Traumatic Brain Injury: Evaluation, Treatment, and Rehabilitation
A traumatic brain injury (TBI), or concussion, can leave a person with lifelong symptoms and disability, requiring a multidisciplinary approach to the management of this condition. In this, our third installment in our series on TBI, we will describe the evaluation and treatment of mild TBI from different clinical perspectives. The three authors come from different training and medical backgrounds (neurology, neuropsychology, and physical medicine & rehabilitation). Using their unique backgrounds, the authors describe the cellular mechanism of TBI as gleaned from high-grade imaging devices, review neuropsychological evaluation for patients with TBI, and provide an overview of a comprehensive approach to lifelong treatment within a comprehensive physical medicine and rehabilitation model.1
Part 1 of this series described the biomechanics and pathophysiology of traumatic brain injuries, as well as their symptoms: post-concussion syndrome, post-traumatic headache, and migraine. Part 2 of this article series discussed treatments for TBI-related headaches.
TBIs can occur any time, any place, and from myriad sources. The recent coverage of sports-related concussions and improvised explosive device/combat-related explosions in the armed forces has brought more awareness of the subject to the public eye. But, TBIs are not new. According to the Centers for Disease Control and Prevention, approximately 1.7 million TBIs occur every year in the US,2 accounting for close to a million and a half emergency room visits, and over 50,000 deaths.3 Sports-related TBI raises the specter of repeated TBIs, which can lead to chronic traumatic encephalopathy (CTE).4
The majority of mild TBI survivors recover fully 3 to 4 weeks after the injury, but a significant minority (10%-20%) continue to experience symptoms months (acute post-concussion disorder [PCD]) and even years (chronic PCD) after their injury.5
Physical complaints after mild TBI include headache, dizziness, photophobia, phonophobia, fatigue, nausea, insomnia, vision impairment, and seizures. Cognitive complaints include decreased arousal, attention, and concentration, as well as short-term memory loss.
Despite its high incidence and profile, TBI and its many post-concussional clinical issues (Table 1) are not addressed in medical school training. The available pool of clinicians who are interested and actively work in this area of medicine is quite small but growing. The good news is that the specialized tools for evaluation and treatment of the many symptoms that result from TBI are expanding. Indeed, this has been a multidisciplinary effort.
Cellular and Neurotransmitter Changes
In the period after a TBI, there are multiple changes in neurotransmitters (glutamate, serotonin, norepinephrine, acetylcholine, histamine, opioid receptors, etc), as well as cellular and neuronal dysfunction, all of which contribute to behavioral and executive function impairments. For example, extracellular glutamate is profoundly altered after TBI. This contributes to the acute pathophysiology of TBI and its symptoms. (Editor’s Note: for more on the pathophysiology of concussion, see Part 1 of this series.>6 Research in the rat model indicates that inflammation-induced alterations in calcium-mediated glutamate release and glial regulation of extracellular glutamate contribute to increased extracellular glutamate in the striatum.7 In addition, blockade of dopamine5receptors in the hippocampus eliminates late long-term potentiation, suggesting that synaptic plasticity in the hippocampus depends upon on interaction between glutamate and dopamine.8
Diaschisis—functional depression or loss of neuronal activity in an area of the brain that, although removed from the site of TBI, is anatomically connected via neuronal pathways—can be permanent or may improve over time due to synaptic plasticity, changes in cortical reorganization, or properties of neurotransmitter function and cerebral glucose utilization. Thus, recovery from a TBI requires a form of brain plasticity and, presumably, can be influenced by rehabilitation and/or medications.9
Calcium influx into injured neurons can result from activation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor,10-12 as well as from opening of voltage-gated calcium channels (VGCCs)13 and release of intracellular calcium stores.14 This excess calcium contributes to cell damage and death.15
One of the authors (JCK) has presented data showing improvement of impairments in executive function, attention, concentration, and memory with treatment using either acetylcholinesterase inhibitors or NMDA-type glutamate receptor antagonists.16,17 After treatment, patients had clear-cut improvements in many subtests of the Halstead-Reitan Neuropsychology Battery (HRB), a widely used assessment of cognitive function.
In addition, limited pre-clinical data indicates that specific L- and N-type VGCC antagonists have potential for treating TBI patients. The mechanisms of action for these antagonists, however, have not been well characterized.
Another neurotransmitter system that is profoundly altered after severe TBI is norepinephrine. A recently proposed double-blind placebo-controlled study (DASH After TBI study) will look at the beta-blocker propranolol (Inderal, others), and the alpha2 agonist clonidine (Catapres, others) in the treatment of severe TBI and prevention of norepinephrine rise after injury.18
TBI of any form can cause cognitive, behavioral, and immunologic changes at any point after the injury. This complicates the problem of misdiagnosis of mild TBI, which can cause long-term neurological deficits. TBI of any severity disrupts the blood-brain barrier, leading to infiltration of immune cells into the brain and subsequent inflammation and neurodegeneration. TBI-induced central and peripheral immune responses affect the disease outcome. Much more active research is needed in this area, as outlined recently in an excellent review.19