Advanced quantitative analysis of the sub-retinal pigment epithelial space in recurrent neovascular age-related macular degeneration

<div><p>To quantitatively evaluate changes in the sub-retinal pigment epithelial (RPE) space and determine the association with recurrent neovascular age-related macular degeneration (AMD). Twenty-two eyes treated with intravitreal aflibercept for treatment-naïve neovascular AMD were studied retrospectively. The sub-RPE area, volume, and central retinal thickness (CRT) were evaluated 1 and 2 months after the loading phase using spectral-domain optical coherence tomography. Recurrence was defined as newly detected neovascular activity during the 6 months after the loading phase. In eyes with recurrent AMD, the sub-RPE area increased significantly (<i>P</i> = 0.036) from 1 to 2 months after the loading phase and the sub-RPE volume increased marginally (<i>P</i> = 0.06). Subgroup analysis showed significant (<i>P</i> = 0.008 and <i>P</i> = 0.016, respectively) increases in the sub-RPE area and volume in typical AMD. In eyes with no recurrence, no significant changes occurred in the two parameters. No significant CRT changes occurred in eyes with or without a recurrence. A quantitative analysis demonstrated an increased likelihood of the sub-RPE space shortly after the loading phase in eyes with recurrent AMD; no changes occurred in eyes without a recurrence. These early changes in the sub-RPE space could indicate disease activity and are valuable for predicting recurrences of neovascular AMD.</p></div

Changes of the sub-RPE area and volume in all cases after aflibercept therapy.

<p>1 M = 1 month after the loading phase; 2 M = 2 months after the loading phase.</p

Spectral-domain optical coherence tomography imaging obtained from an 82-year-old man with type 1 choroidal neovascularization.

<p>(Top row) At baseline, the B-scan shows a sub-RPE space with subretinal fluid and subretinal hyperreflective material. The RT map shows the presence of fluid (orange); the central retinal thickness (CRT) is 270 microns. The RPE elevation map shows the sub-RPE space (red); the sub-RPE area and volume are 1.5 mm² and 0.08 mm³, respectively. (Second row) One month after the loading phase, the subretinal fluid has disappeared from the B-scan and RT map, and the CRT has decreased to 175 microns. The RPE elevation map shows the decreased sub-RPE space; the area and volume are 0.3 mm² and 0.01 mm³, respectively. (Third row) Two months after the loading phase, the B-scan and RT map are stable compared to the previous month; the CRT is unchanged at 175 microns. In contrast, the RPE elevation map shows a considerably larger pigment epithelial detachment (PED) compared with the previous month; the area and volume are 0.9 mm² and 0.03 mm³, respectively. (Bottom row) At the time of recurrence at 5 months after the loading phase, the B-scan shows that a sub-RPE space developed with subretinal fluid. The RT map shows the presence of fluid again (yellow), and the CRT has increased to 251 microns. The RPE elevation map shows an increase in the area of the sub-RPE; the area and volume are 1.0 mm² and 0.05 mm³, respectively.</p

Changes of the sub-RPE area and volume in eyes with typical AMD after aflibercept therapy.

<p>1 M = 1 month after the loading phase; 2 M = 2 months after the loading phase.</p

Whole Exome Analysis Identifies Frequent <i>CNGA1</i> Mutations in Japanese Population with Autosomal Recessive Retinitis Pigmentosa

<div><p>Objective</p><p>The purpose of this study was to investigate frequent disease-causing gene mutations in autosomal recessive retinitis pigmentosa (arRP) in the Japanese population.</p><p>Methods</p><p>In total, 99 Japanese patients with non-syndromic and unrelated arRP or sporadic RP (spRP) were recruited in this study and ophthalmic examinations were conducted for the diagnosis of RP. Among these patients, whole exome sequencing analysis of 30 RP patients and direct sequencing screening of all <i>CNGA1</i> exons of the other 69 RP patients were performed.</p><p>Results</p><p>Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of <i>CNGA1</i> (four patients), <i>EYS</i> (three patients) and <i>SAG</i> (one patient) in eight patients and potential disease-causing gene variants of <i>USH2A</i> (two patients), <i>EYS</i> (one patient), <i>TULP1</i> (one patient) and <i>C2orf71</i> (one patient) in five patients. Screening of an additional 69 arRP/spRP patients for the <i>CNGA1</i> gene mutation revealed one patient with a homozygous mutation.</p><p>Conclusions</p><p>This is the first identification of <i>CNGA1</i> mutations in arRP Japanese patients. The frequency of <i>CNGA1</i> gene mutation was 5.1% (5/99 patients). <i>CNGA1</i> mutations are one of the most frequent arRP-causing mutations in Japanese patients.</p></div

Sequence data of all six identified <i>CNGA1</i> mutations in this study.

<p>A-1 to F-1 show the normal sequence data for the <i>CNGA1</i> gene. A-2 to F-2 show the sequence data for heterozygous <i>CNGA1</i> mutations (c.191delG, c.265delC, c.G860A, c.G1271A, c.1429delG and c.G2042C, respectively). A-3 and B-3 show the sequence data for homozygous <i>CNGA1</i> mutations (c.191delG and c.265delC).</p

Pedigrees identified with arRP-causing mutations or potential arRP-causing variants.

<p>The solid squares (male) and circles (female) represent affected patients. The proband of each family is indicated by a black arrow. Unaffected family members are represented by white icons. The slash symbol indicates deceased individuals. The doubled line indicates consanguineous marriage. The generation number is shown on the left.</p

Ophthalmic findings in five patients with retinitis pigmentosa with compound heterozygous or homozygous <i>CNGA1</i> mutations.

<p>BCVA = decimal corrective visual acuity; ERG = electroretinography; M = male; F = female.</p><p>Ophthalmic findings in five patients with retinitis pigmentosa with compound heterozygous or homozygous <i>CNGA1</i> mutations.</p