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Repetitive Head Injury Syndrome

  • Author: David Xavier Cifu, MD; Chief Editor: Craig C Young, MD  more...
Updated: Mar 27, 2014


Primary head injury can be catastrophic, but the effects of repetitive head injuries must also be considered. Second-impact syndrome (SIS), a term coined in 1984, describes the situation in which an individual sustains a second head injury before the symptoms from the first head injury have resolved.

See Pediatric Concussion and Other Traumatic Brain Injuries, a Critical Images slideshow, to help identify the signs and symptoms of TBI, determine the type and severity of injury, and initiate appropriate treatment.

Also, see the Football Injuries: Slideshow to help diagnose and treat injuries from a football game can result in minor to severe complications.

The second injury may occur from days to weeks following the first. Loss of consciousness is not a requirement of this condition, the impact may seem relatively mild, and the athlete may appear only dazed initially. However, this second impact causes cerebral edema and herniation, leading to collapse and death within minutes. Only 17 cases of confirmed SIS have been reported in the medical literature. Thus, the true risk and pathophysiology of SIS has not been clearly established.

Importantly, even if the effects of the initial brain injury have already resolved (6-18 mo post injury), the effect of multiple concussions over time remains significant and can result in long-term neurologic and functional deficits. These multiple brain insults can still be termed repetitive head injury syndrome, but they do not fit the classification of SIS. True SIS would most likely have a devastating outcome.

A study of American high school and college football players demonstrated 94 catastrophic head injuries (significant intracranial bleeding or edema) over a 13-year period.[1] Of these, only 2 occurred at the college level. Seventy-one percent of high school players suffering such injuries had a previous concussion in the same season, with 39% playing with residual symptoms. On the other hand, results from a study of concussion by the National Football League demonstrated no cases of SIS or catastrophic head injury in players returning to play in the same game after resolution of symptoms.[2]

The outcome of multiple minor head injuries over a prolonged period has not been well studied and is not well understood. The preponderance of data assessing the impact of repetitive head injuries on short- and long-term neurologic (cognitive) performance has been focused on the sports of boxing and American football.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]

Numerous studies of professional boxers have shown that repeated brain injury can lead to chronic encephalopathy, termed dementia pugilistica.[12, 13, 14, 15] Likewise, the autopsies of 2 former professional football players with a history multiple concussions demonstrated changes that were consistent with chronic encephalopathy.[5, 6] Another investigation of retired professional football players showed a 3-fold increase of depression in players with a history of 3 or more concussions.[3] Older studies of American and Australian rules football showed no effect from repetitive mild head injuries.[11] However, more recent studies of collegiate football players showed an association between multiple concussions and reduced cognitive performance, prolonged recovery, and the increased likelihood of subsequent concussions.

Evidence has also been gleaned from other sports that involve head impact. Nonrandomized studies of soccer players who have had multiple minor concussions have demonstrated that these individuals performed worse on neuropsychologic tests compared with a control group.[16, 17, 18, 19]

Neuropsychologic testing is the standard for monitoring cognitive recovery after concussion. However, 2 studies suggest that abnormalities in visual motor and motor cortex function persist after neuropsychologic testing has normalized.[8, 20] Slower recovery in patients with a second concussion was also seen.

Basic science research is also ongoing. Experiments in concussed rats demonstrated prolonged abnormalities in metabolic markers of brain activity when a second impact was administered at 3 days[21, 22] This implies there may be a metabolic window of vulnerability to a second impact that leads to chronic or prolonged symptoms. Clinically useful biomarkers for brain injury are also being investigated.

