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Current status of traumatic brain injury research in Malaysia: A systematic review

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. In 2009, the National Trauma Database Malaysia reported that nearly 80% of traumas in the population were caused by road traffic accidents, with 64% of these cases related to TBI. Despite these concerning reports, TBI reporting systems and research are still limited in Malaysia. Thus, this systematic review aimed to identify and evaluate the available literature on TBI in Malaysia in order to uncover the status of TBI research in Malaysia. A comprehensive literature search was performed on four databases (PubMed, Embase, Medline and Scopus) regarding TBI in Malaysia. Critical evaluation of 60 relevant articles after application of inclusion and exclusion criteria have indicated that TBI research in Malaysia may have significant limitations in representing the actual TBI population and was lacking in basic TBI research. Thus, there is a dire need for government and private institutions to provide support for the advancement of TBI reporting and the progression of basic, clinical and translation TBI research in Malaysia. This will create a deeper understanding of TBI, contributing to global TBI knowledge, and advancing the development of efficient interventions for Malaysians with its population heterogeneity taken into consideration.


INTRODUCTION
Traumatic brain injury (TBI) is not just a single event, but a disorder with a high mortality and morbidity rate worldwide (Hyder et al., 2007;Rubiano et al., 2015). In 2018, a paper in the Journal of Neurosurgery referred TBI as a 'silent epidemic', and their model estimated that annually around 64 to 74 million new TBI cases were reported worldwide (Dewan et al., 2018). Interestingly, they showed that the major risk factor for TBI was road traffic accidents, which were greatest in Southeast Asian and African countries (56% of global TBI cases, respectively) (Dewan et al., 2018). Although global mortality and morbidity rates are yet to be accurately determined, the Centre for Disease Control and Prevention (CDC) reported that an average of 155 people in the USA dies daily from TBI (Centers for Disease Control and Prevention, 2019).
Despite these alarming figures, the multidimensional cascades of secondary injury pathologies of TBI, which include but are not limited to neuroinflammation, mitochondrial dysfunction, and glutamate

OPEN ACCESS | SYSTEMATIC REVIEW ISSN: 2576-828X
excitotoxicity, still lack sufficient understanding, thus leading to ineffective treatment and prevention strategies (Pavlova et al., 2018). These secondary injury mechanisms of TBI may often persist for months to years later and are often associated with the later development of a range of neurological disorders such as Alzheimer's disease (Fleminger et al., 2003;Nemetz et al., 1999), Parkinson's disease (Gardner et al., 2015), Amyotrophic Lateral Sclerosis (Chen et al., 2007) and even neuropsychological disorders (Fann et al., 2009). Thus, TBI may not only affect the quality of people's lives, but it also may create a substantial economic burden as well (Coronado et al., 2012), especially when accounting the cost associated with their long-term outcomes. Middle-income countries like Malaysia are especially more prone to these burdens, given the high incidence rate of traffic accidents coupled with the possibility of inadequate trauma care facilities especially in district general hospitals (Sethi et al., 2002), leading to poorer outcomes post TBI (MaHTAS, 2015).
In Malaysia, TBI was deemed as one of the top three common admissions reported in intensive care units (Rai et al., 2017), which was not surprising given the number of road traffic accidents reported annually. Nevertheless, actual nationwide incidence rate and statistics on TBI remain underreported, especially when accounting for non-road accident TBI cases, such as falls or abuse. The National Trauma Database Malaysia (NTrD) governed by the Ministry of Health, took the initiative to report TBI cases in Malaysia annually. However, only 4 reports, thus far, have been published, with the last report only updated in the year 2011. Furthermore, these reports only included major trauma cases, that were identified by 8 participating hospitals in Malaysia, and consisted of various types of traumas, instead of being TBI specific. Underreporting of the actual number of trauma cases was even recognized as a limitation by the report, but a solution to this problem was not discussed. In brief, the 2011 report showed that in the year 2009, nearly 80% of trauma cases in Malaysia were due to road traffic accidents, which mainly affected many younger (15-24, 34%) males (87%) (Jamaluddin et al., 2011). These figures are likely still valid to this day. Although the survival rate may be higher than the death rate among Malaysian trauma patients (Jamaluddin et al., 2011), follow up studies have yet to be effectively established or recorded, to determine the long-term outcomes post-TBI, despite the recovery in these patients.

