外伤性癫痫危险因素分析

目的 调查颅脑创伤(TBI)患者外伤性癫痫(PTE)的发生率、发作类型、危险因素及其认知功能等.方法 对我院脑系科中心2004年9月至2007年9月之间好转出院的TBI病例进行回顾性调查和电话随访及回访.纳入资料完整及能随访的患者共2023例.结果 (1)2 023例TBI患者中有98例出现PTE,其发生率为4.84%,高发年龄段为51～70岁和10岁以下.65例(66.32%)患者的PTE发生于外伤后1年以内;(2)TBI病情重、高龄、皮层损伤、蛛网膜下腔出血、多次手术治疗及受伤早期痫性发作均可增加PTE的发病率;(3)PTE 患者认知障碍和性格发生变化的发生率高于非PTE患者(P＜0.05).结论 癫痫发生与TBI严重程度、受伤年龄、损伤部位、影像学表现、治疗方法和伤后临床表现等有关.

Abstract：

Objective The purpose of this study was to investigate the incidence of posttraumatic seizure and epilepsy,the seizure type of epilepsy,risk factors of epilepsy and Recognition function.Methods The TBI cases discharged after the improvement from September 2004 to Septemher 2007 were retrospectively investigated and visited by telephone and 2023 cases was brought into study.Results (1)98 cases suffered PTE and the incidence of PTE was 4.84%;the age of high incidence was 51～70 years old and less than 10 years old. 65 cases(66.32%)occurred in less than one year after trauma.(2)Serious injury,old age,cortical injury,subarachnoid hemorrhage,many surgical treatment and early epileptic seizure after injury would increase the incidence of PTE(P＜0.05).(3)The incidence of cognitive impairment was higher in patients with PTE than non-PTE patients(P＜0.05).Conclusion The risk of posttranmatic seizure and epilepsy is correlation with the severity of TBI,age,injury location,imaging findings,treatment methods and clinical manifestations after injury.     

液压脑损伤大鼠行为学和脑电图的研究

目的 通过液压脑损伤大鼠行为学和脑电图的研究以探讨其在外伤后癫痫中的研究价值.方法 建立液压脑损伤动物模型并进行为期3个月大鼠行为学和脑电图的观察、记录.结果 液压脑损伤后50只大鼠死亡19只,存活的31只中有11只出现癫痫.癫痫的发作形式主要表现为面肌痉挛、点头样运动,其次为四肢抽搐、翻转跳起等.液压脑损伤后第2个月为癫痫发生的高峰期.癫痫发作时同期脑电图可见癫痫样放电.液压脑损伤后部分非癫痫大鼠脑电图表现为1～5导联波幅增高、频率增快.结论 液压脑损伤后癫痫动物模型与临床外伤后癫痫相似,与其他外伤后癫痫动物模型相比,更具有研究价值.     

From traumatic brain injury to posttraumatic epilepsy: What animal models tell us about the process and treatment options

A large number of animal models of traumatic brain injury (TBI) are already available for studies on mechanisms and experimental treatments of TBI. Immediate and early seizures have been described in many of these models with focal or mixed type (both gray and white matter damage) injury. Recent long-term video-electroencephalography (EEG) monitoring studies have demonstrated that TBI produced by lateral fluid-percussion injury in rats results in the development of late seizures, that is, epilepsy. These animals develop hippocampal alterations that are well described in status epilepticus–induced spontaneous seizure models and human posttraumatic epilepsy (PTE). In addition, these rats have damage ipsilaterally in the cortical injury site and thalamus. Although studies in the trauma field provide a large amount of information about the molecular and cellular alterations corresponding to the immediate and early phases of PTE, chronic studies relevant to the epileptogenesis phase are sparse. Moreover, despite the multiple preclinical pharmacologic and cell therapy trials, there is no information available describing whether these therapeutic approaches aimed at improving posttraumatic recovery would also affect the development of lowered seizure threshold and epilepsy. To make progress, there is an obvious need for information exchange between the trauma and epilepsy fields. In addition, the inclusion of epilepsy as an outcome measure in preclinical trials aiming at improving somatomotor and cognitive recovery after TBI would provide valuable information about possible new avenues for antiepileptogenic interventions and disease modification after TBI.     

Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy

Posttraumatic seizures develop in up to 20% of children following severe traumatic brain injury (TBI). Children ages 6–17 years with one or more risk factors for the development of posttraumatic epilepsy, including presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or occurrence of posttraumatic seizure were recruited into this phase II study. Treatment subjects received levetiracetam 55 mg/kg/day, b.i.d., for 30 days, starting within 8 h postinjury. The recruitment goal was 20 treated patients. Twenty patients who presented within 8–24 h post‐TBI and otherwise met eligibility criteria were recruited for observation. Follow‐up was for 2 years. Forty‐five patients screened within 8 h of head injury met eligibility criteria and 20 were recruited into the treatment arm. The most common risk factor present for pediatric inclusion following TBI was an immediate seizure. Medication compliance was 95%. No patients died; 19 of 20 treatment patients were retained and one observation patient was lost to follow‐up. The most common severe adverse events in treatment subjects were headache, fatigue, drowsiness, and irritability. There was no higher incidence of infection, mood changes, or behavior problems among treatment subjects compared to observation subjects. Only 1 (2.5%) of 40 subjects developed posttraumatic epilepsy (defined as seizures >7 days after trauma). This study demonstrates the feasibility of a pediatric posttraumatic epilepsy prevention study in an at‐risk traumatic brain injury population. Levetiracetam was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at‐risk population.     

创伤性癫痫的治疗进展

创伤性癫痫(PTE)是指继发于外伤性脑损伤(TBI)的反复出现的自发性癫痫发作。其发病机制复杂,治疗效果不一。本文旨在简要介绍近年来在PTE的动物模型研究,临床治疗方面所取得的进展,以期能够对临床治疗有一定的参考价值。     

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis

Background

Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE.

Aims

To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis.

Methods

We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance.

Results

TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective.

Discussion

Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment.

Conclusion

It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.     

Clinical epidemiology of posttraumatic epilepsy in a group of Chinese patients

ObjectiveTo explore the incidence, types of onset, and risk factors of posttraumatic epilepsy (PTE).MethodsThis is a retrospective follow-up study of patients discharged from the Affiliated Hospital of the Medical College of the Chinese People's Armed Police Forces between September 2004 and September 2008 with a diagnosis of traumatic brain injury (TBI).ResultsComplete clinical information was available on 2826 patients. Of the 2826 TBI patients, 141 developed PTE, providing an incidence rate of 5.0%. Twenty-four cases (0.8%) had posttraumatic seizures (PTS), of which 16 (66.7%) continued to experience after the acute phase of their TBI, accounting for 5.0% of the total PTE cases. A total of 125 cases (88.7%) were diagnosed as presenting with late-stage seizures, occurring from 10 days to three years after TBI (93/141 (66.0%) presented within six months after the TBI, 14/141 (9.9%) between six and twelve months, 22/141 (15.7%) between one and two years and only 12/141 (8.5%) between two and three years after the TBI. The severity of PTE was rated mild, medium, and severe in 3.6%, 6.9%, and 17% of the TBI patients. Multiple regression analysis was carried out to identify factors contributing to the risk of developing PTE. Five parameters contributed to the model: Older age, greater severity of brain injury, abnormal neuroimaging, surgical treatment, and early-stage seizures.ConclusionAge, severity of brain injury, neuroimaging results, treatment methods, and early-stage seizures are independent risk factors of PTE.     

Imaging biomarkers of posttraumatic epileptogenesis

Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300 000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long‐term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large‐scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.     

Epileptiform activity in traumatic brain injury predicts post‐traumatic epilepsy

We hypothesize that epileptiform abnormalities (EAs) in the electroencephalogram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first‐year post‐traumatic epilepsy (PTE₁). We analyze PTE₁ risk factors in two cohorts matched for TBI severity and age (n = 50). EAs independently predict risk for PTE₁ (odds ratio [OR], 3.16 [0.99, 11.68]); subdural hematoma is another independent risk factor (OR, 4.13 [1.18, 39.33]). Differences in EA rates are apparent within 5 days following TBI. Our results suggest that increased EA prevalence identifies patients at increased risk for PTE₁, and that EAs acutely post‐TBI can identify patients most likely to benefit from antiepileptogenesis drug trials. Ann Neurol 2018;83:858–862     

A population‐based study of risk of epilepsy after hospitalization for traumatic brain injury

Purpose: This study was undertaken to determine the risk of developing posttraumatic epilepsy (PTE) within 3 years after discharge among a population‐based sample of older adolescents and adults hospitalized with traumatic brain injury (TBI) in South Carolina. It also identifies characteristics related to development of PTE within this population. Methods: A stratified random sample of persons aged 15 and older with TBI was selected from the South Carolina nonfederal hospital discharge dataset for four consecutive years. Medical records of recruits were reviewed, and they participated in up to three yearly follow‐up telephone interviews. Results: The cumulative incidence of PTE in the first 3 years after discharge, after adjusting for loss to follow‐up, was 4.4 per 100 persons over 3 years for hospitalized mild TBI, 7.6 for moderate, and 13.6 for severe. Those with severe TBI, posttraumatic seizures prior to discharge, and a history of depression were most at risk for PTE. This higher risk group also included persons with three or more chronic medical conditions at discharge. Discussion: These results raise the possibility that although some of the characteristics related to development of PTE are nonmodifiable, other factors, such as depression, might be altered with intervention. Further research into factors associated with developing PTE could lead to risk‐reducing treatments.     