Update on chronic traumatic encephalopathy

The effects of single or multiple TBIs in later-life are poorly understood, particularly in mild TBI (mTBI). Recent studies suggest that even mTBI can lead to an increased risk of later-life cognitive impairment and neurodegenerative disease, especially when repeated injuries are involved.[23, 24, 25] TBIs of mixed severity have been associated with an elevated incidence of Alzheimer disease (AD) and other dementias[26, 27, 28] and a reduced age of onset for AD,[29] although not in all studies.[30]

It has long been suspected that repeated concussions can result in dementialike symptoms many years after injury, a condition labeled chronic traumatic encephalopathy (CTE). The brain structures damaged in CTE are critical for memory and executive function.[31, 32]

CTE has been studied in boxing, wherein retired boxers developed dementia at a higher rate and a younger age compared with the general population.[33] More recently, brain autopsies of athletes in various sports with confirmed CTE have demonstrated tau-immunoreactive neurofibrillary tangles and neuropil threads,[25, 34] suggesting that pathological processes similar to AD may be involved.

A critical gap in the literature exists with respect to later-life neuropsychological functioning after TBI. In a study of individuals with TBI of varying initial severity, researchers found later-life cognitive impairments when compared with a control group in the areas of episodic memory, short-term memory, visuospatial processing, object naming, and semantic processing.[35] Regarding CTE specifically, neuropsychological deficits have been observed but appropriate norms do not exist.[36]

A meta-analysis found no cognitive effects in 289 amateur boxers[37] ; however, a large survey study suggested that multiple concussions increase the risk of later-life cognitive dysfunction. Recently, the diagnosis of mild cognitive impairment (MCI, also known as insipient dementia) and self-reported memory problems were more common among football players who reported 3 or more concussions than those who reported none.[23, 24] Although several cross-sectional studies in sports injury populations have been performed later in life, the long-term effects of TBI in nonsports populations (military, civilian) remain poorly defined.

The possibility of a link between mTBI and CTE or early dementia has widespread implications for military service members and veterans. TBI is an important source of morbidity in the ongoing global war on terrorism (GWOT).[38] TBI has been called the "signature injury" of Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND), affecting up to 20% of all service members deployed in theatre. More than 233,000 TBIs have been officially reported in OIF/OEF/OND between 2000 and 2012 (, nearly 80% of which are mild.[39] Explosive munitions in the form of improvised explosive devices (IEDs) have caused the overwhelming majority of these identified cases. The prevalence is likely higher than the above-reported numbers, given the frequency of blast exposure in the GWOT and the fact that mTBI may go unrecognized during and even after deployment.

Missed or delayed diagnosis of mTBI is attributed to the subtlety of symptoms, the overlap of clinical signs and the common effects of heightened arousal and activity in times of combat, a lack of knowledge as to the specifics of diagnosis and detection, greater attention paid to more visible concomitant injuries, and a reduced subjective awareness related to cognitive deficits in the acute period on behalf of the injured service member.[40]

At present, a definitive diagnosis of CTE is made on postmortem examination, using a battery of immunohistochemical markers to define pathognomonic histopathologic features of this disease process, such as tau-immunoreactive neurofibrillary tangles and neuropil threads. There are no clear in vivo diagnostic tools to diagnose CTE. Identification of such a tool or set of tools would provide key data to clinicians caring for this patient population, aid in conducting epidemiological studies to explore the natural history of CTE, and provide objective diagnostic endpoints to support clinical trials to explore therapies for this disease process. Much more attention in recent years has been put towards the early detection of dementia than that of CTE.

In recent years, significant effort has been devoted to the creation of imaging agents that selectively accumulate at sites of interest and emit a signal that can be detected by either positron emission tomography (PET) or single-photon emission computed tomography (SPECT). In contrast to CT and MRI sequences, PET and SPECT have the significant advantage of providing information on changes occurring at the cellular or molecular level. To date, a number of targeted imaging agents have been cataloged at the NIH MICAD Web site:

In studies of aging, sensory and motor changes have been observed that precede dementia in the domains of olfaction, eye movement, and balance. Olfactory impairment has been identified as a preclinical marker of AD.[41] Olfactory function is also reduced after brain injury.[42, 43]

