Fig. 10.1
Typical example of a microcystic macular edema (MME) in a patient with a compressive optic neuropathy. Thickness maps of ganglion cell layer (GCL) and inner nuclear layer (INL) are shown. For comparison, the author’s GCL and INL are shown at the same scale below. Areas affected from ganglion cell loss display a darkening in infrared imaging in a C-shaped perifoveal distribution pattern. The edema is characterized by vertical vacuolar spaces and thickening of the inner nuclear layer in OCT sections (localization indicated with white bar)
Shortly after the first report of MME, the specificity of MME for demyelinating disease was questioned by two concurrent letters to the editor: (1) Balk et al. described presence of MME in a patient with relapsing isolated optic neuritis and severe optic neuropathy [6], and (2) Abegg et al. found MME in a patient with a chiasmal glioma, thus a lesion far from the affected retina [7]. Later, MME was also described in patients with Leber’s hereditary optic neuropathy [8], autosomal dominant optic neuropathy [9, 10], glaucoma, and more; none of those cases were associated with MS. This led to the conclusion that MME in multiple sclerosis is caused indirectly by MS-associated optic neuropathy, and thus severity of optic neuropathy might be a better marker for MS.
Even though MME is clearly not exclusively present in MS, the use of MME in MS might still be valid. To date, there is no evidence against the role of MME as a predictor of disease progression. However, further research is required to investigate whether INL thickness is a predictor that is independent of ganglion cell layer thickness. This could possibly be achieved by a reanalysis of the existing data of Saidha et al. [2].
Microcystic Macular Edema in Optic Neuropathy
With the exception of Burggraaff et al. [11], all reports on MME showed presence of optic atrophy. One possible reason was segmentation algorithm failure in the Burggraaff study due to severe retinal pathology. Our finding of a case with MME from a chiasmal glioma raised the possibility that MME might be a sign of optic neuropathy rather than retinal inflammation as hypothesized in the initial reports. The retinal lesion in a patient without ocular disease indicated that MME might originate from a retrograde degeneration. Soon it became clear that pathologies at the level of the optic disk or along the optic nerve, thus outside the macula, were sufficient to cause MME.
Several case reports and case series showed that optic neuropathy of any etiology may lead to MME: These include compressive optic neuropathy [7, 12], anterior ischemic optic neuropathy [12], autosomal dominant optic neuropathy [9], glaucoma [13], Leber’s hereditary optic neuropathy [8], MS-associated optic neuropathy [1, 2], NMO-associated optic neuropathy [4, 5], relapsing isolated optic neuritis [6], Tanzanian endemic optic neuropathy [14], etc. (Table 10.1 [1, 2, 4–6, 8, 10–15]).
Pathology | Prevalence of MME | Atrophy | References |
|---|---|---|---|
Multiple sclerosis | 15/318 patients (4.7 %) 10/164 patients (6 %) 1/129 patients (1 %) | Mild | [1] [2] [6] |
Neuromyelitis optica | 5/25 patients (20 %) 10/39 patients (26 %) | Severe | [4] [5] |
Compressive optic neuropathy | 9/53 eyes (17 %) | Severe | [12] |
Glaucoma | 6/160 patients (4 %) 15/85 eyes (17 %) | Moderate | [13] [15] |
Tanzanian endemic optic neuropathy | 16/113 patients (14 %) | Severe | [14] |
Ischemic optic neuropathy | 3/36 eyes (8 %) | Moderate | [12] |
Hereditary optic atrophy | 2/14 eyes (14 %) 2/49 patients (4 %) 30/40 eyes (75 %) 10/“several hundred” patients | Severe | [12] [10] [15] [8] |
Primary retinal disease (MS and optic neuropathy excluded) | 128/1045 patients (12 %) | Severe | [11] |
MS | 26/611 (4 %) | Mild |
The temporal relation of MME appearance and onset of optic neuropathy is still unclear. In one reported case of a new-onset anterior ischemic optic neuropathy, we found that MME was present 4 months after onset but not 10 days after disease onset [13] (Fig. 10.2). This indicates a delayed development of the edema. Also disease without progression or extremely slow progression, such as autosomal dominant optic atrophy (ADOA), may be associated with MME [9, 10]. These observations suggest that MME gradually develops a few weeks after onset of optic neuropathy and then remains stable for months, possibly for a lifetime.
Fig. 10.2
Example of a case with retrograde maculopathy without microcystic macular edema. A patient with an optic tract lesion on the left from bleeding of a cavernous hemangioma. Thickness map of ganglion cell layer (GCL) shows a loss of ganglion cells in nasal macular areas (top left). A macular OCT section (location indicated with a white bar) shows no vertical vacuoles in the area affected by ganglion cell loss and yet increased inner nuclear layer thickness on the right side of the area indicated with a white bar. Thickness map of inner nuclear layer (INL) shows relative nasal thickening. Top right panels show location of OCT with the corresponding thickness values of the peripapillary nerve fiber layer
The anatomy of MME is well described: It is restricted to the inner nuclear layer and forms a C shape around the fovea, thus not affecting the fovea and the temporal raphe. It is associated with a loss of retinal nerve fibers and ganglion cell loss [12]. The overall retinal thickness may not change, as thickening of INL may counterbalance ganglion cell layer thinning (Fig. 10.1).
We found that youth is a risk factor for the development of MME [12]. This finding awaits confirmation. Also it is not clear whether youth truly is an independent risk factor, or rather MME has a higher prevalence in diseases that affect the young more commonly.
Microcystic Macular Edema in Primary Retinal Disease
Up until the report of Burggraaff et al., MME was strictly associated with optic neuropathy and the associated ganglion cell loss. Burggraaff et al. defined MME as “lacunar areas of hyporeflectivity with clear boundaries in the INL” in at least two adjacent scans. Based on that definition, they identified MME in patients with age-related macular degeneration, epiretinal membranes, postoperative lesions, diabetic retinopathy, vascular occlusion, MS (with/without optic neuritis), optic neuropathy, central serous chorioretinopathy, and other causes. This observation raises the possibility that MME may not be limited to optic neuropathy but may be present in other conditions too. Given the fact that the authors included cases with a clearly vascular cause of the edema, such as diabetes, this shows that MME may be a morphological special case of cystoid macular edema [16]. However, several reports have shown the absence of leakage in fluorescein angiography in MME associated to optic neuropathy (Fig. 10.3). Thus, the lack of leakage in fluorescein angiography might be a good possibility to separate MME from cystoid macular edema. On this background, the observation of Singer et al. is of interest: They showed macular changes that match the description of MME, including normal fluorescein angiography, in patients with epiretinal membranes. Even though Sigler et al. doubted altogether that MME is a separate clinical entity [16], they showed convincing evidence of MME in a primary retinal disease without a vascular origin [9].
