Microperimetric Biofeedback Training for Children with Idiopathic Infantile Nystagmus Syndrome: a Short-and-Long Term Analysis

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The patients were followed for short and long term. 25 cases (9.3 ± 2.3 years old) trained on the MAIA microperimeter for 80 minutes delivered within 4 weekly sessions. They were followed for the short (1 week to 1 month) and long term (22 patients, from 8 months, up to 5 years). Binocular distance and near vision, fixation stability (FS), reading speed, contrast sensitivity, and QoL showed a significant improvement post-BT on short and long term. Stereopsis did not improve. Distance and near vision improved 1 ETDRS line, contrast improved 2 lines on 10% contrast Colenbrander Test, reading speed improved 22 words/minute, and QoL 1.3 points. FS could be measured in 48% of the cases, and improved 38%. BT had a significant long lasting positive effect on visual functions and QoL in children with idiopathic nystagmus. This research suggests that, as a low cost-benefit therapy, BT may become a new therapeutic option for these cases. Biological sciences/Neuroscience Biological sciences/Psychology Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Neurology nystagmus biofeedback quality of life low vision vision rehabilitation microperimeter Figures Figure 1 Figure 2 Figure 3 Introduction Infantile idiopathic nystagmus syndrome occurs in 31% of all pediatric nystagmus cases, being the most common cause of nystagmus is oculocutaneous albinism. 1 , 2 Idiopathic nystagmus is almost always bilateral, conjugate, and occurs in the horizontal plane, in upgaze and downgaze, with little variability. 3 As a general rule, although the visual acuity is not profoundly decreased, contrast sensitivity, stereopsis and other visual functions may be affected. Consequently, this can negatively impact quality of life (QoL). 4 In the presence of low vision or marked abnormal head posture, interventions are warranted. Current therapies include muscle surgery, the use of optical devices, oral drugs, topical drugs, and botulinum toxin injections. 5 – 11 Low vision rehabilitation interventions with magnifiers may be necessary. However, distance vision is the most difficult to improve in low vision patients, requiring the use of telescopes or head worn video magnifiers. Current therapies aim to improve oculomotor balance, so the foveation time increases. With the advent of microperimetry, which makes it possible to observe the ocular movements and train it simultaneously, the audio-luminous biofeedback training (BT) module became available. 12 BT on the microperimeter has been used for twenty years in vision rehabilitation, promoting eccentric viewing deployment and improving visual functions after central vision loss. 13 – 15 Our research group has studied the use of BT to improve fixation stability (FS) in idiopathic nystagmus cases. We used the MAIA microperimeter to train 10 children in a prospective pilot study that compared pre-and-post-BT visual functions 1 week after training. 16 , 17 The study showed an improvement in distance and near vision, contrast sensitivity, reading speed, parental questionnaire of quality of life, stereopsis, and a trend for improvement in fixation stability. In this prospective pre-and-post case series we hypothesized that these improvements would be maintained for a longer period in an extended cohort. This would encourage vision rehabilitation using BT, yielding a new therapeutic option for idiopathic nystagmus syndrome cases. Methodology This was a prospective case series study. Children with idiopathic nystagmus syndrome were followed for more than 8 months post-BT for visual functions and QoL, comparing pre- and post-BT on short (1 week to 1 month) and long term (8 months to 5 years). The study was approved by the University Health Network Research Ethics Board. The research followed the principles of the Declaration of Helsinki. All patients and their legal guardians signed an informed consent form and assent when pertinent. The study is registered at ClinicalTrials.gov, identifier: NCT04142307. The children were referred from the Hospital for Sick Children, Toronto, Canada for the LVR service from the University of Toronto. The inclusion criteria were idiopathic infantile nystagmus previously