Postconcussion Syndrome: A Review of Pathophysiology and Potential Nonpharmacological Approaches to Treatment

The Physician and Sportsmedicine November 2012, Volume 40, Issue 4, pp. 73-87 Joseph C. Maroon, MD; Darren B. LePere, BS; Russell L. Blaylock, MD; Jeffrey W.Bost, PAC: This article has 157 references FROM ABSTRACT The incidence of all-cause concussions in the United States is 1.6 to 3.8 millionannually, with the reported number of sport- or recreation-related concussionsincreasing dramatically, especially in youth sports.The use of roadside bombs in Iraq and Afghanistan has propelled the incidence ofconcussion and other traumatic brain injuries to the highest levels ever encounteredby the US military. The wars in Iraq and Afghanistan cause about 300 concussions per month. There is a marked increase in post-concussion syndrome (PCS) and the associatedcognitive, emotional, and memory disabilities associated with the condition.There have been no significant advancements in the understanding or treatment ofPCS for decades. The current management of PCS mainly consists of rest, reduction of sensoryinputs, and treating symptoms as needed.Recently, researchers have proposed that activation of the immune inflammatoryresponse may be an underlying pathophysiology that occurs in those whoexperience prolonged symptoms after a concussion. This immune inflammatoryresponse is known as immunoexcitotoxicity. KEY POINTS FROM THIS ARTICLE: 1) Most traumatic brain injuries (TBIs) are mild traumatic brain injuries (mTBIs)and are often referred to as concussions. These concussions can cause long-termdisability. 2) Most signs and symptoms of a cerebral concussion spontaneously resolvewithin 2 to 7 days, including: * Headache * Nausea * Visual disturbance * Balance abnormalities 3) Up to 15% of concussion individuals may experience prolonged andintractable physical, cognitive, emotional, and/or sleep disturbances that result insevere debilitation the so-called post-concussion syndrome (PCS). Thesesymptoms often result in significant disruption and even withdrawal from school,job, or military activity. 4) Post-concussion syndrome requires at least 3 symptoms for a minimum of 4weeks following a head injury, including: * Headache * Dizziness * Sleep problems * Psychological disturbances * Cognitive disturbances 5) Management of PCS includes rest and reduction of sensory input fromschoolwork, computers, and any processing of new information. 6) In PCS, imaging technology (CT, MRI, diffusion tensor imaging, PET) are lessthan optimal because they do not document changes in brain neurochemistry. 7) Following an impact to the head, a cascade of biochemical, immunological,and excitotoxic events occur, mediated by the innate and adaptive immune systemsin the central nervous system. 8) When a person sustains a TBI, it is well recognized that there is a massiverelease of glutamate and aspartate, primarily from astrocytes and microglia cells,which overstimulate glutamate receptors. This results in an influx of calciumthrough the cellular membrane and subsequent neuronal toxicity and cell death. This is called the excitotoxic reaction, and contributes to PCS and to chronictraumatic encephalopathy (CTE)." 9) Microglia are the macrophages of the brain and spinal cord. In brain injury,the microglia become activated, releasing a series of immune factors, such asreactive oxygen species (ROS), inflammatory prostaglandins, and excitotoxins inthe form of glutamate, aspartate, and quinolinic acid. 10) Immunoexcitotoxicity and microglial activation is central to a number ofneurodegenerative diseases, including Alzheimers disease, Parkinsons disease,amyotrophic lateral sclerosis, and vascular dementia. 11) The lingering symptom of headache, cognitive disturbances, and memoryimpairment of PCS are linked to excitotoxic neurotransmitters and inflammatorycytokines. PCS following TBI may represent a persistent, low-grade, chronicallysmoldering neuroinflammatory response. 12) The short-term symptoms of concussion, such as immediate confusion anddisorientation, usually resolve within minutes to several hours and are probably dueto electrochemical changes. 13) A limited activation immunoexcitotoxicity inflammatory response producesprotracted headaches, fogginess, and poor concentration, which resolve within aweek in most cases. 