Repeatability of quantitative metrics derived from MR diffusion tractography in paediatric patients with epilepsy

Objective:

To quantify the test–retest repeatability of mean diffusivity (MD) and fractional anisotropy (FA) derived from diffusion tensor imaging (DTI) tractography in a cohort of paediatric patients with localization-related epilepsy.

Methods:

30 patients underwent 2 DTI acquisitions repetition time/echo time (ms), 7000/90; flip, 90°; b-value, 1000 s mm⁻²; voxel (mm), 2 × 2 × 2]. Two observers used Diffusion Toolkit and TrackVis (www.trackvis.org) to segment and analyse the following tracts: corpus callosum, corticospinal tracts, arcuate fasciculi, inferior longitudinal fasciculi and inferior fronto-occipital fasciculi. Mean MD and mean FA were calculated for each tract. Each observer independently analysed one of the DTI data sets for every patient.

Results:

Segmentation identified all tracts in all subjects, except the arcuate fasciculus. There was a highly consistent relationship between repeated observations of MD (r = 0.993; p < 0.0001) and FA (r = 0.990; p < 0.0001). For each tract, coefficients of variation ranged from 0.9% to 2.1% for MD and from 1.5% to 2.8% for FA. The 95% confidence limits (CLs) for change ranged from 2.8% to 6% for MD and from 4.3% to 8.6% for FA. For the arcuate fasciculus, Cohen''s κ for agreement between the observers (identifiable vs not identifiable) was 1.0.

Conclusion:

We quantified the repeatability of two commonly utilized scalar metrics derived from DTI tractography. For an individual patient, changes greater than the repeatability coefficient or 95% CLs for change are unlikely to be related to variability in their measurement.

Advances in knowledge:

Reproducibility of these metrics will aid in the design of future studies and might one day be used to guide management in patients with epilepsy.Epilepsy is a common neurological condition defined by recurrent unprovoked seizures that affects 1% of the population, including 1 in 200 children.^1,2 Unlike in adults, developmental lesions predominate as the source of seizures in children; in particular, focal cortical dysplasia is the most common anatomical substrate for intractable epilepsy in the paediatric population.³ A high proportion of epilepsies occurring in the setting of cortical malformations are pharmacoresistant,⁴ highlighting the importance of alternative management strategies. In appropriately selected patients who fail medical management, surgical resection of the dysplastic cortex can be curative. In such cases, pre-operative identification and complete resection of the structural lesion are important prognostic factors.^5,6 Decision making surrounding the pursuit of invasive alternatives is rarely straightforward, however, and in practice relies heavily on supplementary information provided by novel diagnostic techniques.Although surgical management is an attractive option for many patients with focal seizures, medical therapy continues to be adopted as the “safe” strategy in a significant portion of this population. However, there is good evidence to suggest that ongoing seizures and treatment with antiseizure medication might be associated with progressive alterations in white matter integrity.^7–9 Furthermore, these same ongoing processes can contribute to progressive functional decline.^10,11 As such, the ability to confidently identify progression of network alterations in an individual patient with epilepsy, whether on the basis of ongoing seizure activity, antiseizure medication or both, would be of great value to informed decision making surrounding potential surgical intervention.With the advent of diffusion-weighted imaging (DWI), the microstructural properties of a tissue of interest can be non-invasively probed at a spatial scale that is otherwise unattainable using even the most advanced structural MR techniques. Diffusion tensor imaging (DTI) is a variation on the theme of DWI, which quantifies water motion in three orthogonal dimensions and, therefore, is better able to capture the anisotropic tendencies of diffusion in highly organized tissues, such as cerebral white matter.¹² Numerous scalar metrics can be derived from the tensor; the most commonly referenced are mean diffusivity (MD) and fractional anisotropy (FA). MD provides a measure of overall incoherent motion within a voxel without regard for direction and reflects tissue organization at the cellular level.¹³ Increased MD is a common manifestation of white matter pathology of diverse aetiology.^14–16 By contrast, FA provides a measure of the degree to which a single direction of water motion dominates overall diffusivity in a voxel. As such, FA has been shown to be a relatively robust measure of white matter integrity.^17–21 Diffusion tractography is an extension of DTI in which the directional tendencies of water diffusion are used to create three-dimensional representations of white matter tracts based on their structural coherence.^22,23 In many instances, the functional role of the constructed pathways is at least in part known, which enables assessment of brain parenchymal abnormalities in terms of functional systems.^16,24DTI and diffusion tractography already occupy a prominent place in epilepsy research, and they are increasingly used to guide clinical management of epilepsy patients.^7,25–30 Although preliminary results are promising, a thorough understanding of the test–retest reproducibility of metrics derived from DTI will be crucial to the widespread application of this technique. Such knowledge would inform the design of both cross-sectional and longitudinal studies, including appropriate sample size selection. Furthermore, the clinical utility of such quantitative techniques will be predicated on an understanding of their intrinsic variability at the level of the individual. In particular, an understanding of what represents true difference at the individual level will be required to ascribe significance to changes in these metrics that occur in an individual patient. To date, however, the reproducibility of quantitative metrics derived from tractography has not been widely studied and, in particular, there are very few data from either the paediatric or epilepsy populations.³¹ The goal of this study, therefore, was to measure the repeatability of MD and FA derived from DTI tractography in a cohort of paediatric patients with localization-related epilepsy.