High Dose Omega-3 Fatty Acids in the Treatment of Sport Related Concussions

In the United States, an estimated 1.7 million people sustain a traumatic brain injury (TBI)
annually; associated with 1.365 million emergency room visits and 275,000 hospitalizations
annually with associated direct and indirect cost estimated to have been 4 billion in the
United States in 2000. Furthermore, the US Center for Disease Control and Prevention
estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities
annually.3 However, these figures grossly underestimate the total burden of traumatic brain
injuries (TBIs) and concussions, because many individuals suffering from mild to moderate
TBIs do not seek medical attention.

Even though concussion is a type of TBI that has been frequently used interchangeably with
mild TBI in the medical literature; mild refers to the initial impact rather than the
long-term sequelae from the injury. Historically, the definition of concussion has not been
well defined, until the 3rd International Conference on Concussion in Sport (Zurich 2008)
defined concussion as a complex pathophysiological process affecting the brain, induced by
traumatic biomechanical forces. Several common features that incorporate clinical,
pathological and biomechanical injury constructs that may be utilized in defining the nature
of concussive head injury include: Concussion may be caused either by a direct blow to the
head, face, neck or elsewhere on the body with an "impulsive" force transmitted to the head.
This injury typically results in the rapid onset of short-lived impairment of neurologic
function that resolves spontaneously. It may result in neuropathological changes, but the
acute clinical symptoms largely reflect a functional disturbance rather than a structural
injury. It results in a graded set of clinical signs and symptoms that may or may not involve
loss of consciousness. Resolution of the clinical and cognitive symptoms typically follows a
sequential course; however, it is important to note that, in a small percentage of cases,
post-concussive symptoms may be prolonged. No abnormality on standard structural
neuro-imaging studies is seen in concussion. Current data shows that on average 91% of
athletes who sustain a concussion have their symptoms and cognitive impairment resolved in 7
± 1.5 days and balance deficits resolved by day 5.13 Currently the main treatment for
concussion is cognitive and physical rest until symptoms resolve with a graduated return to
activity.

The neuropathological changes after a concussion result in functional disturbances and the
clinical syndrome results from the depolarization and potassium efflux from neurons that
trigger the release of excitatory amino-acids like glutamine, which in turn activate
N-methyl-D-aspartate (NMDA) receptors and form a pore through which calcium enters the
neuron. A large influx of calcium into the cell triggers the lysis of arachidonic acid,
calpain activation and initiation of apoptosis, and the formation of reactive oxygen species
(ROS). Studies have shown that the incorporation of omega-3 fatty acids into the cell
membrane has been associated with decreased generation of intracellular ROS and consequent
diminished activation of redox-sensitive transcription factors, such as the nuclear factor-
κβ system, modifying the expression of pro-inflammatory genes. Incorporation of omega-3 fatty
acids also appears to alter the properties of lipid rafts and caveolae, contributing to
membrane fluidity, hormone-receptor binding and the function of membrane associated proteins
are affected. Omega-3 fatty acids are also associated with decreased levels of markers and
mediators of inflammation such as the cytokines interleukin-1β and tumor necrosis factor
(TNF-α).

Mills et al looked at the effects of omega-3 fatty acid supplementation in a head injury
model in rats. Docosahexaenoic acid (DHA) was started approximately 24 hours after injury, in
the following doses: 10 mg/kg/day for group 1 and 40 mg/kg/day for group 2. The number of
beta-amyloid precursor protein (APP)-positive axons was used to measure the level of injury.
There was a significant quantitative difference of 182 ± 44.6 APP-positive axons in
un-supplemented animals versus sham-injured animals (control animals), which had 4.1 ± 1.3
APP-positive axons per square millimeter. Group 1 showed 26.1 ± 5.3 and group 2 showed 19.6 ±
4.7, APP-positive axons. It is notable that the omega-3 fatty acid supplementation groups had
a significantly reduced number of APP-positive axons at 30 days after injury to levels
similar to those in uninjured animals. This study shows pathologic improvement with high dose
omega-3 fatty acid supplementation, specifically DHA, in a head injury rat model. However,
there are no current human studies in the medical literature that look at omega-3 fatty acid
supplementation in the treatment of concussions. Does high dose omega-3 fatty acid
supplementation in Division I NCAA athletes that have sustained a concussion improve time to
symptom resolution, neurocognition and postural stability and thus decrease the number of
days out of competitive sports? Protocol: Once an athlete qualifies for the study he/she will
be randomly be assigned to either high dose omega-3 fatty acid/DHA supplementation or
placebo. Demographics of the athlete will be obtained which include: age, gender, sport,
academic year, height, weight, BMI, history of prior concussion, migraines, learning
disability, or psychiatric diagnosis. Both groups will undergo standard and usual care for
concussed athletes at East Carolina University. The physician and the athletic training staff
evaluating and clearing the athlete to return to activity will be blinded.

