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“Sapienza” University of Rome Gagliardi A, Facciolo G, Vingolo E.M.

Eye - Fixation meaning and evaluation in patients with AMD: a microperimetric biofeedback study.

Corresponding Author: Arianna Gagliardi Email: Arianna.gagliardi@yahoo.it

Purpose: to evaluate fixation behaviour and other linked–visual functions in patients with AMDtraining a new PRL, in sessions, using biofeedback (BFD) technique with microperimeter MAIA. Materials and methods: Were selected 15 patients (27 eyes) with Age-related macular degeneration that underwent to a rehabilitative protocol as follows: distance and near visual acuity, reading speed test, MAIA microperimetry, analysis of fixation and central retinal sensitivity. Each patient underwent 10 training sessions of 10 minutes for each eye, performed once a week. All the before-mentioned tests were repeated at the end of low-vision rehabilitation that was after 10 weeks. Statistical analysis was performed using Student’s test. P values less than 0.05 were considered statistically significant.

Results: near visual acuity was 36.4 at baseline and 11.7 at the end of the study; this result was statistically significant with p<0.05; reading speedimproved from a mean value of 25w/min at the beginning of the study to 45 w/min at the end, and was accompanied by a decrease in the character size that could be read by the patient (from 36.4 to 11.7); this value was statistically significant with p<0.05.

Last but not least Student’s t test evidenced a statistically significant increase in average fixation stability (p=0.0023) basing on both Fujii and BCEA methods; moreover the mean single point retinal sensitivity value improved from 6,42 dB (± 2,18) to 9, 24 dB (DS±4.73) with p<0.05.

Conclusions: fixation analysis appears to be a valid and functional parameter in AMD patients treatment, maybe too much under estimated. Its stability and

training, generating new â&#x20AC;&#x153;good PRLâ&#x20AC;? by use of microperimeter biofeedback, guarantees an important improvement in quality of vision and, more general, in the way of life.

Introduction Age-related macular degeneration (AMD) causes central scotoma and irreversible visual damage leading loss of visual acuity and difficulties in patient autonomy due to weak ocular control and fixation instability. In a normal eye fovea is the main reference on the retina while in AMD lack of fixation determines that the patient can no longer perform visual tasks as reading or doing near works. So that most individuals adapt to their way to see in consideration of visual impairments using for fixation, very often without their conscious knowledge, healthy eccentric parts of the retina.

These eccentric retinal areas utilized by the patients are also called preferred retinal loci or PRLs and they play role of a “new-established fovea”(also known as pseudo-fovea) or vicariant macula.

PRLs can be single or multiple and can develop on any part of the residual retina, however the highest retinal sensitivity areas and physically closer to the lost foveola are first candidates to assume new retinal functions. Moreover several papers showed that it is possible training these areas as PRLs and consequently adjust visual performances and, as better as possible, the ocular fixation3-19-20-21-22-28.

The aim of our study is to evaluate if in patients with AMD training a new PRL, in sessions using biofeedback (BFD) technique with microperimeter MAIA, may improve fixation behavior and other functional parameters.

Materials and methods We recruited 15 patients (10 female and 5 male) and examined a total of 27 eyes with AMD, who had comeat the Ophthalmology Unit of the “Alfredo Fiorini” (Terracina) Hospital, “La Sapienza” University of Rome.

Age range of patient was from 64 to 85; inclusion criteria were low vision (i.e. better eye lower than 20/60) with an unstable fixation and diagnosis of AMD. The diagnosis based on a complete examination of the anterior and posterior segment, which involved microperimetry, fluorescein angiography and ocular coherence tomography (OCT). We excluded from the study patients not collaborative, braindamaged or with cognitive impairment, highly myopic eyes (>6D) and subjects with significant media opacities or with other ocular pathologies that affect vision.

The study protocol was approved by the Ethics Committee of our institution and conformed to the Declaration of Helsinki. Patients gave their informed consent before data collection.

Following informed consent, subjects were evaluated by the ensuing procedures: - Airlie House Charts (EDTRS Chart): distance visual acuity charts used to assess the best distance spectacle-corrected visual acuity (BCVA) in units

of log minimum angle of resolution (logMAR) each letter of the chart corresponding 0.02 log MAR units.