Study Selection and Inclusion Criteria
The following inclusion criteria were applied during study selection: 1) peer-reviewed original research articles that investigate traumatic brain injury within Malaysia only, 2) articles with full-text availability. The following exclusion criteria were applied as well: 1) articles labelled as symposiums, editorials, book chapters, conference papers, case reports, reviews and systematic reviews, 2) articles which were not in the English language, 3) duplicated articles, 4) articles that did not focus its investigation on traumatic brain injury, and 5) articles that did not have an association with Malaysia in terms of research or a Malaysian institutional affiliation. The selection of studies was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Moher et al., 2015).

Quality Appraisal
The quality of the selected articles included in this systematic review was assessed using different tools. The prospective and retrospective studies were appraised using the Quality Assessment Tool for Quantitative Studies by The Effective Public Health Practice Project (EPHPP) (Project, 1998) (Table S1). The cross-sectional studies were evaluated using the recently introduced but validated Appraisal tool for Cross-Sectional Studies (AXIS tool) (Downes et al., 2016) ( Table S2). Critical Appraisal Skills Programme (CASP) tool was used to evaluate the case-control studies (CASP, 2018) (Table S3), while the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to appraise randomized clinical/controlled trials (RCTs) studies (Higgins et al., 2011) (Table S4). The quality and risk of bias of the selected animal studies included in this systematic review were assessed using the Systematic Review Centre for Laboratory animal Experimentation Risk of Bias (SYRCLE RoB tool) (Hooijmans et al., 2014) (Table S5). Unfortunately, currently, there is no wellvalidated critical appraisal tool for the validation and computational studies included in this review.

RESULTS
The initial literature searches retrieved 686 articles: 89 articles from PubMed, 186 articles from EMBASE, 316 articles from Scopus and 95 articles from Medline. Three hundred and one duplicated articles were removed, and 385 articles were screened based on the exclusion criteria for peer-reviewed original research articles only. Finally, the abstracts of the 201 articles were screened for relevancy, where 141 articles were found to be irrelevant to the aim of this systematic review; their investigation was not focused on traumatic brain injury and was not investigated in Malaysia. To be noted, there were 5 case reports identified (before the exclusion criteria) that were relevant to the aim of this review but were not included for critical appraisal as case reports provide bias and insufficient information for effective evaluation of the findings.
Thus, a total of 60 studies were selected for critical appraisal as per PRISMA guidelines ( Figure 1) and were systematically evaluated in this review. The 60 articles were further categorized into 17 clinical, 34 epidemiology studies, 6 preclinical animal studies and 3 computational model studies for ease of evaluation. The characteristics and significant findings of the selected studies were summarized in Table 1.

