Association of HLA-B*1502 and*1511 Allele with Antiepileptic Drug-induced Stevens-Johnson Syndrome in Central China

Previous studies have demonstrated a strong association between carbamazepine（CBZ）-induced Stevens-Johnson syndrome（SJS） and HLA-B 1502 in Han Chinese. Here, we extended the study of HLA-B 1502 susceptibility to two different antiepileptic drugs, oxcarbazepine（OXC） and phenobabital（PB）. In addition, we genotyped HLA-B 1511 in a case of CBZ-induced SJS with genotype negative for HLA-B 1502. The presence of HLA-B 1502 was determined using polymerase chain reaction with sequence-specific primers（PCR-SSP）. Moreover, we genotyped HLA-B 1502 in 17 cases of antiepileptic drugs（AEDs）-induced cutaneous adverse drug reactions（cADRs）, in comparison with AEDs-tolerant（n=32） and normal controls（n=38） in the central region of China. The data showed that HLA-B 1502 was positive in 5 of 6 cases of AEDs-induced SJS（4 CBZ, 1 OXC and 1 PB）, which was significantly more frequent than AEDs-tolerant（2/32, 18 CBZ, 6 PB and 8 OXC） and normal controls（3/38）. Compared with AEDs-tolerant and normal controls, the OR for patients carrying the HLA-B 1502 with AEDs-induced SJS was 6.25（95% CI： 1.06–36.74） and 4.86（95% CI： 1.01–23.47）. The sensitivity and specificity of HLA-B 1502 for prediction of AEDs-induced SJS were 71.4%. The sensitivity and specificity of HLA-B 1502 for prediction of CBZ-induced SJS were 60% and 94%. HLA-B 1502 was not found in 11 children with maculopapular exanthema（MPE）（n=9） and hypersensitivity syndrome（HSS）（n=2）. However, we also found one case of CBZ-induced SJS who was negative for HLA-B 1502 but carried HLA-B 1511. It was suggested that the association between the CBZ-induced SJS and HLA-B 1502 allele in Han Chinese children can extend to other aromatic AEDs including OXC and PB related SJS. HLA-B 1511 may be a risk factor for some patients with CBZ-induced SJS negative for HLA-B 1502.

Low-velocity simultaneous bilateral femoral neck fracture following long-term antiepileptic therapy:A case report

BACKGROUND Simultaneous bilateral femoral neck fractures are relatively rare injuries.They are usually associated with underlying metabolic bone disorders or systemic diseases.Long-term use of narcotics and bisphosphonates can also result in similar fracture patterns;however,association of this fracture type with longterm use of antiepileptic drugs is not very common.Only one such case has been reported in the literature.This article describes the second.CASE REPORT We report a case of simultaneous displaced bilateral femoral neck fractures in a 50-year-old epileptic patient,who had taken phenytoin for the past 3 years.The fractures were a result of low-velocity injury following a fall from the bed.The fractures were managed with a bilateral hemi-replacement arthroplasty.Oral bisphosphonates were given to improve the bone quality in the post-operative period.The patient had a good post-operative outcome,that was sustained throughout the entire follow-up period of 1 year.CONCLUSION Antiepileptic drugs should be supplemented with bisphosphonates and vitamin D to improve bone quality and prevent fractures in epileptic patients.

Comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury:a randomized clinical trial

