SSC 2B Group A6 Word VersionIntroduction

Legendary NFL centre Mike Webster was an icon in the world of American football; honoured as an All-Pro no less than seven times, he played 17 seasons and a total of 245 games, and was eventually honoured with a place in the Pro Football Hall of Fame in January 1997.1

Following retirement, the man nicknamed “Iron Mike” slowly and painfully became unrecognisable as the sporting giant and family man those close to him knew and loved. He became excessively introverted, and was prone to sudden bursts of rage that eventually caused the breakdown of his marriage.2 He took a cocktail of medications for psychological symptoms such as anxiety, anger and depression, as well as a whole variety of analgesics. His son Garrett described how he would repeatedly stun himself with a Taser gun to free himself from pain.3 In 2002, Mike died aged 50.

Following an autopsy it transpired that Mike was suffering from a neurodegenerative disease known as chronic traumatic encephalopathy (CTE). This marked a turning point in how those involved in sport all around the world regarded the significance and consequences of head injuries in athletes. Whilst the neurodegenerative effects of concussion have been well documented for many years, it was now being questioned whether those everyday minor collisions, or "sub-concussive hits" (SH), that seemed previously so inconsequential were in fact insidiously leading to the progressive neurodegeneration seen in Mike Webster.

This website aims to investigate:

The initial pathophysiological effects of SH, and how these can be detected. Click here.

The long-term manifestations of repetitive SH in athletes. Click here. Protocols used to evaluate and manage sub-concussion in sport, and how these

could be developed in the future to prevent current problems and raise awareness. Click here.

Short-Term Effects

By its very definition, symptoms commonly associated with concussion, such as confusion, amnesia and dizziness4, are absent following a sub-concussive hit (SH), making diagnosis and subsequent management difficult to implicate. Because of this, data on the short-term effects of sub-concussion is in the minority, as accurately identifying test subjects poses multiple difficulties.

Scanning techniques such as functional MRI5 can measure the short-term changes in neurological function, and analysis of samples from cadavers may be the most useful for measuring physiological changes. However, for obvious reasons the latter technique cannot be carried out in the short-term on live subjects.

In this section we examine modern techniques that are currently being researched in order to increase the amount of data available on the short-term effects of SH. This may help us fully understand the long-term implications for athletes sustaining multiple hits over a career.

Biomarkers

Although not clinically diagnosable, sub-concussive hits (SH) produce detectable changes6. The blood-brain barrier (BBB) acts as a division between the brain and circulating blood, reducing the permeability of the brain, contributing to its immune privilege6,7. As blood-brain barrier disruption (BBBD) follows immediately after traumatic brain injury (TBI), a diagnosis and measurement of head trauma after repeated SH may be possible with two biomarkers; one of BBB integrity and the other of brain injury6.

A sudden gap in the endothelial tight junctions of the BBB results in a rapid increase of serum S100B levels, a protein found in astrocytes, making this a highly sensitive technique for detecting BBBD6,8. A study by Marchi et al. tested the hypothesis that serum S100B elevation can be measured in football players after SH. They also hypothesised that players who suffer repeated S100B surges due to BBBD develop autoimmunity against S100B8. This is because it is a brain-specific protein and may be perceived as an antigen upon entering the serum, stimulating an immune response. The autoantibodies produced (anti-S100BAb) are pathogenic to the brain when they gain access to it through BBBD7,8.

Blood samples were collected to measure pre- and post-game S100B and anti-S100BAb levels. Elevations in serum S100B were found only in players that suffered repeated SH (P<0.01). There was no correlation between raised S100B and number of impacts to the rest of the body, demonstrating that surges are specific for impacts to the head. A Head Hit Index (HHI) was also calculated using a questionnaire and film review. The questionnaire required players to recall number of significant impacts to the head and presence of acute symptoms. As a positive correlation between S100B elevations and HHI (P<0.01) was found, surges are dependent on the number of head collisions and their severity. The fact that no players experienced a concussion throughout the study and S100B elevations returned back to pre-game levels within 24 hours after the game, shows there is rapid return to baseline levels in the absence of concussion8.