Publication Overview of Population Studies
The human/population studies included 34 epidemiological studies which can be further characterized into 3 case-control, 7 prospective cohorts, 6 prospective longitudinal, 7 retrospective and 11 crosssectional studies, as well as 17 clinical studies which included 7 randomized controlled trials (RCT), 9 prospective observational and 1 validation studies (Table 1). There was a wide range in the type of population studies conducted in Malaysia, with epidemiological studies, mainly cross-sectional studies, is the most sought-after form of study methodology and clinical studies, especially validation studies, being the least investigated thus far ( Figure 2B). Population-based research on TBI in Malaysia has increased at an exponential rate every 5 years (Figure 2A), starting with the first publication recorded in 1988 by Pratap-Chand and his colleagues, that investigated the diagnostic usage of cognitive evoked potential to determine cognitive dysfunction after a concussion (Pratap-Chand et al., 1988) (Table 1). Most researchers chose to focus their investigations on the functional outcome post TBI (30%), followed by diagnostic (18%), prognostic (10%) and relationship (10%) studies and finally an almost equal spread in all other areas of investigations ( Figure 2D). Studies whereby their aim of investigation was in rehabilitation, quality of life of patients or caregivers, epidemiology and tool assessment, had only a single study in each Midline shift, duration of coma and duration of transport were found to be significant variables associated with bad outcome (Kumaraswamy et al., 2002) NEUROSCIENCE RESEARCH NOTES | 2020 | VOLUME 3 | ISSUE 4 | PAGE 7 Treatment-care 12-30 years; 69M, 13F Severe Significant difference in proportions of good outcomes between the multimodality group, patients that underwent a single intracranial-based monitoring method and the group that received no monitoring (Isa et al., 2003) Cost 18-75 years; 57M, 5F Severe The application of M3 for severe TBI was more cost-effective than BNM  Prognostic 17-69 years; 47M, 5F Severe The outcome at 6 months post treatment between the two modality groups was not statistically significant    Kumaraswamy et al., 2002), which aimed at investigating the functional outcome in patients post TBI, and only one study that investigated the impact on caregivers of TBI patients, with a follow up for more than 5 years (Mazlan et al., 2016). Majority of the studies looked at acute (24-72 hours) or subacute (weeks) effects of TBI, especially those with research aimed at diagnosis after TBI.
Nearly 25% of the population studies were published in Malaysian journals such as Malaysian Journal of Medical Sciences, and more than 50% of the population studies were published in high ranking journals; Q1 and Q2 journals, according to SCImago journal ranking ( Figure  2C). There was no observable correlation between type of study or research aim with the publication journal ranks. Quality assessments on the publications revealed that the population-based studies had five studies (3 cross-sectional and 2 RCTs) which may be biased due to lack of blinding and sample size justification, while quality assessment of the rest of the population based studies and preclinical animal studies showed unbiased methodology and reporting of their results (see Supplementary S1-S5).

Population Sample Overview
Most of the studies have sampled the adult population (18 years and above); 21 studies had a population average age in their 30s, 15 studies in their 20s and only 1 study had a mean population age of 46.13 years ( Figure 3A). Ten studies investigated TBI in children or in a paediatric population (18 years and below). Four of the population studies had an undefined mean population age, but stated their population age range to be 18 years and above. In most of the studies with a wide age range for participant recruitment, participants in their 20s to 30s reported the most TBI cases, especially due to road accidents, which accounts for around 70-90% of all TBI cases in nearly all the selected population studies. One study by Sharda et al (2014), found that road traffic accidents, especially those involving motorbikes, was the most common cause of TBI among the 12-30 years old age group (Sharda et al., 2014). While the younger population were at higher risk of attaining TBI, some of the selected studies suggested that there was a negative correlation between the outcomes of TBI (especially cognitive effects) and age (Asha'Ari et al., 2011;Sharifuddin et al., 2012;Veeramuthu et al., 2014;Vijian et al., 2020). In contradiction, some studies also suggested no significant effect between age and functional outcome or prognosis (Abdullah et al., 2005;Abdullah et al., 2018;Kan et al., 2009;Kiflie et al., 2006;Ludin et al., 2019).
Interestingly, when calculating and stratifying the number of participants in each of the studies sample population according to gender, a large gender difference was noticed in the age groups 10s, 20s and 30s, with males predominating the population by more than 1000 participants in the 20s and 30s age group ( Figure 3B). Females were clearly underrepresented in the Malaysian population TBI studies. Nevertheless, a number of studies indicated no significant relationship between gender differences and measures of TBI, except a recent study by Abdullah et al. (2020) that witnessed male TBI patients having a higher calorie intake than their female counterpart at discharge day (Abdullah et al., 2020).
As for racial representation, most of the TBI population studies had a 6:2:1:1 ratio of Malays: Chinese: Indian: Other minorities, respectively. Cumulatively, the Malay population represented 62% of the pooled sample of all the population studies, with Chinese following at 16% of the pooled sample, Indians at 12% and finally the other minority ethnicities such as the indigenous Malaysians making up the remaining 10% of the pooled sample ( Figure 3C). Only one study utilized religion as a characteristic of their sample (Abdullah et al., 2018). Twenty-six studies did not identify the ethnicity of their population, while 7 studies had an unequal representation of the Malaysian population ethnicity; only had one or two of the ethnicities represented. Among the studies that had a good ethnicity representation, only two studies suggested that ethnicity heterogeneity had a significant influence on the TBI outcome (Ali et al., 2013;Jeng et al., 2008).