BACKGROUND： Liver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries （DILI） in children. Although withdrawal of the causative agent is the only proved treatment for DILI, in some dinical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with antioxidant actions for the management of DILl. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy. METHODS： This randomized, open-label, clinical trial evalu- ated 55 children with epilepsy who were on antiepileptic treat- ment and experienced DILL The children were randomized to receive either silymarin （5 mg/kg per day） or folic acid （1 mg per day） for one month and were followed up for three months. RESULTS： Liver enzymes significantly decreased in both groups. The decrease trend in alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were stronger in the folic acid group compared to silymarin group （P=0.04 and P=0.007, respectively）. At the end of the study patients in the folic acid group had significantly lower ALT （P=0.04）, AST （P=0.02）, and gamma-glntamyl transferase （GGT） （P〈0.001） levels and also higher percentage of normal ALT （30.7% vs 3.4%, P=0.009） and AST （42.3% vs 0%, P〈0.001）, and GGT （23.1% vs 0%, P=0.008） values compared to the patients in the silymarin group. No rebound elevations in ALT, AST and GGT levels or adverse reactions were noted in neither of the study groups.CONCLUSION： Although both treatments were safe and effective in decreasing liver enzymes, folic acid seems to be superior to silymarin in the management of DILl.

Tall gastrodis tuber combined with antiepileptic drugs repairs abnormal perfusion foci in focal epilepsy

One hundred patients with focal epilepsy were recruited for the present study and their seizures controlled with antiepileptic drugs. The patients then orally received a capsule of tall gastrodis tuber powder, a traditional Chinese drug, and underwent single photon emission computed tomography, long-term electroencephalogram, and CT/MRI. Blood drug levels were monitored throughout the study. Before treatment with tall gastrodis tuber, 35 of the 100 cases had abnormal CT/MRI scans; 79 cases had abnormal single photon emission computed tomography images; 86 cases had abnormal electroencephalogram; and a total of 146 abnormal perfusion foci were observed across the 100 subjects. After treatment, the number of patients with normal single photon emission computed tomography images increased by 12; normal electroencephalogram was observed in an additional 27 cases and the number of patients with epileptiform discharge decreased by 29 （34% of 86）; the total number of abnormal perfusion foci decreased by 52 （36%） and changes in abnormal loci were visible in 65 patients. These changes indicate that the administration of tall gastrodis tuber in combination with antiepileptic drugs repairs abnormal perfusion foci in patients with focal epilepsy Our results demonstrate that traditional Chinese drugs can repair abnormal perfusion foci and, as such, are a promising new pathway in the treatment of focal epilepsy.

Chronic antiepileptic drug use and functional network efficiency: A functional magnetic resonance imaging study

AIM To increase our insight in the neuronal mechanisms underlying cognitive side-effects of antiepileptic drug(AED) treatment.METHODS The relation between functional magnetic resonance-acquired brain network measures, AED use, and cognitive function was investigated. Three groups of patients with epilepsy with a different risk profile for developing cognitive side effects were included: A "low risk" category(lamotrigine or levetiracetam, n=16), an "intermediate risk" category(carbamazepine, oxcarbazepine, phenytoin, or valproate, n=34) and a "high risk" category(topiramate, n=5). Brain connectivity was assessed using resting state functional magnetic resonance imaging and graph theoretical network analysis. The Computerized Visual Searching Task was used to measure central information processing speed, a common cognitive side effect of AED treatment. RESULTS Central information processing speed was lower in patients taking AEDs from the intermediate and high risk categories, compared with patients from the low risk category. The effect of risk category on global efficiency was significant(P < 0.05, ANCOVA), with a significantly higher global efficiency for patient from the low category compared with the high risk category(P < 0.05, post-hoc test). Risk category had no significant effect on the clustering coefficient(ANCOVA, P > 0.2). Also no significant associations between information processing speed and global efficiency or the clustering coefficient(linear regression analysis, P > 0.15) were observed. CONCLUSION Only the four patients taking topiramate show aberrant network measures, suggesting that alterations in functional brain network organization may be only subtle and measureable in patients with more severe cognitive side effects.