Researchers have recently demonstrated that early neuromotor impairments are predictive of late global outcome after TBI.[44] Using video-oculography, saccadic eye movement abnormalities have been described in patients with cortical neurodegeneration (AD) and/or nigrostriatal neurodegeneration (Parkinson disease).[45] Furthermore, eye movement abnormalities have been identified in adults with postconcussive syndrome.[46] Research has also demonstrated the utility of a mobile video-oculography device.[47, 48]

Finally, balance impairments (as measured by computerized posturography (CPT) are more common in dementias of all types compared with controls[49] and have been demonstrated acutely after mild TBI.[50] CPT score is predictive of recurrent falls in persons with balance and vestibular disorders.[51]

Tau proteins (collectively termed "total-tau") are a logical indicator of CTE and, more broadly, TBI-onset neurodegeneration. Total-tau in cerebrospinal fluid (CSF) is one of the most predictive biomarkers for clinical use in neurodegenerative disorders associated with cognitive impairment.[52] While serum total-tau has been less predictive than CSF for age-onset neurodegenerative disease (eg, AD), it has been demonstrated to be discriminative in other pathologic causes of brain dysfunction, including higher-risk mTBI patients.[53]

Given the unique pathology associated with CTE and tau accumulation more broadly and around blood vessels, it is entirely plausible that long-term neurodegeneration following trauma may selectively present elevated serum-tau levels. It is further postulated that long-term serum-tau levels in posttraumatic subjects will be less age-dependent than CSF-tau levels in age-onset neurodegeneration. The authors’ contention is entirely consistent with the known pathobiology of CTE, specifically the excessive tau accumulations seen across broad cortical areas with a focus around blood vessels in regions of geometric inflection that are most stressed by the deformation forces of brain trauma.

CTE has also been characterized by widespread TDP-43 proteinopathy.[54] TDP-43 is involved in regulating translation in mitochondrial RNA in the brain. It has been associated with the physiological response to traumatic axotomy.[55] Blood levels of TDP-43 are elevated in association with a variety of neurodegenerative conditions, to include frontotemporal lobar degenerations, amyotrophic lateral sclerosis (ALS), and AD.[56, 57] However, no publication to date has examined it as a biofluid marker for CTE. As in the case of tau, TDP-43 fibrillaries accumulate at anatomical points of geometric inflection in the brains of CTE subjects. Given that trauma focuses deformation forces in these areas, it is highly plausible that TDP-43 accumulation is in contact with the compromised microvasculature and, as such, would be present in the blood of trauma patients with latent CTE.

Beta-amyloid (Ab) peptides are yet other biomarkers with diagnostic and prognostic utility for a broad number of neurodegenerative disorders.[52] Ab plaques are common immediately after TBI,[58] and Ab continues to accumulate in traumatized axons that survive.[59] Recently, it has been reported that Ab plaques are diffusely yet widely present throughout the brains of moderate-to-severe TBI subjects at 1 year or longer following injury.[58] Plaques were also found to be predominantly in a fibrillary form that resembled AD pathology more than acute TBI. Importantly, diffuse, widespread fibrillary Ab accumulation resembles CTE pathology.[60] Until recently, CSF has been the only biofluid found to provide reliable Ab measures. However, the latest blood Ab assays are providing predictive and prognostic performance in MCI and AD that is considered particularly useful for longitudinal monitoring and so it holds relevance to the present application.[61]

While blood assays are most often developed for disease biomarkers, urine provides certain distinct advantages. Precedence exists in the form of a urine assay for neural thread protein (NTP), which is already available as a clinical test for neurodegenerative disorders.[62] Recently NTP has shown particular promise for the early prediction of AD.[63] Importantly, NTP is related to tau pathobiology in connection with neurodegeneration,[62] and is thus likely to correlate with other tauopathies such as CTE. In addition to NTP, urine may also provide ready access for Ab measures. Complicating blood Ab assays is the interaction with predominant protein. However, normal renal filtration removes this confound, allowing smaller metabolites, possibly Ab peptides, to be detected more easily. The authors further suspect that smaller breakdown products of tau protein may be accessible in urine for the same reasons, which are readily detected by total-tau antibody.[64]

