Review
Domi T1, Mikulis D2, McAndrews MP3, Dlamini N1, deVeber G1
1Neurosciences and Mental Health; 2 Toronto Western Hospital; 3Krembil Research Institute,
Corresponding Author
Trish Domi, PhD
Research Associate | Stroke Imaging Lab for Children
Neurosciences and Mental Health
The Hospital for Sick Children
Peter Gilgan Centre for Research & Learning
686 Bay Street, 8.9801-3
Toronto, ON, M5G 0A4
Institute of Medical Science | University of Toronto
P: 416.813.7395 | F: 416.813.5242 |
Email: trish.domi@sickkids.ca
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Introduction
Arterial ischemic stroke (AIS) is an important cause of acquired neurological morbidity in children with motor deficits being the most common.1-3 AIS in the territory of the middle cerebral artery is common, resulting in injury to supratentorial motor systems. Primary motor neurons originating in the central nervous system follow well-defined descending tract called the corticospinal tract. Injury to neurons can cause degeneration of their axons.4 This process is referred to as “Wallerian degeneration” (WD).
Damage to the corticospinal tract is associated with persisting motor impairment in adult stroke 5,6 congenital hemiplegia 7,8, and childhood stroke. The corticospinal tract is the most commonly involved white matter pathway in childhood stroke and will be the focus of this review, with a summary of the basic anatomy and pathological markers of corticospinal tract injury on MRI.
This will be followed by a chronology of the utility of conventional MRI techniques in the evaluation of WD caused by stroke, the investigation of WD in the pediatric stroke population with neuroimaging, and the association with motor outcome.
Evaluation of the Corticospinal Tract
Mapping of the corticospinal tract is traced back to the seventeenth century by Willis (1664) who described the convergence of the corticospinal tracts into the medullary pyramids.9 Although the anatomical location of the corticospinal tract at the supratentorial level and in the brainstem have been well characterized,4, 10-14 some of these historical findings have been challenged since neuroimaging techniques became available. 15, 16 The development and application of MRI techniques provide an in vivo opportunity to advance our understanding of the corticospinal tract, the main neural pathway in the human brain. Despite advances in its evaluation, the somatotopic organization of the corticospinal tract and its exact role in motor function remain to be determined. The advent of non-invasive, neuroimaging has advanced our understanding of the corticospinal tract including its maturation and the development of myelination and specialization of these pathways.16-19 However, there remains a gap in knowledge about the role of the corticospinal tract in motor function in the normal, developing, and injured pediatric brain.
Primer on the Corticospinal Tract - Anatomy and Pathology
The corticospinal tract is the main white matter connection between the motor cortex and the spinal cord. It serves as the main conduit of information between the higher cortical structures and the voluntary musculature.11 Comprised of a large bundle of myelinated axons, the corticospinal tract transmits signals from the motor cortex neurons (the upper motor neurons) to the anterior horn cells of the spinal cord (the lower motor neurons), which then project directly to muscle.14
It is well-known that there are two separate corticospinal tracts. The larger corticospinal tract is the lateral corticospinal tract that is formed by 75–90% of the corticospinal tract fibers that cross over (or decussate) at the medullary decussation.11, 20, 21 From the cortex, the corticospinal tract descends caudally through the corona radiata, and converges on the posterior limb of the internal capsule. From there, it descends through the cerebral peduncles of the midbrain and the basis ponti where the fibers are then separated into bundles by transverse pontine fascicles. The fibers then converge again forming the pyramids of the medulla, thus earning its alternate name, the pyramidal tract. In the lower medulla, 90% of the fibers cross the midline (called pyramidal decussation) and continue to descend in the contralateral CST to the opposite side of the spinal cord. The lateral CST primarily controls the voluntary movement of contralateral limbs. The remaining 10% of the CST fibers that descend from the motor cortex do not decussate in the medulla but descend uncrossed in the anterior (or ventral) CST (Figure 1) and are involved with movement of the muscles of the trunk, neck, and shoulders.29
Studies on the evolution of the motor system suggest that the corticospinal tract is unique to mammals, and its development is associated with the acquisition of dexterous motor skills.22-25
Experimental studies have also demonstrated the functional importance of the corticospinal tract in motor recovery. Preservation of approximately 1/5 of the lateral corticospinal tract fibers is sufficient to ensure restitution of fractionated finger movements.26 Human stroke involving infarction of motor cortices is a clinical model of corticospinal tract damage. Studies confirm that adults patient are unable to carry out fine motor activities of the hands after complete injury of the lateral corticospinal tract.21, 27-29 It has also been shown that reorganization of the corticospinal system is integral to functional motor recovery of the upper limb and hand.30-35
The Role of the Corticospinal Tract in Recovery Following Stroke
WD of descending fiber tracts after ischemic stroke is a well-known phenomenon reflecting fiber tract damage. Ischemic stroke provides an ideal model to study WD due to the focal nature of the injury in the CNS that results in highly selective, regionally specific damage to functional circuits. When the corticospinal tract is involved, this allows ‘downstream’ quantification of the extent of damage to the cortical motor neurons in the cerebral peduncle.