Short-term use of antiepileptic drugs is neurotoxic to the immature brain

Previous studies have shown that the long-term use of antiepileptic drugs can cause nervous system damage. However, short-term antiepileptic drug treatment is frequently given to in-fants, especially neonates, to control seizure. Whether the short-term use of antiepileptic drugs is neurotoxic remains unclear. In the present study, immature rats, 3–21 days of age, were intraperitoneally injected with phenobarbital and/or topiramate for 3 consecutive days. Hema-toxylin-eosin and immunohistochemical staining revealed that phenobarbital and topiramate, individually or in combination, were cytotoxic to hippocampal CA1 neurons and inhibited the expression of GluR1 and NR2B, excitatory glutamate receptor subunits. Furthermore, the com-bination of the two drugs caused greater damage than either drug alone. The results demonstrate that the short-term use of antiepileptic drugs damages neurons in the immature brain and that the combined use of antiepileptic drugs exacerbates damage. Our ifndings suggest that clinicians should consider the potential neurotoxic risk associated with the combined use of antiepileptic drugs in the treatment of seizure.

Effect of Second-generation Antiepileptic Drugs on Diplopia:A Metaanalysis of Placebo-controlled Studies

Different antiepileptic drugs(AEDs) may cause similar adverse effects,one of which is diplopia.However,the AEDs causing diplopia and the dose-response effect of each drug remains uncertain.In this study,we compared several second-generation AEDs to find out whether they would contribute to the risk of diplopia and their effect-causing dose.A meta-analysis was performed on 19 studies in agreement with our inclusion criteria.The results showed that eight commonly used second-generation AEDs(gabapentin,levetiracetam,oxcarbazepine,lamotrigine,pregabalin,topiramate,vigabatrin and zonisamide) could cause diplopia.The reported odds ratios(ORs) ranged from 1.406 to 7.996.Ranking risks from the highest to the lowest ORs of the eight AEDs of any dose resulted in the following order:use of oxcarbazepine(7.996),levetiracetam(7.472),lamotrigine(5.258),vigabatrin(3.562),pregabalin(3.048),topiramate(2.660),gabapentin(1.966),zonisamide(1.406).Taking into account the ORs above,we can conclude that second-generation AEDs of any dose may cause diplopia.However,the levetiracetam-caused diplopia needs to be further studied according to the data(OR,7.472;95% confidence interval,0.375-148.772).These findings ask for better concerns about patients’ quality of life when giving antiepileptic treatments.

Antiepileptic activity of lobeline isolated from the leaf of Lobelia nicotianaefolia and its effect on brain GABA level in mice

Objective:To investigate the anticonvulsant activity of the lobeline isolated from the Lobelia nicotianaefolia in chemoconvulsant-induced seizures and its biochemical mechanism by investigating relationship between seizure activities and altered gamma amino butyric acid(GABA)in brain of mice in Pentylenetetrazol(PTZ) seizure models.Methods:The anticonvulsant activity of the isolated lobelinc(5,10,20 and 30 mg/kg.i.p.) was investigated in PTZ and strychnine induced seizures in mice and the effect of isolated lolieline on brain GABA level in seizures induced by PTZ.Diazepam was used as reference anticonvulsant drugs for comparison.Results:Isolated lobeliue(10,20 and 30 nig/kg.up.) significautly delayed and antagonized(P < 0.050-0.001)the onset of PTZ-induced seizures.It also antagonized strychnine induced seizures.The mortality was also prevented in the test group of animals.In biochemical evaluation,isolated lolieline(5,10and 20 mg/kg,i.p.) significantly increased the brain GABA level.And at dose of 30 mg/kg GABA level showed slight decrease in PTZ model.Conclusions:In our findings,isolated lolieline(20mg/kg) exhibited potent anticonvulsant activity against PTZ induced seizures.Also a biochemical evaluation suggested significant increase in harain GABA level at 20 nig/kg up.of isolated lolieline.Hence,we may propose that lolieline reduces epileptic seizures by enhancing the GABA release supporting the GABAergic mechanism.

Use of antiepileptic drugs in children with brain tumors: A review for acute management

Patients with primary or secondary tumors in the central nervous system may have seizures resulting from direct tissue damage,metabolic abnormalities,infection,or toxic side effects of medications.In pediatric patients,it is more frequent to use drugs to control secondary epilepsy.In this article,we discuss the main nuances of antiepileptic drugs for the proper management of children with central nervous system tumors.

