ME is a group of cellular respiratory chain and energy metabolism disorders caused by deletions or mutations of mitochondrial DNA. CPEO is one of the representative disease types. Skeletal muscle and nerve tissue are highly aerobic tissues in the human body that are prone to be affected by CPEO. Specifically for the eye, the extraocular muscles (including the levator palpebrae muscle) and the retina are easily involved. The involvement of the extraocular muscles manifests as symptoms such as ptosis and paralysis of the external ophthalmoplegia, which can easily catch the patient's attention and become the most common complaint and the first symptom of the disease. The changes in the structure of the retina and optic nerve head are generally not considered to be the clinical features of CPEO and are therefore frequently ignored.
In fact, retinal changes are common signs of mitochondrial diseases affecting the eye. In the existing literature, retinal pigmentation was the only signs found in some CPEO patients. Till now, structural changes in ocular fundus of CPEO patients has not yet been reported. The observation of changes in the structure of the retina requires more accurate examination methods. The development of SD-OCT equipment provides us with such an opportunity to observe the fine structure of the ocular fundus.
We performed OCT scans in 18 patients with mitochondrial disease with extraocular ophthalmoplegia as the main manifestation. Healthy individuals matched for gender, age, and diopter-level group served as the controls to measure and compare the parameters of macula and optic nerve head morphology. The results showed significant changes in these parameters.
The common diseases that result in decreased pRNFLT are ophthalmic diseases, including open-angle glaucoma and myopia. The pattern of RNFL loss in open-angle glaucoma corresponds to the changes of optic nerve head rim, and the most frequently affected areas are the inferior and superior temporal areas, which is related to stress-induced retinal ganglion cell apoptosis. Myopia, with the increase in refraction, can cause RNFL thinning in the nasal sector as well as the inferior and superior sectors. This change was positively correlated with the patient's equivalent spherical refraction and was more pronounced in the cases with moderate–severe myopia. Age and gender are also the influence factors of pRNFLT. It had been reported that the pRNFLT decreases with normal aging and male sex is a significant predictor of increased foveal thickness. Therefore, in addition to the exclusion of eye diseases, age, gender, and diopter degree also should be considered well in the selection of comparative individuals.
For the parameters provided by OCT that are accurate to detect various changes of retina and optical nerve head, this technique has also been applied in several areas in neurology in the last decade. Some neurodegenerative diseases such as Alzheimer disease (AD),[16–19] cognitive impairment,[20,21] dementia,[19,22,23] and Parkinson disease (PD) [24,25] are all found to affect the ocular fundus structure. AD is the most frequent neurodegenerative disease. Although foveal thickness is not considered a useful parameter to detect the atrophy, reduction of IRL, including ganglion cell layer and inner plexiform layer, was observed in the patients of AD. Moreover, the damage of IRL is associated with disease duration and severity. Patients with AD also presented a reduction of pRNFLT, especially in inferior sectors, which were suggested as the earliest sign of AD. PD is another common neurodegenerative disorder, and the macular retinal thickness, especially the IRLT, was found to be reduced in the perifoveal area of PD patients compared to healthy individuals. General pRNFLT, especially in temporal sectors, was affected by PD and reduced significantly. There is a correlation between these ocular findings and the severity of the disease and there OCT parameters were considered as biomarkers of such neurodegenerative diseases. In our study, we found that CPEO, a kind of mitochondrial disease, also had a significant reduction in macular and RNFL.
Unlike these neurodegenerative diseases, in which the loss of the RNFL is more significant in the superior[16,24,29] and temporal sector, the RNFL defect of CPEO is more significant in the inferior sector, followed by temporal sector. Due to the highest density of nerve fibers in the inferior–temporal sectors, the thickness of RNFL may be more affected by degeneration. RNFL thinning of temporal sector was also affected by the damage of photoreceptors at macula and the papillomacular bundle, which was the reason of RTm thinning. Additionally, the thinner layer in retinal thickness of neurodegenerative diseases was IRL, but in CPEO was ORL. The inner retina is comprised of ganglion cell and axon and the outer retina is mainly the cell bodies of the photoreceptor cells. The damages of IRL presented a degenerative disorder of nerve fiber, whereas the reduction of the ORL thickness was mainly caused by the hypogenesis of the photoreceptor cell. Such difference reflects the difference in the effect of these two types of diseases, mitochondrial disease and degenerative disease, on the nerve fiber layer. We suggest that the retinal thickness measured by OCT may be a helpful parameter for the evaluation of mitochondrial disease such as CPEO.
There was significant difference in the rim and nerve head volume between the CPEO group and the control group. The decrease of such volume parameters may be resulted by the low quantity of optical never axon, which was caused by hypogenesis of photoreceptors. Lots of mitochondrial diseases may lead a full axonal loss and the optic disk may turn pale and atrophic, whereas the optical head only had a mild volume decrease in CPEO patients and it may be one of the characters of CPEO.
CPEO is a relatively rare disease and we took nearly 5 years to collect these cases. It is difficult to collect the medical data because of the paralysis of the patients’ eye movement. Most of the patients in this study had severe ptosis, and it was difficult to perform a visual field examination. The lack of visual field results did not allow us to determine whether the changes in RNFL thickness resulted in changes in visual function. The sample size was relatively small and there may be some bias in the selection of the samples. These findings in OCT need to be corroborated in a larger cohort.
In further studies, functional changes should be considered to further refine the study design in a larger sample.
This study was supported by a grant of Beijing Municipal Science and Technology Commission (No. Z151100003915126).
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