Extra-ocular muscle MRI in genetically-defined mitochondrial disease

Abstract

Objectives: Conventional and quantitative MRI was performed in patients with chronic progressive external ophthalmoplegia (CPEO), a common manifestation of mitochondrial disease, to characterise MRI findings in the extra-ocular muscles (EOMs) and investigate whether quantitative MRI provides clinically relevant measures of disease.

Methods: Patients with CPEO due to single mitochondrial DNA deletions were compared with controls. Range of eye movement (ROEM) measurements, peri-orbital 3 T MRI T1-weighted (T1w) and short-tau-inversion-recovery (STIR) images, and T2 relaxation time maps were obtained. Blinded observers graded muscle atrophy and T1w/STIR hyperintensity. Cross-sectional areas and EOM mean T2s were recorded and correlated with clinical parameters.

Results: Nine patients and nine healthy controls were examined. Patients had reduced ROEM (patients 13.3°, controls 49.3°, p < 0.001), greater mean atrophy score and increased T1w hyperintensities. EOM mean cross-sectional area was 43 % of controls and mean T2s were prolonged (patients 75.6 ± 7.0 ms, controls 55.2 ± 4.1 ms, p < 0.001). ROEM correlated negatively with EOM T2 (rho = -0.89, p < 0.01), whilst cross-sectional area failed to correlate with any clinical measures.

Conclusions: MRI demonstrates EOM atrophy, characteristic signal changes and prolonged T2 in CPEO. Correlation between elevated EOM T2 and ROEM impairment represents a potential measure of disease severity that warrants further evaluation.

Key points: Chronic progressive external ophthalmoplegia is a common clinical manifestation of mitochondrial disease. • Existing extra-ocular muscle MRI data in CPEO reports variable radiological findings. MRI confirmed EOM atrophy and characteristic signal changes in CPEO. EOM T2 was significantly elevated in CPEO and correlated negatively with ocular movements. EOM T2 represents a potential quantitative measure of disease severity in CPEO.

Keywords: Chronic progressive external ophthalmoplegia; Kearns-Sayre syndrome; Magnetic resonance imaging; Mitochondrial DNA; Mitochondrial diseases.

Fig. 1

Box plot of control (blue) and patient (green) values in each extra-ocular muscle: range of motion (A), cross-sectional area (B) and T2 relaxation time (C). The box represents 25th – 75th percentiles, the solid line in the box represents the median value, stems are to maximum and minimum values, o = minor outlier; + = major outlier. IO inferior oblique, IR inferior rectus, LR lateral rectus, MR medial rectus, SO superior oblique, SR superior rectus

Fig. 2

MRI of the orbits in the coronal plane displaying a healthy control on the left column (panels A, C, E, G, I) and a patient with chronic progressive external ophthalmoplegia (CPEO) on the right column (panels B, D, F, H, J). Coronal T1-weighted (panels A and B) and corresponding short-tau inversion recovery (STIR, panels C and D) sequences demonstrate T1-weighted hyperintense and STIR-suppressed foci intrinsic to the extra-ocular muscles (EOMs). If the diameter of the focus was approximately equal in all dimensions in the coronal plane it was termed a 'dot’, whilst if unequal it was termed a 'streak’. An example of a ‘dot’ is demonstrated in the right inferior rectus muscle on paired panels A and C, and examples of ‘streaks’ are shown in both lateral recti on paired panels B and D respectively (arrows). Panels E and F demonstrate an example of the regions of interest (ROI) used to calculate the surface area of each of the EOMs within the right orbit in a control volunteer and CPEO patient respectively: superior-rectus levator complex (SR); superior oblique (SO); medial rectus (MR); lateral rectus (LR); and inferior rectus (IR). Central ROI were placed within the same muscles for the T2-relaxometry measurements in order to avoid contamination by the surrounding fat, as demonstrated in panels G and H within the right orbits of a control volunteer and CPEO patient respectively. Panels I and J demonstrate false colour T2-relaxometry maps

Fig. 3

Spearman correlations between clinical and quantitative MRI measures in patients with chronic progressive external ophthalmoplegia (A). A single mean value for each parameter was calculated in each patient for the common regions of interest (superior rectus, inferior rectus, medial rectus and lateral rectus). Range of eye movement (ROEM) correlated with T2 relaxation time. The cross-sectional area did not correlate with either ROEM or disease duration. Scatter plots are shown for T2 versus ROEM (B) and area versus ROEM (C)