Optic nerve diffusion tensor imaging in optic neuritis
Introduction
Diffusion is the random motion of molecules in any fluid system including biological tissue. Diffusion-weighted magnetic resonance imaging (DW-MRI) refers to the process of making magnetic resonance imaging (MRI) sensitive to the molecular motion of water molecules, allowing the Apparent Diffusion Coefficient (ADC) to be measured in one or more directions (Wheeler-Kingshott et al., 2004). This is potentially a useful technique for studying white matter structure, as white matter tracts in the central nervous system consist of bundles of axons usually orientated in the same direction. Water diffusion can occur in any direction but occurs preferentially parallel to the orientation of axons (Takahashi et al., 2000) because their cell membranes and other oriented micro-structures act as barriers to diffusion (Von Meerwall and Fergusson, 1981). Such diffusion is said to be anisotropic and is dependent on the structural integrity of white matter tracts. Diffusion tensor magnetic resonance imaging (DT-MRI) is an extension of DW-MRI in which 6 or more measurements probe diffusion in different directions and is one method by which the diffusion tensor (DT) – a complete description of diffusion in three dimensions – is calculated. Any disruption to white matter tracts or change in axonal membrane permeability would be expected to change DT indices (Horsfield and Jones, 2002, Ford et al., 1998), and in particular to lead to an increase in the mean diffusivity (MD), a measure of average molecular motion, and also to a decrease in fractional anisotropy (FA), a measure of the preponderance of diffusion direction (Basser et al., 1994).
Multiple sclerosis (MS) is a common central nervous system (CNS) disease characterised pathologically by development of multifocal inflammatory demyelinating white matter lesions. It often results in major neurological disability and current disease modifying treatments have limited efficacy. The pathophysiological mechanisms of disease evolution are only partly understood and the use of MR techniques to study the evolution of lesions in vivo is an important tool for obtaining better insights in to such mechanisms. DW-MRI and DT-MRI have supplemented standard MR techniques for studying pathology in vivo. Studies in MS have shown increased ADC and MD with decreased FA in chronic T1-hypointense lesions compared to T1-isointense lesions which is compatible with evidence that T1-hypointense lesions represent more extensive tissue loss (Barkhof et al., 2000, Filippi and Inglese, 2001). FA is lower in acute, gadolinium-enhancing lesions compared to non-enhancing lesions, probably because extracellular oedema alters the anisotropic pattern of diffusion (Werring et al., 1999, Filippi and Inglese, 2001). ADC and MD values are elevated, but the extent may depend upon the lesion age (Werring et al., 1999, Roychowdhury et al., 2000).
Optic neuritis is a common manifestation in MS, and its study offers special opportunities to explore the pathophysiology of individual inflammatory demyelinating CNS lesions. This is because the optic nerve is a discrete anatomical structure, the function of which can be more reliably assessed by quantitative clinical and electrophysiological measures than is possible for other CNS pathways, e.g. motor function. The lesion of optic neuritis can also be clearly identified with MRI provided that fat-saturation methods are used (Gass et al., 1996). As the optic nerve is almost a pure white matter tract, it should lend itself to study with DT-MRI.
There are, however, particular challenges associated with in vivo imaging of the optic nerve with MRI (Barker, 2000), and especially with DW-MRI/DT-MRI (Barker, 2001). The optic nerves are small, mobile structures surrounded by CSF and orbital fat. High resolution CSF and fat-saturated techniques are desirable particularly as these minimise the effects of partial volume in quantitative imaging. DW-MRI is sensitised to microscopic motion of water molecules, but this raises additional problems as it is extremely sensitive to macroscopic motion to which the optic nerves are susceptible due to eye movement. Furthermore, the high resolution needed to image small structures such as the optic nerve results in low MR signal-to-noise ratio (SNR) which needs special attention during image processing and analysis. Until recently, attempts at DW-MRI of the optic nerve have been restricted to measuring the ADC along a limited number of diffusion directions (Iwasawa et al., 1997, Freeman et al., 1998, Wheeler-Kingshott et al., 2002a, Hickman et al., 2005) and have therefore not obtained the full DT which can provide rotationally invariant indices including MD, FA, and diffusion eigenvalues. A CSF- and fat-suppressed zonal oblique multislice echoplanar imaging (ZOOM-EPI) sequence (Wheeler-Kingshott et al., 2002a) has recently been developed further in the optic nerve by increasing the number of diffusion directions from three to six, thus allowing full DT analysis and the calculation of MD and FA in healthy volunteers (Wheeler-Kingshott et al., 2004). In the current study, we present the results of DT-MRI in a cohort of patients who had a previous episode of unilateral optic neuritis and compare the findings with those obtained in healthy controls. The aims of the study were to investigate if the rotationally invariant indices produced by the DT were different in nerves affected by optic neuritis, and whether any changes were related to measures of visual function and/or electrophysiological markers of optic nerve function.
Section snippets
Subjects
Twenty-five patients with a single previous attack of acute unilateral optic neuritis and no recurrence were recruited from the case records of the Neuro-ophthalmology clinic, Moorfields Eye Hospital, London. In all patients, appropriate investigations had been made to exclude an alternative aetiology to the optic neuropathy. In order to study a range of visual deficits, there was a deliberate selection bias towards those with incomplete visual recovery. Patient demographic data are summarised
Clinical data of patients
Table 1 summarises patient demographics including range of visual function.
Electrophysiology data
Table 2 presents the electrophysiology data. In affected eyes, there was no correlation of visual acuity with electrophysiological measures but the visual field mean deviation correlated with the whole field (r = 0.46, P = 0.03) and central field (r = 0.46, P = 0.03) VEP amplitudes, and colour vision (√FM 100-Hue score) was correlated with whole field VEP (r = −0.49, P = 0.02), central field VEP (r = −0.69, P < 0.001),
Discussion
Using a ZOOM-EPI technique that was specifically developed for investigating the optic nerve, it was possible to measure the full DT in the optic nerves of controls and patients with previous unilateral optic neuritis in clinically acceptable scan times, with fat- and CSF-suppression to minimise partial volume effects. This was achieved by increasing the number of diffusion directions from three (sufficient for ADC measurement only) to six, and by using a high number of averages for each
Acknowledgments
The NMR Research Unit is supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland. We thank Dr. Simon Hickman for helpful comments.
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