Currently East Carolina University employs a regimented return-to-play protocol for every
student-athlete that has sustained a concussion. As part of their pre-participation physical,
all student-athletes will have a baseline computerized postural stability test using Biodex
BioSway and a computerized neurocognitive test using ImPact. At the time of injury a Sport
Concussion Assessment Tool 2 (SCAT2) is administered by a certified athletic trainer, and the
student-athlete is withdrawn from participation if they are symptomatic and/or have deficits
noted. The same day a concussion is suspected a repeat Biodex postural stability test will
also be administered and the student-athlete is given a detailed information sheet on
instructions for monitoring and follow-up. A repeat Impact neurocognitive test will then be
administered within 24 hours after the injury. The student-athlete is then seen and examined
by a sports medicine physician to review the results, perform a clinical exam and confirm the
diagnosis. The student-athlete is then evaluated daily with a modified Symptom Evaluation
Questionnaire found on the SCAT2 by an athletic trainer. When the student-athlete is
asymptomatic with activities of daily living (ADLs) for 24 hours, he/she then begins a
non-contact return to play protocol resembling Zurich's beginning with a supervised
cardiovascular challenge. This includes 30 minutes of supervised light aerobic activity on a
treadmill or stationary bike. If the athlete is asymptomatic with the cardiovascular
challenge then he/she can progress to noncontact sport specific drills the subsequent day. If
the athlete is still doing well he/she can progress their non-contact training drills and
start light resistance training the following day. If the student-athlete remains
asymptomatic through the non-contact activity progression, he/she then re-takes the
computerized neurocognitive test, postural stability assessment and is re-evaluated by the
physician. If the postural stability assessment and neurocognitive test are back to baseline
the athlete is then cleared at the discretion of the treating sports medicine physician to
return to full unrestricted activity. However, if a student-athlete's symptoms continue by
day 7 both Impact and Biodex BioSway evaluation will be re-administered. This will be
repeated again at 14 days and 30 days post-injury if the student-athlete continues to be
symptomatic.

Inclusion Criteria:

1. East Carolina University NCAA Division I athlete.

2. Have sustained a concussion within the past 24 hours.

3. A neurological exam not consistent with concern for an intracranial hemorrhage or
other significant pathology.

4. Must be at least 18 years old.

Exclusion Criteria:

1. Subjects with a recent prior concussion within the past 30 days.

2. Subjects with a history of moderate to severe TBI that has required hospitalization or
resulted in prolonged signs and/or symptoms (>3 weeks).

3. Subjects with a known neurological diagnosis associated with impaired cognitive
function other than Attention Deficit Hyperactive Disorder or Attention Deficit
Disorder.

4. Subjects already routinely using omega-3/DHA supplementation.

5. Subjects with a known allergy to algae, omega-3 fatty acid, or any component of the
formulation.

6. Subjects currently requiring anticoagulants (ie: Warfarin), anti-platelets (ie:
aspirin, Plavix) or any Non-steroidal anti-inflammatory drugs (ie: Ibuprofen,
Naprosyn).

7. Subjects with known liver pathology or significantly elevated liver function tests
(greater than 3 x normal).

8. Subjects with a current lower extremity injury that will affect postural stability
testing.