Diffuse axonal injury: Novel insights into detection and treatment

Journal of Clinical Neuroscience 16 (2009) 614–619

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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn

Review

Diffuse axonal injury: Novel insights into detection and treatment Xue-Yuan Li a, Dong-Fu Feng b,* a b

Department of Neurosurgery, No. 3 People’s Hospital Affiliated to Shanghai Jiao Tong University College of Medicine, Shanghai 201900, China Department of Neurosurgery, No. 3 People’s Hospital Affiliated to Shanghai Jiao Tong University College of Medicine, No. 280 Mo-He Road, Shanghai 201900, China

a r t i c l e

i n f o

Article history: Received 30 January 2008 Accepted 1 August 2008

Keywords: Biochemical markers Coma Diffuse axonal injury Neuroimaging Specific treatment

a b s t r a c t Diffuse axonal injury (DAI) is one of the most common and important pathologic features of traumatic brain injury. The definitive diagnosis of DAI, especially in its early stage, is difficult. In addition, most therapeutic agents for patients with DAI are non-specific. The CT scan is widely used to identify signs of DAI. Although its sensitivity is limited to moderate to severe DAI, it remains a useful first-line imaging tool that may also identify co-morbid injuries such as intracerebral hemorrhage. Recently, investigations have sought to apply advanced imaging techniques and laboratory techniques to detect DAI. Meanwhile, some potential specific treatments that may protect injured axons or stimulate axonal regeneration have been developed. We review some new diagnostic technologies and specific therapeutic strategies for DAI. Ó 2008 Elsevier Ltd. All rights reserved.

1. Introduction Diffuse axonal injury (DAI) in patients with traumatic brain injury (TBI) is associated with significant morbidity, and often leads to significant neuropsychological sequelae and burdensome health care costs. DAI typically occurs when the head is subjected to shear-strain forces, with most lesions emerging at the interface between regions of the brain that have different tissue densities, such as at the junctions between gray and white matter. Classically, although neuroimaging can detect features such as petechial hemorrhages suggestive of DAI, a definitive diagnosis could only be established by immunostaining for b-amyloid precursor protein (b-APP) at autopsy. However, recent advances in both neuroimaging and laboratory techniques have allowed for more subtle lesions to be detected earlier, potentially allowing the diagnosis of DAI in the acute phase. This introduces the possibility of DAI treatment early in the course of the injury, which has the potential to positively affect outcome. In this review, we explore the potential value of new diagnostic technologies in identifying DAI, and suggest potential clinical applications. 2. Coma as an indicator of DAI DAI is characterized clinically by the rapid progression to coma in the absence of specific focal lesions. DAI is arguably the major cause of post-traumatic unconsciousness. In this setting, loss of consciousness may last only minutes, or it may result in prolonged

* Corresponding author. Tel./fax: +86 021 56693614. E-mail address: [email protected] (D.-F. Feng). 0967-5868/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.08.005

coma, depending on the nature and severity of the underlying injury. In a hallmark study, Gennarelli et al. demonstrated that DAI can be the sole contributor to post-traumatic unconsciousness. They observed that non-human primates developed immediate and prolonged coma in the absence of focal lesions when subjected to non-impact rotational acceleration.1 DAI was the only type of tissue injury noted in pathological examination of these animals. In subsequent studies, other authors used Adam’s classification to categorize DAI as mild, moderate, or severe. They proposed that any acceleration or deceleration could cause a mild case of DAI, in which brief loss of consciousness occurred.2 At its most severe, patients with DAI who survive rapidly lapse into coma, and remain unconscious, vegetative, or severely disabled until they die. The duration of coma in TBI patients correlates with the severity of DAI lesions identified by neuroimaging. In one prospective study, in which 21 DAI patients underwent MRI within 24 hours of injury, a positive correlation was established between the duration of unconsciousness and the maximal signal intensity of the corpus callosum.3 This suggests that coma duration in DAI may be an indicator of the extent of axonal damage. However, a recent report described a patient with findings consistent with DAI on MRI who manifested no coma in the first 11 hours of injury, challenging the classical association of DAI with rapid-onset coma.4 He et al. reported that coma depends not only on the ultimate distribution of axonal pathology, but also on the plane of the causative rotational head acceleration.5 Axonal injury in the brainstem appears to be one of the primary factors responsible for the generation of coma in DAI.6 Therefore, based on MRI findings, as well as on the depth and duration of coma after TBI, one can infer the existence of DAI and to some degree estimate its severity, but a definitive diagnosis cannot be established pre-mortem.

