Synopsis

We report a long-term study of three de novo diagnosed Wilson disease patients with neurological form who repeatedly underwent magnetic resonance imaging and neurological examinations for 2 years after treatment initiation. The quantitative measurement of susceptibility revealed higher values in basal ganglia and thalamus compared to controls which correspond to higher iron accumulation.

Degree of iron load reflected the clinical severity of neurological impairment. Thus, we can suppose that the increase of the brain iron concentration can be a marker of suboptimal response to anti-copper therapy and unfavorable outcome.

Introduction

Wilson disease (WD) is an inherited disorder of copper metabolism that can be divided into neurological and hepatic form. However, in addition to copper disturbances the iron accumulation is also present in the brain of the neurological form of WD and it is not clear, whether brain iron concentration influences the clinical outcome and response to the anti-copper treatment.

We report a long-term study of three de novo diagnosed WD patients who repeatedly underwent magnetic resonance imaging and neurological examinations for 2 years after treatment initiation.

Subjects and Methods

Three males (36.4, 38.7, and 35.8 y/o at a day of the first MRI examination) with genetically confirmed neurological form of WD were examined at baseline and then repeatedly for 20 months after the initiation of de-coppering treatment. Each check-up visit consisted of brain MRI and neurological examinations including the neurologic subscore of Unified Wilson Disease Rating Scale (UWDRS). As a control group 6 age-matched healthy volunteers were examined by the same protocol. All subjects were informed about the study protocol and signed informed consent approved by the local ethical committee.

Quantitative susceptibility mapping (QSM) was performed in addition to the standard MRI examination at 3T MR system (Siemens Trio) with 12-channel birdcage head coil.

QSM maps were reconstructed from a 3D multi gradient recalled echo (GRE) sequence (TR=40 ms; six TEs between 5.22 and 34.64 ms; FA=15°; voxel resolution = 0.8×0.8×2 mm; BW=450 Hz/pixel). Phase images were reconstructed offline using a virtual reference coil approach.¹ QSM maps were reconstructed using Laplacian-based phase unwrapping, V-SHARP and MEDI algorithm.^2-4 Due to motion artifacts, the third and sixth susceptibility measurements of the patient WD2 had to be excluded. Regions of interest (caudate nucleus (CN), putamen (Put), globus pallidus (GP) and thalamus (Th)) were manually segmented using ITK-SNAP software.

Results

No differences had been observed between left and right hemisphere, therefore the QSM values were calculated without lateral discrimination. The baseline and 16-18 months susceptibility together with an actual UWDRS values are shown in Table 1. The time evolutions of susceptibility values and UWDRS score are demonstrated in Figures 1 and 2.

With one exception (putamen values of the patient WD3), increased susceptibility values were found in every region of each patient compared to controls (see Figure 1). Moreover, steep increase in the QSM values in all regions of interest was observable in the patient WD1 that corresponded to the increased UWDRS value. In contrary, the patient WD3 showed stable levels of the iron content within selected regions that were only slightly elevated in comparison to healthy controls.

Discussion

It is known that susceptibility values reflect the iron content in the tissue. In this context we can confirm higher iron accumulation in the studied regions in all our patients compared to the healthy controls.

Our previous longitudinal WD case study showed that profound gradual iron accumulation in the deep grey matter may be associated with brain atrophy and unfavorable outcome.⁵ This observation is complemented with the present results showing that WD patient with gradually increased cerebral iron concentration has more severe disease course compared to patients with stable brain iron content.

Although interactions of a copper and iron metabolism are not fully understood, based on our findings, we may presume that brain iron concentration may reflect inadequate treatment response. However, it is uncertain whether iron alters pharmacological properties of chelating drugs, or directly damages brain tissue by its oxidative character.

Conclusion

Acknowledgements

References

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