Diffusion Tensor Imaging of the Optic Nerve in Subacute Anterior Ischemic Optic Neuropathy at 3T

Discussion

The ON is a simple and well-defined white matter tract emanating from retinal ganglion cells. Although conventional MR imaging has been used to detect ON atrophy and sheath dilation,^11,12 performing in vivo diffusion measurements on the human ON remains very challenging because of its small size, motion, the presence of magnetic field susceptibility artifacts, and high signal intensity from the surrounding orbital fat and CSF.

In DTI, ADC is a widely used parameter that measures the magnitude of diffusion of water molecules within cerebral tissue. FA measures the fraction of the magnitude of diffusivity that can be ascribed to anisotropic diffusion, which is thought to reflect fiber attenuation, axonal diameter, and myelination in white matter. FA is calculated from the 3 eigenvalues (λ₁, λ₂, λ₃) of the diffusion tensor. Of the 3 eigenvalues, the largest is the principal eigenvalue (λ_‖), representing the diffusion coefficient along the principal direction of diffusion parallel to the nerve; the other 2 are the diffusion coefficients orthogonal to the nerve. The average of the 2 orthogonal eigenvalues is expressed as λ_⊥.

Hickman et al⁸ used ZOOM EPI to determine in vivo ADC changes in patients with optic neuritis. Their results showed that the mean ADC of the affected ON correlated with the clinical and electrophysiologic parameters in the chronic ON lesions; their findings suggest that the ADC value is a potential surrogate measure of axonal disruption in the chronic postinflammatory ON lesion. However, DTI parameters, such as FA, are sensitive to the underlying structure of the tissue and are expected to be particularly sensitive to pathologic changes such as edema and myelin loss. Diffusion measurements in animal models and excised tissues have shown the importance of measuring anisotropy, as well as contributions from λ_‖ and λ_⊥, to various pathologies such as axonal and myelin injury.^13–16

A study⁹ of patients with optic neuritis by using the ZOOM DTI technique revealed abnormalities within the ON, consisting of elevation of the mean orthogonal eigenvalue λ_⊥ and MD and reduction of the mean FA in affected nerves compared with clinically unaffected contralateral nerves and control nerves. The mean principal eigenvalue λ_‖ was significantly increased in affected nerves compared with contralateral unaffected nerves but not compared with control nerves. There was a significant correlation of the whole-field VEP amplitude with MD (r = −0.57, P = .006) and λ_⊥ (r = −0.56, P = .007). Their results suggest that ON DTI measurements may provide an indication of the structural integrity of axons. Wheeler-Kingshott et al¹⁷ also used a ZOOM DTI technique in healthy controls and derived the mean FA, λ_‖, and λ_⊥values of the ONs on both sides across 10 healthy volunteers.

The ZOOM technique is not the only one able to evaluate the ON with full diffusion tensor measurements. For example, Koch et al¹⁸ performed DTI by using a single-shot stimulated-echo acquisition mode with center-out phase-encoding, which has the advantage of being less sensitive to susceptibility-induced artifacts, and generated images of the ON on DTI parameter maps such as FA. Chabert et al¹⁹ used another type of acquisition method (non-Care-Purcell-Meiboom-Gill fast spin-echo) and obtained results very similar to those of Wheeler-Kingshott.¹⁷

A conventional DTI protocol was modified by Techavipoo et al²⁰ to acquire images with fat and CSF suppression and field inhomogeneity maps of contiguous coronal sections covering the whole brain. The technique was applied to healthy volunteers and patients with multiple sclerosis with and without a history of unilateral optic neuritis. They found that ON tractography became feasible after distortion correction. The diffusion measurements from the healthy volunteers were in good agreement with the literature. The diffusion measurements before and after geometric distortion correction were not significantly different. Thus a practical DTI protocol was provided to study the human ON.

