Biochemical and Neurochemical Sequelae After Mild Traumatic Brain Injury
Biochemical and Neurochemical Sequelae After Mild Traumatic Brain Injury
Although numerous studies have been carried out to investigate the pathophysiology of mild traumatic brain injury (mTBI), there are still no standard criteria for the diagnosis and treatment of this peculiar condition. The dominant theory that diffuse axonal injury is the main neuropathological process behind mTBI is being revealed as weak at best or inconclusive, given the current literature and the fact that neuronal injury inherent to mTBI improves, with few lasting clinical sequelae in the vast majority of patients.
Clinical and experimental evidence suggests that such a course, rather than being due to cell death, is based on temporal neuronal dysfunction, the inevitable consequence of complex biochemical and neurochemical cascade mechanisms directly and immediately triggered by the traumatic insult.
This report is an attempt to summarize data from a long series of experiments conducted in the authors' laboratories and published during the past 12 years, together with an extensive analysis of the available literature, focused on understanding the biochemical damage produced by an mTBI.
The overall clinical implications, as well as the metabolic nature of the post-mTBI brain vulnerability, are discussed. Finally, the application of proton MR spectroscopy as a possible tool to monitor the full recovery of brain metabolic functions is emphasized.
At present, TBI is a major public health concern and a leading cause of disability worldwide. In European countries, the annual incidence of TBI is estimated at between 100 and 1967 per 100,000 persons, with mild and moderate TBI accounting for 80%–95% and severe TBI accounting for about 5%–20% of all cases. It has been calculated that the ratio of the occurrence of mTBI to that of sTBI is approximately 22:1. In the US, 1.5–8 million people per year suffer from TBI ranging from mild to severe. A proportion of these patients ranging from 75% to 90% is classified as mildly injured.
These wide ranges of annual incidence are probably due to the fact that an unknown proportion of mTBI victims do not seek any medical attention, but it might also be due to the fact that there is still confusion and inconsistency among researchers and organizations in defining and understanding this type of trauma.
Mild TBI has, indeed, too many synonyms, including brain concussion, mild head injury, minor head injury, and minimal TBI. Even the terms "head" and "brain" have been used interchangeably.
Historically, the most often used system for grading the severity of craniocerebral trauma is the Glasgow Coma Scale (GCS), which permits 120 possible mathematical combinations of eye, verbal, and motor scores, and contains rather crude scoring categories. We all know that different patients with the same GCS score of 15 may not function at the same level.
Given the limitations of the GCS, other parameters, like posttraumatic amnesia and loss of consciousness, have been increasingly scrutinized during the past 10 years. Loss of consciousness was no longer considered a necessary condition for the diagnosis of mTBI, and there was soon a general agreement among experts that the criterion of posttraumatic amnesia must be used with great care because it may be easily under- or overestimated. Therefore, there currently are no objective biological measures to determine the degree of severity of the neuropathology of this condition.
Conversely, the general view that mTBI is a very common entity but should not be considered a very serious injury, leading only to transient disturbances, is mainly supported by the absence of structural brain damage on traditional neuroimaging. If mTBI was as "mild" as we might think, it would be difficult to explain the actual complex management of these patients, which may involve various health care professionals, including family doctors, behavioral psychologists, clinical psychologists, neuropsychologists, neurologists, psychiatrists, neuroophthalmologists, neurosurgeons, physiatrists, nurses, occupational therapists, and physical therapists. Furthermore, long beyond the typical recovery interval of 1 week to 3 months, at least 15% of persons with a history of mTBI continue to see their family physician because of persistent problems. Because of such enormous social impact, the number of literature reports addressing many different clinical aspects of mTBI has grown annually during the past 2 decades.
The problem is that to date, due to the formidable challenge of studying this type of cerebral damage in the laboratory, most of the reported experimental data have been obtained in more severe levels of injury, with very little information on the biochemical modifications occurring in mild injury as a function of time after impact. It appears clear that the biochemical and molecular processes triggered by mTBI, where hardly any discernible cell death occurs, are likely to be, at least in part, different from those present following severe injury.
This report is an attempt to recap the results of a series of previously published experiments produced during the past 12 years by a single group of investigators, all focused on understanding the pathophysiology of a "mild" injury to the brain, where apparently there is nothing "obviously" harmful. These findings have been further discussed in light of the most recent findings from other laboratories worldwide.
