NEUROSURGICAL FOCUS Neurosurg Focus 39 (3):E10, 2015 Diffusion tensor imaging to visualize axons in the setting of nerve injury and recovery Thomas Anthony Gallagher, MD,1,2 Neil G. Simon, PhD, FRACP,3,4 and Michel Kliot, MD2 Departments of 1Radiology and 2Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 3Prince of Wales Clinical School, University of New South Wales, Sydney; and 4Department of Neurology, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia Successful management of peripheral nerve trauma relies on accurate localization of the injury and grading of the sever- ity of nerve injury to determine whether surgical intervention is required. Existing techniques, such as electrodiagnostic studies and conventional imaging modalities, provide important information, but are limited by being unable to distinguish severe nerve lesions in continuity that will recover from those that will not. Diffusion tensor imaging (DTI) and tractogra- phy of peripheral nerves provide a novel technique to localize and grade nerve injury, by assessing the integrity of the nerve fibers across the site of nerve injury. Diffusion tensor imaging and tractography also hold promise as markers of early nerve regeneration, prior to clinical and electrodiagnostic evidence of recovery. In the present review, the tech- niques of peripheral nerve DTI and tractography are discussed with respect to peripheral nerve trauma, with illustrative cases demonstrating potential roles of these novel approaches. http://thejns.org/doi/abs/10.3171/2015.6.FOCUS15211 KEY WORDS peripheral nerve trauma; diffusion tensor imaging; tractography; MRI; nerve regeneration ERIPHERAL nerve trauma is common, frequently af- This review discusses the current approaches to mea- fecting younger people of working age. Neuropraxic suring nerve injury and recovery, the evolution of diffu- nerve injuries may result in initially severe deficits, sion tensor imaging (DTI) for the monitoring of nerve Pbut produce no lasting functional abnormalities after the degeneration and regeneration, and illustrative clinical ap- provoking insult is eliminated. In patients with axonal plications of DTI in the nerve injury clinic. injury (with axonotmetic and neurotmetic histopathologi- cal changes), outcomes range from complete spontaneous Assessments in Nerve Injury functional recovery with mild axonotmetic nerve injuries, to no spontaneous functional recovery with neurotmetic Clinical and Electrodiagnostic Approaches nerve injuries. It is in the group of patients with axonal Current approaches to diagnosing, quantifying, and injury where appropriate interventions may improve func- monitoring peripheral nerve trauma include clinical as- tional outcomes, but selection of appropriate patients is es- sessment and electrodiagnostic studies, supplemented by sential to optimize results. imaging and intraoperative electrophysiological studies in The development of a noninvasive means to identify appropriate cases.13 These assessment modalities provide axonal loss and early regeneration has important implica- invaluable information, but each one has limitations. tions for the management of patients with peripheral nerve Clinical assessment provides information regarding trauma, in particular the early identification of patients the distribution of the nerve injury, potential contribut- with severe nerve lesions that are unlikely to spontane- ing mechanisms, and functional status. However, clinical ously regenerate. Such a tool may facilitate early surgical examination is insensitive to early spontaneous recovery, exploration in appropriate patients and avoid unnecessary because muscle or limb movement may not be detectable surgical interventions in others. when only a small number of motor units have re-innervat- ABBREVIATIONS DTI = diffusion tensor imaging; EMG = electromyography; FA = fractional anisotropy; MRC = Medical Research Council; TA = tibialis anterior. SUBMITTED April 29, 2015. ACCEPTED June 16, 2015. INCLUDE WHEN CITING DOI: 10.3171/2015.6.FOCUS15211. ©AANS, 2015 Neurosurg Focus Volume 39 • September 2015 1 Unauthenticated | Downloaded 10/08/21 05:35 AM UTC T. A. Gallagher, N. G. Simon, and M. Kliot ed. Secondary changes in joints and ligaments may fur- information that fully characterizes a diffusion tensor. ther confound the clinical picture. The diffusion tensor is a matrix of values that quantifies In terms of electrodiagnostic studies, nerve conduction the amount (eigenvalues l1 l2 l3) and principal directions studies provide a means to quantify the extent of nerve in- (eigenvectors e1 e2 e3) of diffusion in any given voxel in jury, although these are insensitive to smaller increments tissue of interest, including a nerve. The magnitude and of nerve