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1.
The genetic generalized epilepsies (GGEs) are mainly genetically determined disorders. Although inheritance in most cases appears to be complex, involving multiple genes, variants of a number of genes are known to contribute. Pathogenic variants of SLC2A1 leading to autosomal‐dominant GLUT1 deficiency account for up to 1% of cases, increasing to 10% of those with absence seizures starting before age 4 years. Copy number variants are found in around 3% of cases, acting as risk alleles. Copy number variation is much more common in those with comorbid learning disability. Common variant associations are starting to emerge from genome‐wide association studies but do not yet explain a large proportion of GGEs. Although currently genetic testing is not likely to yield a diagnosis for most patients with GGEs, it can be of great importance in specific clinical situations. Providers should consider the individual patient's history in determining the utility of genetic testing. 相似文献
2.
Engel J. Jr. 《The Italian Journal of Neurological Sciences》1995,16(1-2):9-16
There are many forms of human partial seizures and many human localization-related epilepsies. Idiopathic epilepsies undoubtedly have pathophysiologic substrates different from those of symptomatic epilepsies, and there is evidence that some forms of limbic epilepsy involve different epileptogenic mechanisms than neocortical epilepsies. Although these mechanisms are best studied and understood by direct investigations of patients, this is often impractical and experimental animal models are also necessary. The use of experimental animals requires that the relevance of each model to a human condition be determined. Human epilepsies are comprised of multiple component parts which can be modeled independently. For instance, acute animal models provide opportunities to study epileptic seizures, but chronic models are necessary for investigation of processes relevant to epileptic conditions, such as epileptogenesis, transition from interictal to ictal state, and long-term consequences of epilepsy. Interactions between localized epileptic activity and cerebral maturation can also be studied in the animal laboratory. Experimental animal models of human partial seizures and localization-related epilepsies can be used to further investigations on basic mechanisms that cannot be pursued in patients, and to develop hypotheses concerning the fundamental neuronal processes underlying epilepsy and epilepsy-related phenomena that subsequently can be validated in patients. In addition, it would be of great clinical utility to develop animal models of partial seizures or localization-related epilepsy that could be used cost-effectively to screen potential antiepileptic drugs.Original research reported by the author was supported in part by Grants NS-02808, NS-15654 and GM-24839, from the National Institutes of Health, and Contract DE-AC03-76-SF00012 from the Department of Energy. 相似文献
3.
Structural brain abnormalities in genetic generalized epilepsies: A systematic review and meta‐analysis
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According to the International League Against Epilepsy (ILAE) definition, no structural abnormalities are present on a standard brain magnetic resonance image in genetic generalized epilepsy (GGE) patients. However, recent studies raise contradictory evidence with increasing use of quantitative magnetic resonance imaging techniques. Following PRISMA guidelines, a systematic, quantitative review was conducted using 28 peer‐reviewed, case–control studies published after 1989. Furthermore, a meta‐analysis with a random‐effect model revealed differences in structural brain abnormalities between GGE patients and controls. Significant structural differences between GGE and healthy controls were observed with volume reductions in whole brain, thalamus, putamen, caudate, pallidum, and supplementary motor area. Furthermore, gray matter volume reduction in the right and left hemispheres, thalamus, and insula, and surface area reduction in the caudal anterior cingulate cortex were revealed, along with gray matter increase in the medial frontal gyrus. Due to methodological differences, findings should be interpreted with caution. Nevertheless, contrary to the ILAE definition, it would appear that structural brain abnormalities may be present in GGE patients. Findings are consistent with a hypothesis regarding the underlying involvement of the thalamocortical networks in the generation of generalized spike‐wave discharges, but structural abnormalities appear to extend outside these regions to potentially involve attention and other cognitive domains. 相似文献
4.