- MNREAD acuity charts testing reading acuity, reading rate and criticalprint size. So near visual acuity at 25 cm, or nearer, corrected with an add selected for age and a +4.00 (1x) reading lens on top of this.

- Reading speed test (words/minute) closely related to reading acuity. For each eye reading speed was measured by reading of black letters (Types New Roman) on a white background at a distance of 25 cm, or nearer, corrected with an add selected for age and a +4 (1x) reading lens on top of this.Patients were instructed to read each sentence aloud, as fast as possible, without skipping words (character size was adapted to patientsâ&#x20AC;&#x2122; visual acuity choosing the smallest seeing size).

- MAIA microperimeter (2009, Centervue Italia-Padova) performing the fixation stabilitytest and the microperimetry of the macular area by using the automated program, the Expert Test of 4-2 strategy. An eye-tracking system continuously registered eye position relative to anatomic landmarks and compensated for stimulus projection location. So it ensured that pointto-point correspondence existed between the stimulus and the measured retinal location during the test and on subsequent tests. Moreover the eye mapped the fixation location during the examination also quantifying patientâ&#x20AC;&#x2122;s fixation stability and fixation location characteristics according to Fujii (2001). In this way considering the repetitiveness of spatial location the newPRL was automatically identified by instrument software and was marked with a different color on the screen display. To set the reference of eye alignment during the rest of the test in the first 10 seconds of examination, the instrument calculated the PRL location on spatial positioning of 250 points of fixation. This has been obtained when patients dedicated their highest attention to the fixation target and no stimuli are projected. This is also called PRL-High This location point is used by the instrument for a second estimate of PRL location that was calculated at the end of the examination, and it is the reference point for all tested points.

This was the PRL-Low. Both location estimates were represented graphically on the screen or print displays with different colors. So the instrument automatically calculated fixation stability estimates relative to the PRL-Low location. The fixation stability analysis provided by the instrument was displayed according both to Fujii method and BCEA calculation. BCEA is based on the minor and major axes of an ellipse area covering fixation eye movements and takes into account 2SD measures of each recorded eye movement. The results are expressed in square degrees.

Then, we assessed scotoma size and density and the central retinal sensitivity (10°) by Microperimetry. We carried out these test each eye separately.

After the complete clinical-functional analysis, each patient underwent 10 training sessions of 10 minutes for each eye, performed once a week using the MAIA biofeedback technique. Subjects were asked to move their eyes according to an audio feedback which advised them whether they were getting closer to the target fixation position chosen as new PRL. Frequency of such audio feedback increased thorough a continuous bleep when fixation was overlapped onto the target. On the contrary the audio feedback decreased for intensity and frequency when fixation was unstable and “fluctuating” away from the target. The fixation on preferred retinal target (PRT) has been made successful as long as possible in order to stimulate cerebral plasticity. All the before-mentioned tests were repeated at the end of low-vision rehabilitation that was after 10 weeks. Statistical analysis was performed using Student’s test. P values less than 0.05 were considered statistically significant.

Results Mean distance best corrected visual acuity (BCVA) was 1.02 logMAR (DS±0.03) at the baseline assessment and 0.79logMAR (DS±0.07) at the end of visual rehabilitation. This result was not statistically significant with p=0.054.

Near visual acuity, based on the mean critical print size value, improved from 36.4 to 11.7; this result was statistically significant with p=0.031.

Reading speed improved from a mean value of 25w/min at the beginning of the study to 45 w/min at the end, and was accompanied by a decrease in the character size that could be read by the patient (from 36.4 to 11.7); this result was statistically significant with p= 0.031.

Fixation analysis and retinal sensitivity According to Fujii classification, at the beginning of visual rehabilitation the eyes examined were divided as follows: 1) Stable fixation, if more than two thirds of the fixation points were inside a circle centered on the PRL-Low: 0 eyes; 2) Relatively unstablefixation if more than one third of fixation points but no more than two thirds were inside a circle centered on the PRL-Low:17 eyes; however only 2 of these tended to a more stable fixation, so to be considered “at the limit” between this category and the previous one;

3) Unstable fixation if less than one third of fixation points were inside a circle centered on the PRL-Low: 10 eyes.

The percentage mean of fixation points included within 2° was 32.58% (DS±17.98), while within 4° was 62.12% (DS±22.41).