Type of TBI severity was fairly well investigated in the population studies, with severe TBI (GCS <8) investigated in 36% of studies, followed by mild TBI (GCS 13-15) and lastly by moderate TBI (GCS 9-12) ( Figure  3D). Only thirteen studies investigated all three TBI severities within their population sample and showed that TBI severity affects the functional outcome and diagnosis post TBI, whereby severe TBI showed poorer outcomes.
According to the 2019 road accident statistics, reported by the Royal Malaysian Police (PDRM, 2020a), Selangor had the highest number (darkest orange colour) of road accidents cases followed by Johor and then Wilayah Persekutuan (WP) Kuala Lumpur ( Figure 4A). However, the TBI participants sampled for the population studies were mainly from areas surrounding WP Kuala Lumpur with 18 studies, followed by Kelantan with 17 studies ( Figure 4B). A large proportion of the studies sampled their TBI population from the University Malaya Medical Centre (UMMC) or from the General Hospital Kuala Lumpur (GHKL), both situated in Kuala Lumpur. In Kelantan, the TBI participants was mainly sampled from the University Sains Malaysia (USM) Hospital. Therefore, the publication affiliations for these TBI studies were majorly from USM (Kelantan campus and hospital) with 23 TBI studies published by their researchers, followed by University Malaya researchers publishing 12 TBI population studies in total ( Figure 5). Interestingly, although Jeng et al (2008) sampled his population from GHKL, the sample contained TBI patients from various Malaysian states that were part of referrals to GHKL (Jeng et al., 2008). However, the differences in the Malaysian states were not significantly correlated with the aim of their study.

Basic Science Research
The literature search revealed that basic science research or preclinical research in the TBI field was very scarce in Malaysia, with only 9 studies; 6 animal studies and 3 computational studies, ever to be published and all only within the last decade (Table 1). The preclinical animal TBI studies were performed only by two research groups; one from University Malaya with articles published by Khalin I. et al. and the other from University Sains Malaysia with articles published by Muthuraju S. and his colleagues. Both groups used adult (11-13 weeks of age) male mice to investigate functional outcomes and interventions post TBI ( Figure 6). Khalin et al. applied the weight drop injury model Khalin, Jamari, et al., 2016) while Muthuraju et al. applied the fluid percussion injury (FPI) model to inflict TBI in their animals (Muthuraju et al., 2014;Muthuraju et al., 2012;Muthuraju, Taha, et al., 2013). While both groups used similar mice breed as their animal model, Khalin et al. used two variations for each of their published studies in 2016; C57BL/6 mice  and C57BL/6N mice (Khalin, Jamari, et al., 2016), and Muthuraju et al. used the C57BL/J6 mice consistently in all their published studies ( Figure 6). Although Khalin et al. claimed that their injury model achieved severe TBI, Muthuraju et al. did not specify their injury severity resulted from their injury model. Regardless, all six of the preclinical studies suggested cognitive or motor deficits as well as neuronal damage that were significantly evident post injury, which may be reversed to sham levels, using different interventions such as BDNF , normabaric hypoxia treatment (Muthuraju et al., 2014;Muthuraju, Taha, et al., 2013) and enriched environment (Muthuraju et al., 2012).