Ayse Deniz Elmali Stphane Auvin Thomas Bast Guido Rubboli Michalis Koutroumanidis 《Epileptic Disord》2020,22(4):399-420
Idiopathic or genetic generalized epilepsies (IGE) constitute an electroclinically well‐defined group that accounts for almost one third of all people with epilepsy. They consist of four well‐established syndromes and some other rarer phenotypes. The main four IGEs are juvenile myoclonic epilepsy, childhood absence epilepsy, juvenile absence epilepsy and IGE with generalized tonic‐clonic seizures alone. There are three main seizure types in IGE, namely generalized tonic‐clonic seizures, typical absences and myoclonic seizures, occurring either alone or in any combination. Diagnosing IGEs requires a multidimensional approach. The diagnostic process begins with a thorough medical history with a specific focus on seizure types, age at onset, timing and triggers. Comorbidities and family history should be questioned comprehensively. The EEG can provide valuable information for the diagnosis, including specific IGE syndromes, and therefore contribute to their optimal pharmacological treatment and management. 相似文献
5.
S. R. Benbadis 《Acta neurologica Scandinavica》2005,112(S181):63-67
Idiopathic generalized epilepsies (IGEs) are a well defined group of epilepsies, with onset predominantly in childhood. Recent evidence suggests that IGEs may also be prevalent but under-diagnosed in adults. IGEs respond well to appropriate treatment and 80–90% of cases become fully controlled. However, correct identification of IGE and selection of a broad-spectrum antiepileptic drug (AED) is crucial if cases of 'pseudo-intractability' are to be avoided. Preliminary evidence suggests that some of the newer AEDs are broad spectrum and may offer advantages in the treatment of IGEs. There is strong evidence that childhood-, adolescent- and adult-onset IGEs share biologic determinants and are best viewed as a spectrum or continuum of conditions. The diagnosis of IGE, even as a group, is very important for proper management. 相似文献
6.
Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies 总被引:3,自引:0,他引:3
PURPOSE: Several studies have shown that carbamazepine (CBZ) may aggravate idiopathic generalized epilepsy (IGE). Oxcarbazepine (OXC) is a new drug chemically related to CBZ. We report six cases of juvenile IGE with a clear aggravation by OXC. METHODS: We retrospectively studied all patients with IGE first referred to our epilepsy department between January 2001 and June 2003 and treated with OXC. RESULTS: During this period, six patients were identified. All had an aggravation of their epilepsy in both clinical and EEG activities. OXC had been used because of an incorrect diagnosis of focal epilepsy or generalized tonic-clonic seizures (GTCSs) of undetermined origin (no syndromic classification of the epilepsy). Before OXC, only one patient had experienced a worsening of seizures with an inadequate drug (CBZ). Four had juvenile myoclonic epilepsy, one had juvenile absence epilepsy, and one had IGE that could not be classified into a precise syndrome. OXC (dosage range, 300-1,200 mg/day) was used in monotherapy in all of them except for one patient. Aggravation consisted of a clear aggravation of myoclonic jerks (five cases) or de novo myoclonic jerks (one case). Three patients had exacerbation of absence seizures. One patient had worsened dramatically and had absence status, and one had de novo absences after OXC treatment. The effects of OXC on GTCSs were less dramatic, with no worsening in frequency in three and a slight increase in three. CONCLUSIONS: OXC can be added to the list of antiepileptic drugs that can exacerbate myoclonic and absence seizures in IGE. 相似文献
7.
Hempelmann A Taylor KP Heils A Lorenz S Prud'homme JF Nabbout R Dulac O Rudolf G Zara F Bianchi A Robinson R Gardiner RM Covanis A Lindhout D Stephani U Elger CE Weber YG Lerche H Nürnberg P Kron KL Scheffer IE Mulley JC Berkovic SF Sander T 《Epilepsia》2006,47(10):1682-1690
PURPOSE: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. METHODS: Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. RESULTS: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. CONCLUSIONS: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening. 相似文献
8.
