Acta Medica 2021; 52(2): 102-108 acta medica REVIEW A Review of Traumatic Axonal Injury Dicle Karakaya1, [MD] ABSTRACT ORCID: 0000-0003-1939-6802 Traumatic brain injury is a major cause of mortality and neurological Ahmet İlkay Işıkay2, [MD] disability worldwide and varies according to its cause, pathogenesis, ORCID: 0000-0001-7790-4735 severity and clinical outcome. This review summarizes a significant aspect of diffuse brain injuries – traumatic axonal injury – important cause of severe disability and vegetative state. Traumatic axonal injury is a type of traumatic brain injury caused by blunt head trauma. It is defined both clinically (immediate and prolonged unconsciousness, characteristically in the absence of space-occupying lesions) and pathologically (widespread and diffuse damage of axons). Following traumatic brain injury, progressive axonal degeneration starts with 1Hacettepe University, Faculty of Medicine, Department disruption of axonal transport, axonal swelling, secondary axonal of Neurosurgery, Ankara, Turkey disconnection and Wallerian degeneration, respectively. However, traumatic axonal injury is difficult to define clinically, it should be Corresponding Author: Ahmet İlkay Işıkay considered in patients with Glasgow coma score < 8 for more than six Hacettepe University, Faculty of Medicine, Department hours after trauma and diffuse tensor imaging and sensitivity-weighted of Neurosurgery, Sıhhiye/Ankara, Turkey imaging MRI sequences are highly sensitive in its diagnosis. Glasgow Phone: +90 312 305 17 15 coma score at the time of presentation, location and severity of axonal E-mail: [email protected] damage are prognostic factors for clinical outcome. https://doi.org/10.32552/2021.ActaMedica.467 Keywords: Diffuse, traumatic, axonal, injury. Received: 29 May 2020, Accepted: 9 March 2021, Published online: 8 June 2021 INTRODUCTION Traumatic axonal injury (TAI) is a distinct it is not diffuse but actually widespread and/or clinicopathological topic that can cause severe multifocal [3]. neurological disability, vegetative state and The initial and the basic definition of TAI is a mortality. Although this term is used as a separate clinicopathological diagnosis that causes severe definition, in 1956, Strich was described as ‘diffuse disability, vegetative state or death after head degeneration of white matter’ in a group of trauma, in the absence of a space-occupying patients with severe posttraumatic dementia [1]. lesion, without a lucid interval, with sudden and She showed that shearing injuries at the moment prolonged loss of consciousness. It is pathologically of the rapid acceleration or deceleration trauma, characterized by widespread and disseminated were responsible for the morphological changes in damage of axonal fibers in the brainstem, especially white matter and produced diffuse degeneration in the pontomesencephalic junction next to the of the cerebral white matter [2]. Thereafter, Adams superior cerebellar peduncle, the parasagittal white introduced diffuse axonal injury, and graded matter and corpus callosum [3,4]. according to its pathological findings [3,4]. In the past few decades, some authors, also as in this It is a component of injury in 40-50% of emergency review, preferred ‘diffuse traumatic axonal injury department admissions due to traumatic brain (dTAI)’ or ‘traumatic axonal injury (TAI)’ instead of injury (TBI) and one of the most common cause of diffuse axonal injury (DAI) to describe the etiology severe injury and vegetative condition after closed- of the axonal injury and the pathology because head trauma [5]. Moreover, there is evidence 102 © 2021 Acta Medica. All rights reserved. Acta Medica 2021; 52(2): 102-108 Karakaya and Işıkay such as post-traumatic deposition of Aβ and tau Histopathological Features proteins, and Aβ plaques and axonal Aβ deposits Axons in white matter are particularly susceptible seen in approximately one-third of patients who to acceleration-deceleration trauma due to their died shortly after trauma have shown that this viscoelastic structure, anisotropic arrangement, progressive axonal degeneration may play a role in linear microtubules and neurofilaments, and the the development of neurodegenerative disorders, axolemma surface being larger than the axoplasm including Alzheimer’s disease [6,7]. volume [12]. Etiology The first consequence of the dynamic deformation of the white matter pathways during trauma is the Motor vehicle crashes (MVC) are the major cause of accumulation of substances, such as amyloid β TAI. It is thought that TAI is present as a component precursor protein (APP) carried along the axons, in of TBI in all traffic accidents in which the patient axonal swellings with disruption of normal axonal has lost consciousness. In