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Traumatic brain injury: recognition and treatment options for mild injury and what can we learn from failed clinical trials.

Over the past several years, there has been increasing media coverage of the dangers of head trauma and especially of the repeated traumas seen in many professional sports and experienced by deployed military troops. Symptoms attributed to chronic head trauma include depression, apathy, anxiety, cognitive changes, attention issues, and aggression. Damage occurs in two parts during a traumatic brain injury (TBI); the cumulative insult to brain tissue is generally attributed to both the primary injury (mechanical damage from shearing, tearing or stretching of neurons, blood vessels, and other cellular structures) and secondary injury mechanisms, including the release of excitatory neurotransmitters, mitochondrial dysfunction, depolarization, and the initiation of inflammatory and immune processes that can compromise the blood-brain barrier (BBB) and contribute to edema, increases in intracranial pressure, and ischemia. (1,2)

There is emerging evidence that the disruption in the BBB allows passage of a protein into the immune system where it triggers an inflammatory autoimmune response, and that even subconcussive hits to the head contribute the levels of this protein as well as autoantibodies. (3) In other words, a significant portion of the damage done in a TBI occurs in the hours/days/months after the event and repeated head trauma that is too minor to cause a concussion is causing an inflammatory reaction in the brain, which leads to a wide array of symptoms, including many that are among the most commonly reported mental health issues faced by Americans in general.

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Many have taken the headlines and high-profile stories of injury as reasons to keep their children from playing high-contact sports, or called for changes in regulations for the use of safety gear, which are all good efforts to prevent the primary event from occurring. (4) However, regardless of precautions taken, head injuries remain remarkably common even in the general population, with falls, motor vehicle accidents, and assaults among the most common causes. (5) Most people have had at least one, and possibly several, incidences of concussion or head trauma in their lives. There are some populations in which the incidence of brain injury is higher than average, including children under age 4, teens, and the elderly. Concussion rates are as high as 4% in children and adolescents, although these events are often underreported, as the signs and symptoms can be subtle, delayed, and varied. (6) Mild brain injury is underdiagnosed even among those who seek treatment in trauma centers, and it is still estimated that more than 1.7 million people in the US suffer from a TBI annually. (7,8) Additionally, 10% to 20% of returning veterans have suffered a traumatic brain injury, the majority of which are classified as mild but can still lead to post-concussive syndromes that increase the risk for PTSD and suicide. (9)

Recognizing these injuries and providing proper care as soon as possible is imperative for recovery, as secondary injury mechanisms can continue far beyond the original incident, and symptoms can persist for months. Early intervention requires accurate and prompt diagnosis, and while severe TBI patients are likely to be seen in trauma centers, those experiencing mild trauma may not even realize that they have experienced a brain injury. Assessment of the severity of a TBI is typically done using the Glasgow Coma Scale (GCS), a 3-15 point scale that assesses a patient's level of consciousness and neurological function, although this scale is not as sensitive to mild injuries. (10) Common symptoms of mild brain injury often include vague symptoms such as fatigue, headaches, sleep disturbances, depression, irritability, anxiety, and cognitive changes. These symptoms may not appear for days or weeks after the injury, making diagnosis difficult, and in up to 20% of patients they may persist beyond a year following the injury. (11,12)

The primary immune defense mechanism in the central nervous system (CNS) is the stimulation of microglial cells, specialized macrophages that when activated, secrete inflammatory cytokines, free radicals, and excitotoxins such as glutamate and aspartate. (13) Once activated by an initial event, these cells remain primed and, when they receive subsequent stimulation, can be hyperreactive, requiring a smaller stimulus to release even higher levels of pro-inflammatory substances. (14) The subsequent stimulation may be additional trauma, but may also be a toxic insult, infection, or inflammatory immune signals from elsewhere in the body, and these incidences may be separated by several months. (15)

Initial treatment for those who are identified as having experienced a brain injury typically involves avoiding vigorous activities, the use of NSAIDs or other anti-inflammatory methods, and close monitoring. Much of the ongoing research in treating TBIs is focused on limiting the secondary injury processes, including inflammation and excitotoxicity; however, more than 30 phase III clinical trials for TBI treatment have failed, despite exhibiting promising preclinical data. (16,17)