When damage occurs to the corticospinal tract due to either direct injury to the CST pathways, or injury to the cell body, salient neuroimaging features that correspond to the injury have been documented.36-38 39 Since the fiber pathways of the corticospinal tract are well defined at various levels throughout the brain, including the posterior limb of the internal capsule (PLIC), cerebral peduncle, basis pontis, and medullary pyramid38, WD of the corticospinal tract is easily recognized both pathologically, and with two-dimensional cross-sectional imaging methods.37 A key finding was that infarcts in the motor cortex of one cerebral hemisphere were associated with atrophy of the ipsilateral brainstem. This was later affirmed to be readily visible in humans as focal loss of volume within ipsilateral brainstem on gross postmortem examination in humans.40 Focal atrophy in the brainstem has since become a signature characteristic of the chronic phase of WD in the CNS.
Numerous factors are involved in the brain’s response to injury. Few of these factors have been isolated, reliably measured, and associated with clinical outcome. Previous studies of motor outcome after stroke relating to lesion size and location demonstrate a degree of variability in recovery that is unexplained by these factors.41 Neither lesion size nor location is predictive alone, and the combination of these lesion characteristics is not consistently incorporated into outcome studies. Lesion location alone may fail to fully explain the extent of motor impairment because the extent to which motor fibers remain intact cannot be easily determined.42 Clinical observations in the adult stroke population suggest that the initial levels of motor deficit, and the extent to which recovery takes place, depends on corticospinal tract integrity.27, 43-48
Since the corticospinal tract is the largest descending white matter fiber bundle and serves as the major neuronal pathway for motor function in the human brain28, 46, it is critical to the successful development and maintenance of motor functions. Optimal neural function relies upon the smooth integration of neural impulses from many spatially segregated but functionally related brain regions.16 The speed of neural transmission depend on the function of the neuronal synapses, the condition of white matter pathways linking these networks nodes,49 and the structural properties of the connecting fibers, including axon diameter and thickness of the myelin sheath.16 Any change or destruction to these properties of these fibers such as those caused by stroke, would disrupt motor function. There is abundant evidence indicating that therapies that improve motor status in the chronic stroke state generally do so by promoting plasticity in the cortex and other brain structures, and that the CST is a critical efferent pathway by which these changes are expressed. 27 28–30, 50, 51
Wallerian Degeneration: Injury to the Corticospinal Tract
The corticospinal tract forms an anatomically discrete, compact collection of large numbers of axons that makes it easily identifiable in the central nervous system (CNS). As the axon is dependent on the cell body for survival, when injury occurs to the neuronal cell body, changes occur in axons that can be observed distal to the neuronal injury. This sequence of events is referred to as Wallerian degeneration (WD), after Augustus Waller the physiologist who first made these observations.41 WD is the term used to describe secondary degeneration of axons and their myelin sheaths from numerous causes, including stroke. WD in the brain is most commonly identified in the corticospinal tract, but can also occur along other white matter tracts (see Chen et. al (2016) for review). 52
The mechanisms of motor recovery following stroke likely involve recruitment of various pathways within the corticospinal tract. In the adult stroke literature, it has been suggested that these mechanisms may be grossly classified into two categories: 1) motor recovery by a corticospinal tract and 2) motor recovery by a non-corticospinal tract. The mechanisms that have been reported are: 1) adaptation of the ipsilateral motor pathway from the unaffected motor cortex to the affected extremities, 2) peri-lesional reorganization within the stroke hemisphere, 3) recovery of a damaged lateral corticospinal tract, and 4) participation of the secondary motor areas.