Regarding BCEA analysis the extension of the area encompassing the 63% of fixation points was 11.69°2 (DS±9.45) on average, while the area encompassing the 95% of fixation points was on average 54.75°2 (DS±28.13).

At the end of low vision rehabilitation the eyes were again divided as follows: 1) Stable fixation, if more than two thirds of the fixation points were inside a circle centered on the PRL-Low: 4 eyes; 2) Relatively unstable fixation if more than one third of fixation points but no more than two thirds were inside a circle centered on the PRL-Low: 18 eyes; 8 of them increased their fixation leading towards a stable one.

3) Unstable fixation if less than one third of fixation points were inside a circle centered on the PRL-Low: 5 eyes.

The percentage mean of fixation points included within 2° was 59.73% (DS±21.24), while within 4° was 89.35% (DS±4.15).

BCEA analysis had the area encompassing the 63% of fixation points half-reduced with 5.67°2 (DS±3.86), while the area encompassing the 95% of fixation points reduced more than half of the beginning one with 18.51°2 (DS±13.93).

Student’s t test evidenced a statistically significant increase in average fixation stability (p=0.0023) and the mean single point retinal sensitivity value improved from 6,42 dB (± 2,18) to 9, 24 dB (DS±4.73) with p<0.05.

Discussion Fixation is the period that lies between two saccadic eye movements and that allows us to maintain on the foveola the object of interest as stable as possible.

Actually the eye is never completely static during a “fixation task”: small involuntary eye movements are made whilst fixating. These fixation eye movements include drift, physiological tremor and microsaccades that act to keep the retina in motion compensating for head movement and neural adaptation23 (Martinez-Conde, 2006). In healthy observers using central fixation, the magnitude of these eye movements is small, and all fixations fall within a few minutes of arc of the target center. This ability to maintain steady fixation is impaired in people with central scotoma like in AMD. Low vision patients with macular disease develop functional adaptations aimed at maximizing residual functional vision. One such adaptive strategy attempts to reduce the impact of loss of macular vision by using an eccentric retinal area empowered to assume functionally macular role. They are the so-called PRLs. Establishment of such loci is however directly linked to oculomotor abilities, but PRLs are often closer to the retinal scotoma and unsuitable to carry out the wished visual tasks34-35-36 (TaritaNistor, L- Gonzalez, E- Markowitz, S).

The first aim of our study was that to realize a relocation of PRL to loci with highest retinal sensitivity creating a TRL (target retinal locus) or PRT, as indicated

by MAIA developers, here hence a more stable fixation.

The results of our study are surprising: at the beginning of the study no eye had a stable fixation, at the end, 15% of them reached it. Moreover only 5 eyes as opposed to 10 of the beginning had an unstable fixation.

These results arise from a complete analysis of fixation based on both Fujii and BCEA methods. Fujii’s classification underlines a growth of percentage of fixations within a circle of 2 and 4° diameter (from 32,58% to 59,73% he first and from 62,12% to 89,35% the second), and BCEA evaluation underlines that the area encompassing the 95% of fixation points was reduced more than half of the beginning one. Nevertheless regarding Fujii we andother researchers, because of its limitations, have recently pointed out the weaknesses of this classification system. First of all that it does not make allowances for the typical elliptical nature of fixationdistribution: for this reason, it discards much useful information and has a mere qualitative meaning. On the other hand, a more complete method of quantifying stability is to calculate the area of a bivariate contour ellipse encompassing a given proportion of the highest density eye position samples. This calculation takes into account the correlation between the horizontal and vertical positions and is relatively straightforward6(Caldara, R.- Miellet, S, 2011).

Biofeedback is a psychoâ&#x20AC;&#x201C;physiological way to voluntary control a non-voluntary parameter, this usually is done by acoustic modulation on the parameter37 (Vingolo et al.2009).

As regards biofeedback techniques applied to vision, various authors824 (Contestabile et al. 2002; Mezawa et al. 1990) have proposed different visual rehabilitation techniques ad instruments using biofeedback strategies ranging from basic systems, such as Accommotrac Vision trainer and IBIS (Improved Biofeedback Integrated System), to more complex instruments such as the fundus related MP-1 microperimeter or the more innovative MAIA15 (Giorgi et al.2005).

