Christina Frennesson

Patients with AMD and a large absolute central scotoma can be trained successfully to use eccentric viewing, as demonstrated in a scanning laser ophthalmoscope

Twenty patients with age-related macular degeneration, an absolute central scotoma and a mean visual acuity of 0.04 (20/475) were studied. A scanning laser ophthalmoscope (SLO) was used for microperimetry and determination of preferred retinal locus, often located to the left of the retinal lesion (corresponding to a location to the left of the visual field scotoma), which is considered unfavorable for reading. All 20 patients were trained to use a new and more favorable retinal locus for reading, above (or occasionally below) the retinal lesion (corresponding to a location below or above the visual field scotoma), first by reading scrolled text under simultaneous fixation monitoring and instruction in the SLO and then by reading printed text, using high magnification (mean 14.3x). For the 18 patients who learned to use eccentric viewing, reading speed with adequate magnification prior to training was 9.0+/-5.8 words/min. With training (mean 5.2 hours), it increased significantly (p<0.001) to 68.3+/-19.4 words per min. Training of eccentric reading has thus proved to be very successful.

Decreased Thickness and Integrity of the Macular Elastic Layer of Bruch's Membrane Correspond to the Distribution of Lesions Associated with Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. In its severest form, choroidal neovessels breach the macular Bruchs membrane, an extracellular matrix compartment comprised of elastin and collagen laminae, and grow into the retina. We sought to determine whether structural properties of the elastic lamina (EL) correspond to the region of the macula that is predilected toward degeneration in AMD. Morphometric assessment of the macular and extramacular regions of 121 human donor eyes, with and without AMD, revealed a statistically significant difference in both the integrity (P < 0.0001) and thickness (P < 0.0001) of the EL between the macular and extramacular regions in donors of all ages. The EL was three to six times thinner and two to five times less abundant in the macula than in the periphery. The integrity of the macular EL was significantly lower in donors with early-stage AMD (P = 0.028), active choroidal neovascularization (P = 0.020), and disciform scars (P = 0.003), as compared to unaffected, age-matched controls. EL thickness was significantly lower only in individuals with disciform scars (P = 0.008). The largest gaps in macular EL integrity were significantly larger in all categories of AMD (each P < 0.0001), as compared to controls. EL integrity, thickness, and gap length in donors with geographic atrophy did not differ from those of controls. These structural properties of the macular EL correspond spatially to the distribution of macular lesions associated with AMD and may help to explain why the macula is more susceptible to degenerative events that occur in this disease.

Location and stability of a newly established eccentric retinal locus suitable for reading, achieved through training of patients with a dense central scotoma.

Six patients, median age 71 years, with a dense central scotoma in one eye and a median visual acuity of 0.06 (20/330) in the same eye, were all (100%) shown by means of fundus photography including a fixation target to preferably use an unfavorable retinal locus for fixation, i.e., within the lesion (scotoma). None of the patients was able to read novel text with the affected eye. A computer and video display system were used to determine the most suitable area above or below the visual field scotoma (below or above the retinal lesion) for reading and the magnification needed at this eccentricity. The same setup was also used for an introductory training in reading single words as well as scrolled text with the aim of establishing a preferred retinal locus (PRL) at a favorable, eccentric position, the trained retinal locus (TRL). Thereafter, the patients were provided with strong positive lenses (median power, 40 D) for reading printed text at a very short reading distance (median, 2.5 cm), first single words, above and below which help lines were printed to facilitate eccentric fixation, and finally, novel text. The total training time was 4 to 5 h. Thereafter, fundus photography showed that five of the patients (83%) used their TRL as their PRL. Reading speed was 71 words per minute (median). Our results seem to indicate that an eccentric PRL favorable for effective reading can be established through training and that a fairly low number of training sessions is required. (Optom Vis Sci 1998;75:873–878)

ARPE-19 retinal pigment epithelial cells are highly resistant to oxidative stress and exercise strict control over their lysosomal redox-active iron.

