March 6, 2022
emergening treatments for concussions cover

emerging treatment and diagnostics for concussion

introduction

The growing number of concussions and mild traumatic brain injuries (mTBI) with the lack of evidence-based treatment options is a continuous health concern for sports medicine providers. There continues to be an evolving field in the management of persistent post concussive symptoms (PPCS).  Due to the lack of evidence-based treatment options, post-concussion protocols mainly consist of symptomatic treatment to prevent a recurring concussion and to expedite the recovery process. Patients with a concussion history are three times more likely to have an incidental concussion when compared to those without a concussion history.  Of those people who develop PPCS, up to 25 % of them will experience prolonged PCS, where the symptoms continue for over six months [1].

Concussion basics and management principles were covered previously ( Role of vestibular and vision therapy, PPCS treatment, PPCS pharmacology, PPCS Imaging, PPCS Basics.  The goal of the current post is to look into the emerging diagnostic studies and treatment options for concussion and persistent post concussive symptoms.

Most sports medicine providers will need to evaluate athletes for concussion while covering events.  The most common test still remains the SCAT test (most updated SCAT-5) for athletes or patients 13 and above.  Some sports (such as football, hockey) will sometimes modify the test (usually Maddocks questions to match sport) and normative data has been growing [2].  The SAC (Standard Assessment of Concussion), BESS (Balance Error Scoring System), TGT (tandem gait test) and King-Devick test all remain viable sideline assessment tools. VOMS and eye tracking are also used frequently during sideline assessments depending on the provider’s training.  Efforts are being made to make these testing options available on cell phone or tablet applications.  This would make the storage and normative data easier to access compared to paper charts or tests

Image 1.  Questions arising with concussion diagnostics.  Adopted from [19].

diagnostic testing

In regards to other diagnostic testing, biomarkers are the focus of many studies that are current and ongoing.  Glial fibrillary acidic protein (GFAP) and ubiquitin c-terminal hydrolase (UCH-L1) are FDA approved for mild TBI detection. UCH-L1 rises in minutes to hours, GFAP rises in hours to days, and tau rises over the course of days.  GFAP has notably correlated with intracranial pathology on computed tomography (CT) across the spectrum of TBI, with an area under the receiver-operating characteristic curve (AUC) >0.88 [3].  S100 calcium-binding protein B (S100B) has been a focus of many ongoing studies.  One study by Shahim and colleagues found that S100B at 1-h post-injury was significantly correlated with time to resolution of symptoms, but other studies have been inconsistent [4].  The results of studies involving tau proteins have also shown conflicting results [5].

One other recent biomarker study in military individuals reported significant elevation of interleukin-6 levels in concussed military personnel less than 8 h following injury. This was the first reported observation of blood levels IL-6, IL−10, and TNFα in a combat environment to evaluate biomarker consequences of concussions sustained during combat deployments.  This study may also warrant further studies in the future dealing with sport related concussion [6].

Studies evaluating less common blood biomarkers, including kynurenine metabolites, SNTF and AMPAR have yielded promising results in the limited research conducted to date, with moderate to large effect sizes reported [7].  Several studies utilized biomarkers in other fluids, including saliva, CSF and urine. Salivary cortisol was found to correlate only with perceived stress, and did not correlate with postconcussion symptoms or days to symptom resolution [8].

additional treatment updates

The most common recommendation following a concussion immediately is prescribed rest. This rest consists of symptom-limited cognitive and physical rest for no less than 24 hours.  Rest is recommended due to the sensitive condition of the brain following a concussion due to the changes in brain homeostasis and there have not been many changes to this current recommendation.

However, it is becoming more common to prescribe sub-symptom exercise after 24 to 72 hours,  depending on the athlete or patient.  It has been reported that children and adolescents showed more symptoms overall in patients prescribed strict rest.  Prolonged strict physical inactivity can lead to further development of secondary symptoms, such as depression, anxiety, and fatigue [9-10].   An additional study showed patients who were prescribed strict rest reported more symptoms 10 days after initial injury than those who were not restricted from moderate cognitive and physical activity [9-10].

Osteopathic cranial manipulative medicine (OCMM) is a non-pharmacologic method that has recently been evaluated as a potential alternative treatment. OCMM is based on the idea that the anatomy of the cranium reflects the human body as a whole.  A previous study showed that 95 % of patients who have had a TBI showed at least one pattern of cranial strain and 87 % had at least one or more bony motion restrictions [11] .Approximately 71 % of the participants who completed the two treatment sessions of OCMM showed improvements in their post-concussive symptoms with no adverse effects in one small study [12].  Another case series with 11 retired professional football players showed that ten sessions of specific craniosacral therapy resulted in improvements in pain intensity, ROM, memory, cognition, and sleep in concussed patients [13].  This has been shown to be safe and may be an option for patients suffering from PPCS with resistant symptoms.

Hyperbaric oxygen therapy (HBOT) has been researched as a treatment method for PCCS. HBOT involves a chamber that is slowly pressurized to 1.5–3 times higher than normal air pressure with pure oxygen [14].  The proposed mechanism of action is through the promotion of angiogenesis. Angiogenesis stimulated with hyperbaric oxygen can potentially increase brain perfusion with better cerebral blood flow (CBF) and cerebral blood volume (CBV).  HBOT requires a high level of compliance and a substantial amount of time investment as each session consists of 60 minutes, making future studies difficult. 

pharmacologic agents

Currently, there are no established guidelines for pharmaceutical therapy in the treatment of PCS and mTBI symptoms. However, based on the symptom presentation, pharmaceutical therapy, ranging from over-the-counter analgesics to prescription antidepressants have been explored for potential benefits.