The preclinical computational studies had no similarities in methodology or in research group. Based on Table 1, Alazani et al. (2018) was focused on a creating a predictive model for TBI disease classification using mathematical formula and equations (Alanazi et al., 2018), while Taha et al. (2015) had proposed a mathematical model that studies the kinematic parameters surrounding the impact of a soccer ball on a head resulting in TBI (Taha et al., 2015). Similarly, Norli et al. (2018) had developed a virtual software (Finite Element) that may be used to understand and predict the mechanics of head injury in patients based on the impact velocity information available on the sustained TBI (Norli et al., 2018).    This review observed an exponential increase in TBI publications in Malaysia within the last two decades, which could be a reflection towards the increased awareness of TBI research globally, as well as the increased number of TBI cases in Malaysia (Jamaluddin et al., 2011). The increment in TBI cases could be an indirect result of Malaysia's economy growth which may enable more Malaysian citizens, especially adolescence, to afford motor vehicles. In conjunction with the increase in TBI cases and awareness, the type of study design and TBI research aims have expanded as well, as more researchers collaborate with hospitals and universities to provide a better understanding of traumatic brain injury within Malaysia and globally. While Malaysian TBI research has been well cited and received in high impact journals, Malaysia is still a couple of steps behind in producing high throughput and high quality TBI research as compared to leading TBI experts in high income countries such as Australia, America, Europe and China (Tropeano et al., 2019). This is alarming as global TBI incidence reports have stated that countries in Southeast Asia, such as Malaysia have the highest number of reported TBI cases, which are majorly due to motor vehicle accidents (Dewan et al., 2018). In support, the latest 2019 Malaysian road accident report by the Royal Malaysian Police (PDRM) have shown that the number of road accidents in Malaysia affected about 1.74% of the population every year and at an increasing rate of 10,000 to 20,000 cases yearly (PDRM, 2020a). Given that the number of TBI fatalities were decreasing in the past years (PDRM, 2020b), indirectly indicating an increase in TBI survivors, more studies investigating the secondary outcomes post TBI are therefore much needed in Malaysia.
Secondary outcomes of TBI included cognitive deficits, motor impairments, disease progression such as epilepsy and neuropsychiatric disorders, which have all been reported globally (Kozlowski et al., 2013;Lucke-Wold et al., 2015;Nicholl & LaFrance, 2009;Rabinowitz & Levin, 2014) and in Malaysia (Abdul Rahman et al., 2018;Abdullah et al., 2005;Abdullah et al., 2018;Ali et al., 2013;Chan et al., 2010;Kumaraswamy et al., 2002;Liew et al., 2009;Ludin et al., 2019;Nandrajog et al., 2017;Shadli et al., 2011;Veeramuthu et al., 2015;Veeramuthu et al., 2017;Veeramuthu et al., 2014). It is quite well known globally that TBI is not just a static event but an ongoing evolving disease that often leads to functional and psychiatric impairments in the later years following injury (McKee & Daneshvar, 2015), despite initial recovery. Thus far, only a limited number of studies have investigated this post injury outcome progression, with 2-3 years being the furthest outcome followed up in TBI patients (Abdul Rahman et al., 2019;Abdul Rahman et al., 2018;Ahmedy et al., 2020;Kumaraswamy et al., 2002). Thus, with mental health problems slowly shedding its taboo coat in Malaysia, emphasis should be given in investigating long term (at least 10 years) cognitive and neuropsychiatric deficits, as well as the later progression into brain diseases after TBI in future studies. Moreover, future retrospective studies on the influence of childhood or young age TBI on the mental health during old age, may shed light on the prevalence of TBI-related mental impairments in Malaysia, which in turn will propagate and mould TBI intervention studies to prevent these secondary outcomes of TBI.  (Sariaslan et al., 2016) were at higher risk for poorer prognosis post TBI and were more vulnerable to long term impairments, with TBI in children having been related to late development of functional outcomes and neurodegeneration (Sariaslan et al., 2016). Gender-wise, while males have reported a higher TBI incidences, females have reported a higher fatality rate and poorer TBI prognosis, based on GCS scores, in some studies (Biswas et al., 2017;Kraus et al., 2000;Munivenkatappa et al., 2016;Wright et al., 2014), despite studies suggesting the neuroprotective effects of female hormones against TBI secondary outcomes (Deutsch et al., 2013;Ma et al., 2019). Despite these findings, majority of the Malaysian TBI population studies had not taken age (33 articles) or gender (36 articles) differences into statistical account. Among those that did account for age and gender in their results, only age was shown to have significantly affect and negatively correlate with the prognosis and functional outcome in TBI patients, while gender differences were mostly insignificant. The latter could be a result of the small sample size and gender disproportioned recruitment/participation of TBI patients in the studies.