Working Definition of WD
The term WD remains in use for any form of anterograde degeneration of axons and their myelin sheaths, whether secondary to death of the cell body, or injury of the proximal axon. This term anterograde is applied to this type of nerve degeneration because the sequence of injury follows the usual direction of nerve conduction away from the cell body.36 Here, WD will refer to anterograde degeneration of the corticospinal tract following arterial ischemic stroke.
A Historical Timeline of Evaluating Wallerian Degeneration
In 1849, British physiologist Augustus Waller studied the response of peripheral nerves to transection in animal models, initially lesioning the hypoglossal nerve in a frog. He made the seminal observation that following transection of a peripheral nerve, the distal portion of the nerve undergoes progressive degeneration.53 He described this as anterograde degeneration involving both the axon and its myelin sheath distal to the axonal or cell body injury. He concluded that the separation of a fiber from its parent cell body was the critical causative event. He anticipated the role of a ‘‘trophic influence’’ which maintains axonal integrity in the uninjured nerve, but is unable to maintain integrity in the injured or severed nerve due to the separation from the cell body54. His method became a major means of tracing the origin and course of nerve fibers and fiber tracts, and the term Wallerian Degeneration (WD) was subsequently used to describe these microscopic changes in the peripheral nervous system (PNS).55
Subsequently, WD changes were also described in the central nervous system (CNS) where interruption of neuronal cell body or proximal fibers that reside entirely in CNS also causes distal degeneration. Although WD in the PNS and CNS are similar in that axonal destruction antedates the degeneration of myelin, the processes are different in other ways. A key difference between in the WD changes in the CNS and PNS is the fate of the parent neuron.56 In the CNS, WD was believed to signify irreversible loss of neuronal function as there no evidence of axonal regeneration, whereas axons in the PNS were found to regenerate rapidly.57 The time course of WD, until recently, was believed to vary in these two systems with WD in the CNS taking months and years to evolve,58-61 compared to only 7–14 days in the PNS.59, 62 Recent evidence shows that WD in the CNS occurs much earlier than previously reported. This is described as “pre-WD” or “acute WD” and is detectable in the first week after injury63 64 (see section below: Acute and Subacute MRI findings of Wallerian degeneration in pediatric stroke).
Degenerative Stages of WD
Neuroimaging Evaluation of Wallerian Degeneration
CT – Imaging Chronic Wallerian Degeneration
The opportunity to detect and study WD in the CNS in vivo became available with the advent of cross-sectional imaging of the brain. CT provided sufficient resolution to visualize the brain and cerebrospinal fluid volumes. In 1983, Stovring et al. published the first study to correlate CT findings with WD. In this study, CT scans of 37 chronic stroke patients (average 5.5 years post stroke), with large unilateral infarcts involving the motor cortex were studied. A clear relationship between the location and size of cortical infarcts, and the presence of WD in the brainstem was found. WD was not found when infarcts were classified as ‘small’, however ‘large’ infarcts involving the motor cortex demonstrated the presence of WD consistently. The authors described WD as “focal unilateral atrophic changes in the mesencephalon and pons at the sites of the descending corticospinal tract.38 This was the first study to document – radiographically – a correlate of WD associated with motor cortex infarction.
Visualizing Wallerian degeneration on CT imaging relies upon the detection of atrophy of the corticospinal tract that is mainly limited to the chronic stages of WD. In the chronic phase, the severity and duration of damage to the corticospinal tract can lead to gross visible atrophy of the cerebral peduncles. CT cannot, however, detect or study WD in the acute to subacute (< 4 weeks) time period following injury and is subject to significant ‘bone artifact’ from the skull projected over brainstem structures.