diagnosed accordingly by electroretinogram and other tests as needed, age 5–17 years, and ability to follow the stimuli and training instructions. The exclusion criteria were the presence of other ocular diseases and secondary nystagmus. Visual Acuity, Contrast, Reading Speed, and Stereopsis Assessment During the screening and follow up visits, the patients were assessed for Binocular Best Corrected Visual Acuity (BBCVA) for distance with ETDRS charts at 4 meters, and binocular Colenbrander 100% ETDRS chart for near vision, using the best correction. Contrast Sensitivity was assessed with the Colenbrander 10% ETDRS chart, which is suitable for children. Reading speed was assessed with the Minnesota Low-Vision Reading Test (MNRead) App on the iPad using the best binocular near correction. Stereopsis was assessed with the Frisby Stereo Test at the maximum distance possible for the best stereoacuity. Fixation Stability The 20” fixation test was performed on baseline and follow up visits. Preferred retinal locus or fixation points on the microperimetry report were assessed with the MAIA microperimeter (Centervue, Padova, Italy). The fixation stability (FS) was calculated by the MAIA software using 2 different methods: 1) according to Fuji’s classification, the percentage of fixation points that fall within a 1° circumference radius centered on the fovea (P1), and within a 2° circumference radius centered on the fovea (P2); and 2) a 63% bivariate contour ellipse area (BCEA) calculated by the MAIA microperimeter. 18 The raw data points registered were collected from the MAIA for each test. The FS test represents up to 500 fixation points, as the MAIA registers the points at 25Hz. Quality of Life QoL was assessed with the Children’s Visual Function Questionnaire (CVFQ), version 3, 2004. Questions 2–34 were suitable for and used in this study. 19 Biofeedback Training Sessions On top of the fixation test report, a fixation training target (FTT) was selected at the foveola on the MAIA screen. Only the eye with the better visual acuity or FS was delivered BT on the microperimeter.Each session included BT attempts of 20 minutes, plus resting time, that was also given on demand. In each BT session a standard LED fixation target (FT) consisting of a small red circle of 0.76° was presented by the microperimeter, accompanied by audio and luminous stimuli in a synchronous manner. As the nystagmus frequency increased, the audio decreased the frequency of the beep presented. The patient was guided to try to control the eye movements to instinctively make the sound on the audio feedback become more frequent until it became a continuous sound. This signaled to the patient that the best oculomotor control had been achieved, and at this moment a white dot appeared filling the interior of the circle. Altogether, this consisted of a bimodal audio-luminous stimulation. A video illustration of this method is available at: https://drive.google.com/file/d/1eD2tuqUX0oDnUljkEImIpUVMmKFbR-9p/view?usp=sharing . The BT protocol involved 4 consecutive weekly sessions of training. P1 and P2 values were collected for every training session. A follow up visit occurred 1 week to 1 month post-BT (short term follow up), and a long-term follow up visit after 8 months post-BT. Primary and Secondary Outcomes Primary outcome measures selected for analysis were BBCVA for distance and near, FS (P1, P2, BCEA), reading speed, contrast sensitivity, stereopsis and QoL CVFQ scores. Secondary outcomes were BT P1 and P2 performance results for each session (Table 1 ). Table 1 Outcomes, Biofeedback Training, Visit Testing and Treatment Schedule V1 V2 – V5 V6 V7 Baseline BT sessions 1 week follow-up Long term follow-up Fixation Stability: P1 (%fixations up to 1 0 from fovea) P2 (%fixations up to 2 0 from fovea) BCEA 63% BBCVA distance and near Reading speed (MNRead App), Contrast sensitivity, (Colenbrander 10% chart), Stereopsis (Frisby Stereotest), QoL parental Children’s Visual Function Questionnaire 4 weekly sessions − 20 min MAIA Microperimeter Trained retinal locus (TRL) → foveal fixation Monocular - better BCEA P1 (%fixations up to 1 0 from fovea) P2 (%fixations up to 2 0 from fovea) All baseline tests repeated All baseline tests repeated Statistical Analysis Data analysis was based on descriptive statistics that include frequency distributions, a measure of central tendency (mean) and a measure of dispersion (standard deviation). Statistical comparison between the measures was made by t-tests. ANOVA repeated measures test was used for comparisons. Differences were considered statistically significant at a p-value of less than 0.05. Correlation coefficient, confidence interval at 95%, and Cohen’s d coefficient were calculated for the variables. Results Twenty five patients with idiopathic nystagmus were included in the study. 