One recent study was performed using fluoxetine for treatment of PPCS.  In an open-label pilot study, five patients who have experienced mild to severe TBI were given fluoxetine hydrochloride 20−60 mg/day. These patients had either no or moderate depression and had no history of previous antidepressant use. The participants were assessed for cognitive and memory function based on the HAM-D scale at baseline and after eight months of fluoxetine treatment. Although only a small size, there was a statistically significant improvement in the severity of symptoms including mood and memory.  Improvements were also seen in attentional-motor speed tasks and a letter-number sequencing subtest, reflecting the level of a “working memory” of the patients [15].

Amantadine is a medication that has been researched specifically for headaches in PCS. As a NMDA receptor antagonist, amantadine has previously been studied for its use in other TBI symptoms, such as impulsive behavior and disinhibition caused by frontal lobe disorders.  IN a retrospective study, thirty-three patients were prescribed amantadine for postconcussive syndrome after traumatic brain injury. Post-traumatic headaches (PTHs) were improved in 80% of patients who completed a full trial of amantadine (100 mg twice daily for 2 months).. Patients had improvement in headaches even if the medication was prescribed years after the initial trauma, but little improvement was noted in other symptoms such as poor memory, dizziness, and personality changes [16]. 

Image 2.  Comprehensive persistent post concussive symptoms (PPCS) general recommendations.  Adopted from [9].

Sleep disturbances are commonly reported in children with persistent post-concussion symptoms (PPCS).  Melatonin is a very commonly prescribed supplement for this due to its natural characteristics.  A recent randomized trial with 72 children showed improved sleep efficacy and improved depressive symptoms with 10 mg at night without any significant side effects noted [9].

Due to the resemblance of post traumatic headaches to migraines and the lack of evidence-based PTH treatment options, patients are often prescribed migraine treatments, such as triptans [4]. More invasive procedures, such as Botox and facet blocks, have gained popularity.  Only case reports and case series exist for management of PPCS.

Similarly, individuals may go on to develop a migraine disorder following a concussion.  Abortive medicines have been used in the past, but newer agents are emerging. The frequency of posttraumatic migraine has been reported to be as high as 86% in athletes following sports-related head trauma, thus emphasizing the prevalence of post traumatic migraines. Fremanezumab (Ajovy) and erenumab (Aimovig) are used by some providers who go on to develop these and have anecdotally shown promise.

There has been some concern recently with excessive vitamin C intake in patients recovering from a concussion.  Following a concussion, there is an excessive release of glutamate in the brain due to the depolarization of neurons, leading to a cascade of reactions that causes further cellular damage and ROS production.  A study utilizing lipid peroxidation assays (LPOs) showed that vitamin C significantly increases the oxidant effects of glutamate, leading to further ROS damage [18].

Image 3.  Mechanism of cellular damage by Vitamin C. Adopted from [18]

summary

In conclusion, the prevalence of mTBIs and the lack of evidence-based treatments is a growing public health concern.  There remains a large amount of treatment and practices that are in need of further research in all areas of concussion diagnosis and management.  It is important for sports medicine providers to continue to follow along and provide the most up to date evidence-based care.

References

  1. S. Tal, A. Hadanny, E. Sasson, G. Suzin, S. Efrati, Hyperbaric oxygen therapy can induce angiogenesis and regeneration of nerve fibers in traumatic brain injury patients, Frontiers Hum. Neurosci. 11 (2017) 508
  2. Echemendia, Ruben J., et al. “Neuropsychological assessment of professional ice hockey players: a cross-cultural examination of baseline data across language groups.” Archives of clinical neuropsychology 35.3 (2020): 240-256.
  3. Wang KK, Yang Z, Zhu T, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018;18(2): 165-180.
  4. Shahim P, Tegner Y, Wilson DH, Randall J, Skillbäck T, Pazooki D, Kallberg B, Blennow K, Zetterberg H. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 2014;71(6):684.
  5. Gill J, Merchant-Borna K, Jeromin A, Livingston W, Bazarian J. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017;88(6):595–602.
  6. Edwards, Katie A., et al. “Interleukin-6 is associated with acute concussion in military combat personnel.” BMC neurology 20.1 (2020): 1-10.
  7. Meyer, Jessica, et al. “The relationship between fluid biomarkers and clinical outcomes in sports-related concussions: a systematic review.” Brain injury 34.11 (2020): 1435-1445.
  8. Hutchison MG, Mainwaring L, Senthinathan A, Churchill N, Thomas S, Richards D. 2017. Psychological and physiological markers of stress in concussed athletes across recovery milestones. J Head Trauma Rehabil. 32(3):E38–E48. 
  9.  K.G. Harmon, J.R. Clugston, K. Dec, B. Hainline, S.A. Herring, S. Kane, A.P. Kontos, J.J. Leddy, M.A. McCrea, S.K. Poddar, M. Putukian, J.C. Wilson, W.O. Roberts, American Medical Society for Sports Medicine position statement on concussion in sport, Br. J. Sports Med. 53 (2019) 213–225
  10.  P. Grabowski, J. Wilson, A. Walker, D. Enz, S. Wang, Multimodal impairment-based physical therapy for the treatment of patients with post-concussion syndrome: a retrospective analysis on safety and feasibility, Phys. Ther. Sport 23 (2017) 22–30,
  11. P.E. Greenman, J.M. McPartland, Cranial findings and iatrogenesis from craniosacral manipulation in patients with traumatic brain syndrome, J. Am. Osteopath. Assoc. 95 (1995) 182.
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19. Reece, Jenna T., et al. “A biomarker for concussion: the good, the bad, and the unknown.” The Journal of Applied Laboratory Medicine 5.1 (2020): 170-182.