Retinal glymphatic system: an explanation for transient retinal layer volume changes?

The most extensive exchange of letters in the history of Brain (Gelfand et al. 2012). was about a minuscule region of the eye, the retinal inner nuclear layer (INL). With the advent of optical coherence tomography (OCT), a forgotten autopsy observation was restored to the top of the current research agenda in multiple sclerosis (MS) (Gelfand et al. 2012). Severe atrophy of the retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) was associated with subtle changes in the INL whilst the outer retinal layers were completely preserved (Müller 1857). Whilst very cautious about potential INL changes1, Heinrich Müller was howevermore convinced about the existence of secondary (retrograde) axonal degeneration. Histological analysis of the macaque monkey eye following lesions to the chiasm and occipital cortex provided experimental evidence for retrograde trans-synaptic degeneration reaching the GCL with associated changes in the INL (van Buren 1963). Lesions of the optic chiasm led to thinning of the RNFL and GCL with the formation of cystic spaces in the INL which “were irregularly rounded and the larger contained fine strands of tissue and debris”. Occipital cortex lesions, by contrast, did not affect the INL or any of the outer retinal layers. These INL changes are the likely histological equivalent of what has been called “microcystic macular oedema” (MMO) (Gelfand et al. 2012). I will later return to the debate surrounding MMO in an attempt to explain the next relevant observation, the increase in INL thickness in the absence of obvious MMO. Increased thickening of the pooled outer plexiform and inner nuclear layers was found to be associated with signs of inflammation in MS (Saidha et al. 2012). Together these studies raised the possibility that MMO and INL thickening might be comparable to an MRI “T2 lesion” and could be useful as a surrogate outcome for treatment trials in MS (Petzold 2012). In this issue of Brain, Knier et al. report that disease-modifying treatment in patients with MS efficiently controlled inflammatory disease activity and was associated with INL volume reduction (Knier et al., 2016).