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3. Neuroimaging features of DAI 3.1. CT scanning and conventional MRI Conventional MRI (cMRI) (MRI using T1-weighted, T2weighted, fluid attenuated inversion recovery [FLAIR] and gradient echo sequences) is more sensitive than CT scanning for detecting axonal injury-related lesions, although both methods are widely used. CT examination, still the initial imaging study of choice for head-trauma patients, is readily available, fast, and sensitive in detecting hemorrhage. In contrast, cMRI allows the nature and extent of both hemorrhagic and non-hemorrhagic cerebral tissue injuries to be determined at higher resolution, especially within the posterior fossa and deep white matter. However, acquiring the appropriate sequences takes significantly longer than with CT scans; in addition, many patients are too unstable to have an MRI upon initial presentation. In the most severe cases of DAI, axonal pathology is often accompanied by intraparenchymal hemorrhage, which is clearly visible on CT. Early hemorrhagic lesions are associated with hypertension, and are frequently surrounded by hypodense areas representing cytotoxic edema, axonal destruction, or tissue necrosis.7 However, when used to evaluate mild to moderate DAI, cMRI is demonstrably superior to CT scanning in detecting petechial hemorrhages and non-hemorrhagic lesions. Thus, CT and MRI each have their own benefits in the clinical assessment of head-trauma patients. Hemorrhagic DAI lesions vary in signal intensity depending on the age of the blood involved and the sequence employed. By detecting paramagnetic properties of iron-containing heme moieties, gradient recovery echo (GRE) images are very sensitive to microhemorrhages. GRE detects a greater number of small hemorrhagic lesions than other sequences, with the results showing a positive correlation with the Glasgow Coma Scale score (GCS).8 GRE is also able to detect all areas responsible for focal neurological signs 1 month after injury. Non-hemorrhagic lesions are typically more evident on T2-weighted imaging, particularly FLAIR sequences, which allow a better visualization of injured tissue by reducing signal interference from cerebrospinal fluid (CSF). In one prospective study,9 33 patients with a normal CT scan, but abnormal neurological status, were examined with cMRI within 48 hours. The authors noted that cMRI revealed more non-hemorrhagic lesions than CT scans, and that the presence of non-hemorrhagic lesions was associated with a relatively good clinical outcome. In contrast, in another study, which used FLAIR to quantify the affected white matter volume within 2 weeks of injury, total DAI volume was correlated with patient outcome, as measured by the Glasgow Outcome Scale - Extended. The authors concluded that this method could be used to stratify injury severity.10 Clearly, the use of CT scanning and MRI has greatly improved the detection of pathological tissue changes in DAI. However, both CT and MRI probably underestimate the extent of axonal damage, as most of this damage is microscopic. This is supported by the observation that many patients with severe TBI have minimal changes detected by CT scans or MRI. Therefore, recent investigations have sought to apply advanced imaging techniques to the measurement of tissue injury in DAI. 3.2. Advanced MRI techniques Newer and more sensitive imaging techniques better visualize tissue damage and monitor dynamically the intracranial metabolic changes following head trauma. Diffusion-weighted imaging (DWI) was initially investigated in the context of DAI because of its ability to detect the cytotoxic edema occurring after acute stroke. Head trauma leads to an alteration of local diffusion, and DWI is more sensitive than cMRI for the