MR Imaging Signal – Temporal Detection of WD
The introduction of MRI in the 1980s was a significant advance in our ability to image tissues during life. MRI provides advantages over CT scanning in the detection and study of WD. First, MRI provides higher contrast resolution showing greater differences between gray matter, white matter, CSF, and most importantly pathological tissue compared to CT. Second, although CT spatial resolution is higher (0.5 mm isotropic voxels) than clinical MRI scans (1 mm in-plane resolution voxels at best), the ability to more clearly define differences between tissues such as CSF-brain boundaries and internal brain structure provides advantages for volumetric analysis as well. Third, since CT is plagued by “beam-hardening” artifacts caused by the bones of the skull base, MRI visualization of posterior fossa structures is superior to CT. This allows the detection of pathological tissue where even small shifts in water concentration and structure (chemical changes) become visible. The latter characteristic of MRI imaging provides an opportunity to demonstrate signal intensity abnormalities that evolve in white matter tracts during early stages of WD preceding the final atrophic stage. MR therefore has significantly advanced our ability to both detect and study much earlier stages of WD in the corticospinal tract in comparison to CT imaging.
Jolesz et. al (1983) published the first MRI study identifying changes due to WD in vivo using MR spectroscopy to study WD of the sciatic nerves in rats.68 Following transection of the sciatic nerve, MRI spectroscopy was applied 15 days later to compare the water content in the degenerated axons with those of the non-transected contralateral sciatic nerve. They reported that the average water content in the degenerated nerves was 25% greater compared to intact nerves. These increases in water content produced during the process of nerve degeneration contributed to signal changes; specifically, longer T1 and T2 relaxation times on MR images. They predicted that these longer relaxation times would also be found in the distal axons of transected nerves in the human CNS 68. The high sensitivity of proton MR to small shifts in water concentration in tissues, including secondary abnormalities in the white matter tract have enabled ongoing studies to date.
In the early years following Jolesz’ study, several case reports of prolonged MRI T1 and T2 relaxation times in the white matter of humans with primary neuronal or axonal disorders in the CNS were reported.69, 70 71 However, the seminal papers on the MR imaging characteristics of WD in the CNS were published by Kuhn et al., (1988). They reported the first series where MR signal characteristics in the white matter of patients with primary disorders of the CNS were studied systematically. Images from 23 patients were studied for signal abnormalities in the white matter tracts that may had been affected by a primary CNS disorder. The most common primary pathology was cerebral infarction (n=17). In all but 3 patients, a band of abnormal signal contiguous with the primary lesion extended along the anatomical pathway of white matter tracts emanating from the affected cortex. The signal abnormality in the white matter tracts was consistent with WD, characterized by a subtle decrease of T1 signal intensity with no contrast enhancement. The most common location of this signal abnormality was within the descending corticospinal tract in the lesioned hemisphere.36
The importance of this large case series was the demonstration that a non-invasive modality, namely MRI, could provide a sensitive method of evaluating WD in the living human brain. The authors interpreted the changes in signal intensity characterized by prolonged T1 and T2 relaxation times as representing degenerated axons distal to the primary injury of the motor cortex elicited by the primary disease process.36 They also characterized WD as a lesion with prolonged T1 and T2 signal visualized in an area of the ipsilateral brainstem corresponding to the known course of the corticospinal tract on at least two contiguous slices.
In the subsequent year, Kuhn et al. (1989) went on to describe the characteristics and temporal, changes of these signal abnormalities on T2-weighted images. Prior studies using MRI to study WD were limited to findings in the brain at 3 months or more following onset of disease.36, 69, 70 To examine changes in signal intensity over time, Kuhn et al. prospectively evaluated MR findings in 43 patients with acute cerebral infarction. Patients were scanned immediately following onset of acute stroke and eight patients with acute hemiplegic stroke were imaged in serial assessments every week for several months post-stroke. They found WD was not visible during the first month after insult, but at 4 weeks, a well-defined band of hypointense (dark) signal appeared on T2-weighted images in the topographic distribution of the corticospinal tract. By 10-14 weeks after the insult, they observed that this hypointensity converted into a hyperintensity. The time trajectory of the hypointense signal was that it first appeared 4 weeks after cerebral infarction and persisted up to 14 weeks, after which the signal became permanently hyperintense. Subsequently, in the chronic stage (as early as 4 months post-stroke) accompanying ipsilateral brain stem atrophy in the corticospinal tract was observed in the same locations as prior chronic signal abnormalities 37, (see Table 2 below).
