Multiple Sclerosis: The Eyes Have It
Multiple Sclerosis: The Eyes Have It
Abstract & Commentary
By Marc Dinkin, MD, Assistant Professor of Ophthalmology, Weill Cornell Medical College. Dr. Dinkin reports no financial interest in this field of study.
Synopsis: Pathological study shows atrophy within the inner nuclear layer of the retina and uveal tract inflammation in eyes from patients with multiple sclerosis
Source: Green A, et al. Ocular pathology in multiple sclerosis: Retinal atrophy and inflammation irrespective of disease duration. Brain 2010;133:1591-1601.
In a landmark study in Brain, Ari Green and colleagues reported on the largest ocular pathology series in patients with multiple sclerosis. A total of 132 eyes of 82 patients were compared with 16 eyes of patients with other neurological disease and analyzed with haematoxylin and eosin staining, while a subset of eyes were stained for astrocytes, inflammatory cells and tight junctions. The authors found that 79% of eyes in the MS group showed atrophy of the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGC) vs. only 19% of control eyes, confirming prior pathological studies and a plethora of clinical studies utilizing optical coherence tomography (OCT). Furthermore, 29% of eyes of relapsing-remitting or secondary-progressive MS patients showed peri-venular cellular infiltrates in the RNFL and RGC layers. While the presence of retinal periphlebitis has been demonstrated in prior pathological studies and in some clinical cases, the authors made the novel finding that this inflammation was independent of disease duration, confirming that retinal involvement is not a rare, late finding in MS.
The most salient finding of the study was prominent atrophy in the inner nuclear layer of 40% of MS eyes vs. 0% controls, with a sparing of the outer nuclear layer, answering the longstanding question of how deeply the retina is affected by the disease. The authors make a strong argument that atrophy of the inner nuclear layer is based on trans-synaptic degeneration since it correlated with RGC loss, the latter of which was always more prominent, and since it never occurred in cases of acute MS.
While uveitis has rarely been associated with clinical MS, the authors showed that 72% of MS eyes contained some combination of iris stromal inflammation, pupillary margin pigment layer eversion and iris neovascularization, vs. only 25% of controls. The authors theorize that such changes result from a distressed retina since vascular changes correlated with retinal atrophy, although a direct effect on the uveal tract remains a possibility.
Finally, optic nerve head analysis demonstrated a high prevalence (70%) of perivenular gliosis, with variable effects on the architecture of the nerve, confirming findings of prior studies.
Commentary
This study benefits not only from its status as the largest ocular pathological study of MS, but from the fact that the bulk of patients died prior to the advent of disease-modifying agents, so that the findings are likely to reflect MS in its untreated state. The categorization of patients into subtypes of MS allowed the authors to demonstrate differences such as the relative scarcity of perivascular inflammation in the primary progressive patients. The inclusion of an "other neurological disease" control group strengthened the study, although it should be noted that the disease duration in this control group was considerably shorter than in the MS group. As mentioned, the authors' discovery of inner nuclear layer atrophy and uveal tract inflammation in a significant proportion of MS patients makes a great contribution to our understanding of the extents of MS' effect on the eye and non-myelinated structures in general. Furthermore, the presence of retinal inflammation and gliosis may help inform our interpretation of layer segmentation in patients with MS in the future.
The study was limited by the dearth of clinical data in the study patients. Most importantly, there was no clinical data on the frequency of optic neuritis in the MS patient population so conclusions could not be made regarding the relative effect on the retinal elements by serial episodes of optic nerve inflammation vs. the chronic background effects of the disease. Clinical data on the prevalence of anterior ocular disease would have been informative in light of the high frequency of iris neovascularization and stromal inflammation observed pathologically.
The observation of "frequent" optic nerve cupping in the study patients corresponds poorly with clinical observations that demyelinating optic neuropathies lead to temporal pallor and ultimately a flat and atrophic disc. The finding is particularly difficult to interpret because the authors did not specify its actual frequency, and because pathological cupping was defined as any excavation or indenting of the optic disc. The low stringency of this definition would likely include a good proportion of the aged population, since while only 1%-2% of patients in the UK have definite glaucoma, a much greater proportion have physiologic cupping and are labeled as glaucoma suspects. Clinical comparison of optic nerve cupping in multiple sclerosis patients compared with aged-matched controls might help confirm or repudiate this relatively controversial pathological finding. Finally, as the authors point out, findings in one pathological area of an eye might have unblinded investigators to some extent as they searched for pathology in other tissues.
These critiques aside, this study has clearly broken new ground in definitively establishing atrophy and inflammation in the inner nuclear layer of the retina and within the iris. Its findings are sure to contribute greatly to our understanding of the pathophysiology of multiple sclerosis and inspire further investigations into its effect on the retina and surrounding ocular structures.
Pathological study shows atrophy within the inner nuclear layer of the retina and uveal tract inflammation in eyes from patients with multiple sclerosisSubscribe Now for Access
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