Clinical Implications of Basic Research
Current concepts: Diffuse axonal injury–associated traumatic brain injury,☆☆,

https://doi.org/10.1053/apmr.2001.25137Get rights and content

Abstract

Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA. Current concepts: diffuse axonal injury–associated traumatic brain injury. Arch Phys Med Rehabil 2001;82:1461-71. Objectives: To review the probable physical, physiologic mechanisms that result in the medical and neuropsychologic complications of diffuse axonal injury (DAI)–associated traumatic brain injury (TBI). Data Sources: Various materials were accessed: MEDLINE, textbooks, scientific presentations, and current ongoing research that has been recently reported. Study Selection: Included were scientific studies involving TBI, particularly direct injury to the axons and glia of the central nervous system (CNS) in both in vitro and in vivo models. These studies include pathologic findings in humans as well as the medical complications and behavioral outcomes of DAI. Studies that addressed animal models of DAI as well as cellular and/or tissue models of neuronal injury were emphasized. The review also covered work on the physical properties of materials involved in the transmission of energy associated with prolonged acceleration-deceleration injuries. Data Extraction:Studies were selected with regard to those that addressed the mechanism of TBI associated with DAI and direct injury to the axon within the CNS. The material was generally the emphasis of the article and was extracted by multiple observers. Studies that correlate the above findings with the clinical picture of DAI were included. Data Synthesis: Concepts were developed by the authors based on the current scientific findings and theories of DAI. The synthesis of these concepts involves expertise in physical science, basic science concepts of cellular injury to the CNS, acute medical indicators of DAI, neuropsychologic indicators of DAI, and rehabilitation outcomes from TBI. Conclusions: The term DAI is a misnomer. It is not a diffuse injury to the whole brain, rather it is predominant in discrete regions of the brain following high-speed, long-duration deceleration injuries. DAI is a consistent feature of TBI from transportation-related injuries as well as some sports injuries. The pathology of DAI in humans is characterized histologically by widespread damage to the axons of the brainstem, parasagittal white matter of the cerebral cortex, corpus callosum, and the gray-white matter junctions of the cerebral cortex. Computed tomography and magnetic resonance imaging scans taken initially after injury are often normal. The deformation of the brain due to plastic flow of the neural structures associated with DAI explains the micropathologic findings, radiologic findings, and medical and neuropsychologic complications from this type of injury mechanism. There is evidence that the types of cellular injury in TBI (DAI, anoxic, contusion, hemorrhagic, perfusion-reperfusion) should be differentiated, as all may involve different receptors and biochemical pathways that impact recovery. These differing mechanisms of cellular injury involving specific biochemical pathways and locations of injury may, in part, explain the lack of success in drug trials to ameliorate TBI. © 2001 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

Section snippets

Incidence and social cost

There are approximately 500,000 new cases of TBI admitted to hospitals in the United States each year,1, 2, 3 and the incidence requiring hospitalization is estimated to be approximately 200 to 225 per 100,000 population.1, 2 Currently, it is estimated that brain injuries account for 12% of all hospital admissions in the United States.4

Transportation-related injuries of all types are responsible for approximately 50% of TBI within the United States.5, 6, 7 The predominant mechanism in most

Human data

DAI was initially described by a pathologist.16 These findings were noted to occur in patients who died from a severe TBI following a high-speed transportation injury. On histologic examination, the patients were noted to have neuronal anatomic changes of diffuse axonal degeneration. It has been stated that DAI is a misnomer. It is not diffuse throughout the whole brain, but rather it is predominant in discrete regions of the brain following high-speed, long-duration deceleration injuries.

MVCs

Current animal and physical models

It is difficult to correlate the severity of injury in humans with the current models. The GCS,13 the Disability Rating Scale,30 and the length of posttraumatic amnesia31 cannot be used to assess the outcomes of animals subjected to a TBI. Yet despite the number of experimental neurotrauma in vitro models developed to date, there has not been a reliable, cost-effective in vivo model to mimic mild, moderate, and severe DAI seen in humans.32, 33 Stretching of the axon has been used as an in vitro

Morphologic and biochemical changes in DAI

DAI is characterized microscopically by widespread damage to axons in the cerebral hemispheres, the cerebellum, and the brainstem and is a consistent feature of TBI.8, 24, 25 Traumatically induced axonal damage may be triggered first by focal intraaxonal change involving the neurofilament subunits.45 This neurofilament change is due to either direct mechanical failure of the axonal cytoskeleton or the initiation of a biochemical event that causes neurofilament disassembly.

The histologic

Axonal Changes

A characteristic feature of DAI is a prolonged progression of secondary events that may ultimately result in axonotmesis (interruption of the axon of a nerve followed by complete degeneration of the distal segment). The probable sequence of events was recently summarized by Maxwell et al.33 After injury, there is a depolarization followed by a focal loss of axonal transport as a result of disruption of the cellular organelles. One of the consequences of DAI is direct intracellular injury from

Clinical findings

Severe DAI is usually associated with impairment of consciousness, which begins at the moment of injury.8, 24, 39, 47 It is assumed that DAI has occurred whenever there is any loss of consciousness.5 The GCS may more accurately reflect the amount of midbrain and brainstem injury than cortical injury and, thereby, be a more accurate predictor of outcome with regard to DAI than some other measures of TBI, such as the amount of cortical contusion noted on CT scanning.8

Because the diagnosis can be

Relationship to neuropsychologic complications

Although a broad range of cognitive deficits is possible following TBI, deficits in specific areas seem to predominate. Difficulties with encoding and retrieving new information, commonly referred to as memory abilities, are common following TBI and are often accompanied by problems in information processing and executive skills.81, 82, 83 The percentage of individuals with severe TBI displaying impaired performance on neuropsychologic tests reaches a maximum on tests involving rapid mental

Summary

Before therapeutic rehabilitation interventions are considered, there must be considerable forethought given to the existence of DAI. Further research is necessary to delineate the clinical treatments that are most applicable to the patients who have suffered DAI.