E. Kharazmi M. Peltola M. Fallah T. Keränen J. Peltola 《Acta neurologica Scandinavica》2010,122(3):196-201
Kharazmi E, Peltola M, Fallah M, Keränen T, Peltola J. Idiopathic generalized epilepsies: a follow‐up study in a single‐center.Acta Neurol Scand: 122: 196–201.© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To characterize adult patients with idiopathic generalized epilepsies (IGEs) with precise evaluation and to assess factors related to refractoriness. Materials and methods – Hospital records of all our patients with IGEs (n = 128) were evaluated in 2005 and followed‐up until 2008. Results – In 2005, 76% of patients were 1‐year seizure‐free. Seizure freedom increased to 82% during the 3‐year follow‐up. Seizure freedom was not significantly associated with age, age at diagnosis, epilepsy duration, exposure to inappropriate initial antiepileptic drug (AED), or delay time between starting initial AED and appropriate AED. Women constituted 78% of patients with merely provoked seizures. In 58% of women with recent seizure, one to two avoidable precipitating factors, such as lack of sleep, alcohol, and forgetting to take AED, were observed. In 2008, all patients with no medication, 91% of monotherapy patients, 60% of patients on two AED, and 14% of patients on three AED were seizure‐free. Conclusions – Most of patients with IGEs can be successfully treated with monotherapy. Refractory seizures in some patients may be because of avoidable factors, especially in young women. 相似文献
9.
Aguglia U Gambardella A Le Piane E Messina D Russo C Oliveri RL Zappia M Quattrone A 《Acta neurologica Scandinavica》1999,99(4):219-224
OBJECTIVES: To describe the electroclinical features of the idiopathic generalized epilepsies (IGEs) with versive or circling seizures. METHODS: Sixteen patients with versive or circling seizures and interictal electroclinical features of IGE were studied. Patients with insufficient clinical or imaging data, with a follow-up period less than 1 year or with partial seizures in addition to the versive or circling ones were excluded from the study. All patients underwent full interictal clinical and neurophysiological studies. The EEG patterns of 13 versive or circling seizures from 4 patients were also analyzed. RESULTS: A specific IGE syndrome was recognized in 9 out of the 16 patients (56%). More specific, 1 patient had childhood absence epilepsy (CAE), 4 had juvenile absence epilepsy (JAE), and 4 had juvenile myoclonic epilepsy (JME). No specific IGE syndrome was recognizable in the remaining 7 patients (44%). These 7 patients had a juvenile epileptic syndrome (mean age at onset of seizures was 15.7 years) characterized by versive or circling seizures followed or not by generalized tonic-clonic fits. Three main EEG patterns were identified during versive or circling seizures: 1) generalized spike-and-wave discharges at 3-4 cps; 2) generalized polyspike-and-wave discharges at 1 to 2.5 cps beginning with generalized fast activity at 12-14 cps, and 3) generalized spike-and-wave discharges at 3-4 cps intermingled with fast activity at 12-14 cps. Most patients had good response to treatment on a single drug regimen (mainly valproic acid). CONCLUSIONS: Versive or circling seizures may occur in the context of an IGE. Although many individuals share the features of different IGE syndromes including CAE, JAE and JME, a consistent number of patients, who show circling or versive seizures solely, remain without a specific syndromic diagnosis. When occurring in the context of IGE, circling or versive seizures do not worsen the prognosis. 相似文献
10.
Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies
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This study aimed at defining clinical predictors of drug resistance in adults with genetic generalized epilepsy (GGE) who were treated with a broad spectrum of antiepileptic drugs. Of a cohort of 137 unselected adult GGE patients with long‐term follow up, clinical and demographic data, putative prognostic factors (e.g., psychiatric comorbidities, electroencephalography [EEG]), treatment response, and data indicative of social status were collected. Fifty‐eight patients had seizures within the past year. Thirty‐three patients met the definition of “drug‐resistant epilepsy” according to the International League Against Epilepsy (ILAE) definition. Psychiatric comorbidities, age at first diagnosis, and absences were associated with worse seizure control, whereas focal changes in EEG remained without prognostic impact. Resistance to valproic acid was the most important prognostic factor for refractory seizures. Resistance to valproic acid had a specificity of 100% to identify patients with drug resistance and correlated strongly with bad social outcome and seizure burden. Conversely, 21.2% of all patients with refractory seizures according to the ILAE definition later became seizure free (mainly with valproic acid). Our data suggest that “drug resistant GGE” must not be declared unless patients were adequately treated with valproic acid, and advocate resistance to valproic acid as a new clinical biomarker for drug‐resistant GGE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here . 相似文献
11.