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detection of DAI. In a study that examined 25 patients with DAI within 48 hours of the inciting trauma, DWI identified 310 shear injuries consistent with DAI out of 427 lesions counted by all sequences combined (followed by T2/FLAIR [n = 248] and GRE [n = 202]). Furthermore, DWI uncovered 70 lesions that were not detected by cMRI. Most DWI-positive lesions showed decreased diffusion (65%), potentially indicating cytotoxic edema.11 However, one recent study reported that DWI was superior to FLAIR in evaluating DAI lesions of the fornix, while in the corpus callosum and gray-white matter junction, DWI had no advantage.12 These conflicting findings may be at least partially due to differences in timing. DWI imaging in the former study was typically performed within 20 hours, whereas in the latter, the time at which patients underwent imaging was much more variable (a range of 20 hours to14 days; mean 3.7 days). In DAI regions there is an evolution from restricted diffusion (cytotoxic edema) to unrestricted diffusion (vasogenic edema).13 Some studies have recently attempted to determine the relationship between various DWI variables and clinical status. Zheng et al. reported that mean apparent diffusion coefficient (ADC) values were positively correlated with the duration of coma in DAI patients.14 Ezaki et al. found that DWI could predict clinical outcome in DAI patients.15 Diffusion tensor imaging (DTI) may be more sensitive to DAI lesions than cMRI (studies well summarized by Hurley15). The most informative neuroanatomic locations in which to apply DTI for the identification of DAI have been debated. One study, involving 20 patients and 15 healthy controls, measured the fractional anisotropy (FA, a scalar measurement of diffusion anisotropy, generally considered an index of injury to white matter) values of multiple locations, and correlated these with clinical scores. The FA values in the splenium and internal capsule of patients were correlated with both the acute GCS at the time of injury and the Rankin scores at the time of discharge. No similar correlation was observed for the thalamus and putamen.16 In contrast, another investigation recruited 20 patients and 14 aged-matched controls in order to investigate global white matter integrity. Mean FA histograms were globally diminished compared with controls in all cases, including mild TBI patients. In addition, the FA parameters were correlated with the injury severity index (by GCS) and with posttraumatic amnesia (PTA).17 The authors concluded that, in detecting white matter injury, the whole-brain white matter approach may have no clear superiority over a regional approach, but that quantifying the white matter damaged may provide additional prognostic information. Other investigators studied the specificity of DTI for DAI. Donald et al. used DTI to analyze the impact-induced mouse model of DAI. This allowed them to directly compare DTI findings with a histological assessment of axonal injury. They noted that axial diffusivity and relative anisotropy were reduced in the pericontusional corpus callosum and external capsule with normal cMRI. Changes in the relative anisotropy were negatively correlated with the density of b-APP. The anterior commissure displayed no reduction of axial diffusivity and relative anisotropy, consistent with the absence of histological evidence of axonal injury.18 This suggests that DTI is highly sensitive to axonal injury, and in addition may have a high negative predictive value. The sensitivity of DTI in this context has been corroborated in another study, which noted that the axial diffusivity derived from DTI accurately matched the pattern of axonal damage.19 Donald et al. found that a decline in axial diffusivity was apparent within 3 hours in areas of histologically confirmed axonal injury,18 which suggests that DTI may be a sensitive tool in detecting DAI in the superacute phase. A modification of GRE, susceptibility weighted imaging (SWI), increases the ability of GRE to detect hemorrhagic lesions, thereby improving the detection of DAI by illuminating minute