Kuhn et. al. (1989) suggested that the evolution of signal intensity changes over time represented differences in the way that structural components of the injured tissue within white matter evolved during WD.37 They theorized that the dark signal intensity on the T2-weighted images between weeks 4 and 14 was the result of a transitory increased lipid-to-protein ratio during this phase of WD. This was a pivotal finding and implied that MR imaging had the potential to corroborate the dynamic, histochemical stages of WD described in post-mortem specimens a century earlier. These studies prompted subsequent investigations aimed at refining the diagnosis of WD using MR imaging. Over the next decades, as MR techniques evolved, the ability to image the various stages of WD improved.
The beginning of commercial MRI systems in the 1980s, the only sequence used was single spin-echo technique for T1- and T2-weighted imaging. The main disadvantage of this sequence was the long acquisition time required. In the late 1980s, the introduction of multi-echo spin echo vastly improved imaging speed. Since that time, there have been dramatic advances in MRI hardware and imaging techniques have facilitated rapid growth of clinical applications and research. Today’s conventional MRI techniques include sequences that can characterize tissue damage in the acute phase of injury using diffusion weighted imaging. Thus, MRI has enabled the investigation of the sequential stages of WD by associating radiographic features that can be temporally correlated with documented histopathological changes.
MRI Correlates and Biochemical Findings of the Degenerative Stages in Wallerian Degeneration
The first stage of WD, acute stage, occurs from several days up to 4 weeks after injury. It is characterized by the disintegration of axonal structures seen as axonal swelling and fragmentation on histology.65 In this acute stage, physical disintegration occurs within the axon without substantial biochemical changes in the adjacent myelin. Myelin sheaths begin to break down during the acute stage, however the fragmented sheaths retain the staining properties of healthy myelin. Kuhn et al. (1989) described that during early WD when both axonal and myelin breakdown are known to occur, T2-weighted MR images remained normal. They concluded that the absence of signal abnormality on conventional MR images reflected a lack of biochemical changes in the myelin. The belief that conventional MR imaging showed no changes during the acute phase of WD persisted.7,72-75 However, following these studies, acute WD has been detected as increased T2 weighted signal and have more recently been found to correspond with histological findings of acute biochemical changes in the process of WD.67,76
The second stage of WD, the subacute stage (from 4 to 14 weeks) is characterized by rapid destruction of the myelin fragments produced during the acute stage. By 3 months, most of the myelin has been broken down into simple lipids. Some of these substances are in the process of being removed by phagocytosis.70 During this phase, myelin protein breakdown occurs initially without lipid breakdown; this process alters the protein-lipid ratio and results in hyperintense signal intensity on T2- weighted images. Of note, this finding may be more of historical value, as this was observed on conventional spin echo T2-weighted sequence as opposed to fast spin echo (FSE) sequences prevalent today where hyperintensity represents fat on FSE T2-weighted sequences.77 Consequently, the hypointensity on T2-weighted sequence reported by Kuhn et al during this second stage is thought to not occur on today’s FSE T2-weighted imaging.
In the late, subacute stage, Stage 3, the myelin sheath has almost disappeared, and remaining elements of the sheath are characterized by the presence of increased edema, further lipid breakdown, gliosis and changes in water content and structure. In this stage, the myelin sheath has almost disappeared and gliosis occupies the space left by the degenerated axon and myelin sheath.69, 70 This results in the tissue becoming hydrophilic (ie. water bonding) leading to hypointensity on T2-weighted signal intensity due to the increase in H2O content. Finally, in the fourth, or chronic stage of WD (several months to years), volume loss occurs reflecting atrophy53, 71, 78 (Table 2). This structural change is seen as unilateral volume loss of the brain stem on MR or CT images (Figure 3).
