Retinal crystals may be present in a wide range of disorders from hereditary to drug-induced, from systemic to local retinal.15, 16
In type 2 MacTel, retinal crystals have some distinguishing characteristics.1, 2, 4, 5
In our study, retinal crystals were present in 46% of 443 MacTel patients at baseline, and nearly two thirds of these cases were bilateral. Crystals appeared highly reflective at wavelengths ranging from 488nm (blue) to 820nm (IR). In infrared images, typically only a subset of crystals seen in BLR or RF images were detectable. Considering the confocal characteristics of the SLO, this may simply be due to a tilt of the retina relative to the focal plane. The crystals also exhibited specular reflection such that multiple frames of the same retinal area taken at slightly different angles showed a variation in the number and location of the crystals. As a rule, more crystals are likely to be present in the retina than those detectable in any single fundus image.
Retinal crystals in MacTel are typically distributed in an annular pattern within an approximately 4000µm diameter circular area centred on the fovea, with a sparing of the central approximately 700µm. A gap in this annular pattern was seen temporal
of the fovea, corresponding to the horizontal raphe. This is remarkable as many other signs of the disease appear first or occur predominantly in this region.
Within this annular area, the crystals were arranged along the ganglion cell axons in the NFL. To our knowledge, this pattern of crystals is only seen in MacTel and in Sjögren-Larsson Syndrome (SLS).17, 18
At late stages of MacTel, the distortion of the retina due to vascular remodelling, fibrosis and pigment plaques may break up this pattern. In some late-stage eyes, only a few crystals were apparent surrounding the pigment plaques or fibrotic post-neovascular scars. This pattern has been reported also in other neovascular conditions and is thus probably not specific for MacTel.19
The retinal area affected by crystals coincides closely with that affected by other features of the disease. A circumfoveal band of increased reflectivity seen in CBR images, the loss of retinal transparency in CF and RF images, the loss of macular pigment and fluorescein leakage all seem to affect this region. Also, in our study, the amount of crystals showed statistically significant associations with the loss of retinal transparency, a loss of MPOD and with fluorescein leakage.
The implications of these observations are not known, however, they may suggest further Müller cell involvement in the pathogenesis of type 2 MacTel. Müller cells are radially oriented support cells traversing the retina from the inner vitreal border (ILM) to the distal end of the outer nuclear layer. They have an extended funnel shape, a higher refractive index than their surrounding tissue, and are oriented along the direction of light propagation. Müller cells have been shown to act as optical fibres within the retina.20
A disruption of their structure may explain a loss of retinal transparency even without significant oedema. In our study, retinal crystals did however also show a statistically significant association with a minimal level of retinal thickening in all subfields.
The cell processes of Müller cells enclose regions of the perikarya and fascicles of axons of the ganglion cells, within the NFL, processes from their footplates surround the nerve fibres bundles.21
In our study, high-resolution retinal images obtained using adaptive optics confirmed our findings based on stereoscopic fundus images and SD-OCT imaging, crystals seem to be located superficially within the NFL, in close proximity of the nerve fibres. Individual ganglion cell axon diameters vary in the range of 0.6–2.0µm depending on the type of ganglion cell of their origin. Midget ganglion cells with thinner axons are found more frequently within the macular area.22
We estimate the size of individual crystals to approximately 5µm or larger, this together with their often confluent distribution suggests that crystals are more likely to be located around the nerve fibre bundles, possibly within Müller cell foot-plates, rather than within individual axons. A similar conclusion was drawn in the case of tamoxifen crystals, and other crystals such as canthaxanthine and beta carotene also form in the innermost retina.
Müller cells play a role in retinoid metabolism including cone pigment regeneration and they show avid phagocytic activity.21
While the origin and chemical composition of the crystals are not known, based on their distribution and reflective properties, we hypothesize that they may be composed of retinoids originating in the visual cycle and be located within the Müller cell footplates and processes surrounding the nerve fibres. We also found a significant association between the amount of crystals and the presence of a break in the IS/OS junction line which may further support this hypothesis. Significant associations with increased retinoid intake via the diet or by supplementation were however not demonstrable in our study.
We found an association between the amount of crystals and fluorescein leakage. Macular pigment loss was also associated with the amount of retinal crystals in our study. Müller cells extend branches that interdigitate with retinal neurons and glial cells and their processes ensheath the retinal capillaries and may contribute to the blood-retina barrier.21
The role of Müller cells in the metabolism of macular pigment is not clear, however, in a histological study of a MacTel eye, Powner et al.23
found a depletion of Müller cells as well as vascular abnormalities within an area of the same extent as the loss of macular pigment. The distribution and associations of retinal crystals found in our study thus further implicate Müller cells in the pathogenesis of MacTel.
The reflective properties of the crystals are compatible with those of retinoids but also with those of lipids. Retinal crystals arranged along the nerve fibres, central cystoid spaces and a loss of luteal pigment seen in MacTel are also the ocular manifestations of SLS, which raises the possibility of similarities in the metabolic pathways responsible for the pathogenesis of the two diseases. SLS is an autosomal dominant hereditary systemic metabolic disorder characterized by deficient microsomal fatty aldehyde dehydrogenase (FALDH) activity, resulting in an accumulation of fatty aldehydes and alcohols in body tissues. SLS is however also associated with severe extraocular manifestations including cognitive deficiencies, spastic diplegia, and congenital ichtyosis.17, 18
Further insight into the physical and chemical properties of retinal crystals in MacTel may provide clues to the metabolic pathways involved in the pathogenesis of the disease.