regeneration or deterioration. Electromyography direction of the largest movement of diffusion are given (EMG) is more sensitive than clinical examination to de- by l1 and e1, respectively. tect mild muscle denervation10 and early muscle re-inner- With these tools, diffusion of water in each voxel can vation. Electromyography may also provide an indication then be modeled and elegantly visualized as a 3D ellipsoid. of the time course of the nerve injury in partial injuries if If there are no barriers to diffusion (e.g., muscle fibers, this is not clear from the history. However, EMG will not nerve fascicles), diffusion is assumed to be isotropic, wan- detect nerve regeneration before nerve fibers have reached ders equally in all directions, and the diffusion tensor pre- the target muscle, which may necessitate several months dicts a perfect 3D sphere (l1 = l2 = l3). Intact myelinated of monitoring before a nerve starts to regenerate and reach nerves and fascicles tend to constrain and direct diffusion the target muscle, particularly in more proximal nerve in- strictly along a dominant, principal pathway (anisotropic juries. diffusion), and the tensor predicts a series of successive, Intraoperative electrophysiological studies may provide elongated cigar-shaped ellipsoids that serve as a proxy for important information regarding the severity of nerve in- the delicate microstructure of the nerve itself.4,9 jury and the likelihood of spontaneous regeneration and Additional metrics that can be derived from the diffu- help guide treatment choices, in particular for those pa- sion tensor include axial diffusivity (l1, along the princi- tients in whom grafting and other reconstructive proce- pal direction) and radial diffusivity (l2 + l3 ÷ 2, perpen- 5,7 dures are needed. However, these studies are necessarily dicular to the nerve). Another common metric is fractional invasive. anisotropy (FA), an index of how different the principal directions of diffusion are, which ranges from 0 to 1. High Imaging in the Setting of Nerve Injury and Recovery FA along the course of a nerve indicates that it is directing Imaging is frequently performed in the setting of nerve diffusion very strictly in 1 direction along its axis, with- injury. Muscle imaging, including MRI and ultrasound, out gaps or defects. For example, intact and healthy nerves has a role in the work-up of nerve injuries.12 In particular, should register as cigar-shaped ellipsoids with high FA. muscle imaging identifies changes of denervation edema Nerve injury, such as injury to myelin and/or axons, is as- within days,3,15 before the appearance of fibrillations on sociated with reduced FA (i.e., less anisotropic water dif- EMG, and hence may be useful in the hyperacute setting fusion, more spherical ellipsoids).16 Fractional anisotropy to determine the pattern of muscle denervation. How- increases during nerve regeneration.14 ever, it has not yet been elucidated whether the presence Diffusion tensor (DT) tractography uses methods that of acute muscle edema may distinguish between a severe draw directionally color-encoded streamlines that visually neuropraxic lesion and one involving axonal injury. link dominant directions of diffusion (eigenvectors) across Magnetic resonance neurography, which indicates a se- many voxels in a target tissue. In general, many different ries of MRI sequences that include a heavily fat-saturated mathematical propagation algorithms exist for DT trac- T2-weighted sequence,1 may provide information about tography. Most of them usually accept certain user-defined the location of nerve injury, the anatomical context of the FA thresholds, tract-length constraints, turning-angle con- nerve injury, and associated soft-tissue injury. Emerg- straints, and desired regions of interest before calculating ing 3D anatomical sequences, including T2-weighted the most likely route through the tissue. If highly reliable and STIR SPACE (sampling perfection with application- diffusion data are acquired, the resultant 3D fiber bundle optimized contrasts using varying flip-angle evolutions; is a proxy for nerve fascicles.8 Siemens USA), have introduced greater anatomical de- tail; the 3D-image volume can be rotated and tilted in any orientation while maintaining a high degree of anatomi- Clinical Applications cal fidelity. This provides a means for advanced image Diffusion tensor imaging outside of the brain often postprocessing to best profile longer stretches of nerves, requires adjustment of MRI parameters to optimize the which often assume nonorthogonal courses (e.g., brachial image acquisition, and exams must be tailored to the re- plexus). Magnetic resonance neurography can depict T2- gion of interest. Diffusion weightings ranging