Results also indicated that repeated elevations throughout the season are sufficient to provoke the production of anti-S100BAb as approximately 50% of the football players experienced a progressive rise in their anti-S100BAb titer in serum, and players with the highest titers of anti-S100BAb were also those that experienced the greatest S100B surges throughout the season8.. Anti-S100BAbs are thought to persist over time and have been linked to  CTE , Alzheimer’s disease and early cognitive decline 7 .

This study provides a useful understanding into the immediate pathophysiology of SH as it shows that BBBD does occur. It also provides links to neurodegenerative diseases that could manifest in later life. However, data sets are only complete for 15 players. This is a small study sample and may reduce reliability of the results. The use of questionnaires in acquiring information

to calculate HHI introduces recall bias, however given the setting of the data collection it probably was the best method to use.

Biomarkers of brain damage, e.g. ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), are proteins produced in the CNS following brain injury, unlike biomarkers of BBBD which are found in the brain under normal circumstances6.

A study by Puvenna et al aimed to measure changes in serum level of UCH-L1 in football players after SH, and to establish any relationships between UCH-L1 with S100B, and beta-2 transferrin (a biomarker of CSF leakage). Positive controls were clinically-diagnosed mTBI (mild TBI) patients, and negative controls were patients undergoing routine blood tests6. For the 15 football players used, methods were very similar to the study on BBBD above, presumably because many of the authors were involved in both studies. There was no correlation between UCH-L1 and HHI, or serum levels of S100B (p=0.16) and beta-2 transferrin (p=0.22) in the football players6. This indicates that brain injury does not occur in SH and a relationship between BBBD and brain injury does not exist in these players. The lack of difference in levels of UCH-L1 in patients with mTBI compared to negative controls supports the findings of a study by Papa et al which showed that UCH-L1 correlated with brain injury severity in severe TBI rather than mTBI6,7.

S100B levels were able to discriminate between those with mTBI and those without, as well as predicting TBI severity. UCH-L1 was unable to do this 6. This finding is important as it indicates that S100B levels can be used to diagnose TBI in players after SH and predict its severity.

This study is useful as it measures UCH-L1 in conjunction with other proteins. However, further research is needed to discard the role of UCH-LI in SH. Serum samples were taken within one hour from the end of the game, the speed at which this protein rises post-injury is unclear but a previous study found that UCH-L1 was elevated 12 hours after6. Perhaps more time was needed before serum samples were obtained to produce more accurate results.

Animal Models

Difficulties assessing short-term effects of sub-concussion in humans have created a niche for the use of animal models. Whilst this has clear limitations, and greatly reduces how accurately results can be extrapolated to reflect the human profile, studies of this sort do provide a baseline for further investigation.

In 2011, Shultz et al investigated the behavioural and histochemical effects of sub-concussive hits (SH) on rats9. Using a method called mild lateral fluid percussion (mLFP) they simulated a force proportional to a SH on a human in 32 rats, followed by either a short (24hr) or long (4 week) recovery period. Following this, rats underwent behavioural testing, in which anxiety-like behaviour, spatial cognition, locomotor and social behaviours were evaluated. On completion of behavioural testing, the rats were sacrificed and coronal sections of brain tissue were obtained, stained and analysed for the presence of CD68 labelled microglia, GFAP and other biochemical markers of brain injury.

The first point of interest in this study is the conclusive lack of behavioural differences observed between the rats who received mLFP and the control group. This was consistent across both long and short-term recovery groups, and highlighted a complete lack of emotional, cognitive or sensorimotor behavioural markers. Whilst this in itself does not give us any further insight into the effect of sub-concussion on the brain, it does corroborate the lack of presenting symptoms found in humans, and suggests a certain degree of consistency between animal models and the human profile.

There were, however, some interesting findings in terms of the immunohistochemistry of the brain sections following staining and analysis, including:

A significant increase in CD68 labelled microglial cells in the sub-concussion group compared to the control group. This demonstrates the presence of an acute neuro-inflammatory response following sub-concussion, in the clear absence of behavioural markers.