李素萍 《中国神经再生研究》2011,15(20):3767-3770
背景:骨质疏松的发病机制十分复杂,但又不能直接在人体上进行实验,需要复制类似人类骨质疏松的动物模型进行研究。
目的:全面分析各种骨质疏松动物模型的造模方法及优缺点,为今后研究骨质疏松症,在模型选择上提供参考。
方法:电子检索中国知识资源总库(CNKI)系列数据库和ESBCO Medline数据库1990-01/2010-07收录的骨质疏松模型的相关综述和论文报告。中文检索词为“骨质疏松,动物模型”;英文检索词为“osteoporosis,animal models”。共检索到469篇相关文献,对文章进行初审,纳入文献主题内容与此文联系紧密;原创、论点论据可靠的试验文章;观点明确,分析全面的文章。排除内容陈旧或重复文献及试验设计中不是采用随机对照试验的文章。
结果与结论:共纳入符合标准的38篇文献。目前用于骨质疏松症研究的动物模型主要有诱发性动物模型和转基因动物模型。各种骨质疏松动物模型可能只侧重于表现该疾病的某种病因、某一阶段、某些主要症状及某些病理生理变化,必须根据研究目的,选择合适的造模方法和实验动物。 相似文献
12.
PURPOSE: To describe the long-term outcome of childhood-onset secondarily generalized epilepsies (SGEs). METHODS: Children were identified from the Nova Scotia population-based epilepsy study (n=692). Onset of epilepsy was between 1977 and 1985, and follow-up was mainly in 2003. SGE was defined as having a mixture of more than one generalized seizure types including myoclonus, akinetic/atonic, tonic, or atypical absence, plus an interictal EEG with generalized spike-wave (irregular or slow) and/or multifocal spikes. RESULTS: SGE was identified in 80 children, 11.6% (80 of 692) of all childhood epilepsy. Forty percent did not fit into a currently accepted syndrome (such as Lennox-Gastaut, myoclonic-astatic or West). Seizure onset was in the first year of life in 60%, with only 9% later free of intellectual or physical handicap. Sixty-five percent (11 of 17) with Lennox-Gastaut had preceding West syndrome. During a median follow-up of 20 years, mortality was 24% (n=19), and 53% (n=42) had persistently intractable seizures. Surprisingly, 22 (28%) had >or=5 years of terminal remission (West, 31%, 10 of 32; Lennox-Gastaut, 0, none of four; myoclonic-astatic, 56%, five of nine; undefined, 31%, 10 of 32). At the end of follow-up, nearly 90% of patients fell into one of three outcome categories: death, 19 (24%); alive with intractable epilepsy, 31 (39%); or in remission for >or=5 years, 21 (26%). CONCLUSIONS: Many children with SGE have ill-defined epilepsy syndromes. SGE is characterized by early age at onset, high rates of handicap, intractability, and death, although one third achieve complete seizure control with a long terminal remission. 相似文献
13.