14) After a concussion it is extremely important to prevent a second injury beforethe brain is completely healed. A second impact initiates brain vasoreactive edemawith resultant severe malignant brain swelling, which if not recognized and treatedpromptly, it may be fatal. 15) A second brain injury before complete recovery accelerates microgliaactivation. The initial injury primes the microglia a state in which microgliaupregulate the production of proinflammatory cytokines. Primed microglia releasesignificantly higher levels of proinflammatory cytokines/chemokines andexcitotoxins than normal, causing prolonged brain immunoexcitotoxicity. 16) Both glutamate and quinolinic acid can produce tau proteins and stimulate β-amyloid accumulation in both Alzheimers disease and in CTE. 17) A number of natural plant products and extracts, such as fish oil, resveratrol,green tea, and curcumin, among others, may offer similar effects in the treatmentof AD and other immunoexcitotoxicity-associated neurodegenerative disorders. These compounds work by suppressing or affecting microglial activation states aswell as the excitotoxic cascade and inflammatory mediators, and promoting therelease and generation of neurotrophic factors essential for CNS healing. 18) Nonsteroidal anti-inflammatory drugs are the most common cause of drug-related morbidity and mortality reported to the US Food and Drug Administrationand other regulatory agencies around the world. 19) Omega-3 essential fatty acids (EFAs), vitamin D3, curcumin, resveratrol andother polyphenols, and magnesium have all been shown to clinically reduceinflammation, reduce microglial activation, affect excitotoxic cell signalingprocesses, and are used worldwide to treat inflammatory-related conditions. 20) The major components of omega-3 EFAs, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), can inhibit production of proinflammatory eicosanoids. 21) The proinflammatory prostaglandin E2 (PGE2), made from omega-6 EFA(arachidonic acid [AA]) found in all cellular membranes, can be downregulatedthrough competitive inhibition due to the enhanced production of prostaglandin E3(PGE3) from EPA, which is also incorporated into cellular membranes. 22) CTEs mechanisms of immunoexcitotoxicity and microglia activation arereduced by both EPA and DHA. 23) Docosahexaenoic acid (DHA) constitutes > 25% of brain phospholipids,maintaining membrane integrity, fluidity, excitability, and function. 24) Oral supplementation of DHA for 30 days following TBI significantly decreasesthe number of swollen, disconnected, and injured axons, attenuates glutamateinducedneuronal injury and death. 25) Omega-3 EFAs increase neuronal survival following brain injury by reducingexcitoxicity through inhibition of glutamate-induced neuronal toxicity. 26) Therapeutic EPA+DHA dosing for TBI is a total of 1.5 to 5.0 g per day. 27) Vitamin D significantly promotes immune function and reduces theinflammatory response. 28) Vitamin D can limit the extent of TBI injury by reducing cerebral edema,inflammatory response, necrosis, and apoptosis. Vitamin D decreases glutamate-induced neuronal death. 29) Curcumin is a flavonoid compound found in the Indian spice turmeric. It haspotent anti-inflammatory, antioxidant, and antineoplastic effects. 30) Curcumins anti-inflammatory actions arise from inhiibition of proinflammatory mediators, including cytokines and NF-κB and inhibition of COX-1and COX-2. It may be a comparable alternative to NSAIDs without the unacceptableside effects. 31) Curcumin has been found to prevent apoptosis, as well as decrease edemafollowing TBI and ischemia. 32) The suggested dosage of curcumin supplementation for TBI is 400 to 600 mgtaken 3 times per day. 33) Resveratrol is a plant-based polyphenol antimicrobial. It is a powerfulantioxidant with cardioprotective, antineoplastic, and anti-inflammatory effects. 34) Resveratrol may extend the life span, slow the development of chronicneurodegenerative disease, and improve patient outcome following stroke, cerebralischemia, spinal cord injury, and TBI. 35) Resveratrol is anti-inflammatory by suppressing pro-inflammatory PGE2synthesis, and inhibiting TNF-α- and IL-1β-induced NF-κB activation. 36) Resveratrol significantly reduces glutamate release TBI. 37) Moderate resveratrol wine consumption significantly reduced the risk of ADin population studies. 