25 patients completed the short term visit (1 week to 1 month after ) and 22 patients completed the long term follow up visit (more than 8 months after BT). The average age of the patients was 9.3 ± 2.3 years, 60% were male, and 40% trained the right eye. 22 of the patients were tested after 1.6 ± 1.3 years from BT sessions, ranging from 8 months to 5 years post-BT (Table 2). Table 2: Baseline Demographic Characteristics IINS Variable Total (N = 25 patients) Age (years), Mean ± SD 9.3 ± 2.3 Male N (%) 15 (60.0) Right eye, N (%) 10 (40.0) Follow-up period (years, Mean ± SD) 1.6 ± 1.3 For most variables, on short-and-long-term, the Cohen’s d coefficient showed a medium size effect, and the correlation coefficient showed a strong or very strong association. These and the confidence intervals were also shown on tables 3 and table 4. Figures 1 and Figure 2 illustrate the progression of the variables. Table 3: Size effect, Confidence Interval, Correlation Coefficient, and P Values for Pre-and- Long Term Post-BT Variable n Cohen’s d Size effect CI 95% Cor coefficient Correlation P FS BCEA 11 0.59 Medium -2.69, 13.40 0.91 Very Strong 0.04 FS P1 12 -0.69 Medium -29.77,-1.72 0.37 Moderate 0.03 FS P2 12 0.60 Medium -20.07,-2.08 0.69 Strong 0.02 Distance Vision Long Term 23 0.66 Medium 0.08,0.14 0.93 Very Strong <0.0001 Near Vision Long Term 23 0.7 Medium 0.03,0.15 0.49 Moderate 0.003 Reading Speed Long Term 16 0.52 Medium -37,-8.9 0.82 Very Strong 0.003 CVFQ QoL Long Term 15 0.49 Small -2.3,-0.43 0.82 Very Strong 0.007 Contrast 22 1.02 Large 0,0.05 0.58 Moderate 0.0001 Table 4: Size effect, Confidence Interval, Correlation Coefficient, and P Values for Pre-and-Short Term Post-BT Variable n Cohen’ d Size effect CI 95% Cor coefficient Correlation P Distance Vision Short Term 25 0.5 Medium 0.05,0.11 0.93 Very Strong <0.0001 Near Vision Short Term 25 0.67 Medium 0.04,0.13 0.74 Strong <0.001 Reading Speed Short Term 17 0.55 Medium -36.07,-12.18 0.85 Very Strong <0.001 CVFQ QoL Short Term 15 0.49 Small -2.25,-0.41 0.83 Very Strong 0.007 Contrast 22 0.82 Large 0.05,0.15 0.73 Strong 0.0001 Figure 1: Fixation Stability pre-and-post-Biofeedback Training (BT) Figure 2: Best Corrected Binocular Distance Vision, Binocular Near Vision, Reading Speed, Contrast Sensitivity, and QoL questionnaire progression Training Performance The training performance analysis across the sessions showed that P2 was significantly higher during the second session compared to the first , from 57.4 ± 23% to 63.3 ± 21.5% (R=0.85, p=0.01), P1 and P2 were significantly higher on the third training session compared to the first session, from 28.3±16.9% to 34.1±17.2% for P1 (R=0,80, p=0.009), and 57.4 ±2 3% to 65.8±16.3% for P2 (R=0.71, p=0.013). There was no significant difference from the fourth to the first training sessions for P1 but a trend for P2, from 57.4 ± 23% to 64.6 ± 18.7% (R=0.56, p=0.07). ANOVA showed a significant improvement in the performance for P2 overall, F (3,100)= 3.0, p=0.03. Fixation Stability For the FS measures, we verified a low percentage capture of fixation points by the MAIA compared to the total 500 points expected for normal cases. This can be explained as idiopathic nystagmus may have a speed of 25.3 degrees/second on average, and the MAIA registration reaches 20 degrees in diameter, which could have not being enough to capture all eye movements. 