Brain Tumours and Prophylactic Antiepileptic Drug Prescribing Patterns by Neurosurgeons Practising in Australasia

Prescribing patterns amongst practising Australasian neurosurgeons regarding the use of prophylactic antiepileptic drugs (AEDs) in patients with newly diagnosed intrinsic brain tumours are not well established. This study aimed to determine the rate of prophylactic AED prescribing in this clinical context and to determine if there were some particular factors that influenced prescribers in their decision. A survey was conducted, and of the 91 respondents, 23 (25.3%) prescribed prophylactic AEDs. No neurosurgeons practising in New Zealand prescribed, whereas within Australian states/territories, prescribing was most common in Western Australia (3/4, 75.0%) and Queensland (8/18, 44.4%) and less common in the Australian Capital Territory (0/2, 0.0%) and South Australia (1/7, 14.3%). The most commonly prescribed first-line AED was phenytoin (n = 15, 68.2%) followed by levetiracetam (n = 5, 22.7%). The duration of prescription varied from 1 week to 6 months, with 6 weeks chosen by most prescribers (n = 7, 35%). Important factors that influence the decision to prescribe include tumour location and a history of previous seizure/s, whereas the presence of oedema or haemorrhage and patients’ age do not seem to be major influences amongst prescribers.

The Use of Antiepileptic Drugs in Acute Neuropsychiatric Conditions: Focus on Traumatic Brain Injury, Pain, and Alcohol Withdrawal

Antiepileptic drugs (AEDs), have demonstrated efficacy treating a number of acute conditions, encompassing a broad range of symptoms and syndromes, in addition to being first-line treatment for epilepsy. Clinically, since their inception, AEDs have been used off-label for acute and chronic medical conditions, both as primary and as adjuvant therapies. In this review, we describe the observed clinical effectiveness of AEDs across a set of commonly encountered acute conditions in the general hospital: traumatic brain injury, pain, alcohol withdrawal. In describing the individual benefits and usages of specific agents, the applicability of these agents to other common neuropsychiatric conditions may be further explored.

Antiepileptic Drug-Induced Apoptosis Was Prevented by L-Type Calcium Channel Activator in Cultured Rat Cortical Cells

Experimental data have shown that antiepileptic drugs cause neurodegeneration in developing rats. Valproate (VPA) is the drug of choice in primary generalized epilepsies, and carbamazepine (CBZ) is one of the most prescribed drugs in partial seizures. These drugs block sodium channels, thereby reducing sustained repetitive neuronal firing. The intracellular mechanisms whereby AEDs induce neuronal cell death are unclear. We examined whether AEDs induce apoptotic cell death in cultured cortical cells and whether calcium ions are involved in the AED-induced cell death. VPA and CBZ increased apoptotic cell death and induced morphological changes that were characterized by cell shrinkage and nuclear condensation or fragmentation. Incubation of cortical cultures with VPA or CBZ decreased phospho-Akt levels. CBZ decreased the intracellular calcium levels. On the other hand, FPL64176, an L-type calcium channel activator, increased the intracellular calcium levels and prevented the AED-induced apoptosis. Glycogen synthase kinase-3 inhibitors, such as alsterpaullone and azakenpaullone, prevented the AED-induced apoptosis. These results suggest that intracellular calcium level changes are associated with AEDs and apoptosis and that the activation of glycogen synthase kinase-3 is involved in the death of rat cortical neurons.

