgery on quality of life in patients with refractory epilepsy.A systematic review and meta-analysis of the literature were conducted and selected studies included 2 groups of refractory epilepsy patients, surgical and nonsurgical.The studies were assessed using the Newcastle–Ottawa Scale. The primary outcome was the seizure-free rate. The secondary outcome was quality of life. Adverse events were also reviewed.After screening, a total of 20 studies were selected: 8 were interventional, including 2 randomized controlled trials, and 12 were observational. All of the studies comprised 1959 patients with refractory epilepsy. The seizure-free rates were significantly higher for patients who received surgery compared with the patients who did not; the combined odds ratio was 19.35 (95% CI = 12.10–30.95, P < 0.001). After adjusting for publication bias the combined odds ratio was 10.25 (95% CI = 5.84–18.00). In both the interventional and observational studies, patients treated surgically had a significantly better quality of life compared with the patients not treated surgically. Complications were listed in 3 studies and the rates were similar in surgical and nonsurgical patients.Our meta-analysis found that for patients with refractory epilepsy, surgical treatment appears to provide a much greater likelihood of seizure-free outcome than nonsurgical treatment, although there is a need for more studies, particularly randomized studies, to confirm this conclusion. Based on more limited data, surgical treatment also appeared to provide a better quality of life and did not seem to increase complications.

Surgical treatment for epilepsy in 17 children with tuberous sclerosis-related West syndrome

The efficacy of surgery for the treatment of epilepsy in patients with West syndrome secondary to tuberous sclerosis is unclear. The charts of 17 patients with tuberous sclerosis and secondary West syndrome who underwent a one-stage surgical resection with a combined palliative operative procedure were reviewed. Engel classification was used to classify the patients with regard to seizure status following surgery. After surgery, 11 patients were in Engel class I, 4 in class II, and 2 in class III. The EEG after surgery was normal in 8 patients, significantly improved in 8, and without significant improvement in 1 patient. Six patients had a recurrence of seizures after surgery, which included 3 patients with continuing spasms and 3 patients where the spasms had resolved but had developed either partial seizures or generalized tonic-clonic seizures. There were significant improvements in the Gesell Developmental Schedules for motor field (P=0.003), adaptive field (P=0.003), language field (P=0.033), and personal-social field (P=0.007). Thus, a one-stage surgical approach can be used to produce satisfactory outcomes in young children with tuberous sclerosis who have secondary West syndrome and seizures that do not respond to conventional antiepileptic therapy, even in when there are multiple epileptogenic foci.

Expression of the interleukin 17 in cortical tubers of the tuberous sclerosis complex.

The role of interleukin 17 (IL-17) to epilepsy-associated cortical tubers of tuberous sclerosis complex (TSC) is unknown. We investigated the expression patterns of the IL-17 and IL-17 receptor (IL-17R) in cortical tubers of TSC compared with normal control cortex (CTX). We found that IL-17 and IL-17R were clearly upregulated in cortical tubers at the protein levels. Immunostaining indicated that IL-17 was specifically distributed in the innate immunity cells (DNs, GCs, astrocytes, and microglia) and adaptive immunity cells (T-lymphocytes) as well as the endothelial cells of blood vessels. The overexpression and distribution patterns of IL-17 may be involved in the epileptogenicity of cortical tubers in TSC.

Expression of bone morphogenetic protein-4 in the cortical lesions of focal cortical dysplasia IIb and the tuberous sclerosis complex.

Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are malformations of cortical development (MCDs) and are frequently associated with medically intractable epilepsy. Previous studies have indicated that developmental abnormalities during the early stages of cortical development contribute to the onset of these diseases. Bone morphogenetic protein-4 (BMP-4) is a well-documented key regulator of cortical development. To understand the potential roles of BMP-4 in the cortical lesions associated with MCDs, we investigated the expression pattern of BMP-4 in surgical specimens from patients with FCD IIb (n = 8) and TSC (cortical tubers; n = 12), and age-matched normal cortices (CTX) (n = 8) from autopsy samples were used as controls. The immunohistochemical results demonstrated that the overall immunoreactivity of the BMP-4 staining was diminished in the dysplastic cortices of the FCD IIb and TSC samples compared to the CTX samples. Moderate to strong BMP-4 immunoreactivity, however, was observed in malformed neurons, including dysmorphic neurons, giant neurons, balloon cells, giant cells, and reactive astrocytes. The confocal analysis demonstrated that most malformed neurons expressing BMP-4 were co-labeled with neuronal rather than astrocytic markers, indicating a neuronal lineage. Moreover, the decreased BMP-4 expression within the dysplastic cortex was confirmed by western blot analysis. In conclusion, the downregulation and altered cellular distribution of BMP-4 protein observed in MCDs suggests that BMP-4 may be involved in the pathogenesis of abnormal cortical development.

