Retinal Hyperreflecting Foci Associate With Cortical Pathology in Multiple Sclerosis

Abstract

Background and ObjectivesMicroglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS).MethodsAt baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study.ResultsCompared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count (p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA (p = 0.017) and rNEDA (p = 0.002).DiscussionWe found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation.Classification of EvidenceThis study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA.

Hyper-Reflecting Foci in Multiple Sclerosis Retina Associate With Macrophage/Microglia-Derived Cytokines in Cerebrospinal Fluid

“…Inasmuch as a widespread microglial activation has been demonstrated by histological and neuroimaging (advanced MRI and PET techniques) studies in MS ( 26 ), this disease may constitute an ideal pathological field, where the origin of HRF is clarified and microglial behavior during the course of CNS inflammatory disorders is analyzed. In a previous study, we found that INL HRF count correlated with both inflammatory cortical pathology and INL thickness, suggesting HRF parallel gray matter rather than white matter damage in RRMS ( 6 ). These findings were in line with histological observations supporting a pivotal role for microglia and a marginal role for T cells in both retinal and cortical pathology in MS ( 27 ).…”

“…All MS patients underwent spectral domain OCT (Spectralis; Heidelberg Engineering, Carlsbad, CA; Heidelberg Eye Explorer version 1.7.0.0) examination of both eyes, in a dark room without the injection of any mydriatic agent. In line with recent publications ( 3 , 6 , 14 ), the analysis of the central linear scan of the macular map, crossing the fovea, was considered for HRF counting. HRF were counted in the area included between two perpendicular lines to Brunch’s membrane traced at 1,500 μm both temporally and nasally from the center of the fovea.…”

“…Interestingly, beside advanced neuroimaging methodologies that have been tested for the in vivo evaluation of activated microglia in the brain, OCT with a single linear scan through the macula proved to identify and correlate the HRF with different parameters of local inflammation and damage ( 3 , 5 , 7 – 10 ). Moreover, a strong correlation of HRF with cortical lesion load and clinical and radiological disease activity have been observed in MS ( 3 , 6 ).…”

“…As a matter of fact, HRF have been observed in pathologies not associated with retinal lipid deposition. Moreover, in relapsing–remitting multiple sclerosis (RRMS) HRF are increased compared to healthy controls ( 3 ) and associated with MRI parameters of cortical inflammation ( 6 ). Finally, the reported association between HRF and inflammatory markers (i.e., IL-8, V-CAM-1) in aqueous humor in patients with intractable macular edema also speaks in favor of the microglia-origin hypothesis ( 7 ).…”

Multiple sclerosis and circadian rhythms: Can diet act as a treatment?

“…In recent years, the neurodegenerative component of the disease has been re‐emphasized; manifold neuropathological and advanced neuroimaging studies have shown cortical lesions and cortical and deep gray matter damage from the earliest disease stages that contribute significantly to long‐term disability, including cognitive impairment 37–39 (Figure 1). Also, the optic nerve and retina, which are part of the CNS, are frequently affected from early on, as mirrored by numerous optical coherence tomography (OCT) studies showing retinal atrophy with loss of axons and retinal ganglion cells in eyes with and without prior optic neuritis 40–43 . Lesions and more subtle tissue damage in the spinal cord that predominantly manifest in the cervical cord significantly contribute to disability, especially impaired ambulation with reduced walking distance and bowel–bladder problems 44 (Figure 1).…”