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Inflammatory pathophysiology in concussion and multiple sclerosis

By Brian Hainline

There are many parallels between concussion and multiple sclerosis (MS). The medical and scientific community currently understands concussion in a manner similar to how multiple sclerosis was understood thirty years ago. In part, this is because concussion had not caught the attention of neuroscientists thirty years ago in the same manner as MS. Back then, there was an emerging unifying hypothesis about MS that implicated a neuro-inflammatory response that attacked the covering of the central nervous system axons. This hypothesis led to a global search for objective biomarkers of MS, to aid in both diagnosis and treatment.

Multiple sclerosis is an autoimmune disease of the central nervous system in which the myelin of axons – the covering of the axons – becomes dysfunctional in the setting of neuro-inflammation. Nerves in the central nervous system are surrounded by lipid-based material called myelin, which facilitates fast and efficient electrical activity from one nerve to the next -- electrical activity that is the basis of thought, movement, vision, balance and all other sensori-motor function. Because it involves the destruction of the myelin sheath that covers nerve tissue, MS is classified as a demyelinating disease . When myelin breaks down, the nerve impulses travel more slowly and less efficiently, which causes neurological dysfunction that correlates to the region of the brain that is affected. Demyelination refers to the process of myelin breakdown as a result of a neuro-inflammatory process directed against myelin, resulting in the formation of dense, scar-like tissue called sclerosis (also known as lesions). The clinical presentation is myriad because axonal dysfunction can occur at any level within the central nervous system; it may be at a single locus or at multiple loci. The affected region of the brain determines the clinical manifestation(s). For example, if the pre-frontal lobe is affected there may be difficulty with executive function. If the brainstem is affected, there can be any combination of dizziness, loss of neuromuscular control, and difficulty with visual tracking.

What is important in MS is to define anatomically the lesion or lesions, and to define the underlying process responsible for the lesion. Localizing the lesion and identifying its underlying pathophysiology leads to effective treatment, which is directed at improving function through neuro-plasticity at the level of the lesion(s), and delivering an immune-modulating agent that will neutralize the inflammatory pathophysiologic process. Neuro-plasticity means that the brain can repair itself and can even regenerate. Furthermore, neuro-plasticity refers to more effective synaptic transmission of neurochemicals through the production of neurotrophic factors. Neurotrophic means that a brain neurochemical is produced because of an effective stimulus, and the neurochemical leads to any combination of a proliferation of new blood vessels, improved and enhanced receptor function and prevention of cell death. If you do not address the lesion in MS and provide a behavioral incentive for neuro-plasticity, then improvement for the non-self-limiting attack will be delayed, incomplete or non-existent. If you do not address the inflammatory pathophysiologic process in MS, then improvement for a non-self-limiting attack will be delayed, incomplete, or non-existent. If improvement is incomplete, or worse, if the inflammatory condition persists, then the microglia (the brain’s white blood cells) will shift to a destructive phase by releasing toxic chemicals that, if unchecked, lead to cell death.

In the worst case scenario, MS progresses in a chronic and progressive manner, ultimately leaving the patient with severely impaired cognition and impaired neuro-muscular control. Unfortunately, we do not understand the mechanism by which this progressive degenerative phase begins.

Concussion is a condition of the central nervous system in which the axons become dysfunctional in the setting of an acute traumatic event that causes axonal shearing brought about by sudden rotational forces to the skull and brain. Many scientists believe that a neuro-inflammatory process results from the axonal shearing, and this process may perpetuate axonal dysfunction. The clinical presentation is myriad because the axonal dysfunction can occur at any place within the central nervous system, and it may be at a single locus or at multiple loci. The affected region of the brain determines the clinical manifestation. For example, if the pre-frontal lobe is affected there may be difficulty with executive function. If the brainstem affected, there can be any combination of dizziness, incoordination, and difficulty with visual tracking. 

Thirty years ago, the standard treatment for MS was to rest, and to hope that the neuro-inflammatory process would discontinue, and that the axons would recover from their transient demyelinating state. Often, the patient would be treated with high dose corticosteroids, although that intervention was never proven to shape long-term success. There were no standard imaging studies for MS other than a CAT scan of the brain, which rarely, if ever, identified the lesion(s). Magnetic resonance imaging (MRI) scanners were in their infancy, and there were no MR-biomarkers identified for MS. (A biomarker is a medical test that provides objective results, such as a blood test that indicates heart muscle damage, or an imaging test that provides conclusive evidence of abnormal tissue.) There were also only crude biochemical biomarkers. Thus, the diagnosis was largely clinical, with little or no active treatment options. Today, there are many objective biomarkers for diagnosing MS, including MRI, biochemical studies and electrophysiological tests. There are also effective behavioral and immune-modulating agents that have been demonstrated to lessen the impact and burden of the disease.

Today, the standard treatment for concussion is similar to MS thirty years ago. The patient is advised to rest, with the hope that the pathophysiological process discontinues, that the axons recover from transient physiological dysfunction and that any axonal neuro-inflammatory process discontinues.  There are no standard imaging studies for concussion other than a CAT scan of the brain, which rarely, if ever, identifies the lesion(s). MRI protocols for concussion are in their infancy, and there are no MR-biomarkers identified that are concussion-specific. There are only crude biochemical biomarkers, none of which have been validated. Thus, the diagnosis is largely clinical, with little or no active treatment option.

It has been speculated that the worst-case scenario of repetitive concussion is chronic traumatic encephalopathy (also known as CTE), which is a disease that progresses in a chronic and progressive manner, ultimately leaving the patient with severely impaired cognition and neuro-muscular control. Unfortunately, we do not understand the mechanism by which CTE begins.

Unlike MS from thirty years ago, we do not have a single active pharmacological treatment option for concussion, although a neuro-inflammatory blocking agent delivered intra-nasally is currently in Phase II studies, which means that it has not yet been tested on humans. Unlike MS today, we have no validated objective biomarkers for diagnosis, and there are no proven pharmacological strategies that lessen the impact and burden of the condition.

The sudden rise in concussion awareness has paved the way for a deeper understanding of concussion pathophysiology. Although the medical and scientific community states that concussion is a pathophysiological process without identified brain damage, current research suggests that concussion may be both a physiological and anatomical condition. For example, one study of patients with mild traumatic brain injury utilized a high field MRI magnet and identified micro-hemorrhages in a pattern consistent with axonal shearing. Other studies that utilize MRI diffusion tensor imaging protocols demonstrate acute disruption of axons following concussion. Thus, the definition of concussion will likely change (there are currently over 40 working definitions) in a manner to account for the location of the lesion(s) and the underlying pathophysiological process. It does not suffice to simply identify symptoms without localizing the lesion(s) and to assume that the dysfunction is purely a physiological disturbance. Like in MS, this passive diagnosis and management may suffice for many cases because the “attack,” we hope, may be self-limiting.  But it is no longer enough to hope. That is why the NCAA has become a leader in supporting research that will bring us closer to identifying objective biomarkers for concussion. Through such research, we will one day have a working definition of concussion that makes better sense.

Last Updated: Nov 12, 2013