Possession of the APoE-ε4 allele is a risk factor for dementia.[33] Carriers may have altered brain activity, even at a young age.[65] Long-term, but not short-term, effects of TBI may be influenced by APOE. APOE was not associated with poorer neuropsychological performance 1 month after mild or moderate TBI.[66] However, TBI was found to increase AD risk of APOE 10-fold[67] and cognitive decline after 30 years was greater in TBI patients with the APoE-ε4 allele compared with those without.[68] Environmental factors, in particular multiple concussions, may influence the effects of APOE. Boxers with the APoE-ε4 allele who had participated in many bouts were more likely to have CTE, while the allele was not a risk factor in boxers who had only experienced a few fights.[58]

Certainly, more research is needed to better understand the chronic and catastrophic effects of repetitive head injuries.

For patient education resources, see the Back, Ribs, Neck, and Head Center and Dementia Center, as well as Concussion and Dementia in Head Injury.




United States

The National Center for Catastrophic Sports Injury Research in Chapel Hill, NC, reported 35 cases of SIS among American football players from 1980-1993. Seventeen were confirmed by necropsy, surgery, or magnetic resonance imaging (MRI) findings. Eighteen were probable cases of SIS, despite inconclusive necropsy findings.

The number of reported SIS cases increased from 1992-1998, but this increase is thought to be due to more frequent recognition and reporting. Some clinicians believe that SIS is overreported. Boden et al reported an average of 7.08 catastrophic head injuries per year in high school football, compared with 0.15 for college football from 1989-2002.[1] The incidence was 0.67/100,000 for high school players and 0.21/100,000 for college players. Thirty-nine percent of the affected athletes reported playing with residual symptoms.[1] There were 8 fatalities, of which 1 individual had cerebral edema as the only radiographic finding. It was unclear as to whether a second impact occurred in this case.

With the advent and improvement of the helmet in American football and with the introduction of new rules that make spearing illegal, the incidence of head-injury fatalities has decreased from 2.64 cases per 100,000 persons in 1968 to 0.20 cases per 100,000 persons since 1977. The US Centers for Disease Control and Prevention estimates a 20% rate of concussion from football brain injuries (predominantly high-school and college level), which equates to an estimated 300,000 concussions per year.

Collins et al showed that 20% of the college football players they studied had 2 or more concussions during their career.[7] Furthermore, a study by Daniel et al found that the symptoms of an estimated 60,000 football players who suffer concussion may persist for 4 or more months in up to 24% of these individuals.[20]

The US Consumer Product Safety Commission tracks product-related injuries through its National Injury Information Clearinghouse. According to the Consumer Product Safety Commission, an estimated 311,766 sports-related head injuries were treated at US hospital emergency departments in 2004.

Schulz et al reported on a prospective cohort study of North Carolina high-school athletes followed from 1996–1999.[69] Subjects were clustered by school and sport, and the sample included 15,802 athletes, with 1–8 seasons of follow-up per athlete. Concussion rates ranged from 9.36 concussions per 100,000 athlete-exposures in cheerleading to 33.09 concussions per 100,000 athlete-exposures in football, where "athlete-exposure" is 1 athlete participating in 1 practice or game. The overall rate of concussion was 17.15 concussions per 100,000 athlete-exposures.

Cheerleading was the only sport for which the practice rate of concussions was greater than the game rate.[69] Almost two thirds of cheerleading concussions involved 2-level pyramids. Concussion rates were elevated for athletes with a history of concussion, and they increased with the increasing level of body contact permitted in the sport.