In summary, MRI provides excellent visualization of anterograde WD in the human brain. Alteration of the Tl and T2 relaxation times in the corticospinal tract confirms WD in the impaired tract distal to the cell body following the course of the degenerated pathways. The correlation between these signal changes and WD have been reported on histology.41
Identifying WD on imaging studies is relevant for several reasons. In patients with infarction, the accurate identification of WD avoids misinterpretation of signal abnormalities distant from the primary infarct as separate areas of ischemic injury. In addition, development of WD, (implying irreversible loss of tissue), might be expected to correlate with irreversible loss of function and persistent clinical disabilities after cerebral infarct.79
Chronic WD and Neurological Outcome Following Pediatric Stroke
Building upon the earlier studies characterizing MRI markers of WD, subsequent studies examined the relationship between WD and motor outcome. Adult stroke studies have shown a strong correlation between Wallerian degeneration and motor outcome.5, 6, 80 Sonada et al., (1992) evaluated WD as T2 signal intensity in the brainstem and its cross-sectional extent was measured in the cerebral peduncles. WD was identified in 57.6% patients (N=172) and found to correlate significantly with motor impairment. Notably, upper extremity impairment contributed most to the presence of Wallerian degeneration in multivariate analysis. Their study included both patients with infarctions and hemorrhages, both showed similar rates of WD. They concluded that the extent of Wallerian degeneration was helpful in establishing the prognosis with respect to motor impairment in the upper extremity. A number of studies examining adult stroke have since described WD.5, 6, 80-83 Together, these studies have consistently shown that Wallerian degeneration correlates with neuromotor outcome and may be a predictor of motor impairment.
In the pediatric population, reports of WD consist of case reports and series of unilateral hemispheric lesions, primarily stroke, acquired in the perinatal time period. Over the first ten years of life, myelination, synaptogenesis, and the maturation of fully functioning neuronal circuits are ongoing.16, 84 This is particularly so in the child under 2 years of age. Studying focal brain lesions acquired after the newborn period would offer further insights into WD and its impact on the brain as early development proceeds.
In perinatal stroke studies including congenital hemiplegia, researchers have documented asymmetry of the cerebral peduncles to be associated with poor outcome. Only few reports in the neonatal stroke population have evaluated peduncular asymmetry and motor outcome . Kirton et al. (2007) reported a robust association with WD and motor outcome following neonatal stroke. Among the 29% with poor motor outcome (residual hemiparesis) at long term follow-up, all had WD. In contrast, WD was not found in any of the 71% if neonates with good outcome. Infarct volume was also assessed but did not correlate with outcome.63 Other studies have reported neuroimaging characteristics of stroke that predict motor outcomes in neonates.7, 72, 74, 85 However, in these studies, WD was not quantified and neonatal and presumed perinatal ischemic stroke populations were combined despite the differences in outcomes between these stroke types.
In the congenital hemiplegic population, several well-designed studies have shown that WD is correlated with severe motor deficits. The degree of WD in the corticospinal tracts of children with congenital hemiplegia is reported to correlate with the distribution and severity of hemiplegia.7, 17, 72, 74, 85-87 These studies also report that the severity of outcome has a higher correlation with peduncular asymmetry than infarct size.7, 8 These findings imply that evaluation of the corticospinal tract is a reliable indicator of the extent of damage to the motor system. They also suggest that the degree of damage to the corticospinal tract may be more predictive of motor outcome than lesion characteristics, including volume and location.