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hemorrhages. A previous study examined 7 patients with DAI, imaged from 2 days to 8 days after injury, and found that hemorrhagic lesions were much more visible on SWI than on conventional GRE.20 SWI depicted a total of 1038 hemorrhagic DAI lesions, with a total hemorrhage volume of 57,946 mm3, while GRE depicted 162 lesions with a total volume of 28,893 mm3. SWI depicted a higher mean number of lesions in all patients than GRE. Most (59%) individual hemorrhagic DAI lesions seen on SWI were small (<10 mm2), whereas most (43%) lesions seen on GRE images were larger (10–20 mm2). A later study compared the extent of parenchymal hemorrhage in 40 pediatric DAI patients with initial clinical variables, and outcomes 6 to 12 months after injury.21 Children with lower initial GCS scores (<8), or prolonged coma, had a greater average number and volume of hemorrhagic lesions, and poorer outcomes, while those with normal outcomes or mild disability had suffered fewer hemorrhagic lesions with a smaller lesional volume. Based on these findings, SWI appears to be superior to GRE in detecting microhemorrhagic lesions, and allows a more accurate estimation of the extent of DAI following brain injury. Magnetic resonance spectroscopy (MRS), which can assess neurochemical alterations after brain injury, has been used to provide early prognostic information in TBI patients. Recently, several MRS studies have demonstrated its potential in detecting DAI. Smith et al. used localized proton MRS (1H-MRS) to examine regions of the pig brain after rotational acceleration injury, and detected a 20% reduction in the ratio between N-acetyl aspartate (NAA, a neuronal marker) and creatine (Cr) (i.e. NAA/Cr).22 Regions with reduced NAA/Cr ratios were then confirmed as DAI at autopsy, supporting the hypothesis that NAA loss may, at least in part, reflect DAI. Another study examined 14 mild TBI patients, and found significant reductions in NAA/Cr and NAA/choline (Cho), as well as increases in Cho/Cr ratios, compared with controls in brain regions with normal cMRI, thereby demonstrating the high sensitivity of MRS in identifying diffuse brain injury.23 The evolving MRI profile of non-hemorrhagic DAI lesions is shown in Table 1. 4. Biochemical markers Despite the utility and sophistication of imaging techniques, they have decided limitations in the acute phase, particularly for patients requiring ventilators, cardiac monitors, or other medical equipment. Accordingly, neurosurgeon-scientists have sought sensitive and specific biochemical surrogate markers for brain damage. Among them, two potential serum and CSF biomarkers of brain injury are being intensively studied. S-100B is part of the acidic calcium-binding protein family, which is predominantly localized in glial and Schwann cells, with a consequently high specificity for central nervous system (CNS) white matter. In contrast, Table 1 Evolution of non-hemorrhagic DAI lesion appearance on MRI Type of MRI sequence

Pathophysiology

T2-weighted

Cytotoxic/extracellular edema

DWI DTI SWI MRS

Time

12

Cytotoxic edema Interruptive axolemmal, axonal leakage18 Paramagnetic blood breakdown products20 Aberrant metabolism

Not less than 1 day About 3 hours12 About 3 hours18 No less than 1 day20 Moment of injury

Superscript numbers indicate reference. Pathophysiology = pathological changes of DAI detected by imaging techniques. Time = the typical point when non-hemorrhagic DAI lesions appear on MRI. DAI = diffuse axonal injury, DTI = diffusion tensor imaging, DWI = diffusion weighted imaging, MRS = magnetic resonance spectroscopy, SWI = susceptibility weighted imaging.