addition, high-speed transport (primary axotomy). However, stretch collisions of football players or hockey players injury without complete axotomy contributes with rival players can cause TAI. Also, in shaken more to the pathology seen in TAI. These axons baby syndrome, the sudden deceleration which is may appear morphologically normal, but are occurred in repetitive shaking on the coronal plane functionally inadequate [13]. may result in TAI. On the other hand, TAI is rarely seen in simple falls and direct blows to the head Following the trauma, in addition to physical [3,8]. stretch due to deformation of the brain and direct cytoskleteal damage, disruption of membrane Pathophysiology and Biomechanism of TAI permeability and depolarization also occur. These Two main mechanisms are involved in head electrochemical changes trigger the release of injuries: 1) direct contact and 2) acceleration and excitatory neurotransmitters such as glutamate. As glutamate binds to NMDA and AMPA receptors, deceleration. Acceleration forces resulting from calcium entry into the cell increases. Increased sudden movement of the head, initiating the forces cytosolic calcium concentration results in of shearing and compressive strains and typically mitochondrial damage. Moreover, further damage cause two conditions: 1) acute subdural hematoma occurs in the cytoskeletal structure of the axon (ASDH) by tearing of the subdural bridging veins by activation of calcium-dependent proteolytic and 2) TAI, caused by strain and tearing of the axons enzymes (calpain and caspases). Oxidative stress due to the gyrencephalic structure of the brain and and disrupted energy metabolism secondary to the high white matter/gray matter ratio. mitochondrial damage result in neuronal death. These two injuries differ in terms of the duration and Neuroinflammation and microglial activation also plane of the acceleration forces the head is exposed contribute to secondary injury processes. This to. In experimental studies, it has been shown that excitotoxic, oxidative, and inflammatory pathways, ASDH occurs in a relatively short time (5-10 ms) which cause progressive axonal deterioration and with high rates of angular acceleration whereas breakage, is called secondary axotomy [14,15]. TAI is caused by acceleration force occurring in the During this period, axonal retraction balls (axonal coronal plane, lower velocity and longer time (20- bulbs) are formed and the proximal parts of the 25 ms) when compared with ASDH [4,9,10]. axons become undulated. Concurrently, Wallerian degeneration begins at the distal of the axons by For this reason, TAI is frequently seen in high-speed 24 hours. After 3 days, the damaged and separated motor vehicle accidents, shaken baby syndrome segments are surrounded by active microglial cells and falls from a considerable height that are [5]. Progressive myelin degeneration and atrophy of exposed to acceleration-deceleration forces lasting the white matter occur within the first 2 years after more than 1 second in the coronal plane [3,8]. It has TAI and represents the final stage of the process [8]. In been also demonstrated that TAI is an important the study of Mu et al., apoptosis of oligodendrocytes mechanism in cervical spinal cord injury in MVCs in in the corpus callosum and brainstem shows the absence of cervical displacement [11]. oligodendrocyte selective injury in TAI. Axonal © 2021 Acta Medica. All rights reserved. 103 Traumatic Axonal Injury degeneration secondary to demyelination in the moderate (grade 2) TAI, in addition to grade 1, brainstem is another pathological pattern of TAI there is a focal lesion in the corpus callosum. And [16]. Briefly, posttraumatic axonal degeneration lastly, severe (grade 3) TAI is defined since there develops as disruption of axonal transport, axonal are additional focal lesions in the dorsolateral edema secondary to disconnection, and Wallerian brainstem, commonly in the superior cerebellar degeneration, respectively [17]. peduncle [18]. It is obvious that primary brainstem lesions are usually associated with TAI and includes Pathologically, axonal retraction balls, axonal cerebral hemispheres and cerebellum as well as swelling (axonal varicosity) and punctate brainstem [8]. hemorrhages (Strich hemorrhages) are observed in corpus callosum, internal capsule, cerebral Clinical Diagnosis and Evaluation white matter, around the third ventricule, fornix, TAI is a clinical diagnosis and often ‘diagnosis brainstem and cerebellum. The presence of of exclusion’. It is thought that TAI has occurred retraction balls is important for showing complete whenever there is any loss of consciousness. Clinical axonal disruption [7]. presentation is related to its severity. For instance, The histopathological