Bouza et al (1994) conducted the first study to demonstrate that the presence of WD in the corticospinal tracts on MRI was correlated with congenital hemiplegia. Twenty infants with congenital hemiplegia due to remote perinatal stroke lesions were documented to have chronic WD. In this study, WD was assessed by the presence or absence of signal intensity changes in the internal capsule, and by the asymmetry of the upper brainstem (calculated as the ratio of the measurements between the upper brain stem on lesioned and unlesioned hemispheres). They found the correlation between severity of outcome and brainstem asymmetry was stronger than the severity of outcome and infarct size. They also reported a significant correlation between upper limb involvement and brainstem asymmetry.7 Other studies using conventional MRI have also demonstrated that the motor outcome correlates more closely with Wallerian degeneration, manifested by atrophy in the descending corticospinal tracts88, than with infarct size. 8, 72
In any study of motor recovery, it is important to control for the extent of anatomic damage to the primary motor cortex. Quantifying the degree of damage to the corticospinal tract by measuring volume loss in the cerebral peduncles provides a surrogate measure of the degree of damage to the descending motor fibers. By calculating the asymmetry between the stroke affected and unaffected peduncles, an index of the damage to the primary motor cortex and corticospinal tract can be quantified. This method provides a simple way of quantifying the degree of damage to the motor system. This simplified method still maintains validity despite more complex methods of measuring primary motor lesion location and volume. In human stroke models, there is a wide heterogeneity in patient-specific, anatomical stroke features, such as lesion size and location. The degree to which each of these lesion characteristics is associated with motor outcome is not clear. The corticospinal tract (CST) is the final common outflow pathway for motor function. Following stroke, the extent of damage to the CST reflects damage to motor structures attributable to both lesion size and location. Therefore, assessment of the corticospinal tract may provide a better measure of the aggregate damage to the motor system.
Acute WD and Neurological Outcome Following Pediatric Stroke
Since its introduction in the mid-1980s, diffusion-weighted imaging (DWI) has revolutionised stroke imaging. DWI is sensitive to altered tissue water content in tissues. In acute stroke , water movement inside the cell becomes more limited resulting in cytotoxic oedema. DWI is therefore used routinely to detect diffusion restriction in acute stroke. WD in the acute stage can be detected on DWI as areas of reduced diffusion along the corticospinal tract, and on T2 and FLAIR (fluid attenuated inversion recovery) as hyperintense (bright) areas in the same location. 80, 89, 90
The original studies to provide evidence that WD is clinically relevant in predicting outcome, were performed in the chronic phase of WD. In chronic pediatric stroke, WD manifesting as peduncular atrophy is well-described and correlates with hemiparesis severity.7, 88 More recently, DWI findings of restricted diffusion along the corticospinal tract is in fact detectable in the acute52 72 (see Figure 4) and subacute phase74 following stroke.91 In acute neonatal AIS, DWI changes in the corticospinal tract has now been described and correlated with long-term motor outcome.7, 63, 72 Kirton et al. (2007) were the first to describe these changes along the entire course of the corticospinal tract rather than limiting the observations to the brainstem (see Figure 5). They found acute DWI signal abnormalities in 10/14 neonates, all with poor neurological outcomes. Of these, 9/10 neonates had brain stem atrophy, or chronic WD and hemiparesis at follow-up.63
Figure 5. Restricted diffusion signal in the descending corticospinal tract in a neonate with stroke. Left middle cerebral artery infarction (A) results in DWI signal changes throughout the corticospinal tract. Posterior limb of the internal capsule and cerebral peduncle involvement are evident on coronal (B) and sagittal images (C). Signal in the basis pontis and medullary pyramids can be seen on left (D) but not right (E) parasagittal sections. Reproduced with permissions, Kirton. et al, 2007.63
In children with stroke beyond the neonatal period, acute DWI signal along the course of the corticospinal tract are known to be correlated with outcome. Abnormal DWI signal was detected in 20/29 children (69%), with 85% having long term motor deficits. Characteristics of the DWI signal that correlated with hemiparesis included: Any abnormal signal within the course of the corticospinal tract, signal in the midbrain, the percentage of the peduncle affected and the relative volume of the corticospinal tract affected (all p<0.003). In addition, it was found the evolution of signal abnormality increased over time and outlasted infarct DWI changes (see Figure 6). Emergence of DWI signal in the cortispinal tract from the time of clinical event can be documented, but descriptions of evolution over time have been limited.72, 74 90 We observed examples of increased signal over time, often without concurrent increase in infarct diffusion signal. This suggests that the cellular processes affecting the diffusion of water in the corticospinal tract are different from those within the infarct itself. Because this signal can become more evident over the subacute timeframe, it may be missed with conventional stroke neuroimaging protocols when re-imaging with DWI is not routinely performed after the acute period. In addition, all patients had some degree of chronic asymmetry of the peduncles. Both the acute and chronic neuroimaging findings of WD showed a strong correlation of both with poor motor outcome, this suggests that acute DWI signal in the corticospinal tract and chronic atrophy are different stages of the same WD process.