As found by Mezawa et al. auditory biofeedback can be useful for the treatment of patients affected by congenital nystagmus who have been found to report a subjective gain and an improvement of foveation time, amplitude and frequency at the end of the visual training. The effects of biofeedback on visual training have also been exploited in myopia30 (Rupolo et al.1997) and in other macular diseases13-29-38(Pacella et al. 2012 Vingolo et al.2007), reporting often improvements in visual acuity, fixation behavior, retinal sensitivity and reading speed.

The new MAIA microperimeter feedback examination allows us to train the patient to fixate the target with the new PRL (PRT). Sound perception increases the conscious attention of the patient,1-5 (Alpeter et al. 2000; Buia and Tiesinga 2006), thereby facilitating the lock-in of the visual target and increasing the permanence time of the target itself on the retina. This mechanism probably facilitates stimuli transmission between intraretinal neurons as well as between the retina and brain, where the highest degree of stimuli processing takes place, giving like a consequence the support of a remapping phenomenon16 (Higgins E1, Rayner K.).

Cortical neurons located in the retinotopic position corresponding to the scotoma receive some degree of activity from the unimpaired neurons in the area surrounding the lesion. Andrade2 (2001) and Safran31 (1996) demonstrated that these weak connections are gradually reinforced and that the system eventually evolves into a new stable state, in which every neuron once again receives the same amount of activity from the source layer. Plasticity constitutes the basis of behavioral changes as a result of experience. It refers to neural network shaping and re-shaping at the global level and to synaptic contacts remodeling at the local level, either during learning or memory encoding, or as a result of acute or chronic pathological conditions. 'Plastic' brain reorganization after central nervous system lesions has a pivotal role in the recovery and rehabilitation of sensory and motor dysfunction, but can also be "maladaptive"7-18 (Cheung, 2005- Leigh, 2006)Cerebral plasticity has a main role; indeed the BFD effect is related to the brainâ&#x20AC;&#x2122;s ability to perceive an efficient PRL for visual tasks25 (Moxon 2014).

Studies performed by Nilsson26-27(2003) have described the use of multiple PRLs under different light conditions and for different tasks. Patients are often unaware of how and when they use different PRLs, as reported by Schuchardh32-33 (2005) and Crossland9-10-11 (2005). They can prefer the use of a smaller but more sensible area, for example to identify a bus number, or choose a larger and peripheral area to examine a wide scene. Choosing of PRL can change also on the strength of other factors like environmental lighting 17 (Lei H, Schuchard RA).

The absolute certainty is the crucial role played by PRL in everyday activities and is the improvement of quality of life guaranteed by biofeedback 4 (Bressler, 2003).

Finally it should be stressed that the ability of PRL to drive ocular movements, either if it is understood as ability related to the number and characteristics of saccades or as fixation stability, is closely related to reading acuity and to reading speed.

Visual acuity often is the only functional parameter studied in low vision patients to evaluate successful rehabilitative strategies, but usually for distance and barely for near vision. In our opinion reading speed test is more significant because it is more difficult to understand than single letter on Mn read chart.Sometimes near visual acuity reached with low vision aid is due to a bad positioning of new PRLand it is not indicative of a successful and functioning reading and comprehending text,especially in an eccentric fixation localization. This discrepancy is particularly evident in patients in which an absolute scotoma is at the center of a surrounding ring of vision. Useful for single letters but not enough to understand words12-14(Deruaz, 2002 â&#x20AC;&#x201C; Falkenberg, 2007).

Similarly PRL if interrupted by a scotomatous area, on one or both sides, causes lost of word fluency and line drop with difficulties in full comprehension of the text allure26 (Frennesson & Nilsson, 2003). For this reason, in our studyclinic and functional evaluation were pointed out on the basis of traditional tests, but we underlined results obtained with reading speed in terms of words for minute.

Moreovernear visual acuity was calculated in terms of character points to have a fast relationship with reading speed of same size. Also in this case our results were highly significant (p<0.05%).

In conclusion we think that fixation isa new reliablefunctional key-parameter, even though a bitunder estimated in visual rehabilitation practice.

Obviously this must be flanked by a correct medical and surgical treatment for main diseases and a customized low vision strategy that must be centered on a perfect choice of PRL positioning. This usually leads to animprovement in quality of vision of the patients and a recovery, which is not only physical but also psychological, contributing in ameliorating patients and family quality of life.

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