Normal retinal pigment epithelial (RPE) cells are postmitotic, long-lived and basically not replaced. Daily, they phagocytose substantial amounts of lipid-rich material (photoreceptor outer segment discs), and they do so in the most oxygenated part of the body – the retina. One would imagine that this state of affairs should be associated with a rapid formation of the age pigment lipofuscin (LF). However, LF accumulation is slow and reaches significant amounts only late in life when, if substantial, it often coincides with or causes age-related macular degeneration. LF formation occurs inside the lysosomal compartment as a result of iron-catalyzed peroxidation and polymerization. This process requires phagocytosed or autophagocytosed material under degradation, but also the presence of redox-active low mass iron and hydrogen peroxide. To gain some information on how RPE cells are able to evade LF formation, we investigated the response of immortalized human RPE cells (ARPE-19) to oxidative stress with/without the protection of a strong iron-chelator. The cells were found to be extremely resistant to hydrogen peroxide-induced lysosomal rupture and ensuing cell death. This marked resistance to oxidative stress was not explained by enhanced degradation of hydrogen peroxide, but to a certain extent further increased by the potent lipophilic iron chelator SIH. The cells were also able to survive, and even replicate, at high concentrations of SIH and showed a high degree of basal autophagic flux. We hypothesize that RPE cells have a highly developed capacity to keep lysosomal iron in a non-redox-active form, perhaps by pronounced autophagy of iron-binding proteins in combination with an ability to rapidly relocate low mass iron from the lysosomal compartment.

Colour contrast sensitivity in patients with soft drusen, an early stage of ARM

The present institutional study was undertaken in order to determine whether testing of colour contrast sensitivity is valuable in detecting early functional changes in patients at initial stages of age-related maculopathy (ARM). The study included 27 patients with soft drusen as an early sign of ARM and 29 age-matched normals. The area occupied by drusen was determined using a computer program. Colour contrast sensitivity was measured with a computer graphics system. Visual acuity, central visual field (Humphrey Field Analyser) and colour vision (D-15 panel) were normal in both groups. Mean colour contrast sensitivity was significantly lower in patients with early ARM (for the protan axis: p=0.00019, for the deutan axis: p=0.000078 and for the tritan axis: p=0.000096) than in the controls. Interindividual variations were large. There was a tendency towards a bimodal distribution for all three colour axes, most evident for the tritan axis. We found a correlation of the drusen area with the protan and deutan thresholds for the fundus colour photographs r=0.5 (p<0.01) and r=0.4 (p<0.05), respectively, and with the tritan threshold for the angiograms r=0.5 (p<0.05). The findings suggest that colour contrast sensitivity may offer an additional possibility of predicting exudative ARM. Whether the patients with the highest thresholds are those who will be the first to show progression with indications of exudative ARM is not yet known. The patient group will be followed up in order to elucidate this question.

A computer and video display based system for training eccentric viewing in macular degeneration with an absolute central scotoma.

A new approach designed to establish the most suitable area for eccentric viewing and to teach and train patients with severe age-related macular degeneration (AMD) to use the eccentric viewing technique is described. Using a computer and video display based system, as well as software written specifically for this purpose, we investigated and trained ten consecutive patients with AMD. The patients were 80.1 ± 5.6 years old, on average. All of them had an absolute central scotoma. Mean visual acuity was 0.035 ± 0.016. After 30 min of testing, instruction and reading on the screen, followed by 2.6 ± 0.69 one-hour training sessions, on average, with the low vision therapist, reading newspaper and book texts with the aid of hyperoculars or aplanatic systems and a very short reading distance, the patients achieved a reading speed of 58.9 ± 19.7 words/min, significantly (p<0.001) higher than the initial speed when reading on the screen, 11.5 ± 4.5 words/min.

Significant improvements in near vision, reading speed, central visual field and related quality of life after ranibizumab treatment of wet age‐related macular degeneration

Purpose:  To investigate the effects on near visual acuity, reading speed, central visual field and related quality of life of ranibizumab treatment of wet age‐related macular degeneration (AMD).