The ability to reliably identify Wallerian degeneration in the acute phase following injury caused by stroke is highly relevant for prognosticating outcome in pediatric stroke. This body of evidence is of critical importance for families and clinicians because it can be used to select patients for therapeutic interventions. A recent study in the adult stroke population suggests that percent of injury to CST may have utility as an entry criterion in clinical trials of restorative therapies in subacute-chronic stroke because this measure enables study design to identify those patients who have a higher likelihood of achieving clinically important gains.98 With advances in neuroimaging increasing our understanding of neuroplastic reorganization mechanisms in pediatric stroke, and the potential of randomized trials of rehabilitation therapies emerging, prediction of outcome will enhance program selection of patients and improve morbidity and functional motor outcomes.
Wallerian degeneration: an old term only recently validated in pediatric stroke
Acute neuroimaging findings have provided a prognostic marker of outcome in pediatric stroke, but have only recently been validated with histopathological findings. Jones (2012) correlated Wallerian degeneration findings from autopsy specimens with the pre-mortem MRI findings of children exhibiting focal infarcts. Of the seven children included in the study with ischaemic or haemorrhagic infarcts, six had concordant Wallerian degeneration findings on both MRI and post-mortem histopathological examination.76 These results validate the decades of research in pediatric stroke that has characterized the radiographic markers of Wallerian degeneration with histopathology. Together these studies support the neuroimaging findings on conventional MRI to be valid biomarkers of corticospinal tract degeneration in children with stroke.
Future Directions in the Study of Wallerian Degeneration
Degeneration of damaged nerves observed more than 160 years ago by Augustus Waller (Waller, 1850) was long believed to be a passive phenomenon where axons degenerated as a result of death or injury to the neuron. Since then, the field of axon degeneration has progressed, in particular since the discovery of a mouse strain the Wallerian degeneration slow (Wlds) that show resistance to degeneration.99 In this strain, following sciatic nerve transection, the distal axons remained structurally and metabolically intact for up to 2 weeks without physical connection to a cell body. 99, 100 However, its relevance to human disease was limited.
What followed was the discovery of the SARM1 (Sterile Alpha and TIR Motif 1) protein: the first loss-of-function mutation that shows protection against Wallerian degeneration. Deficiency of SARM1 is shown to protect axons robustly following axotomy in vivo and in vitro.101 102 Finding an existing pathway such as this indicates that Wallerian degeneration may have treatable targets. The current understanding of axon degeneration is that it is an active and regulated process similar to apoptosis (or programmed cell death). The key molecular players are currently being identified and their functions are being elucidated (see Loring et al. 2020 and Gerdts et al. 2016 for reviews).103, 104 The future challenge in this field is to leverage these insights to develop therapeutic agents aimed to preserve and restore function in the injured or diseased central nervous system.
Summary
Despite the initial report of WD in 1860, this degenerative process remains current due to the progress that has been made including in vivo neuroimaging markers using conventional MRI, and biochemical insights. The last few decades have revealed a significant association between WD and outcome following stroke in adults, infants and children. Atrophy of the brainstem, a classic neuroimaging marker of WD in the chronic phase is correlated with poor motor outcome in stroke patients. Furthermore, acute neuroimaging markers of WD are predictive of poor motor outcome, providing prognostic information to families and clinicians. However, there is still progress to be made. The current use of advanced neuroimaging techniques such as diffusion tensor and diffusion kurtosis imaging have the potential to reveal information about the process of WD at the microstructural level and the evolution of this active degenerative process. In addition, genetic insights into the mechanisms of WD provide a promising and tangible approach to the improvement of outcome following stroke.
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