Progesterone

One of the seemingly promising areas in treatment of TBI has been the administration of progesterone. Born of the observation that gender influenced clinical outcomes in TBI cases, a hormonal influence on brain inflammation was investigated. (18,19) Progesterone, a steroid hormone produced primarily in the ovaries in women and the testes in men, but also in small quantities in the adrenal glands and in the neurons, has been recognized in several protective mechanisms in regard to neurodegeneration. (20-22) Progesterone receptors are present in the CNS of both men and women. (23)

Progesterone has been shown to reduce cerebral edema, downregulate the inflammatory cascade, decrease postinjury ischemia, reduce glutamate-related excitotoxicity, enhance the effects of GABA, and protect mitochondrial function in animal models. (24,25) Early human models included several randomized, double-blind, placebo-controlled phase II clinical trials, and they showed an improved outcome in progesterone-treated patients, with a lower 30-day and 6-month mortality rate than the controls. These studies didn't consider mild TBI cases; however, the difference between the treatment and control groups was more dramatic in the moderate traumatic brain injury survivors than in those who had experienced severe brain injury. (26,27) Additionally, neither of these phase II trials discovered any complications or adverse events associated with the administration of progesterone. These studies, though small, indicate that progesterone shows great promise as a neuroprotective agent following traumatic brain injury and have led to some larger phase III trials.

Unfortunately, the phase III clinical trials for progesterone were not as promising as their preclinical studies. The two studies released early this year seem to have joined the growing body of failed clinical trials in treatments for TBI. (28,29) While it is possible that progesterone simply doesn't have the beneficial effects that it was thought to have after the first several hundred investigational studies, numerous other factors may influence the outcome of these studies, as well as the findings in phase III trials for other TBI treatments, including the immense variance in the types of injuries that the subjects have experienced, the part of the brain affected, the participants' overall health to start with, potential delays in the initiation of treatment, the subjectivity of diagnosis, and insensitive outcome measures. (30) The participants in both of the failed phase III progesterone trials were severe or moderate TBI patients, with whom recovery is generally slower (and may not be detectable at the 6- or 12-month mark) as well as less likely overall.

While much additional research is needed in the treatment of all TBI cases, including those that are moderate to severe, it may be time to revisit basic anti-inflammatory and neuroprotective strategies, especially those that can be easily employed for the large percentage of TBI cases that are mild, including those "minor" head injuries that may be overlooked due to their delayed and vague symptom presentation. Limiting damage from secondary injury mechanisms is the most important step in controlling symptoms and preventing additional neuronal destruction. In addition to continuing to prevent primary injury to the brain, including wearing protective gear when engaging in higher-risk behavior, it is important to ensure the brain is getting adequate perfusion, that the BBB integrity isn't compromised, and that free radicals and reactive oxygen species produced as part of the immune response are quenched as to not propagate neuronal damage. Many of the following nutrients may be used reactively in the event of a random head injury such as a fall or car accident, as well as proactively for those who are regularly engaging in behavior that puts them in danger, including contact sports or active military combat.

Omega-3 Fatty Acids

Omega-3 fatty acids, including alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexanoic acid (DHA), are essential to maintaining the structural balance of cell membranes throughout the body and have reduced lipid peroxidation and protein oxidation in TBI models. (31) Additionally, omega-3 fatty acids have been shown to increase the levels of brain-derived neurotrophic factor (BDNF), which is required for the survival of neuronal cells, and omega-3 fatty acids are precursors to anti-inflammatory leukotrienes and promote modulation of inflammation in general and neuroinflammation specifically. (32,33)

Vitamin D

A potent regulator of the immune system and inflammatory responses, circulating vitamin D can cross the BBB and therefore limit an inflammatory response. (34) Though there have been few studies on the effects of vitamin D alone on TBI, there has been a favorable outcome using vitamin D in conjunction with progesterone as well as an established relationship between vitamin D deficiency and increased inflammatory cytokines in general. (35,36) Animal studies indicate that vitamin D deficiency correlated with elevated IL-6 and other inflammatory markers post injury compared with vitamin D-replete subjects. (37) Additionally, vitamin D regulates intracellular calcium throughout the body and can down regulate voltage sensitive calcium channels, altering calcium flux that affects neurogenesis, synaptogenesis, myelination, and neurotransmitter release in the brain. (38) Unfortunately, up to one-third of the US population may be deficient in vitamin D. (39) Repletion of this important nutrient preinjury as well as treatment at the time of insult may improve recovery from a TBI and reduce symptoms associated with postconcussive syndrome. (40)