A significant increase in GFAP immunoreactivity in the sub-concussion group compared to the control group. Glial fibrillary acidic protein (GFAP) is an important

intermediate in the production of glial scars following damage to the brain. Raised levels therefore indicate initiation of the scarring process in brain tissue10.

In 2014, Petraglia et al. conducted a similar study in which mice received either single or repetitive impacts and then had sections of their brains stained to look for the presence of GFAP, microglia and phosphorylated tau protein11. Gross anatomy of the brain remained unchanged in both single and repetitive hit groups, however as in the previous study, significant microscopic changes were found, including:

Evidence of a persistent neuroinflammatory response, involving statistically significant increases of GFAP in both single and repetitive hit groups, and marked elevation of activated microglia in the repetitive hit group only, that increased over time.

A persistent increase in hyperphosphorylated tau protein.

Not only does this study reinforce the neuroinflammatory findings from the previous study, it also highlights the significance of, phosphorylated tau, the histopathological hallmark of CTE, in the proposed mechanism of neurodegeneration caused by SH. Not only was the discrete presence of tau found in both single and repetitive hit groups, it was also found that the tau in single hit mice cleared by 6 months post-injury, yet repetitive hit mice showed a continuous and persistent increase in levels of tau over time. This finding places added importance on the fact that it is the repetitive nature of the SH received by athletes over a career that places them on the pathway to neurodegeneration. It also importantly highlights that the body is able to clear tau from the brain independently given time and rest; a point that has important implications for future sports protocols and treatments for both concussion and sub-concussion.

Chronic Traumatic Encephalopathy

It is widely documented that CTE is a long-term consequence of repetitive sub-concussive hits (SH)12 . However, the clinical manifestation is poorly understood and little research has been done into the progression.

A retrospective cohort study by McKee et al. investigated 85 brains, including athletes with a history of repetitive mild traumatic brain injury (mTBI), and 18 control brains, to assess the symptoms associated with varying degrees of CTE. They were examined by an expert neuropathologist; two additional

neuropathologists, who were blinded to the clinical assessment, confirmed the findings12.

The clinical assessment involved a post-mortem interview with next of kin, and covered the history of mTBI, including SH, as well as cognitive and behavioural decline leading up to death. Although both interviewer and interviewee were blinded to the results, the clinical assessment may have been liable to recall bias, with family members either exaggerating or underplaying symptoms. The brains were grouped into various stages of CTE  (I to IV) by assessing the extent and severity of tau pathology12.

The results are illustrated in the table below (click to enlarge):

Data adapted from reference number 12.

The table clearly shows that increasing severity of CTE gives a greater extent of symptoms. Not only do these results help us to understand the clinical manifestation of CTE, but also to trace the pathological progression of the disease throughout the brain12.

The study was conducted well, with all precautions being taken to minimise bias. However the interview design could have introduced multiple forms of bias, and unknown confounding factors such as drug or alcohol abuse may have given clinical symptoms that were assumed to be part of CTE. A prospective study where

subjects were monitored before death would have minimised these limitations, but would be difficult and time consuming to carry out12.

The neuropathology of CTE is well established. 80% of the brains with a history of repetitive mTBI and no controls showed perivascular clusters of p-tau immunoreactive neurofibrillary tangles plus astrocyte tangles and neurofibrillary tangles in the depths of the cerebral sulci or superficial cortical laminae. This pattern and distribution of neurofibrillary tangles has become characteristic and used in epidemiological studies to diagnose CTE, which is distinct from Alzheimer's Disease. Alzheimer's type neurofibrillary pathology, amyloid B deposition and Lewy bodies, were found in some brains, however these were in significantly older subjects, suggesting these were sporadic findings and not related to CTE12.

It is suggested that the pattern and distribution of neurofibrillary tangles described above occur in the first stages of CTE, affecting the superior and dorsolateral frontal cortices12. This is supported by other studies13, 14 which have shown this pathology in brains of 23-28 years olds with a history of mTBI. These were very small case series which had poor control of confounding factors so it is not clear whether results are significant. However, it is convincing that the history of repetitive mTBI is the common factor between the pathologies13.