neuron-specific enolase (NSE), an isoenzyme of the glycolytic enzyme enclose, is found primarily in the cytoplasm of neurons and cells with endocrine differentiation. Both of these markers appear elevated in the serum and CSF of patients with TBI, although S-100B levels seem better correlated with TBI than those of NSE.24 To determine the diagnostic value of an elevation in NSE and S-100B after TBI, their serum concentrations were measured in 104 mild TBI patients, and compared to those of 92 control patients.24 There were differences in the median S-100B and NSE levels between patients and controls, with serum S-100B levels better correlated than NSE levels with TBI severity. Another study compared the S-100B and NSE levels in the CSF and serum to the initial contusion size on CT scan in 13 patients (GCS 6 8)and 17 controls.25 Serum S-100B levels were correlated with contusion size in all patients; in the CSF, both S-100B and NSE were strongly correlated with contusion size. However, as CSF sampling may be impractical, especially in mild injuries, most studies have focused on serum measures. In order to enhance their clinical role, some researchers have begun to combine S-100B and NSE to detect TBI patients. One recent study sampled the CSF and serum of 401 acute care patients within 36 hours of admission, and compared the ability of several biomarkers to discriminate the different types of acute injury. Brain damage secondary to heart failure was indicated by increased NSE and troponin I values, with normal S-100B levels; primary brain trauma was suggested by elevated S-100B and NSE levels; multi-organ dysfunction was associated with elevated S-100B with normal NSE levels.26 The authors hypothesized that NSE was specific to brain, whereas S-100B was mainly released from non-CNS tissues. In contrast, S-100B was described as a sensitive marker of brain damage by another study, which found that patients with head trauma had significantly higher median S-100B levels than patients with extracranial injuries, and that serum S100B levels were also correlated with the severity of brain injury.27 Although extensive extracranial injuries also resulted in elevated S-100B levels, these levels were not affected in limited extracranial injuries without head trauma. The authors reached the conservative conclusion that S-100B has a high negative predictive value a normal S-100B value shortly after trauma should exclude significant brain injury with a high accuracy.27 As part of a further investigation, another study measured the change in S-100B and NSE levels over time in serial venous blood samples taken 1 to 3 days after TBI in 66 patients.28 Patients were divided into three groups: primary cortical contusions, DAI, and those with signs of increased intracranial pressure (ICP) without focal mass lesions. NSE peaked in the first blood sample taken in patients with cortical contusions, whereas S-100B peaked 25–48 hours after head trauma. In patients with DAI, peak concentrations of both proteins were found on day 3 post-TBI. Patients with elevated ICP showed a continuous increase of both markers, with peak levels appearing 49–72 hours after brain injury. Although impractical in clinical contexts, b-APP staining remains the gold standard when it is necessary to unequivocally demonstrate the presence of DAI in experimental and forensic settings. On this premise, some studies have begun to evaluate the utility of b-APP derivatives in identifying DAI. Olsson et al. analyzed the 42 amino acid forms of b-amyloid, Ab (1–42), and two soluble forms of amyloid precursor protein, a-sAPP and b-sAPP, in ventricular CSF (VCSF).29 They also measured Ab (1–42) in plasma from 28 patients using daily serial sampling up to 11 days after TBI. The VCSF-Ab (1–42) levels gradually increased to reach a maximum of 1173% of baseline on day 5–6, while VCSF-a-sAPP levels rose to 2033% of baseline on days 7–11. The elevation of VCSF-bsAPP was slight but significant. In contrast, plasma-Ab(1–42) levels were unchanged after injury. The authors suggested that the presence of b-APP derivatives in the VCSF might indicate axonal injury.

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However, such studies are still scant and the clinical utility of these markers still needs further investigation. Aside from b-APP, the analysis of neurofilaments using immunohistochemical techniques have been used in the pathologic analysis of axonal injury.30 However, most investigations have focused on the utility of neurofilament analysis in axonal degeneration or loss, not on axonal injury subsequent to head-trauma.31 Further work is needed to explore the potential diagnostic value of such techniques in DAI. Several clinical and translational studies have used biochemical markers to evaluate patients with TBI, and some desirable characteristics for these markers have been identified. However, the utility of these biochemical markers remains limited due to their lack of specificity for TBI and their restricted accessibility in clinical practice. Although further work is needed, significant potential exists for the use of biochemical markers to objectively diagnose TBI in symptomatic patients with normal CT scan findings, as occurs in DAI. 5. Potential specific treatments for DAI 5.1. Specific drug treatment The realization that DAI is not an isolated event but rather an evolving pathophysiologic process that may be modified within an as-yet-undefined time window, has led the scientific community to explore therapeutic strategies that may limit the progression of injured but surviving axons toward secondary axotomy. Another active area of research is attempting to stimulate axonal regeneration and repair of damaged neuronal processes. Several therapies are shown to be effective in limiting progression, or regenerating damaged axons, in preclinical or clinical studies. As intracellular calcium accumulates, calcium-induced failure of the mitochondrial respiratory chain leads intact axons to undergo secondary axotomy. In experimental models of DAI, both preinjury intrathecal administration and 30-min-postinjury intracisternal injection of cyclosporine A (CsA) reduced the number of axonal retraction balls, compared to controls.32,33 Results suggested that CsA may diminish axotomy in injured axons by inhibiting the calcineurin-mediated and/or calcium-mediated opening of the mitochondrial membrane transition pore, which subsequently leads to calpain-induced apoptosis. Similar results were observed in two other studies, which applied, in two models of DAI, respectively, CsA and FK506 (a calcium-calmodulin-dependent kinase II antagonist and immunophilin ligand that may be more effective and less toxic than CsA). Both CsA and FK506 could reduce progressive cytoskeletal damage and inhibit secondary axotomy.34,35 However, the CsA treatment reduced the density of damaged axons that exhibited neurofilament compaction (NFC), while FK506 failed to attenuate NFC, suggesting that non-calpain-mediated mechanisms are operant and that additional therapeutic agents targeting NFC may be necessary.36 There are few published studies that examine which dosage of CsA is effective in attenuating secondary progression to axotomy in the injured axon. One investigation, which studied the dose-response of CsA in traumatic axonal injury, proposed that intravenous administration of CsA achieved therapeutic levels in the brain parenchyma, and that 10 mg/kg yielded the greatest degree of neuroprotection against DAI, while levels of 50 mg/kg could be toxic.37 The weak regenerative capacity of CNS axons has been partially attributed to the activity of myelin-derived axon outgrowth inhibitors, which includes Nogo-A, oligodendrocyte-myelin glycoprotein (Omgp) and myelin associated protein (MAP). Nogo-A, MAP, and Omgp bind to the Nogo-66 receptor (NgR), and exert their effects through the p75/LINGO-1 or LINGO-1/TAJ/TROY receptor complexes.38 The inhibitory role of myelin proteins on neuronal

