White Matter Tract Pathology in Pediatric Anoxic Brain Injury from Drowning

Discussion

White matter microstructural abnormalities in children with ABI from drowning were found to largely implicate deep, central white matter regions. Focal differences in fractional anisotropy were detected in the bilateral PLICs and the splenium of the corpus callosum. Focal differences in mean diffusivity were detected in the bilateral superior corona radiata, internal capsules, and external capsules. Regions of the white matter skeleton demonstrating significant abnormalities in both diffusion metrics were thus within the internal capsules and specifically in the posterior limbs. In individual subjects, FA and MD values from both the PLICs and CSTs highly correlated with corresponding motor function scores, but the PLICs were generally more robust as ROIs.

DTI is a powerful, highly clinically relevant, and readily available method for detecting microscopic changes in tissue architecture. Disruption or loss of white matter structural integrity most often manifests as decreased directionality of diffusion or decreased fractional anisotropy, and increased water mobility or increased mean diffusivity.¹⁸ Although a single DTI index (ie, FA) can be a sensitive biomarker for neuropathology, the use of multiple diffusion indices and knowledge of the underlying disease mechanism mitigate its relatively low specificity.^18,19

In pediatric drowning, there is limited knowledge of the extent of brain injury from anoxia, especially in white matter. ABI or hypoxic-ischemic brain injury is most often thought to selectively target gray matter due to its increased metabolic demands and higher concentrations of excitatory neurotransmitter receptors.^4,20 White matter involvement has been much more variable in most anoxic etiologies.²⁰ Despite the important role of structural neuroimaging in the clinical management of children with ABI, its utility in exposing consistent damage across patients and identifying potential prognostic markers has been stunted by heavy reliance on visual inspection (of usually subtle/nonspecific pathology) and a lack of quantitative, group-wise analyses. Diffusion MR imaging is the most sensitive of the structural imaging modalities for detection of ABI. It could especially benefit from more rigorous analysis to better localize injury and ascertain prognostic and therapeutic correlates.²⁰

Our previous voxel-based morphometric analyses in this cohort demonstrated gray and white matter loss in children with ABI that was highly convergent on central subcortical regions, chiefly comprising the basal ganglia nuclei and the PLICs and extending to the thalamus, superior corona radiata, and external capsules.⁶ This topography implicates the distribution of the perforating lenticulostriate arteries, an end-arterial system, and thus suggests an important vascular component to the pathophysiology of pediatric drowning.

The present analysis of TBSS in diffusion MR imaging data entirely supports our white matter voxel-based morphometry findings. In children with ABI, the most affected regions—with reduced FA, increased MD, and the highest average t-statistic values—were within the bilateral PLICs. This data-driven analysis independently confirms the pathology of the PLICs by using the imaging technique/pulse sequence (DTI) and analytic tool (TBSS) most suited and standardized for the study of white matter structures.⁷ Infarct of the lenticulostriate arteries, from cardiovascular dysfunction and systemic hypotension, thus needs to be seriously considered as a factor in the pathophysiology of pediatric drowning due to the corresponding distribution of tissue damage. Alternatively, however, the white matter tissue loss and microstructural disturbances we have observed could be secondary degeneration to predominant injury in the basal ganglia (ie, gray matter) from the hypoxic-ischemic insult. Primary-versus-secondary axonal damage could be differentiated with acute and longitudinal imaging. Primary white matter injury would be appreciated with DWI acutely. Secondary white matter injury would be appreciable after a delay period, likely in the subacute phase, following the process of gray matter damage. This distinction is not possible in the present cohort with chronic hypoxic-ischemic brain injury.

