Optical Coherence Tomography Findings in Chronic Progressive External Ophthalmoplegia
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial encephalomyopathy characterized by ptosis and paralysis of extraocular muscles, often accompanied by multisystem involvement. As a disorder linked to mitochondrial DNA abnormalities, CPEO primarily affects tissues with high oxidative demands, such as skeletal muscles and neural structures. While ocular motility deficits are well-documented in CPEO, structural changes in the retina and optic nerve head remain understudied. This study utilized spectral-domain optical coherence tomography (SD-OCT) to quantitatively evaluate retinal and optic nerve head alterations in CPEO patients, comparing findings with healthy controls and exploring correlations with disease duration and age of onset.
CPEO arises from mitochondrial dysfunction, leading to impaired oxidative phosphorylation and energy production. Pathologically, muscle biopsies reveal ragged-red fibers and cytochrome oxidase-negative fibers. Genetic analyses often identify mitochondrial DNA deletions. Beyond myopathic features, retinal involvement has been sporadically reported in CPEO variants like Kearns-Sayre syndrome, which combines ophthalmoplegia with retinitis pigmentosa and cardiac conduction defects. However, quantitative assessments of retinal architecture in CPEO are scarce. SD-OCT, a non-invasive imaging modality with micron-level resolution, enables precise measurement of retinal layer thickness and optic nerve head parameters, offering insights into neurodegenerative processes.
The study enrolled 18 CPEO patients diagnosed through muscle biopsy and genetic testing, excluding individuals with confounding ocular pathologies like glaucoma or macular degeneration. Age-, sex-, and refractive error-matched healthy volunteers served as controls. Refractive errors were categorized into four groups: normal (spherical equivalent −0.50 to +0.50 D), mild myopia (−0.50 to −3.00 D), moderate myopia (−3.00 to −6.00 D), and severe myopia (>−6.00 D). All participants underwent comprehensive ophthalmic examinations, including SD-OCT scans (RTVue-100, Optovue Inc.) of the macula and optic nerve head.
Macular imaging employed the Macular Thickness Map protocol, measuring retinal thickness at the central fovea (RTm) and average perifoveal thickness within a 6×6 mm grid. The retina was segmented into inner retinal layers (IRL), spanning from the vitreoretinal interface to the outer plexiform layer, and outer retinal layers (ORL), extending to the photoreceptor outer segments. Optic nerve head analysis used the Nerve Head Circle protocol, quantifying six parameters: disc area, cup area, rim area, rim volume, nerve head volume, and cup volume. Peripapillary retinal nerve fiber layer thickness (pRNFLT) was measured globally and across eight sectors (superior temporal, temporal upper, temporal lower, inferior temporal, inferior nasal, nasal lower, nasal upper, superior nasal).
CPEO patients (mean age 32.9±11.4 years) exhibited significant retinal thinning compared to controls (31.0±12.3 years). The macular central fovea (RTm) measured 222.33±29.57 μm in CPEO versus 240.06±18.43 μm in controls (t=−2.135, P<0.05). Outer retinal layer thickness (ORL) showed greater reduction (162.61±21.34 μm vs. 173.56±9.31 μm; t=−1.994, P<0.05), while inner retinal layer (IRL) differences were nonsignificant (63.06±17.87 μm vs. 65.78±9.72 μm; t=−0.565, P=0.57). These findings suggest selective vulnerability of photoreceptor-rich outer retinal layers in CPEO, contrasting with inner retinal changes typical of neurodegenerative disorders like Alzheimer’s disease.
Optic nerve head analysis revealed distinct volumetric changes in CPEO. Rim volume (0.125±0.075 mm³ vs. 0.216±0.105 mm³; t=−2.499, P<0.05) and nerve head volume (0.248±0.124 mm³ vs. 0.367±0.159 mm³; t=−2.103, P<0.05) were significantly reduced, while disc area, cup area, and rim area remained comparable. The diminished volumes likely reflect axonal loss secondary to retinal ganglion cell degeneration.
Global pRNFLT was markedly thinner in CPEO (100.99±10.61 μm vs. 114.85±9.53 μm; t=−4.125, P<0.05). Sectoral analysis highlighted pronounced thinning in the inferior temporal (140.27±18.68 μm vs. 168.16±20.32 μm; t=−4.871, P<0.05) and temporal regions (temporal upper: 82.16±14.33 μm vs. 96.38±18.95 μm; t=−2.126, P<0.05; temporal lower: 74.38±13.97 μm vs. 90.41±20.25 μm; t=−2.892, P<0.05). The inferior nasal sector also showed significant reduction (118.11±20.10 μm vs. 133.64±17.11 μm; t=−2.722, P<0.05). These patterns differ from glaucoma-related RNFL loss, which preferentially affects superior and inferior regions, and myopia-associated thinning, which impacts nasal sectors.
Disease duration strongly correlated with pRNFLT decline (r=−0.583, P<0.05). Longitudinal data indicated that temporal lower (r=−0.463), inferior temporal (r=−0.491), and superior nasal (r=−0.523) sectors deteriorated most rapidly over time. No association was found between OCT parameters and age of onset, suggesting that disease progression—not chronological aging—drives structural decline.
These results position SD-OCT as a sensitive tool for detecting CPEO-related neuroretinal degeneration. The outer retinal thinning contrasts with inner retinal atrophy seen in Alzheimer’s and Parkinson’s diseases, underscoring distinct mechanisms of mitochondrial versus neurodegenerative pathologies. In Alzheimer’s, inner retinal layer loss correlates with cognitive decline, while Parkinson’s preferentially reduces temporal RNFL. CPEO’s predilection for inferior and temporal sectors may reflect heightened metabolic demands in papillomacular bundles or selective vulnerability of large-diameter axons.
Study limitations include the small sample size (n=18) and lack of functional correlation with visual fields or electroretinography. Severe ptosis in CPEO patients hindered reliable visual field testing, precluding assessment of structure-function relationships. Future studies should integrate multimodal imaging, genetic subtyping, and longitudinal follow-up to elucidate progression patterns and therapeutic endpoints.
In conclusion, SD-OCT reveals characteristic retinal and optic nerve head changes in CPEO, including outer retinal thinning, reduced nerve head volumes, and inferior-temporal RNFL loss. These findings advance understanding of mitochondrial disorders’ ocular manifestations and establish OCT biomarkers for disease monitoring. The inverse correlation between pRNFLT and disease duration highlights the potential for OCT to track progression and evaluate interventions in CPEO.
doi.org/10.1097/CM9.0000000000000262
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