The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis

Abstract

Background: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex.

Methods: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed.

Results: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 μm (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 µm (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients.

Conclusion: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.

Keywords: alpha-synuclein; ganglion cell layer; multiple system atrophy; optical coherence tomography; retina; retinal nerve fiber layer.

Figure 1

Anatomy of retinal layers as described by Ramón y Cajal (9), Spanish neuroscientist pioneer in the investigation of the microscopy structure of the nervous system, including the retina, and Nobel Prize Awardee (1906). There are three layers of cells connected vertically (photoreceptors, bipolar cells, and ganglion cells) and horizontal interneurons modulating the signal conduction at two levels: horizontal cells in the conduction between photoreceptors (rods and cones) and bipolar cells in the outer plexiform layer, and amacrine cells between bipolar cells and ganglion cells in the inner plexiform layer. Large ganglion cells [retinal ganglion cells (RGC) projecting to the magnocellular pathway, M-cells] are specialized in motion detection and low spatial frequency achromatic contrast sensitivity. Smaller RGC with thinner axons (RGC projecting to the parvocellular pathway, P-cells) are concentrated in the central retina (macula), and they are responsible for visual acuity, color discrimination, and high spatial frequency chromatic/achromatic contrast sensitivity.

Figure 2

Flowchart of study selection for the meta-analysis.

Figure 3

Forest plots showing the pooled difference in the average thickness of the retinal nerve fiber layer in global and specific quadrants of multiple system atrophy (MSA) versus controls.

Figure 4

Retinal abnormalities in MSA. (A1) Based on their morphology, functions, and projections to specific layers of LGN, there are three main types of ganglion cells in the retina: (1) parasol cells or M-cells (represented in red) (10%): their cell bodies are predominantly located in the peripheral retina, and their axons project through RNFL to sup, nas, and info sectors of the ON head, ultimately reaching the magnocellular layers of the LGN; M-cells are responsible for movement discrimination and low-frequency contrast sensitivity; (2) midget ganglion cells, or P-cells (represented in green) (80%): their cell bodies are predominantly located in the central retina (macula), and their axons project through the papillomacular bundle of the RNFL to the temp sector of the ON head, reaching parvcellular layers of the LGN; their function has been related to fine visual acuity (red–green) color vision and high-frequency contrast sensitivity; and (3) bistratified cells, or K-cells (represented in blue) (10%): their distribution in the retina is similar to P-cells, and their axons synapse with koniocellular layers of the LGN; their function is related to blue–yellow color vision, different aspects of spatial and temp resolution and blind sight. (A2) Retinal map of the distribution of P-cell (green color) and M-cell (red color) bodies and axons. (A3) Tridimensional representation of retina P-, M-, and K-cell fibers and their organization in the intraocular ON (info center): the intraocular ON is the first segment of the ON after ON head, in which RNFL axons penetrate the neural retina, choroid, and sclera to form the extraocular ON. The intraocular ON is divided from proximal to distal in preliminar, intralaminar, and a retrolaminar portions. The intralaminar portion contains the lamina cribrosa, a multilayered network of collagen fibers that insert into the scleral canal wall. When un-myelinated axons of P, K, and M-ganglion cells reach the lamina cribrosa, they become myelinated by the myelin sheath of ON oligodendrocytes, each of them covering several ganglion cell axons. According to current evidences on optical coherence tomography, in MSA, sup, nas, and info sectors of peripapillary RNFL are affected early and severely while temp sectors of peripapillary RNFL and central macular ganglion cell layer are relatively spared. This finding suggests a specific pattern of retina damage in MSA in which M-cells are specifically affected. This hypothesis is physiopathologically plausible, since MSA is a primary oligodendropathy and M-cells with their bigger axons may require higher myelination support from oligodendrocytes. (B) The LGN has layers of magnocellular cells and parvocellular cells that are interleaved with layers of koniocellular cells. In humans, the LGN is normally described as having six distinctive layers. The inner two layers (1 and 2) are magnocellular layers, while the outer four layers (3, 4, 5, and 6) are parvocellular layers. Koniocellular cells are located in additional set of layers found ventral to each of magnocellular and parvocellular layers. Layers 2, 3, and 5 receive inputs from ganglion cells of ipsilateral retina (highlighted in brighter colors), and layers 1, 4, and 6 receive ganglion cell axons from contralateral retina that crossed the chiasm. (C) Primary Visual Cortex (V1). P-cells project to parvocellular layers of the LGN and on to layer 4Cβ of V1. M-cells project to magnocellular layers of the LGN and on to layer 4Cα of V1. K-cells project to koniocellular layers of the LGN and on to the cytochrome oxidase-expressing patches (or blobs) of layer 2/3 and to layer 1. Abbreviations: sup, superior; nas, nasal; temp, temporal; info, inferior; MSA, multiple system atrophy; LGN, lateral geniculate nucleus; RNFL, retinal nerve fiber layer; ON, optic nerve.

Figure 5

Damage mechanisms and progression of retinal M-ganglion cell degeneration in MSA. (1) Early stage of MSA: oligodendrocytes located in the preliminary ON provide myelin sheath to several P-cell and M-cell axons. In the case of M-cells, the level of myelination support is particularly prominent since their axons are larger. ON oligodendrocytes in MSA are potentially susceptible to follow the same cellular pathological cascade that has been proposed for brain oligodendrocytes, with an initial relocalization of p25α into oligodendrocyte soma and ectopic localization of αSyn, leading to a progressive oligodendrocyte swelling. The formation of α-syn-p25α glial inclusions may induce the activation of microglia and the release of inflammatory factors, which further contributes to oligodendrocyte and myelin degeneration. This early oligodendrocyte damage may induce also early injury of M-cell axons favoring the early atrophy of superior, nasal, and inferior sectors of ON head RNFL; (2) Advanced stage of MSA: the severe degeneration of oligodendroglia leads to a loss of oligodendroglial support, which promotes the degeneration of axons of M-ganglion cells. In addition, there is a liberation of misfolded αSyn by oligodendrocytes to extracellular space, which may be taken by adjacent neurons to form misfolded αSyn inclusions within axons and cell bodies of M-cells. Misfolded αSyn inclusions within M-cells further promote neuronal dysfunction and neurodegeneration, with a reactive activation of local ON astroglia. In this phase, there is a severe damage of M-cell axons in the retina (superior, nasal, and inferior sectors of ON) that may also involve to a lesser extent P-cell axons (atrophy of temporal sector of ON RNFL) and their cell bodies (macular GCL atrophy); and (3) End-stage MSA: there is a severe degeneration of M-cell axons and cell bodies that extend also to P-cell axons and bodies, reflected in the retina as a widespread atrophy of peripapillary RNFL (still more prominent in superior, nasal, and inferior sectors) and macular GCL. Abbreviations: MSA, multiple system atrophy; ON, optic nerve; αSyn, α-synuclein; RNFL, retinal nerve fiber layer; GCL, ganglion cell layer. Figure inspired by Ref. (1).

Figure 6

Loss of retinal ganglion cells in the peripheral retina of a patient with multiple system atrophy (MSA). Confocal images of representative areas of whole-mounted retinae (superior–temporal area of the far peripheral retina; distance from the ora serrata: 1–5 mm) labeled with the blue fluorescent Hoechst marker of a patient with MSA (A) and an age-matched normal subject (B). Scale bar is 100 µm. The number of ganglion cells is markedly reduced in MSA compared to the control. See Ref. (6) for additional information.