CTE then slowly progresses over decades to involve more extensive areas of the CNS including the brainstem and spinal cord. 92% of 34 retired professional American footballers in McKee's study were classified as having stage III-IV CTE 12.

Omalu et al found 10 cases of CTE in the brains of 14 athletes whose deaths were sudden or unexpected. Interviews with close family members suggest that there is a syndromic profile of CTE emerging:13

Social and cognitive functioning

Memory and language impairment Executive dysfunction

Mood and behaviour.

Paranoia Anger and agitation over minor issues Mood fluctuation Depression Suicidality

Insomnia

Interpersonal and family relationships

Breakdown of relationships Spousal emotional and physical abuse

Criminal and violent behaviours.

High risk taking Illegal acts Imprudent sexual behaviours

Other

Abuse of alcohol, prescription, and illicit drugs Increasing religiosity Headaches, generalised body aches, and pain

Although the sample size was small and there are typical flaws to the interview method, there is overlap with some of the symptoms in the syndrome and those identified by McKee et al. There is a need for further studies to develop this clinical profile which could aid in diagnosis and treatment of affected athletes.

CTE and Alzheimer’s disease

Such a variety of symptoms were observed in players diagnosed with CTE that the next challenge is understanding their cause and significance. Epidemiological studies have proved the most useful in achieving this.

Randolph et al used multiple surveys to differentiate between cognitively intact and MCI patients in a sample of 513 retired NFL players, plus 81 non-players with a clinical diagnosis of MCI. They found that:

35.1% of players were diagnosed with MCI. The expected prevalence in this population was 5% therefore this was deemed significant15.

The players obtained the same mean score on one of the surveys as the MCI sample. Worryingly, the players were significantly younger (P<0.0001), however this could be explained by an age cut-off of 75 which was only applied to the players15.

It was a large but actively recruited sample so may have attracted players who were already worried about MCI. The response rate was good but ascertainment bias and poor control of confounding factors make it difficult to confidently conclude that prevalence of MCI is increased among players, let alone as a consequence of CTE.

A study investigating 334 deceased NFL players found a four-fold increased risk of mortality from AD compared to the general male US population. CTE is not listed in the International Classification of Diseases so cannot be listed as a cause of death but may have been the primary or secondary cause in patients with AD16.

Blood brain barrier disruption, described previously, is suggested as a possible cause of mild cognitive impairment  which links sub-concussive hits to AD. Consequential anti-S100B antibodies, injected into rat brains, impaired their memory and learning17. In another study, a 9.5-fold increase in serum anti-S100BAb was found in individuals with moderate AD compared to controls, as displayed graphically below18.

As S100BAb can be measured it could potentially be used in screening for AD or CTE in athletes.

CTE and Motor Neurone Disease

Epidemiological evidence shows that Motor Neurone Disease (MND) and CTE are both related to repetitive sub-concussive hits (SH).19

To investigate a possible pathological link between these conditions,  McKee et al. examined the brains and spinal cords of 12 athletes in a retrospective cohort study. 3 athletes had suffered from both CTE and MND, while the other 9 only had CTE. Medical records and interviews with next of kin were used to determine their history of concussion, cognition, behaviour and neurological abnormalities. These interviews were blinded to the results of the neuropathological examination.20

The three athletes with MND presented clinically with muscle weakness, atrophy, spasticity and diffuse fasciculations. All 12 athletes had clinical symptoms characteristic of CTE. Widespread TDP-43 proteinopathy was observed in the brain stem and other associated areas in over 80% of the CTE patients, however this TDP-43 proteinopathy had spread to the anterior horn of the spinal cords in the MND patients. This suggests a common pathological mechanism, caused by repetitive sub-concussive hits, linking the two diseases20. The combination of both CTE and MND has been named Chronic Traumatic Encephalomyelopathy (CTEM), and has been shown to occur in approximately 10% of individuals that develop CTE12. However, there are some limitations to this paper.