Acknowledgements

We appreciate the donation of the pathology and histology slides on human DAI from Cheryl Palmer, MD, in the Department of Pathology, University of Alabama at Birmingham School of Medicine.

References (107)

  • DD Cardenas et al.

    Psychopharmacologic management of traumatic brain injury

    Phys Med Rehabil Clin North Am

    (1992)
  • RF Frankowski et al.

    The descriptive epidemiology of head trauma in the United States

  • JF. Kraus

    Epidemiology of head injury.

  • J Horn et al.

    Rehabilitation of traumatic brain injury

  • ME Sandel et al.

    The case for comprehensive residency training in traumatic brain injury: a commentary

    Am J Phys Med Rehabil

    (1993)
  • LD Lehmkuhl et al.

    Factors that influence costs and length of stay of persons with traumatic brain injury in acute care and inpatient rehabilitation

    J Head Trauma Rehabil

    (1993)
  • Consensus Conference. Rehabilitation of persons with traumatic brain injury. NIH Consensus Development Panel on Rehabilitation of Persons with Traumatic Brain Injury

    JAMA

    (1999)
  • MR Fearnside et al.

    Epidemiology

  • DR. McLellan

    The structural bases of coma and recovery: insights from brain injury in humans and experimental animals

  • M Bennett et al.

    Clinicopathologic observations in 100 consecutive patients with fatal head injury admitted to a neurosurgical unit

    Ir Med J

    (1995)
  • W Max et al.

    Head injuries: costs and consequences

    J Head Trauma Rehabil

    (1991)
  • WR McMordie et al.

    The financial trauma of head injury

    Brain Inj

    (1988)
  • B Jennet et al.

    Management of head injuries

  • J Whyte et al.

    Rehabilitation of the patient with traumatic brain injury

  • SJ. Strich

    Diffuse degeneration of the cerebral white matter in severe dementia following head injury

    J Neurol Neurosurg Psychiatry

    (1956)
  • D Denny-Brown et al.

    Experimental cerebral concussion

    Brain

    (1941)
  • DJ. Pounder

    Shaken adult syndrome

    Am J Forensic Med Pathol

    (1997)
  • AC Duhaime et al.

    Nonaccidental head injury in infants—the “shaken-baby syndrome.”

    N Engl J Med

    (1998)
  • DI. Graham

    Neuropathology of head injury

  • JS Nelson et al.

    Principles and practice of neuropathology

    (1993)
  • PC Blumbergs et al.

    Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury

    J Neurotrauma

    (1995)
  • JH Adams et al.

    Diffuse brain damage of immediate impact type: its relationship to “primary brain-stem damage” in head injury

    Brain

    (1977)
  • JH Adams et al.

    Diffuse axonal injury in head injury: definition, diagnosis and grading

    Histopathology

    (1989)
  • JW Powell et al.

    Traumatic brain injury in high school athletes

    JAMA

    (1999)
  • Y Tegner et al.

    Concussion among Swedish elite ice hockey players

    Br J Sports Med

    (1996)
  • BA. Kakulas

    The applied neuropathology of human spinal cord injury

    Spinal Cord

    (1999)
  • BA. Kakulas

    A review of the neuropathology of human spinal cord injury with emphasis on special features

    J Spinal Cord Med

    (1999)
  • M Rappaport et al.

    Disability rating scale for severe head trauma: coma to community

    Arch Phys Med Rehabil

    (1982)
  • SN Bishara et al.

    Post-traumatic amnesia and Glasgow Coma Scale related to outcome in survivors in a consecutive series of patients with severe closed-head injury

    Brain Inj

    (1992)
  • JW Lightall et al.

    In vivo models of experimental brain and spinal cord trauma

  • WL Maxwell et al.

    A mechanistic analysis of nondisruptive axonal injury: a review

    J Neurotrauma

    (1997)
  • TO McIntosh et al.

    Traumatic brain injury in the rat: characterization of a midline fluid-percussion model

    Cent Nerv Syst Trauma

    (1984)
  • JW. Lighthall

    Controlled cortical impact: a new experimental brain injury model

    J Neurotrauma

    (1988)
  • E Shohami et al.

    Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue

    J Cereb Blood Flow Metab

    (1994)
  • MA Foda et al.

    A new model of diffuse brain injury in rats. Part II: morphologic characterization

    J Neurosurg

    (1994)
  • TA Gennarelli et al.

    Diffuse axonal injury and traumatic coma in the primate

    Ann Neurol

    (1982)
  • JM Meythaler et al.

    A research applicable small animal model of diffuse axonal injury

    J Neurotrauma

    (1998)
  • FA. Bandak

    On the mechanics of impact neurotrauma: a review and critical synthesis

  • AJ McLean et al.

    Biomechanics of closed head injury

  • CK Kroell et al.

    Biomechanics in crash injury research

    ISA Trans

    (1974)
  • Cited by (444)

    View all citing articles on Scopus

    Supported in part by the Centers for Disease Control and Prevention–National Center for Injury Prevention and Control, US Department of Health and Human Services (grant no. R49/CCR403641-11) and the National Institute of Disability and Rehabilitation Research, US Department of Education, Traumatic Brain Injury Model Systems (grant no. H133A980010).

    ☆☆

    No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.

    Reprint requests to Jay M. Meythaler, MD, JD, University of Alabama at Birmingham, R157 Spain Rehabilitation Ctr, 619 19th St S, Birmingham, AL 35249-7330, e-mail: [email protected].

    View full text