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outgrowth is mediated by Rho A, an intracellular regulator of cytoskeletal elongation. Activation of Rho A inhibits axonal growth, whereas inactivation allows axonal regeneration to occur.39 Accordingly, disruption of this signaling pathway allows axons to elongate; this has now been demonstrated both in vivo and in vitro in several models of CNS injury. GrandPré et al. identified a Nogo-66 (1–44) antagonist (NEP144), which blocked Nogo-66-mediated inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin.38 Furthermore, intrathecal administration of NEP1-40 to rats with midthoracic spinal cord hemisection extended recovery of the animals’corticospinal tract and function. Similarly, following spinal cord hemisection injury in rats, soluble function-blocking NgR ectodomain-treated animals sprouted corticospinal and raphe-spinal axonal fibers, and showed improved spinal cord electrical conduction and functional locomotion.40 Targeting the intracellular regulators of Nogo-A was equally effective: inhibition of Rho A with C3 transferase, or inhibition of Rho-associated serine threonine kinase (ROCK) with a competitive antagonist (Y-27632), improved functional recovery.39 The effect of blocking these downstream mediators may be a consequence of inhibiting neurite outgrowth inhibitors, whose signal pathways seem to converge to some degree. Together, these data demonstrate that disruption of NgR and associated intracellular signaling pathways results in the reversal of constitutive inhibition of axon outgrowth that occurs with normal CNS maturation. However, most studies remain in the preclinical stages, and clinical efficacy has yet to be demonstrated. The pathophysiology of TBI is multifactorial, with a series of pathologic processes following the insult that include an exacerbated inflammatory response, increased extracellular glutamate concentrations, and free radical overproduction. Accordingly, the ideal drugs would be able to block multiple cellular events leading to brain damage following TBI. Several studies report the benefits of progesterone on TBI. In the cortical contusion injury model, Djebaili et al. demonstrated that rats treated with progesterone performed better in learning and memory functions, which they attributed to the protective effects of progesterone.41 Christine et al. subsequently showed that progesterone has the ability to improve motor and cognitive outcomes, and to attenuate axonal injury, in varying models of TBI.42 Aside from animal models, one prospective, randomized, placebo-controlled trial, including a total of 159 patients, showed that progesterone administration was effective in the long term in improving neurologic outcomes in acute TBI patients.43 Erythropoietin (EPO) is another neuroprotective agent under investigation. In experimental studies of TBI, administration of recombinant human EPO (rhEpo) not only lowered motor deficits and restored cognitive function, but also preserved axons at the trauma area.44 However, a recent commentator45 hypothesized that EPO could actually enhance the progression of DAI early after TBI, since some studies have shown that EPO may increase calcium influx through T-type voltage-dependent calcium channels,46 suggesting that clinicians may wish to use EPO with caution during the early stages of DAI. Some TBI models show benefit from calpain or caspase inhibitors,47,48 whereas others may respond to neurotrophins.49 However, most neuroprotective agents also act on other types of cells at the same time; thus, systemic side-effects are difficult to avoid. 5.2. Cell transplantation treatment DAI is characterized by progressive axonal degeneration with subsequent neuronal cell loss. The limited regenerative capacity of the CNS suggests that functional recovery following DAI is likely to require transplantation of exogenous cells. As a type of diffuse brain injury, DAI involves extensive lesions in white matter tracts