Powell and Barber-Foss reported a 2-year review of 235 US certified athletic high-school training records. The authors estimated a total of 62,816 cases of mild traumatic brain injury (TBI) annually among high-school varsity athletes, with football accounting for approximately 63% of these cases and a varied incidence among 10 other popular sports.[70]

Matser et al showed that 23% of the amateur soccer players they studied had 2-5 concussions during their career.[16] Boden et al found that the overall prevalence of college soccer-related concussions was 0.6 cases per 1000 athlete-exposures for men and 0.4 cases per 1000 athlete-exposures for women.[17] The authors reported that the vast majority (72%) of these concussions were grade 1, and none were grade 3.[17]

The actual number of athletes who may be affected by repeated minor head injuries is largely unknown.


Functional Anatomy

SIS is thought to occur because of a loss of autoregulation of the cerebral blood flow, which leads to vascular engorgement, increased intracranial pressure (ICP), and eventual herniation. This herniation may involve the medial temporal lobe and may occur medially across the falx cerebri or inferiorly through the tentorium. Herniation can also force the cerebellar tonsils to move inferiorly through the foramen magnum. The athlete's condition rapidly worsens, and brainstem failure occurs in 2-5 minutes.


Sport-Specific Biomechanics

The brain is protected by bone and is cushioned by tough meninges and cerebrospinal fluid. Despite these protective surroundings, blunt-force trauma to the head can cause injury to the site of impact (coup injury) and the site immediately opposite of the impact (contrecoup injury). Factors that dissipate the force (eg, equipment, neck muscle strength) can minimize this trauma.

Contributor Information and Disclosures

David Xavier Cifu, MD The Herman J Flax, MD, Professor and Chairman, Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University School of Medicine; National Director, PM&R Services, Department of Veterans Affairs

David Xavier Cifu, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, Brain Injury Association of America, American Congress of Rehabilitation Medicine, American Medical Association, Association of Academic Physiatrists, National Stroke Association

Disclosure: Nothing to disclose.


David F Drake, MD Bavaria MEDDAC Medical Evaluation Board Physician, Physical Medicine and Rehabilitation/Pain and EMG Consultant

David F Drake, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, Physiatric Association of Spine, Sports and Occupational Rehabilitation, American College of Sports Medicine, International Society of Physical and Rehabilitation Medicine

Disclosure: Nothing to disclose.

Brian D Steinmetz, DO Resident, Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University

Brian D Steinmetz, DO is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Osteopathic Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Russell D White, MD Clinical Professor of Medicine, Clinical Professor of Orthopedic Surgery, Department of Community and Family Medicine, University of Missouri-Kansas City School of Medicine, Truman Medical Center-Lakewood

Russell D White, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Family Physicians, American Association of Clinical Endocrinologists, American College of Sports Medicine, American Diabetes Association, American Medical Society for Sports Medicine

Disclosure: Nothing to disclose.

Chief Editor

Craig C Young, MD Professor, Departments of Orthopedic Surgery and Community and Family Medicine, Medical Director of Sports Medicine, Medical College of Wisconsin

Craig C Young, MD is a member of the following medical societies: American Academy of Family Physicians, American College of Sports Medicine, American Medical Society for Sports Medicine, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Gerard A Malanga, MD Founder and Partner, New Jersey Sports Medicine, LLC and New Jersey Regenerative Institute; Director of Research, Atlantic Health; Clinical Professor, Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey-New Jersey Medical School; Fellow, American College of Sports Medicine

Gerard A Malanga, MD is a member of the following medical societies: Alpha Omega Alpha, American Institute of Ultrasound in Medicine, North American Spine Society, International Spine Intervention Society, American Academy of Physical Medicine and Rehabilitation, American College of Sports Medicine

Disclosure: Received honoraria from Cephalon for speaking and teaching; Received honoraria from Endo for speaking and teaching; Received honoraria from Genzyme for speaking and teaching; Received honoraria from Prostakan for speaking and teaching; Received consulting fee from Pfizer for speaking and teaching.


Invaluable assistance in the preparation of this manuscript was received from Ingrid A. Prosser, MD.

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