Autophagy of iron-binding proteins may contribute to the oxidative stress resistance of ARPE-19 cells

The objective of this study was to elucidate possible reasons for the remarkable resistance of human retinal pigment epithelial (RPE) cells to oxidative stress. Much oxidative damage is due to hydrogen peroxide meeting redox-active iron in the acidic and reducing lysosomal environment, resulting in the production of toxic hydroxyl radicals that may oxidize intralysosomal content, leading to lipofuscin (LF) formation or, if more extensive, to permeabilization of lysosomal membranes. Formation of LF is a risk factor for age-related macular degeneration (AMD) and known to jeopardize normal autophagic rejuvenation of vital cellular biomolecules. Lysosomal membrane permeabilization causes release of lysosomal content (redox-active iron, lytic enzymes), which may then cause cell death. Total cellular and lysosomal low-mass iron of cultured, immortalized human RPE (ARPE-19) cells was compared to that of another professional scavenger cell line, J774, using atomic absorption spectroscopy and the cytochemical sulfide-silver method (SSM). It was found that both cell lines contained comparable levels of total as well as intralysosomal iron, suggesting that the latter is mainly kept in a non-redox-active state in ARPE-19 cells. Basal levels and capacity for upregulation of the iron-binding proteins ferritin, metallothionein and heat shock protein 70 were tested in both cell lines using immunoblotting. Compared to J774 cells, ARPE-19 cells were found to contain very high basal levels of all these proteins, which could be even further upregulated following appropriate stimulation. These findings suggest that a high basal expression of iron-binding stress proteins, which during their normal autophagic turnover in lysosomes may temporarily bind iron prior to their degradation, could contribute to the unusual oxidative stress-resistance of ARPE-19 cells. A high steady state influx of such proteins into lysosomes would keep the level of lysosomal redox-active iron permanently low. This, in turn, should delay intralysosomal accumulation of LF in RPE cells, which is known to reduce autophagic turnover as well as uptake and degradation of worn out photoreceptor tips. This may explain why severe LF accumulation and AMD normally do not develop until fairly late in life, in spite of RPE cells being continuously exposed to high levels of oxygen and light, as well as large amounts of lipid-rich material.

A three-year follow-up of ranibizumab treatment of exudative AMD: impact on the outcome of carrying forward the last acuity observation in drop-outs

Purpose:  To analyse a 3‐year clinical patient cohort of ranibizumab treatment of exudative age‐related macular degeneration (AMD), to investigate the impact on visual outcome of carrying forward the last acuity observation in drop‐outs and to explore possible differences between the early and the late phase of the study.

Clinical studies of X-linked retinitis pigmentosa in three Swedish families with newly identified mutations in the RP2 and RPGR-ORF15 genes

Purpose: To describe new disease-causing RP2 and RPGR-ORF15 mutations and their corresponding clinical phenotypes in Swedish families with X-linked retinitis pigmentosa (XLRP) and to establish genotype-phenotype correlations by studying the clinical spectrum of disease in families with a known molecular defect. Methods: Seventeen unrelated families with RP and an apparent X-linked pattern of disease inheritance were identified from the Swedish RP registry and screened for mutations in the RP2 and RPGR (for the RP3 disease) genes. These families had been previously screened for the RPGR exons 1–19, and disease-causing mutations were identified in four of them. In the remaining 13 families, we sequenced the RP2 gene and the newly discovered RPGR-ORF exon. Detailed clinical evaluations were then obtained from individuals in the three families with identified mutations. Results: Mutations in RP2 and RPGRORF15 were identified in three of the 13 families. Clinical evaluations of affected males and carrier females demonstrated varying degrees of retinal dysfunction and visual handicap, with early onset and severe disease in the families with mutations in the ORF15 exon of the RPGR gene. Conclusions: A total of seven mutations in the RP2 and RPGR genes have been discovered so far in Swedish XLRP families. All affected individuals express a severe form of retinal degeneration with visual handicap early in life, although the degree of retinal dysfunction varies both in hemizygous male patients and in heterozygous carrier females. Retinal disease phenotypes in patients with mutations in the RPGR-ORF15 were more severe than in patients with mutations in RP2 or other regions of the RPGR .