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. 2014 Apr;1(4):290-7.
doi: 10.1002/acn3.46. Epub 2014 Mar 11.

Subtle Retinal Pathology in Amyotrophic Lateral Sclerosis

Free PMC article

Subtle Retinal Pathology in Amyotrophic Lateral Sclerosis

Marius Ringelstein et al. Ann Clin Transl Neurol. .
Free PMC article


Amyotrophic lateral sclerosis (ALS) is characterized by neuro-ophthalmological abnormalities beyond disturbed oculomotor control such as decreased visual acuity and disturbed visual evoked potentials. Here we report retinal alterations in a cohort of 24 patients with clinically definite (n = 20) or probable (n = 4) ALS as compared to matched controls. High-resolution spectral domain optical coherence tomography with retinal segmentation revealed a subtle reduction in the macular thickness and the retinal nerve fiber layer (RNFL) as well as a marked thinning of the inner nuclear layer (INL). Our data indicate an unprecedented retinal damage pattern and suggest neurodegeneration beyond the motor system in this disease.


Figure 1
Figure 1
Optical coherence tomography (OCT) results. The macular thickness and volume were measured in consecutive vertical scans centered on the macula (A). The peripapillary RNFL was evaluated in a circular scan centered on the optic disk (B). The deeper retinal layers were manually segmented in a single horizontal foveal scan (red lines; (C)). The thickness of the different layers was assessed 1. as mean thickness of the entire layers, 2. by the point estimate (P.E.) method (vertical black lines). Scatter plots display the thickness of the RNFL (means ± standard deviation (M ± SD): ALS 93.2 ± 10.7 μm vs. controls 100.0 ± 10.9 μm, P = 0.031; (D)) and the total macular thickness (M±SD: ALS 309.8 ± 17.3 μm vs. controls 318.2 ± 15.7 μm, P = 0.037; (E)) both significantly (*) reduced in ALS patients. The INL is significantly (*) reduced with both segmentation methods (mean thickness M ± SD: 24.7 ± 3.2 μm, p = 0.001; P.E. M ± SD: 37.4 ± 4.6 μm, P < 0.001) compared to controls (mean thickness M ± SD: 27.9 ± 4.3 μm; P.E. M ± SD: 43.3 ± 4.2 μm; (F+G)). No significant differences in the thickness of the mean GCIP (mean thickness, M ± SD: ALS 66.2 ± 6.6 μm vs. controls 66.5 ± 6.6 μm, P = 0.943; P.E., M ± SD: ALS 97.1 ± 8.8 μm vs. controls 100.0 ± 9.2 μm, P = 0.296; (H+I)) and the ONL (mean thickness, M ± SD: ALS 61.6 ± 7.5 μm vs. controls 60.5 ± 7.8 μm, P = 0.526; P.E., M ± SD: ALS 107.7 ± 10.6 μm vs. controls 105.9 ± 12.7 μm, P = 0.603; (J+K)) were detectable. The OPL was thicker in ALS patients when measured as P.E. (M ± SD: ALS 41.3 ± 6.0 μm vs. controls 35.5 ± 7.0 μm, P = 0.001) while the mean OPL thickness did not differ between patients and controls (M ± SD: ALS 29.5 ± 3.6 μm vs. controls 30.9 ± 4.5 μm, P = 0.161; (L+M)). Each point represents the mean of the two eyes of one patient. The mean of all patients is indicated by a horizontal bar. The P-values are indicated (GEE analysis). ALS, amyotrophic lateral sclerosis; GCIP, ganglion cell/inner plexiform layer complex; INL, inner nuclear layer; MT, macular thickness; ONL, outer nuclear layer; OPL, outer plexiform layer; P.E., point estimate; RNFL, retinal nerve fiber layer.
Figure 2
Figure 2
Correlations between the point estimate and mean entire layer segmentation methods and inter-rater reliability for both techniques. The values obtained by the point estimate (P.E.) method correlated significantly with the mean layer thickness for all layers (P < 0.05, Pearson correlation, Pearson r is indicated). The two segmentation methods correlated excellently (r ≥ 0.8) for the GCIP (r = 0.83, P < 0.0001), the INL (r = 0.87, P < 0.0001) and the OPL (r = 0.89, P < 0.0001; (A–C)) and were acceptable (r ≥ 0.5) for the ONL (r = 0.67, P = 0.0017; (D)). The values obtained by two different raters (R1 and R2) using the two segmentation methods are correlated and the intraclass correlation coefficients (ICC) are given. The GCIP measured as mean layer thickness and P.E. showed excellent inter-rater reliabilities (IRR) with ICC of ≥0.9 (mean layer: 0.93; (E), P.E.: 0.90; (I)). The IRR of the other layers were good with an ICC of ≥0.5 (INL: mean layer: 0.63; (F), P.E.: 0.58; (J), OPL: mean layer: 0.57; (G), P.E.: 0.50; (K), ONL: mean layer: 0.57; (H), P.E.: 0.69; (L)). Each point represents the thickness of the retinal layers of the left eye of a patient measured with the indicated methods. The diagonal lines resemble the results of linear regression analyses. GCIP, ganglion cell/inner plexiform layer complex; ICC, intraclass correlation coefficient; INL, inner nuclear layer; Mean, mean layer thickness; ONL, outer nuclear layer; OPL, outer plexiform layer; P.E., point estimate; R, rater.

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