Regardless of the causality of the observed tissue-pathology distribution, the involvement of motor-system components is distinctly striking. The basal ganglia nuclei are integral in motor-information transmission and voluntary movement, and the PLICs largely comprise corticospinal tract fibers carrying motor information from the primary motor cortex to the spinal cord.^6,21 Most important, the prevalent insult to cerebral motor networks reported here is concordant with motor impairment characteristically observed both in the pediatric drowning patient population and in our patient cohort. The ages of children at highest risk for drowning (1–4 years; 2.4-year average in our cohort) may explain these observations to some extent. The maturation of areas serving motor (and sensory) functions is thought to precede that of brain regions underlying higher cognitive functions.²² Thus, younger children (ie, as in this population) may sustain less direct injury to higher order cerebral networks, which remain relatively immature, and greater damage to the more “primitive” and developed motor networks. Nonetheless, the relative sparing of other cerebral networks raises the possibility that these children retain substantial cognitive, perceptual, and emotional capabilities and that they are unable to effectively convey this functional integrity due to motor-system damage. Further examination of this hypothesis with functional neuroimaging methods is strongly indicated.

In addition to localizing the most consistent pathology in drowning-related pediatric ABI and characterizing the functional correlates group-wise, we report extremely high correlations of imaging metrics with motor function at the individual-subject level. Furthermore, with FA and MD values from right and left PLIC ROIs (derived from FA TBSS analysis) and subjects' motor function scores, complete dissociation of subjects in the patient and control groups was possible. This was most effectively conducted in FA data (Fig 2). Evaluation of FA and/or MD values by using PLIC ROIs may help prognosticate and monitor therapeutic effects in children recovering from drowning. This would be especially powerful because each subject could serve as his or her own baseline reference, and longitudinal changes in white matter microstructure could be evaluated for response with time and to interventions. In a perinatal anoxia study, TBSS and diffusion metrics in internal capsule ROIs were indeed able to detect the therapeutic efficacy of hypothermia in infants with neonatal encephalopathy.²³ In another study of patients with chronic stroke, FA measurements in the corticospinal tracts correlated with the potential for motor functional recovery.²⁴ Such analyses would also be feasible and potentially quite useful in the patient population herein described.

To assess the specificity of injury in this cohort, ROI analyses were also implemented in the corticospinal tracts. CST ROIs were derived from a white matter atlas and subjected to the same analysis as the PLIC ROIs. Although high correlations with motor function scores were also measured by using the CSTs, they were not as effective in delineating patient and control subjects. This finding is not surprising considering the origin of the ROIs: The PLIC regions used in the correlation analysis represent the most significant between-group differences in FA (and MD), while the CST regions encompass proximal and distal areas as well. The presence (or relative greater quantity) of crossing fibers in the CST ROIs may also, in part, contribute to this disparity. Injury in pediatric ABI from drowning, nevertheless, does appear to be most specific to the PLICs.

Several future directions are important. Probabilistic diffusion tractography studies are indicated and quite well-informed by the findings reported here. Probabilistic tractography can be implemented at the per-subject level to obtain connectivity indices reflecting intact fiber organization.²⁵ Although the typical method entails seed-to-target connectivity measurements across a tract (ie, the entire CST), our results suggest that it would be more powerful to measure connectivity across the PLICs. Our findings also prompt future clinical applications in targeted MR spectroscopy and endovascular therapies to the lenticulostriate arteries via the middle and/or anterior cerebral arteries, as described in Ishaque et al.⁶ Further testing is warranted via treatment trails in an anoxic brain injury model in nonhuman primates.

This study has limitations. Diffusion-weighted MR imaging is known to be extremely sensitive to subject motion, eddy currents, and magnetic field inhomogeneities.¹⁸ Additionally, we were rather stringent with data inclusion to ensure quantitative analysis of high-quality data. This accordingly resulted in the exclusion of 3 control and 6 ABI datasets, either due to excessive motion in the first instance or inadequate registration within the TBSS analysis thereafter. Thus, we acknowledge that our findings are from a small sample size. Diffusion MR imaging data acquisition would likely benefit from increased sedation of pediatric subjects. We emphasize, however, that substantial (and focal) between-group differences were nevertheless observed at quite high statistical significance levels. We are thereby confident that our findings reflect underlying disease-specific white matter pathology. Nevertheless, we interpret our results as specific to pediatric ABI from drowning and recognize that they may not generalize to other anoxic etiologies or age groups. For clinical purposes, the group-wise study design we use is also a limitation. An alternative for future exploration would be per-subject probabilistic tractography, as discussed above. The most promising method as we see it would involve tractography of the PLICs.