The study mentioned that those with just CTE and without MND did not differ with the MND patients with respect to concussion histories, total year of sport participation, age at death and age of retirement, but does not show any of the data. Considering the small sample size, it is possible a confounding factor could have caused the MND separately to the CTE.20

This is the first study to observe and suggest a pathological link between the two diseases, and it has since been confirmed by further studies.12

Amyotrophic lateral sclerosis (ALS) is a type of MND.  Two further studies have shown a significant link between developing ALS from multiple mTBI’s, and increased mortality. The first by Lehman et al.  used a large of cohort of 3439 American Football players. Details of time and cause of death was obtained from the National Death Index or from death certificates. The players were stratified into two different categories (speed and nonspeed) depending on their position played16.

The graph below illustrates the standardised mortality ratio (SMR) for the different neurodegenerative diseases with the error bars showing their 95% confidence intervals.16

For speed positions, the mortality of both AD and ALS were significantly greater than the general population. Parkinson’s disease and all nonspeed positions were not statistically significant. However, the study also showed that the overall mortality of the cohort was reduced (SMR 0.53) despite the mortality of AD and ALS being 4 times that of the general population. The authors theorise that the increase in repetitive SH in speed positions is the main contributing factor to the increased mortality.16

The study was limited by having just 2 broad position categories and was therefore not able to identify differences within these categories. In addition, the results are based on only 17 subjects having neurodegenerative diseases, and the large confidence intervals reflect this imprecision.16

Further studies have since confirmed these results and advised that the increased mortality of ALS and neurodegenerative diseases need to be balanced by the significantly lower risk of cardiovascular problems and cancer.21

In some individuals, CTE is associated with the development of MND. This occurs when TDP-43 immunoreactive inclusions spread from the brain stem to the anterior

horns of the spinal cord, giving symptoms of  muscle weakness, atrophy, spasticity and diffuse fasciculations.22

An increased mortality when compared with the general population is reported for ALS sufferers who have developed their condition from multiple sub-concussive hits16,21. Implications of this to sport and how the problem can be tackled in the future is discussed here.

 CTE, Depression and Suicide

One study has suggested that executive dysfunction may contribute to depression in athletes with CTE. There were significant differences between 64 current and retired American footballers compared to matched controls in terms of ability to control behaviour, emotional responses and ability to solve problems through planning, organisation and sustaining effort on a 75 item test of executive functioning in everyday activities. The players demonstrated an awareness of the effects of their behaviours on others, but were unable to change their behaviour because of decreased inhibition, possibly resulting in observed depressive symptoms in former athletes23.

In McKee's study, a degree of suicidal ideation and behaviour was prevalent in all stages of CTE12. Changes in mood and behaviour can occur years after the period when repetitive sub-concussive hits (SH) were experienced and are the most concerning to family, friends and carers as well as to the suffering athletes24.

A study by Schwenk et al investigated the prevalence of depression in 1,671 retired professional football players, from a survey which also asked about players’ experiences of a range of life problems.25

14.7% were quantified into a mild to moderate depression category. This was observed as being similar to the rate among the general population, although no exact statistic for this was provided. 7% said their depressive symptoms were making work or home life very/extremely difficult.25

These players were more likely to perceive barriers to getting help, such as feeling embarrassed, weak or that it would be unnecessary25.

Although there was only one question investigating this on the survey, difficulty with chronic pain was the most common retirement problem reported (48%). Other problems included loss of fitness (29%), weight gain (28%), trouble sleeping (28%) and trouble transitioning to life after football (27%).25

Symptoms such as pain, insomnia and social problems were described in the emerging CTE syndrome so it is possible that although it wasn't investigated, some of these players’ symptoms are due to CTE.

This study had a large sample size but had the problem of self-reporting. The study admits that the depression questionnaire has a high rate of false-positives so the prevalence of depression in this sample is likely to be overestimated.  There is questionable generalisability owing to the response rate being 47.9% and no follow-up being carried out on the non-respondents.