Purpose: Patients with idiopathic generalized epilepsies (IGEs) often present with interictal spike‐wave discharges (SWDs) at rest (spontaneous SWDs), during hyperventilation, and in response to photic stimulation (photoparoxysmal response or PPR). Valproic acid (VPA) is a first‐line antiepileptic drug for therapy of patients with IGE. Herein we investigated the effect of VPA on all three types of SWDs in children and adolescents with IGE. Methods: Routine electroencephalography (EEG) during wakefulness, which was recorded before VPA monotherapy and up to four times during the first year of the VPA treatment, was analyzed retrospectively. For the analysis of the VPA effect on spontaneous SWDs and SWDs under hyperventilation, the number and duration of SWDs were counted. SWDs under intermittent photo stimulation (IPS) were classified according to the extent of propagation (grading). Response to VPA treatment (rest/hyperventilation) was defined as a disappearance of SWDs within the year after VPA introduction. Key Findings: Eighty‐four patients (37 male and 47 female, mean age 9.5 ± 4.1 years) exhibited spontaneous SWDs or SWDs under hyperventilation. From this sample, 34 patients exhibited the PPR (7 male and 27 female, mean age 10.1 ± 3.9 years). A significant reduction in the number and duration of spontaneous SWDs and SWDs under hyperventilation was observed in the first 6 weeks of treatment (p ≤ 0.001, corrected, 87.3% responders). This effect remained stable over the 1 year observation period. Concerning PPR, only 4 (12.9%) of 31 patients were classified as responders. The difference between groups of patients with spontaneous/induced SWDs and PPR according to the number of responders was significant (p < 0.001). Significance: This study provides evidence that the effect of VPA on SWDs differs dependent on the types of SWDs. In the majority of patients, spontaneous SWDs and SWDs induced by hyperventilation disappeared, whereas the PPR mostly remained under VPA treatment. These results point to different pathogenetic mechanisms underlying the spontaneous and the evoked generalized epileptic activity in the EEG. 相似文献
14.
Classification of the epilepsies 总被引:5,自引:0,他引:5
The frequency distribution of different types of epilepsy (according to the classification model of the International League against Epilepsy) concerning 402 children is reported. The investigation showed a moderate preponderance of partial as against generalized epilepsies. Elemental and complex symptomatology were about equally frequent. As regards generalized epilepsies, the petit mal group was considerably smaller than most often reported previously; conversely, myoclonic-astatic epilepsy (Lennox-Gastaut's syndrome) was more frequently encountered. The definitory criteria and the concept of the Lennox-Gastaut Syndrome are discussed. 91.8% of the whole pediatric population (age less than 15 years at time of investigation) could be categorized according to the classification model. This, in agreement with earlier investigations on this subject, shows the contemporary international classified model to be useful and relevant. 相似文献
15.
Idiopathic generalized epilepsies with typical absences 总被引:4,自引:0,他引:4
John S. Duncan 《Journal of neurology》1997,244(7):403-411
Idiopathic generalized epilepsy (IGE) comprises several subsyndromes. These are principally: benign neonatal familial convulsions,
benign neonatal convulsions, benign myoclonic epilepsy in infancy, childhood absence epilepsy, juvenile absence epilepsy,
juvenile myoclonic epilepsy, epilepsy with generalised tonic-clonic seizures on awakening. In addition, there are less well-recognized
syndromes, such as eyelid myoclonia with absences. The pathophysiology of the IGE syndromes is not fully understood; it is
evident that typical absences are the result of abnormal oscillations between the thalamus and cerebral cortex. Genetic studies
are in progress to elucidate the biochemical defects underlying the conditions. The clinical and electroencephalographic features
of the individual subsyndromes are distinct, but some patients may be difficult to classify into a particular subgroup. A
correct syndromic diagnosis is important, as treatment strategies differ for patients with the different forms of IGE, and
it is necessary for genetic research.
Received: 4 February 1997 相似文献
16.
We report findings concerning the relationship between electroencephalography (EEG) frequency during spike-and-wave discharges (SWDs) and response to treatment in 21 patients with idiopathic generalized epilepsy (IGE). We studied patients whose EEG contained SWDs lasting at least 4 s. Among these patients, two groups could be distinguished on the basis of a subtle difference in EEG frequency during the first 2 s of the burst. The two groups differed markedly in their clinical response to medication, with the group becoming seizure-free during the next 1-2 years showing a spike-wave onset frequency of > 3.2 Hz, and those not seizure-free < 3.2 Hz (p = 0.0034, sensitivity 75% and specificity 92%). Given this strong effect in a relatively small group, further work is needed to clarify the predictive value of this frequency measure for clinical outcomes in absence epilepsies. 相似文献
17.
