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

Review published: 24 May 2017 doi: 10.3389/fneur.2017.00206 The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis Carlos E. Mendoza-Santiesteban1*, Iñigo Gabilondo2, Jose Alberto Palma1, Lucy Norcliffe-Kaufmann1 and Horacio Kaufmann1* 1 2 Edited by: Ivan Bodis-Wollner, SUNY Downstate Medical Center, United States Reviewed by: Shahnaz Miri, MedStar Georgetown University Hospital, United States Patricija Van Oosten-Hawle, University of Leeds, United Kingdom *Correspondence: Carlos E. Mendoza-Santiesteban carlos.mendoza-santiesteban@ nyumc.org; Horacio Kaufmann Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neurology Received: 14 February 2017 Accepted: 27 April 2017 Published: 24 May 2017 Citation: Mendoza-Santiesteban CE, Gabilondo I, Palma JA, NorcliffeKaufmann L and Kaufmann H (2017) The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis. Front. Neurol. 8:206. doi: 10.3389/fneur.2017.00206 Frontiers in Neurology | www.frontiersin.org Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, NY, United States, Biocruces Health Research Institute, Neurodegenerative Diseases Group, Barakaldo, Spain 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 Abbreviations: αSyn, α-synuclein; DLB, dementia with Lewy bodies; ERG, electroretinography; GCC, ganglion cell complex; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; MSA, multiple system atrophy; MSA-C, multiple system atrophy-cerebellar; MSA-P, multiple system atrophy-parkinsonian; OCT, optical coherence tomography; ONL, outer nuclear layer; OPL, outer plexiform layer; PD, Parkinson disease; PSP, progressive supranuclear palsy; RGC, retinal ganglion cells; RNFL, peripapillary retinal nerve fiber layer; UMSARS, united multiple system atrophy rating scale; VEP, visual evoked potentials abnormalities. 1 May 2017 | Volume 8 | Article 206 Mendoza-Santiesteban et al. The Retina in MSA 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: multiple system atrophy, retina, alpha-synuclein, optical coherence tomography, ganglion cell layer, retinal nerve fiber layer INTRODUCTION Cirrus®), however, do not include the retinal nerve fiber layer at the macula when assessing the GCC. The visual information is highly processed and segregated in the retina and finally conducted using sub-populations of retinal ganglion cells (RGC), whose axons converge in the optic nerve. The classification of RGC sub-populations has evolved from the seminal morphological criteria of Ramón y Cajal (9) to more sophisticated criteria based on morphological, molecular, and genetic properties of the cells, particularly in murine models, with at least 25 RGC sub-populations identified so far (10). Based on their projections and functions, the classification of RGC can be simplified into four main sub-populations: Multiple system atrophy (MSA) is a rare, adult-onset fatal synucleinopathy, a group of neurodegenerative disorders driven by abnormal intracellular aggregation of misfolded hyperphosphorylated fibrillar α-synuclein (αSyn) (1). In MSA, the initial abnormal αSyn deposition occurs in oligodendroglial cells forming glial cytoplasmic inclusions while in other synucleinopathies αSyn deposits occur in neurons forming Lewy bodies and Lewy neurites (2). MSA has common motor and non-motor clinical features with Parkinson disease (PD), but the clinical course of MSA is usually rapid with mean survival below 10 years from diagnosis and with no effective symptomatic or neuroprotective treatments (3–5). Visual symptoms are not frequent in patients with MSA, but recent studies using optical coherence tomography (OCT) showed progressive retinal thinning with a distinctive pattern and anatomic distribution, which has now been confirmed in postmortem studies (6). Because current candidate biomarkers for MSA from blood, cerebrospinal fluid, and brain or cardiac imaging are neither sensitive nor specific or insufficiently explored (7), OCT-detected retinal abnormalities could emerge as a useful biomarker of disease progression (8). In this article, we briefly review the normal anatomy of the retina and perform a literature review of retinal abnormalities as a biomarker in patients with MSA and a meta-analysis on the main results of OCT studies in patients with MSA. Finally, we discuss putative pathological mechanisms that may explain the observed retinal abnormalities in these patients. (a) Midget RGC (80%), projecting to the parvocellular layers of the lateral geniculate body (parvocellular pathway; P-cells). In this review, we refer to these RGC as P-cells, based on their anatomical projections in the lateral geniculate body. (...truncated)