20 Therefore, we excluded from the FS analysis the cases who had registered less than 34 points on the 20” fixation test. This criteria was based on the observation of the points on the MAIA reports. Twelve patients could be measured for FS on baseline and post-BT (short/ long term, the best take was always considered). Using Fuji’s classification, P1 improved significantly from 41.1 ± 18.6% to 56.9 ± 20.6% on long term follow up (p=0.03) and P2 improved from 70.7 ±18.6 to 81.8 ± 17.5% (p= 0.02). For 11 cases, BCEA improved from 9.6 ± 11.8 to 4.2 ± 4.9 02 , CI 95% (0.91-9.69). Figure 3 shows the fixation test (20”) from a baseline visit compared to 1 week post-BT and also the report for a BT session, showing how BT increased the fixation stability. Figure 3: Fixation Stability pre, during, and post-Biofeedback Training (BT) This figure shows how the BT is done and its effect on FS. On the left, the fixation stability is represented through the BCEA 63% (inner ellipse) and 96% (outer ellipse). Each point in green in the graph represents one attempt of fixation.The instability of the fixation is shown by the wideness of the ellipses on the Fixation 20” pre-BT test. At the center, the fixation points fall closer to the center, the point that was set for the training. P1 is represented by the green circle, P2 by the yellow circle, showing BT performance. On the right, the spontaneous fixation stability post-BT improved visibly, shown by a smaller BCEA 63% and 95% areas. Distance and Near Vision BBCVA improved from 0.38±0.18 logMAR to 0.29±0.18 logMAR in the short-term, and to 0.26±0.18 logMAR in the long-term (F(2,66)=36.54, p<0.001). Short-term was significantly better than baseline (p<0.001), and long-term was better than baseline (p<0.001). Near vision improved from 0.09±0.15 log MAR to 0.004±0.1 logMAR on short-term, and to 0.008±0.07 logMAR on long-term (F (2,66)=10.07, p=0.002). Short-term was significantly better than baseline (p<0.001) and long-term was better than baseline (p=0.003). Contrast Sensitivity Contrast sensitivity improved significantly from 0.15 ± 0.16 log units to 0.04 ± 0.1 log units in the short term, and further to 0.02±0.08 log units in the long term (F(2,63=18.99, p<0.001). Reading Speed Reading speed improved from 84.7 ±42.6 to 108.8±43.9 on short term and to 109±44.2 words/minute (wpm) on long term post-BT (F2,45=11.09, p<0.001). Short term was better than baseline (p<0.001) and long term was better than baseline (p=0.003). Stereopsis Stereopsis did not improve in the short term or long term. Quality of life Parental quality of life questionnaire total score improved from 25.9 ± 2.9 to 27.32 ± 2.7 on short term and to 27.3 ± 2.7 on long term post-BT (F(2,42)=9.68, p<0.001). Short term was better than baseline (p=0.007) and long term was better than baseline (p=0.007). Enjoying traveling with the family, improvement in fine near vision tasks such as drawing, painting and reading books are a few examples disclosing the relevance of the BT therapy for these patients. Reports from our patients and their families are found on the media: https://toronto.ctvnews.ca/video/c2856897-new-therapy-gives-4-year-old-new-outlook-on-life. Side Effects No side effects occurred, besides variable tiredness and eye dryness during the training sessions. After BT sessions, in many cases, nystagmus intensity reduction was visible when the patient attempted fixation and if told to remember the BT acoustic signal. This better control also occurred naturally during conversations, playing video games or improving psychological behaviour, as related by the parents. Impressively, some cases who did not fulfill the criteria for driving in Ontario, Canada, improved to the eligible level and were allowed to drive safely. Discussion In this study we present BT as a new non-invasive therapy, with no side effects, showing a significant improvement in visual functions and quality of life in patients with idiopathic infantile nystagmus syndrome, confirming our last studies. 16 , 17 The benefits from BT continued up to 5 years after BT. The last recent advance in the treatment of nystagmus was the use of topical brinzolamide in adults. However, it entails side effects and has to be used continuously to keep its benefits. 10 Differently from central vision loss, BT for idiopathic nystagmus trains the fixation at the fovea, and needs no relocation because the retina is intact. Its mechanisms of action remain not fully understood, but involve brain plasticity. 20 BT for Nystagmus was described as early as 1980 used in other instruments, 21 and since 2018 our team has studied BT on the microperimeter. Microperimeters may be superior to the former BT methods due to its bimodal stimulation, that amplifies multisensory plasticity, and also the recalibration of spatial awareness between vision and audition in sub-cortical (superior colliculus and pulvinar controlling covert attention) and cortical areas (hMT+/V5). 