Benuzzi F Mirandola L Pugnaghi M Farinelli V Tassinari CA Capovilla G Cantalupo G Beccaria F Nichelli P Meletti S 《Epilepsia》2012,53(4):622-630
Purpose: Electroencephalography–functional magnetic resonance imaging (EEG‐fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so‐called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level–dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset. Methods: Twenty‐one patients with IGE underwent EEG‐fMRI coregistration. EEG‐related analyses were run both at the single‐subject and at group level (random effect). The time‐course analysis was conducted for 3 s time windows before, during, and after GSWDs, and they were included until no further BOLD signal changes were observed. Key Findings: Fifteen patients (nine female, mean age 28 years) had GSWDs during EEG‐fMRI coregistration (262 total events, mean duration 4 s). Time‐course group analysis showed BOLD increments starting approximately 10 s before GSWD onset located in frontal and parietal cortical areas, and especially in the precuneus‐posterior cingulate region. At GSWD onset, BOLD increments were located in thalamus, cerebellum, and anterior cingulate gyrus, whereas BOLD decrements were observed in the DMN regions persisting until 9 s after onset. Significance: Hemodynamic changes (BOLD increments) occurred in specific cortical areas, namely the precuneus/posterior cingulate, lateral parietal, and frontal cortices, several seconds before EEG onset of GSWD. A dysfunction of these brain regions, some of which belongs to the DMN, may be crucial in generating GSWDs in patients with IGE. 相似文献
18.
19.
Giampaolo Milior Mélanie Morin-Brureau Johan Pallud Richard Miles Gilles Huberfeld 《Epilepsia》2023,64(5):1175-1189
Animal models of human brain disorders permit researchers to explore disease mechanisms and to test potential therapies. However, therapeutic molecules derived from animal models often translate poorly to the clinic. Although human data may be more relevant, experiments on patients are constrained, and living tissue is unavailable for many disorders. Here, we compare work on animal models and on human tissue for three epileptic syndromes where human tissue is excised therapeutically: (1) acquired temporal lobe epilepsies, (2) inherited epilepsies associated with cortical malformations, and (3) peritumoral epilepsies. Animal models rest on assumed equivalencies between human brains and brains of mice, the most frequently used model animal. We ask how differences between mouse and human brains could influence models. General principles and compromises in model construction and validation are examined for a range of neurological diseases. Models may be judged on how well they predict novel therapeutic molecules or new mechanisms. The efficacy and safety of new molecules are evaluated in clinical trials. We judge new mechanisms by comparing data from work on animal models with data from work on patient tissue. In conclusion, we stress the need to cross-verify findings from animal models and from living human tissue to avoid the assumption that mechanisms are identical. 相似文献
20.
Jun-Xi Dai Nan-Yang Le Jun Cao Yang Wang 《The International journal of neuroscience》2018,128(3):243-254
Purpose/Aim: Animal models of traumatic brain injury (TBI) provide powerful tools to study TBI in a controlled, rigorous and cost-efficient manner. The mostly used animals in TBI studies so far are rodents. However, compared with rodents, large animals (e.g. swine, rabbit, sheep, ferret, etc.) show great advantages in modeling TBI due to the similarity of their brains to human brain. The aim of our review was to summarize the development and progress of common large animal TBI models in past 30 years.
Materials and Methods: Mixed published articles and books associated with large animal models of TBI were researched and summarized.
Results: We majorly sumed up current common large animal models of TBI, including discussion on the available research methodologies in previous studies, several potential therapies in large animal trials of TBI as well as advantages and disadvantages of these models.
Conclusions: Large animal models of TBI play crucial role in determining the underlying mechanisms and screening putative therapeutic targets of TBI. 相似文献