Other studies have investigated rates of depression in retired NFL populations (26,27). Of 1,044 players in a prospective study by Kerr et al 10.2% self-reported being clinically diagnosed with depression. This study collected data on concussions but not SH which could be considered poor controlling of confounding factors. They found a significant positive correlation between the 9-year risk of depression and the number of concussions players experienced (P<0.001). Presuming that players who are more likely to sustain concussion are more likely to sustain SH, we could extrapolate that 9-year risk of depression also increased with an increase in SH. Although, this cannot be concluded until a well-designed study investigates it fully. Methods of diagnosing depression differ between clinicians and there may be self-reporting bias which introduces a degree of unreliability resulting in an under or over estimation of incidence. Although it is not clear whether the prevalence of depression is significant, 82.4% of these players thought their condition limited their activities of daily living.26

It is possible that an increased risk of depression, other problems post-retirement and perceived barriers to seeking help may put a small but important group of all retired NFL players at high risk of adverse life events and an increased risk of suicide. Depression can go undetected if symptoms are vegetative such as sleep disturbance and loss of appetite. This highlights the possible importance of screening for depression in retired athletes26.

There is only level IV evidence in the form of case series which hypothesise that suicide in athletes can be caused by CTE but no causal link has been explained.

Omalu et al diagnosed CTE in 5/5 athletes who had committed suicide or repeatedly tried to. They exhibited major depression, cognitive impairments, body pains plus alcohol and drug abuse.28

4/5 athletes who had committed suicide in another study by Omalu et al, were diagnosed with CTE. A further 4/6 athletes whose deaths were accidental had CTE and 3/4 of these were drug or alcohol related.13

Of 51 CTE-positive brains in McKee et al’s study, 7 had committed suicide, 6 had expressed suicidal thoughts and 6 died from drug and alcohol abuse.12

There is not enough research into the risk of depression in athletes because there is too much selection and self-reporting bias in the research that exists. Research into the risk of suicide in athletes is even more lacking. These were purely observational studies with no statistical analysis, small sample sizes and no controls, so conclusions are not generalisable or reliable. They can only generate hypotheses about a relationship between CTE and suicide.

An estimated 8 to 25 attempted suicides occur per suicide28 so this needs to be investigated in the future with larger, prospective studies including post mortems.

Education

Many members of the general public participate in contact sports such as football, rugby and American football with 1.9 million people playing football in England alone during  2013/14.29

Often these participants are encouraged to take part in these sports by health professionals or family members due to psychological and physical benefits or purely for the enjoyment factor.30

The recent discovery of the link between sub-concussive hits (SH) and long term neurological problems has sparked the debate that players, coaches and referees in sports that contain a risk of head injury should be educated in the effects and causes of these long term problems.

Because of the high number of participants in these sports, SH are an issue that affect a large portion of the population and thus is an important health concern. With a greater level of education about SH players will be capable of make informed decisions about their sport, as well as being able to identify many of the symptoms that can occur from the long term effects.

The following are the predominant areas which it would be useful for members of certain contact sports to be aware of:

There are many possible methods in various different sports that could cause SH. Those in popular sports could include heading the ball in a game of football,31 a whiplash or accidental clash of heads type injury that can occur in rugby,32 or deliberate trauma to the head that is widely reported on in boxing or mixed martial arts.

Many of these injury mechanisms are the same as those that cause more immediately serious concussions which, as a result of increased press coverage and research, are becoming more easily diagnosed.33 Due to this increased medical knowledge there are multiple programs that offer the general public, particularly those involved in high risk sports, education in the diagnosis of concussion. An example of one of these is the International Rugby Boards (IRB) player welfare course which is an online resource available to the general public.34 With this increased awareness many progressive steps have been introduced in order to improve player welfare in relation to concussion. If education about SH became common place it is safe to assume that the same progress would occur in reducing the risks of sub-concussive hits and their effects.

Players should be aware of the presenting symptoms of CTE that SH can potentially cause. This is important in gaining early awareness and therefore better assistance in managing the condition which the player is suffering from.  These first symptoms of CTE include short term memory problems, depression and emotional instability (including uncharacteristic aggression) and suicidal behavior.24

These triggers should alert players to inquire about further investigations as to why they are presenting with these symptoms and if SH could have been a factor. This improved vigilance by patients will improve the NHS’s ability to provide a greater quality of care to patients.

The Future

There are many possible ways in which sports can be made safer for players.

