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To evaluate the influence of short-term carotenoid and antioxidant supplementation on retinal function in non-advanced age-related macular degeneration (AMD).

• Visual acuity of 20/32 or more [0.2 logarithm of minimum angle of resolution (log MAR)]
• 74 letters of Early Treatment Diabetic Retinopathy Study chart
• Extensive (as measured by drusen area) intermediate (125 µm or more) drusen or geographic atrophy not involving the center of the macula.

Based on the fact that several pathologies may influence the bioelectrical responses derived from the macular region:

• Presence of moderate to dense lens opacities
• Implanted intraocular lens
• Presence of corneal opacities
• Previous history of refractive surgery
• Presence of glaucoma or ocular hypertension
• Previous history of intraocular inflammation such as anterior or posterior uveitis
• Previous history of retinal detachment or laser treatment for peripheral retinal diseases
• Presence of diabetes or systemic hypertension under medical treatment
• Previous history of ocular trauma
• Drug therapies with toxic effects on the macula
• Presence of neurologic diseases
• Presence of any sign of advanced AMD (choroidal neovascularization or central geographic atrophy) in the studied eye.

 

Recruitment

93 patients affected by AMD were screened for enrollment in the study. The clinical diagnosis of AMD was based on slit-lamp and indirect ophthalmoscopic examination. Color fundus photographs centered on the fovea were also taken.

Design

Randomized controlled trial with 15 patients receiving daily oral supplementation (T-AMD) and 12 patients receiving no dietary supplementation (NT-AMD). The AMD eyes were compared to 15 eyes from 15 age-similar normal control subjects.

Blinding Used

The stereoscopic photographs were independently analyzed and graded by two masked observers at baseline, six months and 12 months. 

Intervention 

Daily oral supplementation of  vitamin C (180mg), vitamin E (30mg), zinc (22.5mg), copper (1mg), lutein (10mg), zeaxanthin (1mg) and astaxanthin (4mg) for 12 months.

Statistical Analysis

• Inter-individual variability, expressed as data standard deviation (SD) was estimated for mfERG measurements
• Test-retest data of mfERG results were expressed as the mean difference between two recordings obtained in separate sessions ± SD of this difference
• The 95% confidence limits of test-retest variability in normal subjects and patients were established assuming a normal distribution
• In AMD patients, test-retest data were calculated considering the entire cohort of enrolled patients (27 AMD eyes)
• The differences of mfERG responses between groups (control eyes, T-AMD eyes and NT-AMD eyes) were evaluated by one-way analysis of variance
• Changes in mfERG responses observed in T-AMD and NT-AMD eyes after six and 12 months were compared with baseline (pretreatment) values by one-way analysis of variance
• In all analyses, P<0.05 was considered statistically significant. When the P<0.01, it was considered highly statistically significant.

Timing of Measurements

Baseline, six months and 12 months.

Dependent Variables

Multifocal electroretinogram (mfERG) assessments of N1-P1 RADs derived from 0° to 2.5° [ring 1 (R1)], 2.5° to 5° [ring 2 (R2)], 5° to 10° [ring 3 (R3)], 10° to 15° [ring 4 (R4)], 15° to 20° [ring 5 (R5)].

Independent Variables

• Oral supplementation or no dietary supplementation 
• Daily oral supplementation of  vitamin C (180mg), vitamin E (30mg), zinc (22.5mg), copper (1mg), lutein (10mg), zeaxanthin (1mg) and astaxanthin (4mg) for 12 months.

Control Variables

• Age
• Clinical diagnosis of AMD based on Age-Related Eye Disease Study (AREDS) category.

• Initial N: 93 patients (41 males, 52 females)
• Attrition (final N): 27 randomly divided into 15 (six males, nine females) in the oral daily supplementation group and 12 (six males, six women) receiving no dietary supplementation and 15 eyes from 15 age-similar normal control subjects (six males, nine females)
• Age: 
  • Oral daily supplementation group: Mean age 69.4+4.31 years
  • No dietary supplementation group: Mean age 69.6+6.23 years
  • Control group: 69.6+5.1 years
• Ethnicity: Italian
• Location: Italy.

 

A selective dysfunction in the central retina (0° to 5°) was improved by supplementation. No functional changes were present in the more peripheral (5° to 20°) retinal areas. 

The following charts summarize the results.

Multifocal Electroretinogram Responses: 0° to 5° Central Degrees (R1 and R2) 

	Baseline	Six months	12 months
NT-AMD	Highly significant RAD reductions were found compared to healthy controls. P<0.01	Non-significant changes in RADs were found compared to baseline. P>0.05	RAD values were similar to baseline. P>0.05
T-AMD	Highly significant RAD reductions were found compared to healthy controls. P<0.01	Highly significant increases in RADs were found compared to baseline. P<0.01	Highly significant increases in RADS were found compared to baseline. P<0.01

The increases in the T-AMD group found at 12 months were not increased compared to the RADs found at six months.

Multifocal Electroretinogram Responses: 5° to 20° Central Degrees (R3, R4 and R5) 

	Baseline	Six months	12 months
NT-AMD	Non-significant differences in RADs were found compared to healthy controls. P<0.05	Non-significant changes in RADs were found compared to baseline. P>0.05	Non-significant changes in RADs were found compared to baseline. P>0.05
T-AMD	Non-significant differences in RADs were found compared to healthy controls. P<0.05	Non-significant changes in RADs were found compared to baseline. P>0.05	Non-significant changes in RADs were found compared to baseline. P>0.05

 

 

• Untreated eyes with non-advanced AMD (NT-AMD eyes) showed, after six and 12 months, unmodified mfERG responses with respect to baseline conditions. This is in accordance with another study that did not find a progressive reduction in mfERG responses in patients with early AMD. A period of more than 12 months is reported to be necessary to detect a progression of mfERG impairment in the presence of a stable visual acuity.
• In eyes of treated patients (T-AMD eyes), the supplementation with the combination of vitamin C, vitamin E, zinc, copper, lutein, zeaxanthin and astaxanthin induced an increase of mfERG responses derived from the central retina (0° to 5°), whereas no changes in bioelectrical responses were observed in the other retinal areas (5° to 20°). The reduction of mfERG impairment was present after six months of treatment and an additional six months of treatment did not induce a further improvement of mfERGs.
• The normal concentration of lutein and zeaxanthin seems to have a protective role against the development of AMD. The results of this study showed that supplementation of lutein and xeaxanthin induced an increase in mfERG N1-P1 and R2 (zero to five central degrees) RAD, which reflects the functional improvement of preganglionic elements. Overall, there is a significant antioxidant effect which prevents or delays photoreceptor dysfunction or death.

University/Hospital:

CARMIS Study Group

The authors note the following limitations:

• Because of the small number of patients enrolled, the present trial can be considered a pilot study and caution must be taken against drawing general conclusions. The findings must be confirmed in a larger population with a longer follow-up term. Although no side effects were observed in the treated patients, no final conclusions could be drawn regarding safety.
• To clarify whether the improvement observed in T-AMD eyes was supplement dependent, it would be useful to perform mfERG recordings after a period of suspension of antioxidant supplementation. Because antioxidant supplementation is beneficial, the suspension of supplementation and possible decrease in macular functions could be an ethical problem. The author's ethics committee is debating this issue.