A Retrospective Analysis of Stereoelectroencephalography and Subdural Electroencephalography for Preoperative Evaluation of Intractable Epilepsy.

Background: Different methods for intracranial electrode recording have various advantages and disadvantages, and controversy exists regarding the complications of stereoelectroencephalography (SEEG) and subdural EEG. Objective: The purpose of this study was to determine the efficacy and safety of SEEG by comparing it with subdural EEG. Methods: Data from 100 patients who underwent SEEG (n = 48) and subdural EEG (n = 52) to evaluate the epileptogenic zone were collected from June 2011 to June 2015. The evaluation results, surgical outcomes, and complications were compared. Results: No significant differences were noted between the SEEG and subdural EEG groups in identifying the epileptogenic zone or undergoing epileptic surgery. Of the 88 patients who underwent epilepsy surgery after assessment, 59.5% in the SEEG group and 52.2% in the subdural EEG group became seizure free. No significant differences in postoperative seizure control or intelligence improvement were noted. The overall complication rate in SEEG patients (8/48; 16.7%) was lower than that in subdural EEG patients (13/52; 25%), particularly for hemorrhage and infection (4.2 vs. 17.3%, p < 0.05). Conclusions: This retrospective review indicates that SEEG has low associated complications, particularly regarding hemorrhage and infection. SEEG is a safe and effective method for intracranial monitoring.

Upregulations of CRH and CRHR1 in the Epileptogenic Tissues of Patients with Intractable Infantile Spasms.

Infantile spasms (IS) are an age‐specific epileptic syndrome with specific clinical symptom and electroencephalogram (EEG) features, lacking treatment options, and a poor prognosis. Excessive endogenous corticotropin‐releasing hormone (CRH) in infant brain might result in IS. However, the data from human IS are limited. In our study, we investigated the expressions of CRH and its receptor type 1 (CRHR1) in surgical tissues from patients with IS and autopsy controls.

Comparison of Neuronavigation and Frame-Based Stereotactic Systems in Implanting Epileptic Depth Electrodes.

AIM To investigate the application of neuronavigation in the implantation of depth electrodes in patients with epilepsy. MATERIAL AND METHODS Thirty-six patients with epilepsy who were implanted with depth electrodes using neuronavigation were assessed for accuracy of implantation and associated complications. RESULTS In the imaging navigation group, patients were implanted with 2-14 depth electrodes. The average number of implantations was 4.8 electrodes/case. The average implantation error was 2.03 ± 0.98 mm, exhibiting no significant difference compared to the frame-based stereotactic group. In the imaging group, an average of 19.4 min was required to implant each electrode, which was significantly shorter than the time required in the frame group (34.5 min). The temporal lobe was elucidated as the factor that affects electrode implantation accuracy. One patient in the imaging group exhibited a small amount of bleeding, and one suffered from cerebrospinal fluid leakage; however, the overall complication rate in the imaging group was lower than that in the frame group. CONCLUSION Imaging navigation provides better means of depth electrode implantation; its implantation accuracy is similar to that of the frame-based stereotactic method and it is less time consuming and causes less complications, and is especially suitable for stereoelectroencephalography, which requires multiple depth electrodes.

TRIF contributes to epileptogenesis in temporal lobe epilepsy during TLR4 activation

Increasing evidence indicates that inflammatory processes play a crucial role in the etiopathology of epilepsy and seizure disorders. The Toll/IL-1R domain-containing adapter-inducing IFN-β (TRIF) activated several transcriptions leading to the production of pro-inflammatory cytokines in the central nervous system, which suggests a potential role for TRIF in the epileptogenesis of epilepsy. In this study, we investigated the roles of TRIF in human and mice epileptogenic tissues. Western blot and immunohistochemistry assays showed that the expression of TRIF was significantly upregulated in neurons and glial cells in both human epileptic tissues and mouse models, and positively correlated with seizure frequency. TRIF expression positively correlated with high-mobility group box 1 (HMGB1) expression. In TRIF-deficient mice, electroencephalograms displayed a significant decrease in seizure frequency and duration time, while KA induced seizures compared with wild-type (WT) mice. The number and duration time of spontaneous seizures were also decreased in the chronic KA-induced TRIF-deficient mouse models. In TLR4-deficient hippocampal neurons and mouse models, TRIF expression was lower compared with WT mice during HMGB1 and KA stimulation. Meanwhile, in KA-induced TRIF-deficient mouse models, microglia activation was significantly suppressed; pro-inflammatory factors including IL-1β, TNF-α, iNOS, HMGB1 and IFN-β were reduced; and the survival of the neurons in the hippocampus increased compared with WT mice. Our findings suggested that TRIF may be involved in the epileptogenesis of temporal lobe epilepsy, which would make it a potential therapeutic target for the treatment of epilepsy.