Abstract and Introduction
Abstract
Although numerous studies have been carried out to investigate the pathophysiology of mild traumatic brain injury (mTBI), there are still no standard criteria for the diagnosis and treatment of this peculiar condition. The dominant theory that diffuse axonal injury is the main neuropathological process behind mTBI is being revealed as weak at best or inconclusive, given the current literature and the fact that neuronal injury inherent to mTBI improves, with few lasting clinical sequelae in the vast majority of patients.
Clinical and experimental evidence suggests that such a course, rather than being due to cell death, is based on temporal neuronal dysfunction, the inevitable consequence of complex biochemical and neurochemical cascade mechanisms directly and immediately triggered by the traumatic insult.
This report is an attempt to summarize data from a long series of experiments conducted in the authors' laboratories and published during the past 12 years, together with an extensive analysis of the available literature, focused on understanding the biochemical damage produced by an mTBI.
The overall clinical implications, as well as the metabolic nature of the post-mTBI brain vulnerability, are discussed. Finally, the application of proton MR spectroscopy as a possible tool to monitor the full recovery of brain metabolic functions is emphasized.
Introduction
At present, TBI is a major public health concern and a leading cause of disability worldwide. In European countries, the annual incidence of TBI is estimated at between 100 and 1967 per 100,000 persons, with mild and moderate TBI accounting for 80%–95% and severe TBI accounting for about 5%–20% of all cases. It has been calculated that the ratio of the occurrence of mTBI to that of sTBI is approximately 22:1. In the US, 1.5–8 million people per year suffer from TBI ranging from mild to severe. A proportion of these patients ranging from 75% to 90% is classified as mildly injured.
These wide ranges of annual incidence are probably due to the fact that an unknown proportion of mTBI victims do not seek any medical attention, but it might also be due to the fact that there is still confusion and inconsistency among researchers and organizations in defining and understanding this type of trauma.
Mild TBI has, indeed, too many synonyms, including brain concussion, mild head injury, minor head injury, and minimal TBI. Even the terms "head" and "brain" have been used interchangeably.
Historically, the most often used system for grading the severity of craniocerebral trauma is the Glasgow Coma Scale (GCS), which permits 120 possible mathematical combinations of eye, verbal, and motor scores, and contains rather crude scoring categories. We all know that different patients with the same GCS score of 15 may not function at the same level.
Given the limitations of the GCS, other parameters, like posttraumatic amnesia and loss of consciousness, have been increasingly scrutinized during the past 10 years. Loss of consciousness was no longer considered a necessary condition for the diagnosis of mTBI, and there was soon a general agreement among experts that the criterion of posttraumatic amnesia must be used with great care because it may be easily under- or overestimated. Therefore, there currently are no objective biological measures to determine the degree of severity of the neuropathology of this condition.
Conversely, the general view that mTBI is a very common entity but should not be considered a very serious injury, leading only to transient disturbances, is mainly supported by the absence of structural brain damage on traditional neuroimaging. If mTBI was as "mild" as we might think, it would be difficult to explain the actual complex management of these patients, which may involve various health care professionals, including family doctors, behavioral psychologists, clinical psychologists, neuropsychologists, neurologists, psychiatrists, neuroophthalmologists, neurosurgeons, physiatrists, nurses, occupational therapists, and physical therapists. Furthermore, long beyond the typical recovery interval of 1 week to 3 months, at least 15% of persons with a history of mTBI continue to see their family physician because of persistent problems. Because of such enormous social impact, the number of literature reports addressing many different clinical aspects of mTBI has grown annually during the past 2 decades.
The problem is that to date, due to the formidable challenge of studying this type of cerebral damage in the laboratory, most of the reported experimental data have been obtained in more severe levels of injury, with very little information on the biochemical modifications occurring in mild injury as a function of time after impact. It appears clear that the biochemical and molecular processes triggered by mTBI, where hardly any discernible cell death occurs, are likely to be, at least in part, different from those present following severe injury.
This report is an attempt to recap the results of a series of previously published experiments produced during the past 12 years by a single group of investigators, all focused on understanding the pathophysiology of a "mild" injury to the brain, where apparently there is nothing "obviously" harmful. These findings have been further discussed in light of the most recent findings from other laboratories worldwide.
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