Epileptic spasms: a previously unreported manifestation of WDR45 gene mutation

WDR45 mutations cause neurodegeneration with brain iron accumulation, usually presenting with early childhood developmental delay and followed by early adulthood extrapyramidal symptoms. Although various seizure types may occur, epileptic spasms have not been reported for this disease. Our patient initially developed a prolonged, focal‐onset seizure at three months of age and was subsequently noted to have psychomotor delay. At 11 months of age, she developed epileptic spasms. Her EEG showed hypsarrhythmia. An extensive neurogenetic workup and brain MRI, revealing normal data, ruled out other detectable causes of epileptic spasms. Whole‐exome sequencing revealed a de novo, heterozygous deleterious mutation c.400C>T (p.R13X) in WDR45, previously reported to be disease‐causing and associated with early childhood global developmental delay and seizures other than epileptic spasms. We conclude that WDR45 mutations should be considered as a possible aetiology in infants with early‐onset focal seizures and/or in otherwise undiagnosed cases of epileptic spasms.     

Post-traumatic epilepsy: an overview

Post-traumatic epilepsy (PTE) is a recurrent seizure disorder secondary to brain injury following head trauma. PTE is not a homogeneous condition and can appear several years after the head injury. The mechanism by which trauma to the brain tissue leads to recurrent seizures is unknown. Cortical lesions seem important in the genesis of the epileptic activity, and early seizures are likely to have a different pathogenesis than late seizures. Anti-epileptic drugs available for treatment are phenytoin, sodium valproate, and carbamazepine. Newer anti-epileptics are helpful, particularly in patients with associated post-traumatic stress disorders; however, no randomized controlled studies are available to prove that one of these drugs is better than the other. Current evidence is that the treatment of early post-traumatic seizures does not influence the incidence of post-traumatic epilepsy. Routine preventive anticonvulsants are not indicated for patients with head injuries, and treatment in the acute phase does not reduce death or disability rates.     

Simvastatin therapy prevents brain trauma‐induced increases in β‐amyloid peptide levels

Elevations in β‐amyloid peptide (Aβ) levels after traumatic brain injury (TBI) may confer risk for developing Alzheimer's disease in head trauma patients. We investigated the effects of simvastatin, a 3‐hydroxy‐3‐methylglutaryl‐CoA reductase inhibitor, on hippocampal Aβ burden in a clinically relevant head injury/intervention model using mice expressing human Aβ. Simvastatin therapy blunted TBI‐induced increases in Aβ, reduced hippocampal tissue damage and microglial activation, and improved behavioral outcome. The ability of statins to reduce post‐injury Aβ load and ameliorate pathological sequelae of brain injury makes them potentially effective in reducing the risk of developing Alzheimer's disease in TBI patients. Ann Neurol 2009;66:407–414     

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti-inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti-inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells—brain-resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro- and anti-inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain-resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.     

Infantile epileptic encephalopathy with late‐onset spasms: Report of 19 patients

Purpose: Late‐onset spasms (LOS) are epileptic spasms starting after the first year of life. Our aim was to assess the electroclinical features and the follow‐up of the patients with this particular type of epileptic seizure. Methods: We retrospectively included all patients with LOS confirmed by electroencephalography between 1989 and 2008. Clinical and electroencephalographic findings at diagnosis and during follow‐up were collected. The Vineland scale was used to evaluate the neuropsychological outcome. Results: We report 19 patients with LOS of 240 patients with recorded epileptic spasms. Eighteen patients had an epileptic encephalopathy with late‐onset spasms. The ictal electroencephalography (EEG) showed a focal or generalized discharge of triphasic slow‐waves, slow‐spikes, or slow spikes‐waves with fast activities. The interictal EEG usually showed focal or generalized slow‐waves or slow spikes‐waves without hypsarhythmia. LOS were controlled in only six patients. Three developed typical Lennox‐Gastaut syndrome and 10 had a severe epileptic encephalopathy. Neuropsychological outcome was evaluated in 15 patients with the Vineland scale. Cognitive functions were normal in only one patient, whereas severe cognitive delay was observed in 12 of 15. Conclusion: Epileptic spasms may appear after the age of one. They are more frequently observed in patients with epileptic encephalopathy. In few patients this type of seizure was observed before the patients fulfill Lennox‐Gastaut syndrome criteria. In one patient, we diagnosed a focal epilepsy with seizures occurring in cluster. When LOS are related to an epileptic encephalopathy, this epileptic syndrome seems to be linked to refractory epilepsy and severe cognitive outcome unrelated to the etiology.     