Extended Antiepileptic Drug Prophylaxis and Late Onset Seizures in Aneurysmal Subarachnoid Hemorrhage

Background: The indication and optimal duration of antiepileptic drug (AED) prophylaxis after aneurysmal subarachnoid hemorrhage (SAH) remains controversial. Our institution practices routine seizure prophylaxis for variable durations at the discretion of the neurosurgeon and neuro-intensivist. Given the propensity of late onset seizures to progress to chronic epilepsy, we sought to investigate the efficacy of extended AED prophylaxis in reducing the risk of late seizures. Methods: This retrospective study analyzed 36 patients who were admitted to our neurosurgical intensive care unit (NICU) over a 2-year period (1st November 2015 to 31st October 2017). All hospital admissions records, electronic medication records as well as outpatient visits up to 1 year were reviewed. Late onset seizures were defined as seizures occurring more than 7 days post-intervention (or presentation if no intervention was performed) up to 1 year of follow-up. Results: Majority of the patients received Levetiracetam (94%) as seizure prophylaxis and late onset seizures occurred in 6 (17%) of the patients. Those patients who received a greater proportion of in-patient stay with AED prophylaxis had a statistically significant lower risk of developing late seizures (OR = 0.964, 95%, p = 0.02). Although the value tended towards benefit (OR = 0.382) for AED > 21 days in-hospital, the result was not statistically significant (p = 0.307). Conclusion: An extended duration of AED prophylaxis, in particular Levetiracetam, may confer some benefit in reducing risk of developing late seizures. However, the optimal duration of therapy is yet to be determined and further large multi-centered randomized studies are necessary.

Hypersensitive syndrome reaction of antiepileptic drug: two case reports and literature review

Hypersensitivity syndrome reaction of antiepileptic drug （AED） can induce serious cutaneous, hematological and hepatic events. In severe cases, fulminant hepatic failure may necessitate liver transplantation, and most patients die due to the liver failure. Severe adverse cutaneous reactions, including Steven-Johnson syndrome （SJS）, toxic epidermal necrolysis （TEN） and hypersensitivity syndrome, are rare but life-threatening. Its morality rate is as high as 5%-50%. Accurate early diagnosis and timely treatment may contribute to decreased morality rate. In this paper, we reported cases of hypersensitive syndrome reaction to carbamazepine （CBZ） or phenobarbital （PB） in two patients with epilepsy. Clarification of the therapeutic process and the early manifestation of epilepsy may be helpful to improve the epilepsy therapy while avoiding the potential severe adverse cutaneous reactions of AED. The two reported cases highlighted that the therapeutic process of CBZ and PB might lead to the fatal allergic reaction, which was mainly caused by the absence of epoxide-hydroxylase and the defect of hepatocytes.

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Pharmacologic Effects of Cannabidiol and Its Molecular Mechanism

Cannabidiol(CBD)is the active constituent of Cannabis sativa and exhibits a diverse range of pharmacologic effects,including anticancer,antibacterial,anti-inflammatory,antioxidant,and antiepileptic properties.The pharmacologic effects of CBD and its molecular mechanisms are reviewed with the objective of proposing novel approaches for basic research and clinical applications of CBD and related pharmaceuticals.

Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients： A 7-year Study in an Epilepsy Center in China

Background： It is important to choose an appropriate antiepileptic drug （AED） to manage partial epilepsy. Traditional AEDs, such as carbamazepine （CBZ） and valproate （VPA）, have been proven to have good therapeutic effects. However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy. As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research. Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy. Methods： This is a retrospective, long-term observational study. Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate （TPM）, oxcarbazepine （OXC）, lamotrigine （LTG）, or levetiracetam （LEV）, were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated. Results： A total of 789 patients were enrolled. The median time of follow-up was 56.95 months. CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months （95% confidential interval： 30.64~4.07）. CBZ exhibited the highest 12-month remission rate （85.55%）, which was significantly higher than those of TPM （69.38%, P = 0.006）, LTG （70.79%, P= 0.001）, LEV （72.54%, P = 0.005）, and VPA （73.33%, P = 0.002）. CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA. Overall, adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems （8.09%）, rashes （7.76%）, abnormal hepatic function （6.24%）, and drowsiness （6.24%）. Conclusion： This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing tbcal epilepsy as measured by time to first seizure, 12-month remission rate, and retention rate.