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and/or deep hemispheric nuclei. Stem cells, characterized by selfrenewal, site-specific differentiation, and the ability to migrate to targets, have emerged as a suitable cell source for cell replacement therapy following DAI. In vitro studies have shown that embryonic stem cells (ESCs) can differentiate into various types of neurons.50 Recently, Riess et al. found that transplantation of ESCs following fluid-percussion injury, which faithfully reproduced DAI, significantly improved functional outcome on a range of behavioral tasks.51,52 A potential complicating factor, the tumorigenic potential of ESCs, seems to be greatly reduced when cells are predifferentiated in vitro before implantation.52–54 Progenitor cells possess a more restricted lineage potential than do ESCs. Study of NSCs transplanted after fluid-percussion injury has demonstrated that NSCs are able to migrate to the site of damage, differentiate into neurons, enhance motor recovery, and mediate cognitive improvement.55–57 Bone-marrow-derived cells (BMSCs) also have the ability to express neuronal and glial markers. A theoretical advantage of these cells is that they can be harvested from the injured animal, bypassing the issues of cell availability and immunosuppression. The functional outcome of rats that received an experimental brain injury was improved significantly by transplantation of BMSCs.57 Moreover, intravenous58 and intra-arterial59 administration of marrow stromal cells resulted in the cells surviving, migrating to the area of injury, and expressing neural cell markers. Although stem-cell-based therapy has shown promise in the treatment of DAI, the safety and clinical efficacy of transplantation with stem cells requires further evaluation. 6. Conclusion Effort has been devoted to the development of more sensitive diagnostic tools and targeted therapeutic interventions for DAI. However, despite important advances, current clinical imaging tools cannot definitively identify DAI, although they do provide a wealth of useful data that can be used to establish that DAI has occurred. With continued advances in imaging and laboratory techniques, detection of damaged axons in the early stages of injury, using technologies such as DTI, could be refined to yield useful diagnostic techniques. Several biomarkers have also shown promise in discriminating patients with TBI, with clear applicability to the detection of DAI. Potential therapeutic targets aimed at preventing the progression of injured axons to secondary axotomy have been identified. Further investigation is needed to better characterize potential protective mechanisms, as well as their interaction with the pathophysiological processes at work in the evolution of DAI. Insights into these signal transduction cascades may lead to the development of novel drugs, which, when combined with the earlier recognition made possible with new and improved neuroimaging strategies, may enable pharmacologic rescue of these damaged axons. References 1. Gennarelli TA, Thibault LE, Adams JH, et al. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982;12:564–74. 2. Adams JH, Doyle D, Ford I, et al. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 1989;15:49–59. 3. Takaoka M, Tabuse H, Kumura E, et al. Semiquantitative analysis of corpus callosum injury using magnetic resonance imaging indicates clinical severity in patients with diffuse axonal injury. J Neurol Neurosurg Psychiatry 2002;73: 289–93. 4. Corbo J, Tripathi P. Delayed presentation of diffuse axonal injury: a case report. Ann Emerg Med 2004;44:57–60. 5. Xiao-Sheng H, Sheng-Yu Y, Xiang Z, et al. Diffuse axonal injury due to lateral head rotation in a rat model. J Neurosurg 2000;93:626–33. 6. Smith DH, Nonaka M, Miller R, et al. Immediate coma following inertial brain injury dependent on axonal damage in the brainstem. J Neurosurg 2000;93: 315–22.

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