Altering rules in order to reduce the amount of collisions players receive would improve player safety. Many of these changes have been made in American football and rugby, such as forbidding high tackles and the ability for the referee to forbid injured players returning to the  game.35

Specialist committees review rules annually. Changes are usually based on what will reduce injuries and improve the flow of the game. If more focus was placed on reducing the event of sub-concussive hits (SH) many of these could be reduced.

Equipment could be improved in order to provide increased protection to players. A study36 measuring the peak force of footballs being dropped found that there was considerable difference between different designs. Therefore alteration of the football could  reduce the force of possible SH when heading the ball.

Rugby offers no mandatory protective equipment for the head. A study found that 49% of players used a scrum cap as they feel this is a form of protective equipment.37 However this offers no significant protection against concussion and internal injuries but instead improves protection of the soft tissues of the head.38 Adding more head protection to protect against SH may be beneficial to players. The International Rugby Board (IRB) however, says this is not in the interest of safety as players will begin to use the “helmet” to initiate contact, therefore increasing their risk of head injury.

American football on the other hand has a great deal of protective equipment including a solid helmet that the players must wear to protect the head and face during games.39 There have been findings to suggest that the concerns of the IRB are correct in that American football players use the helmet as a weapon to target other players.

The helmets in American football are continuously improved throughout the years to enhance player protection.40 This technology is an area in which this sport excels at reducing the number of concussions. It can be assumed due to this increased protection that the level of SH are also being reduced by the added protection.

A rule which came into effect in 2013 in American footballs college league, the NCAA, is the Targeting Rule: "No player shall target and initiate contact against an opponent with the crown (top) of his helmet and No player shall target and initiate contact to the head or neck area of a defenseless opponent with the helmet, forearm, fist, elbow or shoulder. "This rule highlights both the revision of rules to improve player safety but the fact that it needs to exist highlights the issues with using improved protection as a weapon when  playing.41

There is also the possibility of including testing players for certain bio-markers in order to ascertain if they are at risk of the effects of SH. This could allow players to be removed from games or prevented from playing more games in a short period of time if they are found to be at higher risk.

One overriding theme throughout all of these possible improvements to team games is the need for a change in culture within sport. The officials at the top of each sport right down to the fans need to begin thinking of the seriousness of head injuries in sport and respecting the effect they can have on players’ lives. The current culture of it being just another injury that players can brush off needs to be removed and replaced by one that cares for players and thinks for their long term future.

With these possible changes to improve player safety within sport it is safe to say that many sports as we know them may very well be different in the years to come.

Conclusion

Sub-concussive hits (SH) are under-researched in comparison with concussion, and are only now beginning to gain recognition within international sports. By evaluating studies in this area we were able to suggest how education about SH could be improved, and how it can be used to reduce this risk in the future.

There are limitations to our research:

The majority of investigations into short-term effects were with respect to animal models, data from which cannot necessarily be extrapolated to reflect the human profile.

We did not research risk factors such as age, gender and duration of career, which could alter ultimate long-term manifestations of repetitive SH.

This is a newly emerging area of research, meaning that the majority of studies were retrospective. Ideally we would have included more prospective studies, as these minimise the recall and interview bias present in many of our studies.

Although data on short term effects is limited, there have been interesting developments in current research, including the use of biomarkers and animal models. The underlying model that is emerging from this is that SH initiate both a neuroinflammatory and autoimmune response, that lead to the long term sequelae responsible for neurodegeneration. The presence of biomarkers also has important implications for the recognition, diagnosis and subsequent management of SH.

Chronic Traumatic Encephalopathy (CTE) is the major long-term consequence of repetitive SH, and manifests as memory and language impairment, executive dysfunction, paranoia and suicidality. Using more studies which investigate the presentations of athletes prior to CTE diagnosis post-mortem, a comprehensive syndromic profile can be created and used by healthcare professionals to aid early diagnosis and management of CTE. This has the ultimate aim of improving quality of life and prognosis of affected athletes.

Despite a relative increase in  current awareness of the dangers of SH, changes to rules, equipment, and general attitudes of players need to be both investigated further, and implemented to improve player safety. Ultimately a culture change stemming from increased awareness and education will drive future progression.