38) Resveratrol can exist in either the cis- or trans- form, but only the transformis believed to be bioactive. The typical supplementation range is between 50to 500 mg/day. 39) Magnesium is required for > 300 metabolic processes and plays an essentialrole in modulating transmembrane electrical activity. It is also essential forprotein synthesis, energy metabolism, maintenance of ionic gradients, immunesystem regulation, smooth muscle tone, and calcium regulation. 40) Magnesium decline is thought to play a major role in the neuronalpathogenesis following TBI. Its most predominant neuroprotective action is byacting as a noncompetitive inhibitor of NMDA excitotoxicity by receptor blockade orby decreasing glutamate release. 41) About 63% of adult Americans have insufficient magnesium, and especiallythose who use proton pump inhibitors [antacids]. 42) Food sources for magnesium include legumes, nuts, whole grains, and mostvegetables. The recommended dosage of magnesium is approximately 80 to 420mg/day. 43) Green tea is a powerful antioxidant, containing numerous polyphenoliccompounds called catechins, of which epigallocatechin-3 galate (EGCG) is the mostabundant. These polyphenols in green tea are anti-inflammatory, helping preventcardiovascular disease, cancer, and arthritis. 44) The typical recommendation is 3 to 4 cups of green tea per day, or 1 servingof extract, which contains between 300 and 400 mg. 45) These nutritional approaches for TBI and PCS attack the pathophysiology ofthe disorder, shortening its duration, and not just ameliorating the symptoms. 46) By supporting neuronal function and countering key immunoexcitotoxicitymechanisms, non-pharmaceutical treatments may offer an effective alternative fortreating post-concussion syndrome. COMMENTS FROM DAN MURPHY: The suggested natural products to be used to halt the pathophysiological cascade ofTBI and PCS were: * Omega-3s EPA+DHA * Vitamin D3 * Curcumin * Resveratrol * Magnesium * Green Tea (EGCG) Quinolinic acid activates the N-methyl-d-aspartate receptor (NMDAR) and canlead to axonal neurodegeneration. Quinolinic acid is a potent neurotoxin. Quinolinicacid is an excitotoxin in the CNS. Quinolinic acid may be involved in many psychiatric disorders, neurodegenerativeprocesses in the brain, as well as other disorders. Within the brain, quinolinic acid is produced by activated microglia cells andmacrophages. The quinolinic acid produced in microglia is then released and stimulates NMDAreceptors resulting in excitatory neurotoxiticity. Quinolinic acid destabilizes the cytoskeleton of the astrocytes and brain endothelialcells contributing to the degradation of the Blood Brain Barrier. Quinolinic acid reaches pathological levels in response to inflammation in the brain,which activates the microglia and macrophages. High levels of quinolinic acid canlead to hindered neuronal function or even apoptotic death. When inflammation occurs, quinolinic acid is produced in excessive levels. Thisleads to over excitation of the NMDA receptor, which results in an influx of Ca2+into the neuron. High levels of Ca2+ in the neuron trigger an activation ofdestructive enzymatic pathways that degenerate crucial proteins and increase NOlevels, leading to an apoptotic response by the cell, which results in cell death. Glutamate further stimulates the NMDA receptors, thus acting synergistically withquinolinic acid to increase its neurotoxic effect. Increased levels of quinolinic acid are linked to: * Mood disorders * Depression * Schizophrenia * Neurodegenerative conditions * Amyotrophic lateral sclerosis (ALS) * Mitochondria dysfunction * Alzheimer’s disease * Brain ischemia, stroke * Huntington’s disease * Parkinsons disease * Bacterial infections of the CNS * Systemic lupus erythematosus * Traumatic Brain Injury * Cognitive decline with ageing * Other brain infections, including polio, Lyme disease Antioxidants provide protection against the pro-oxidant properties of quinolinic acid.Natural phenols such as catechin hydrate, Curcumin, and epigallocatechin gallate(found in green tea) reduce the neurotoxicity of quinolinic acid.COX-2 [controls the production of pro-inflammatory eicosanoids fromomega-6 fatty acid arachidonic acid] is upregulated in neurotoxic disordersand is associated with increased ROS production.