Antiepileptic drug-induced multidrug resistance P-glycoprotein overexpression in astrocytes cultured from rat brains

Background Intractable epilepsy may be due to multidrug resistance induced by conventional antiepileptic drugs. The phenomenon is sometimes associated with an overexpression of multidrug resistance gene 1 (MDR 1). The purpose of this study was to determine if the overexpression of MDR 1 could be induced in astrocytes from rat brains in vitro using antiepileptic drugs.Methods Astrocyte cell cultures from postnatal Wistar rats (within 24 hours of birth) were established. Different concentrations of the antiepileptic drugs phenytoin, phenobarbital, carbamazepine, and valproic acid were added to the cultures for 10, 20, or 30 days. The expression of P-glycoprotein (Pgp), the protein product of MDR 1, was investigated with immunocytochemistry. Results Less than 5% of normal, untreated astrocytes had detectable Pgp staining at any time point. Phenytoin, phenobarbital, carbamazepine, and valproic acid induced the overexpression of Pgp in astrocytes in a dose- and time-dependent manner. Significantly higher levels of Pgp staining were detected at therapeutic concentrations of certain antiepileptic drugs (20 μg/ml phenobarbital, 40 μg/ml phenobarbital, and 20 μg/ml phenytoin) on day 30. Upregulation of Pgp was detected when using higher concentrations of phenytoin, phenobarbital, and valproic acid on day 20 and when using higher concentrations of any of the four antiepileptic drugs on day 30. Conclusions Treatment with antiepileptic drugs may contribute to the overexpression in astrocytes of MDR 1 and its protein product, Pgp. The mechanism leading to MDR must be considered in patients undergoing long-term treatment with antiepileptic drugs.

Effects of antiepileptic drugs on bone mineral density and bone metabolism in children: a meta-analysis

Objective： The aim of our meta-analysis was to assess the effects of antiepileptic drugs on bone mineral density and bone metabolism in epileptic children. Methods： Searches of Pub Med and Web of Science were undertaken to identify studies evaluating the association between antiepileptic drugs and bone mineral density and bone metabolism. Results： A total of 22 studies with 1492 subjects were included in our research. We identified：（1） a reduction in bone mineral density at lumbar spine（standardized mean difference（SMD）=-0.30, 95% confidence interval（CI） [-0.61,-0.05]）, trochanter（mean difference（MD）=-0.07, 95% CI [-0.10,-0.05]）, femoral neck（MD=-0.05, 95% CI [-0.09,-0.02]）, and total body bone mineral density（MD=-0.33, 95% CI [-0.51,-0.15]）;（2） a reduction in 25-hydroxyvitamin D（MD=-3.37, 95% CI [-5.94,-0.80]） and an increase in serum alkaline phosphatase（SMD=0.71, 95% CI [0.38, 1.05]）;（3） no significant changes in serum parathyroid hormone, calcium, or phosphorus. Conclusions： Our meta-analysis suggests that treatment with antiepileptic drugs may be associated with decreased bone mineral density in epileptic children.

Models for predicting treatment efficacy of antiepileptic drugs and prognosis of treatment withdrawal in epilepsy patients

Although anteplleptlc drugs(AEDs)are the most effective treatment for epllepsy,30-40%of patlents with epllepsy would develop drug-efacory eplepsy.An accurate,prellminary predlctlon of the efflcacy of AEDs has great clinical signflcance for patent treatment and prognosts.Some studles have developed statstical models and machine-learning algorithms(MLAS)to predlct the fficacy of AEDs treatment and the progression of disease ater treatment withdrawal,In order to provlde asstance for makng cInlcal decslons In the alm of precse,personalzed treatment The fleld of predcton models with statstical models and MLAs's atracting growing Interest and's developing rapldly.What's more,more and more studles focus on the external valldation of the exlsting model In this revlew,we will glve a brlef overvlew of recent developments In this discipline.