In our study, a high-field MR imaging scanner (3T) and increased gradient strength (40 mT/m) with a 12-channel head coil were used to improve the signal intensity–to-noise ratio, an SE-EPI DTI sequence with a higher resolution (0.90 × 0.90 × 2 mm³) was applied to decrease partial volume, and 64 directions were used to obtain better diffusion maps of the ONs. The signal intensity from surrounding fat was suppressed by using a selective spectral-spatial pulse (exciting only water) for excitation, to reduce the partial volume effects. Twice-refocused SE together with a bipolar gradient in the EPI sequence was used to reduce eddy currents. Parallel imaging (GRAPPA, IPAT factor = 2) was used to accelerate the image acquisition and reduce distortion. In this method, the mean FA, λ_‖, and λ_⊥ across 15 healthy volunteers were 0.587 ± 0.023 × 10⁻⁶ mm²s⁻¹, 1702 ± 199 × 10⁻⁶ mm²s⁻¹, and 729 ± 130 × 10⁻⁶ mm²s⁻¹, respectively, which were comparable with the results of Techavipoo et al²⁰ (0.48 ± 0.030, 1651 ± 219 × 10⁻⁶ mm²s⁻¹, and 815 ± 113 × 10⁻⁶ mm²s⁻¹, respectively) from the control ONs on the left side. The mean ADC from control nerves was 1008 ± 111 × 10⁻⁶ mm²s⁻¹, which was similar to that of Hickman et al (928 ± 23 × 10⁻⁶ mm²s⁻¹).⁸

The ADC value represents the diffusivity of water molecules. In cerebral ischemia, restriction in water diffusion occurs within minutes of the onset of ischemic injury. The ADC reaches the lowest value within 24 hours and then slowly increases to reach normal values in approximately 7–10 days.²¹ It then increases and remains at supernormal values. This process is explained by the conversion of cytotoxic edema to vasogenic edema and the increased water content of the tissue. Theoretically, the changes of ADC in ION should be similar to those in cerebral ischemia. Al-Shafai and Mikulis²² reported the findings of diffusion-weighted imaging in a patient with acute ION, and their results demonstrated that the ADC value was decreased at day 2 after the patient's acute worsening. However, our study found that ADC increased significantly and FA reduced significantly in affected ONs compared with unaffected contralateral nerves and nerves of healthy controls, because in our study, the time course between onset and imaging of all patients was from 6 to 30 days, during which the ADCs should be normal or increased rather than decreased. These results are in keeping with the expected ADC pattern as seen in ischemic injury to the brain in the same stage. The ADCs may decrease in acute ION as Al-Shafai and Mikulis reported.²²

Future studies on acute ION would be helpful to obtain the temporal evolution of ADCs in ION. The VEP amplitude is believed to reflect the number of ON fibers in functional continuity.²³ The significant correlation of VEP amplitude reduction with ADC increase in the clinically affected eyes suggests that the increased diffusivity is of functional relevance and may reflect axonal disruption or loss and demyelination.

FA is the most widely used measure of anisotropy in DTI. In this study, the mean FA from affected nerves was lower than that from clinically unaffected contralateral nerves and control nerves; this finding most probably reflects vasogenic edema and the increased water content of tissue, cell lysis, and axonal loss of ONs. However, FA does not describe the full tensor shape or distribution because different eigenvalue combinations can generate the same FA values.²⁴ Thus eigenvalues may be more sensitive than FA in quantifying pathology. This difference may explain the finding that the mean FA decreased significantly in affected nerves but did not correlate with whole-field VEP amplitude in this study. Several recent studies have also suggested that the eigenvalue amplitudes or combinations of the eigenvalues (eg, λ_⊥) demonstrate more specific relationships to white matter pathology.²⁵ The mean of the orthogonal eigenvalues, λ_⊥, reflects diffusion orthogonal to the axis of the ON, whereas λ_‖ represents the diffusion coefficient along the principal direction of diffusion parallel to the nerve. In this study, λ_⊥ changed similar to ADC in that it was significantly increased in affected nerves and correlated with whole-field VEP amplitude. However, the principal eigenvalue, λ_‖, was not significantly different among the 3 groups of ONs. These results were similar to those in optic neuritis,¹⁶ and the possible mechanism for this may be that though some axons are lost following optic ischemia, the remaining axons are still aligned in the same direction along the ON, so the λ_‖ is relatively normal.