Analysis of surgical strategies for children with epileptic spasms

Objective: To investigate surgical prognostic factors in order to establish a surgical plan for children with drug‐resistant epileptic spasms. Methods: We retrospectively analysed 64 children with drug‐resistant spasms who were operated on in Beijing; the electroclinical features, surgical procedures, and surgical outcomes of these children were discussed in detail. We divided the seizure‐free patients into several groups according to imaging, aetiology, and application of stereo‐electroencephalography in order to investigate the extent of the various influencing factors. Results: Fifty‐three (82.8%) patients had favourable outcome, and 11 (17.2%) had unfavourable outcome. Based on the univariate analysis, the factors associated with favourable seizure outcome were interictal high γ frequency (χ 2 = 4.161; p = 0.041), concordance between MRI and interictal epileptic discharges (IEDs) (χ 2 = 6.148; p =0.013), and concordance between PET and IEDs (χ 2 = 4.281; p = 0.039). Concordance between MRI and IEDs (OR = 0.083, 95% CI = 0.014–0.483; p = 0.006) and continuous discharges on electrocorticography (OR = 0.109, 95% CI = 0.019–0.639; p = 0.014) were important factors associated with a favourable surgical outcome. Significance: Resective surgery is an effective treatment for drug‐resistant ES in children. A deeper understanding of the predictors of seizure outcome is beneficial for establishing a standard, one‐stage resection procedure for spasms in order to benefit more patients who have not previously considered surgery. We propose a workflow for presurgical evaluation in children with epileptic spasms.     

重度脑创伤后脑组织氧代谢变化及细胞凋亡与预后关系

目的 :探讨重度脑创伤后脑组织氧代谢变化及细胞凋亡与预后的关系。方法 :动态监测重度脑创伤患者脑组织氧分压、二氧化碳分压、pH值及脑温变化 ,检测脑挫伤灶周围组织细胞凋亡率。分析以上指标变化与预后的关系。结果 :与对照组比较 ,伤后脑组织氧分压和pH值下降 (P <0 0 5 ) ,二氧化碳分压及脑温升高 (P <0 0 5 ) ,脑挫伤灶周围组织存在细胞凋亡 ,以上指标变化与患者预后有关。结论 :重度脑创伤后脑组织氧代谢紊乱及细胞凋亡是影响脑创伤患者预后的重要因素     

Predictors and dynamics of posttraumatic epilepsy

Objectives - The goal of our study was to identify clinical, neurophysiological and neuroradiological variables in severe head trauma (SHT) with predictive value for posttraumatic epilepsy (PTE) and to evaluate the influence of each risk factor for the dynamics of epilepsy. Material and methods - We systematically compared 57 PTE patients with 50 age and sex-matched control patients with SHT and no PTE. Mean follow-up was 8 years.
Results - Of all PTE-patients 68.5% had their first seizure within 2 years after the trauma. Significant risk factors for PTE were focal signs in the first examination ( P <0.01), missile injuries ( P <0.01), frontal lesions ( P <0.01), intracerebral hemorrhage ( P <0.01), diffuse contusion ( P <0.01), prolonged posttraumatic amnesia ( P <0.001), depression fracture ( P <0.01) and cortical-subcortical lesions ( P <0.001). The combination of the last 3 variables conferred a particularly high risk for PTE (logistic regression analysis). Combined seizure pattern, high seizure frequency, AED-non-compliance and alcohol abuse predicted poor seizure control.
Conclusion -The risk for PTE is clearly determined by those variables which correlate with the severity, the extent of tissue loss and the penetrating nature of the brain trauma.     

Converging early responses to brain injury pave the road to epileptogenesis

Epilepsy, characterized by recurrent seizures and abnormal electrical activity in the brain, is one of the most prevalent brain disorders. Over two million people in the United States have been diagnosed with epilepsy and 3% of the general population will be diagnosed with it at some point in their lives. While most developmental epilepsies occur due to genetic predisposition, a class of “acquired” epilepsies results from a variety of brain insults. A leading etiological factor for epilepsy that is currently on the rise is traumatic brain injury (TBI), which accounts for up to 20% of all symptomatic epilepsies. Remarkably, the presence of an identified early insult that constitutes a risk for development of epilepsy provides a therapeutic window in which the pathological processes associated with brain injury can be manipulated to limit the subsequent development of recurrent seizure activity and epilepsy. Recent studies have revealed diverse pathologies, including enhanced excitability, activated immune signaling, cell death, and enhanced neurogenesis within a week after injury, suggesting a period of heightened adaptive and maladaptive plasticity. An integrated understanding of these processes and their cellular and molecular underpinnings could lead to novel targets to arrest epileptogenesis after trauma. This review attempts to highlight and relate the diverse early changes after trauma and their role in development of epilepsy and suggests potential strategies to limit neurological complications in the injured brain.