Curcumin

Curcumin is the principal antioxidant found in turmeric, a plant that is part of the ginger family. There are several mechanisms through which curcumin limits the damage caused by TBI. Supplementation with curcumin prior to injury has been demonstrated to reduce oxidative damage, normalize levels of BDNF, and counteract cognitive impairment after TBI. (41) Acute TBI often results in significant cerebral edema, increased intracranial pressure (ICP), and decreased blood flow. Curcumin has shown promise in reducing cerebral edema, both when given prophylactically and immediately following injury by reducing glial cell activation and increasing the activity of specific aquaporins, which are channels that regulate fluid levels. (42) And even when only administered after an injury, curcumin has been shown to improve patient outcomes by reducing microglial activation and neuronal cell death. (43) Curcumin is safe even at relatively high doses (12 grams/day), although there are some reported issues with the bioavailability of the molecule due to poor absorption and rapid metabolism. Advances in curcumin supplements, including the use of liposomal curcumin, curcumin nanoparticles, and the complementary use of agents that interfere with the metabolism, have greatly improved the clinical efficacy of curcumin. (44) Randomized, double-blind, crossover trials of the lecithin formulation of curcumin (Meriva) have discovered a 29-fold higher total curcuminoid absorption compared with standard curcumin mixtures. (45)

Traumatic brain injuries remain quite common, and while ongoing research is being conducted to find safer and more effective treatments for moderate to severe TBIs, there is much that can be done to prevent and treat mild brain injury beyond increasing helmet use. Because much of the damage in any TBI is due to secondary mechanisms, lowering inflammatory potential in at-risk groups and treatment with agents that help to control secondary insult in the event of a brain injury are needed. Proper screening and diagnosis of subconcussive and mild injury is imperative so that the proper action can be taken. Though there have been many failed phase III trials for TBI treatment, the patients enrolled in those studies were primarily in the moderate to severe category, which not only decreases their chance of recovery but also makes their clinical progress difficult to track. By taking a proactive approach with at-risk populations as well as a more active role in the treatment of mild brain injury, there are many ways we can reduce the chronic effects of head trauma that contribute to the depression, anxiety, and cognitive dysfunction that affect so many people. Additionally, as we learn more about the ongoing inflammatory component of TBI, and especially as we look at that in the context of long-term effects on mood, behavior, and cognition, it's important to acknowledge that there are many things beyond physical trauma that can contribute to inflammation in the brain and CNS, including infections and diet. While it's possible that many people who are experiencing fatigue, depression, anxiety, and difficulty concentrating may be doing so as a result of repeated head trauma, others may be experiencing these symptoms due to the chemicals they have been exposed to, infectious agents, or systemic inflammation. Reducing inflammatory processes in the central nervous system is a likely to be of benefit regardless of the source of insult.

by Sara Wood, ND

Notes

(1.) Loane DJ, Faden Al. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci. 2010 December 1;31(12):596-604.

(2.) Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. 2007;99(1):4-9.

(3.) Marchi N, Bazarian JJ, Puvenna V, et al. Consequences of repeated blood-brain barrier disruption in football players. PloS ONE. March 6, 2013.

(4.) Zemper ED. Analysis of cerebral concussion frequency with the most commonly used models of football helmets. J Athl Train. 1994 Mar;29(1):44-50.

(5.) Traumatic brain injury in the United States: fact sheet [Web page]. Centers for Disease Control and Prevention, http://www.cdc.gov/traumaticbraininjury/get_the_facts.html. Accessed August 22, 2015.

(6.) Wilier B, Dumas J, Hutson A, Leddy J. A population based investigation of head injuries and symptoms of concussion of children and adolescents in schools. Inj Prev. 2004;10:144-148.

(7.) Chambers J, Cohen SS, Hemminger L, et al. Mild traumatic brain injuries in low-risk trauma patients. J Trauma. 1996 Dec. 41(6):976-980.

(8.) Faul M et al. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002-2006. Atlanta, GA: Centers for Disease Control and Prevention; 2010.

