Sports-related Concussions: Diagnosis, Complications, and Current Management Strategies

Jonathan G. Hobbs, MD; Jacob S. Young, BS; Julian E. Bailes, MD


Neurosurg Focus. 2016;40(4):e5 

In This Article

Pathophysiology of Concussion

Although a tissue sample is not indicated during the diagnosis and management of a concussion, this type of trauma is thought to represent a very mild form of diffuse axonal injury with no permanent histological changes. At the cellular level, the axonal stretching from a traumatic force results in mechanoporation, or a disruption in the neural membrane, which allows for an efflux of K+ and an influx of Ca2+.[41,42] These ionic shifts trigger a release of glutamate, which results in an excitotoxic cascade and cognitive dysfunction.[5,59,85] The Na+/K+ pump then tries to restore the ionic balance, and this coupled with mitochondrial dysfunction leads to insufficient adenosine 5'-triphosphate production and an increase in reactive oxygen species.[149,150] The resultant adenosine 5'-triphosphate depletion and reactive oxygen species can generate a lactic acidosis and oxidative dysfunction.[57] These neurometabolic and neurochemical irregularities in conjunction with changes in cerebral perfusion can result in confusion and possibly an LOC, particularly if the dysfunction occurs in the reticular activating system.[67]

There is also a growing interest in the role of inflammation in the pathogenesis of disease following a concussion, particularly with regard to postconcussive disease, which spans a spectrum of diseases including postconcussion syndrome (PCS), prolonged PCS (PPCS), chronic traumatic encephalopathy (CTE), mild cognitive impairment, and dementia pugilistica.[11,116]

Briefly, following an SRC, the traumatic event in the CNS recruits neutrophils and monocytes, which in combination with the microglia and astrocytes already residing in the CNS, secrete inflammatory cytokines and alter their expression of signaling molecules to organize an immunological response.[49] Glial fibrillary acidic protein expression, which is widely used as a marker for astrocyte activation, is significantly upregulated in patients who have suffered a brain injury when compared with controls who have suffered a traumatic nonbrain injury.[102,155] In rodent models, the acute cytokine response following a concussion is remarkably complex but is thought to typically begin with an increase in the proinflammatory molecules interleukin (IL)–1α, IL-1β, and tumor necrosis factor–α (TNFα).[30] While levels of IL-1α show an acute elevation and fall, IL-1β levels tend to remain elevated for a longer period, rise more than other proinflammatory cytokines, rise in an amount relative to the severity of the trauma, and spike more intensely if the concussion is associated with a contusion.[48,151] Although some experiments have demonstrated that the increase in IL-1β expression precedes an increase in neuroprotective factors, others have demonstrated that inhibition of IL-1β expression following an mTBI leads to a reduction in cerebral edema and an improved cognitive outcome.[25,47] Likewise, TNFα appears to play both a neuroprotective and neurotoxic role in the CNS following mTBI, which may reflect differential binding of the molecule to its two CNS receptors.[2,139,154]

More work is needed to determine how the severity of brain injury alters TNFα signaling, the time course for its protective and toxic activity, and how TNFα interacts with other cytokines during the injury process. Additionally, overexpression of IL-6 by astrocytes, which is potently stimulated by TNFα, has been shown to shorten recovery times following cortical freeze injury in mice by reducing apoptotic gene expression and regulating oxidative stress.[123] Furthermore, IL-6 reduces the production of IL-1β and TNFα, which may explain why mice deficient in IL-6 have exaggerated abnormalities following brain injury.[64,69] Finally, it should not come as a surprise that antiinflammatory molecules, the predominant two being IL-10 and transforming growth factor β (TGFβ), are induced after the proinflammatory cytokines to form the negative feedback loop regulating the proinflammatory cascade.[28] Unsurprisingly, the role of these antiinflammatory molecules is similarly murky following mTBI, with mixed results reported regarding their benefit or harm following injury.[132]

The contribution of the immune response and neuroinflammation to both the immediate recovery following a concussion and the long-term sequelae of repetitive concussions should continue to be elucidated, because a thorough understanding of this mechanism may provide logical targets for the use of immunosuppressive agents as therapies to protect against the neurocognitive changes seen following multiple concussions. Nevertheless, some antiinflammatory treatment regimens, such as long-term ibuprofen administration or TNFα inhibitors, have either shown no benefit or adverse effects when used in patients with concussive symptoms or in rodent models of mTBI.[13,76] It remains to be seen to what degree the immune activation following an SRC is protective versus harmful and if the immune system can be manipulated to benefit patients suffering from concussive symptoms.