The current study did not find an association of any DTI parameter with measures of visual function. A previous study by Hickman et al¹¹ used ZOOM EPI to study the optic nerve in 16 patients with optic neuritis at the same 1-year period and found that the ADC of the affected nerve correlated with measures of visual function. However, another study of patients with optic neuritis by Trip et al⁹ by using the ZOOM DTI technique did not find an association of any DTI parameters with measures of visual function, which was consistent with the results of this study. This finding may be explained by the fact that the disease duration in the present study was heterogeneous and DTI measures of ION have different recovery processes compared with optic neuritis. Larger samples of patients with ION with the same disease duration may be helpful in revealing the association of DTI measures with clinical severity, treatment effect, and prognosis. Although there was no correlation between any DTI measures and visual function in the present study, DTI detected the changes of ADC, FA, and λ_⊥ in affected eyes when routine MR imaging findings were normal. Thus DTI measures should be helpful in the diagnosis of ION.

AION typically occurs after 55 years of age, but it can also occur in younger patients. The most important risk factors for developing AION include hypertension, nocturnal hypotension, diabetes mellitus, atherosclerosis, and a small cup in the optic disc. Our results were consistent with the reports.²⁶ In patients younger than 50 years, diabetes mellitus, hypertension, and hypercholesterolemia are associated more strongly with AION than in older individuals.^27,28 In our study, 6 of 26 patients were younger than 50 years. In these 6 patents, 2 had arterial hypertension, 1 had diabetes mellitus, 1 had both arterial hypertension and diabetes mellitus, and 2 had hypercholesterolemia. Therefore, AION should be considered in the differential diagnosis of younger patients with painless optic neuropathy with disc edema at presentation, and these patients require a thorough systemic evaluation for underlying vascular risk factors.

Several limitations of the current study should be addressed. First, to develop a practical protocol with a shorter acquisition time, our approach does not use the CSF suppression technique in DTI of the ON. Because the ON is surrounded by CSF, suppression of CSF signals would purify signals of the ON. Some previous studies have shown that signals from CSF cause underestimation of the diffusion anisotropy measures such as FA.²⁹ However, our measurements of FA, λ_‖, and λ_⊥ were not lower than those in other reports.²⁰ This may be ascribed to a higher b-value (b = 1000 s/mm²) and resolution (0.90 × 0.90 × 2 mm³) with fat suppression to increase the accuracy of measurement, twice-refocused SE with a bipolar gradient in the EPI sequence to reduce eddy currents, and parallel imaging (GRAPPA, IPAT factor = 2) to accelerate the image acquisition and reduce distortion. Second, cardiac gating was not implemented in the current protocol, so the protocol may contain errors from different cardiac cycles. This problem may be alleviated by using high directional resolution of diffusion-weighted directions. However, it seemed that cardiac gating was not necessary for this study because the diffusion-weighted imaging and resultant maps (ADC, FA, and eigenvalues) were of good quality.

In addition, some reports showed that FA values of the brain white matter declined significantly with age in all regions except the splenium.^29,30 The FA values of the ON may also have similar changes with age in brain white matter. These changes would be expected to have some effect on the measurements. However, because we enrolled age- and sex-matched controls, this factor should have a similar effect on both groups and would be unlikely to affect the overall result. Because our protocol has a reasonable acquisition time, which was only 5 minutes 42 seconds, and the entire brain was scanned at the same time, it should be a practical one for the DTI study of the human ON and other parts of the brain without additional scans.