(9.) Bryan CJ, Clemans TA. Repetitive traumatic brain injury, psychological symptoms, and suicide risk in a clinical sample of deployed military personnel. JAMA Psychiatry. 2013;70:686-691.

(10.) Kolaitis G, Giannakopoulos G, Liakopoulou M, et al. Predicting pediatric posttraumatic stress disorder after road traffic accidents: the role of parental psychopathology. J Trauma Stress. 2011 Aug;24(4):414-421.

(11.) Mild traumatic brain injury/concussion [Web page]. Centers for Disease Control and Prevention, http://www.cdc.gov/concussion/signs_symptoms.html. Accessed Sept 8, 2015.

(12.) Katz RT, DeLuca J. Sequelae of minor traumatic brain injury. Am Fam Physician. 1992;46:1491-1498.

(13.) Block, ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007 Jan;8(1):57-69.

(14.) Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci. 2005;25:9275-9284.

(15.) Macciocchi SN, Barth JT, Littlefield LM. Outcome after mild head injury. Clin Sports Med. 1998;17:27-36.

(16.) Xiong Y, Mahmood A, Chopp M. Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs. 2009;14(1):67-84.

(17.) Maas Al, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics. 2010 Jan;7(1):115-126.

(18.) Ratcliff JJ, Greenspan Al, Goldstein FC, et al. Gender and traumatic brain injury: Do the sexes fare differently? Brain Inj. 2007 Sep;21(10):1023-1030.

(19.) Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000 May;17(5):367-388.

(20.) Schumacher M, Hussain R, Gago N, Oudinet J-P, Mattern C, Ghoumari AM. Progesterone synthesis in the nervous system: Implications for myelination and myelin repair. Front Neurosci. 2012;6:10.

(21.) Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol. 1997 May;31(1):1-11.

(22.) Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005; 1049:112-119.

(23.) Camacho-Arroyo I, et al. Intracellular progesterone receptors are differentially regulated by sex steroid hormones in the hypothalamus and the cerebral cortex of the rabbit. J Steroid Biochem Mol Biol. 1994;50 (5-6):299-303.

(24.) Signh M, Su C. Progesterone and neuroprotection. Horm Behav. 2013 Feb;63(2):284-290.

(25.) O'Connor CA, Cernak I, Vink R, et al. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res. 2005;1062:171-174.

(26.) Wright DW et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49(4):391-402.

(27.) Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12(2):R61.

(28.) Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014;372:2457-2466.

(29.) Skolnick BE, Maas Al, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014;371:2467-2476.

(30.) Stein DG. Embracing failure: What the phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015 Aug 14:1-14.

(31.) Michael-Titus AT Omega-3 fatty acids and neurological injury. Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):295-300.

(32.) Kumar PR, Essa MM, Al-Adawi S, et al. Omega-3 fatty acids could alleviate the risks of traumatic brain injury--a mini review. J Tradit Complement Med. 2014;4(2):89-92. doi:10.4103/2225-4110.130374.

(33.) Mills JD, Bailes JE, Sedney CL, Hutchins H, Sears B. Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. J Neurosurg. 2011 Jan;114(1):77-84.

(34.) Smolders J, Moen SM, Damoiseaux J, Huitinga I, Holmoy T. Vitamin D in the healthy and inflamed central nervous system: access and function. J Neurol Sci. 2011;311:37-43.

(35.) Aminmansour B, Nikbakht H, Ghorbani A, et al. Comparison of the administration of progesterone versus progesterone and vitamin D in improvement of outcomes in patients with traumatic brain injury: a randomized clinical trial with placebo group. Adv Biomed Res. 2012;1:58.

(36.) Tiwari S, Pratyush DD, Gupta SK, Singh SK. Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection. Br J Nutr. 2014 Dec 28;112(12):1938-1943.

(37.) Cekic M, Cutler SM, VanLandingham JW, Stein DG. Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats. Neurobiol Aging. 2011;32:864-874.

(38.) McCann, JC, Ames BN. Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction. FASEB J. 2008 Apr;22(4):982-1001.

(39.) Ganji V, Zhang X, Tangpricha V. Serum 25-hydroxyvitamin D concentrations and prevalence estimates of hypovitaminosis D in the U.S. population based on assay-adjusted data. JK Nutr. 2012;142:498-507.