Another factor that may affect TBI measures, which strongly applies to a multiracial country like Malaysia, is ethnicity. Differences in ethnicities in the Malaysian population may create a great heterogeneity effect in the sample, and therefore may potentially affect the TBI outcome and diagnosis. Ethnicity disparities have been suggested to influence TBI outcomes in western populations (Arango-Lasprilla & Kreutzer, 2010;Brenner et al., 2020;Sorani et al., 2009;Staudenmayer et al., 2007), thus may be translated in Malaysia (Ali et al., 2013;Jeng et al., 2008) as well. Genetic diversity and cultural environment differences such as in food, beliefs and lifestyle between the ethnicities, may impact the recovery process post-injury and its functional outcomes (Lequerica & Krch, 2014;Saltapidas & Ponsford, 2008). The study by Saltapidas and Ponsford (2008) showed that culturally diverse populations exhibited varied understanding of TBI, diverse negative emotions and even scored differently in post-injury outcome measurements, and therefore urged health professionals to understand the differences in beliefs among ethnicities that may impact TBI diagnosis and prognosis (Saltapidas & Ponsford, 2008). However, like gender, ethnical differences as a confounder was hardly investigated or mentioned in the Malaysian population studies. Only five studies have acknowledged the ethnicity differences in the sample population (Abdullah et al., 2018;Ali et al., 2013;Jeng et al., 2008;Liew et al., 2009;Sharifuddin et al., 2012), with only one of them statistically proving the significant affect race had on brain injury (Jeng et al., 2008). Interestingly, the study by Ali et al (2013), showed that one of their cognitive tests, the Rey Auditory Verbal Learning Test (RAVLT) was significantly affected by ethnicity (Ali et al., 2013), regardless of TBI and urged future TBI research to account ethnicity differences in their cognitive results.
Taken together, the lack of statistical application and accounting of these factors (age, gender and ethnicity) and possibly others such as time since injury and education, may have stunted Malaysian TBI studies. This is because these factors may affect the pharmacokinetics and pharmacodynamics of treatments (Mangoni & Jackson, 2004;Shah & Gaedigk, 2018;Soldin & Mattison, 2009). Therefore, future TBI studies in Malaysia should account for these factors in order to develop effective precision-based prescriptions to TBI patients, especially since genotype differences between ethnicities may influence treatment strategies. Besides that, future Malaysian TBI studies may also benefit from conducting nationwide TBI sampling and pooling of resources and data across states, which may translate better to the actual TBI population similar to the nationwide PDRM motor vehicle accident reports (PDRM, 2020a).
The lack of preclinical studies in Malaysia should also be of concern, as basic research may provide a more in depth understanding on the pathophysiology of TBI and the pharmacological aspects of interventions, that may manipulate the pathways of TBI and its secondary outcomes. Moreover, basic animal research may help hasten the investigations on factors, especially age and time since injury, influencing TBI, unlike population studies which requires years to see its effects. Therefore, more time, effort, collaboration and funding should be placed into TBI research in Malaysia as a whole, in order to curb these issues and solve the annual ongoing problem of TBI cases and their future secondary outcomes, for the benefit of Malaysian road users and other TBI patients.

CONCLUSIONS
Traumatic brain injury is a devastating disorder that can affect anyone in the world. While the mortality rate reported in Malaysia was low, which may be underreported, it still may significantly impact the nation, both economically and socially, especially when considering the development of long-term outcomes and mental disorders after physical recovery. Despite this concern, TBI research in Malaysia was still found to be in its infancy, especially in the basic research area. Lack of TBI awareness in the population and unrectified limitations in TBI research in Malaysia, may result in devastating outcomes in the future for the Malaysian population and its economy. Given the yearly rise in TBI cases in Malaysia, more funds and support should be allocated into the TBI field, as there is a dire need for more effective TBI reporting systems as well as basic, translation and clinical research to be carried out in Malaysia, for the betterment of its people.