(40.) Wentz LM. Vitamin D status may affect resilience and recovery from mild traumatic brain injury in military personnel. Austin J Nutr Food Sci. 2014;2(5):1030. ISSN: 2381-8980.

(41.) Wu A1, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol. 2006 Feb;197(2):309-317.

(42.) Laird MD, SR S, Swift AEB, Meiler SE, Vender JR, Dhandapani KM. Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem. 2010;113(3):637-648.

(43.) Zhu H, Bian C, Yuan J, et al. Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-[kappa]B signaling pathway in experimental traumatic brain injury. J Neuroinflammation. 2014;11:59.

(44.) Anand P, Kunnumakkara, AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharmaceutics. 2007;4(6):807-818.

(45.) Cuomo J, Appendino G, Dern AS, et al. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 2011 Apr 25;74(4):664-669.

Dr. Wood grew up in Colorado and obtained her undergraduate degree in biochemistry from Colorado College. An enthusiasm for science but a passion for people led her to medicine, and a desire to treat the cause of disease, not just the symptoms, led her to naturopathy. After completing her doctorate at the National College of Naturopathic Medicine, Dr. Wood stayed in Oregon and has a private practice focused on endocrine imbalance, digestive dysfunction, immune support, and cardiovascular health.

In addition to her clinical practice, Dr. Wood is a staff physician with Labrix Clinical Services Inc., where she educates physicians and health care providers around the country about hormonal balancing through development of educational materials, contributions to a webinar series, and lectures at local and national conferences. In 2008 she coauthored a book on andropause titled His Change of Life: Male Menopause and Healthy Aging with Testosterone.
Primary Injury Secondary Injury

Occurs at the moment of initial      Consequences of the immune
trauma and may include:              reaction to the initial trauma
                                     and may include:

* Direct force to the head           * Edema and compression of the
                                       brain

* Impact of the brain against the    * Ischemia and hypoxia causing
  skull                                 cell death

* Shearing or physical tearing of    * Increase in intracranial
  the neurons or blood vessels         pressure

* Damage to the blood brain barrier  * Release of excitotoxic
                                       neurotransmitters

* Bruising or intracranial bleeding  * Formation of oxidative free
                                       radicals

Glasgow Coma Scale

     Eye Movement Verbal   Verbal Skills           Motor Skills

1     Doesn't open eyes       Makes no sounds       Makes no movement

2       Opens eyes in        Incomprehensible      Extension to painful
     response to painful           sounds                stimuli
           stimuli

3       Opens eyes in       Utters inappropriate   Abnormal flexion to
      response to voice            words             painful stimuli

4        Opens eyes        Confused, disoriented   Flexion / Withdrawal
        spontaneously                               to painful stimuli

5            N/A            Oriented, converses     Localizes painful
                                  normally               stimuli

6            N/A                    N/A               Obeys commands

     Severe: < 9           Moderate: 9-12          Minor: >13

Teasdale G. Jennett B Assessment of coma and impaired consciousness A
practical scale Lancet 1974.13(2) 81-4

Suggested therapies for mild TBI

Therapy          Recommended Dosages         Mechanism of Action in TBI

Progesterone    25-50 mg transdermaliy or    * Reduces cerebral edema
                100-200 mg orally for        * Reduces glutamate
                women                          excitotoxicity

                10-20 mg transdermaliy or    * Protects mitochondria
                50-100 mg orally for men

Omega-3 Fatty   3000-4000 mg/day             * Reduces lipid
Acids           * (dosage may need to be       peroxidation and
                altered in those using         maintains cell membrane
                blood thinning agents)         integrity

                                             * Stimulates brain derived
                                               neurotrophic factor
                                               (BDNF)
                                             * Enhance production of
                                               anti-inflammatory
                                               leukotrienes

Vitamin D       5000-10,000 iu/day or        * May reduce IL-6
                dosage required to achieve   * Regulates calcium flux
                60-80 ng/ml in serum         * Modulates immune
                                               response
Curcumin        2-4 g/day of Meriva or
                other highly absorbable
                form                         * Stimulates BDNF
                                             * Reduces cerebral edema
                                             * Reduces microglial
                                               activation and neuronal
                                               death
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Author:Wood, Sara
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Geographic Code:1USA
Date:Dec 1, 2015
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