22 The performance during the training was progressively better across the visits, markedly on session 3 compared to session 1. There was a trend for P2 to improve in the fourth session, which is justifiable, since P2 requires less control of the fixation than P1. As the performance was not better for P1 on the last session, we believe that the brain memory for the fixation oculomotor control was not totally consolidated after four sessions, therefore, there could be room for further improvement. FS BCEA 63% was significantly better post-BT when reliable. Fuji’s classification, the percentage of fixation points within 1 0 (P1) and 2 0 (P2) radius from the fovea during 20”confirmed this improvement. In our observations, nystagmoid movements frequently fell out of the MAIA’s capacity, so it was not possible to measure the FS in 52% of the cases. For the 48% cases measured,the FS improvement suggested better oculomotor control after BT. The literature has also reported significant BCEA improvement post-BT in many different studies. 15 BBCVA and contrast sensitivity, two correlated variables, were positively impacted by BT. Distance vision improvement is a challenge in low vision rehabilitation, since magnification with telescopes or bioptics reduces the visual fields. Indeed, some patients who had low vision before BT did not have it anymore after training. Patients and parents manifested great satisfaction during the sessions and follow up. The improvement of a single ETDRS line for visual acuity may be the difference for being eligible for a driver’s license, psychological comfort for social conversations, reading menus in restaurants, and can never be overemphasized. Driving eligibility in Ontario, Canada, was achieved by some patients from our study when they reached adolescence. These patients would not be able to drive following the expected visual development for the age without BT. Reading speed and near vision critical print size were positively impacted by BT in our study, showing a significant improvement post-BT. Indeed, a reference to better school performance was frequent post- therapy, and some patients who needed to use bifocals as a magnification for near vision did not need them after training. Stereopsis showed a significant improvement in our last study with 10 patients, but was not better on the present cohort post-BT. This may be explained by the fact that, in nystagmus, visual acuity is not related to stereopsis on a linear correlation. 23 QoL CVFQ scores increased significantly after BT. In our last study, it showed improvement in all its subsections, including personality and visual competence. We had many examples of this in this study, including one child who improved her behavior drastically post-BT. The BT protocol used was feasible for application in a clinical setup, although it requires specialized staff training. The BT is a non harmful, inexpensive and non-surgical therapy. BT can be repeated as needed, and we hypothesize that the repetition of the sessions can achieve higher results based on the training performance progression. BT effects were maintained after the sessions. After researching in Cochran, PubMed, and Google Scholar databases, we could not find a study that reported the long term results for BT in children with nystagmus. Unlike brinzolamide therapy, that has to be used three times a day continuously, BT benefits persist after only 4 sessions. Following validation with larger studies, BT could provide a novel and long lasting visual rehabilitation option for patients with idiopathic nystagmus. A limitation of this study was the lack of a Nystagmus Acuity Function (NAFX) to measure the nystagmus amplitude and frequency. Another limitation of this study was the absence of a control group, which should be done on the next study as a randomized controlled clinical trial. Therefore, the continuation of this research is mandatory. Declarations Acknowledgments We acknowledge the efforts of Luminita Tarita-Nistor, PhD and scientist in Low Vision Rehabilitation affiliated to the Krembil Institute, University Health Network, who cooperated with the revision and statistics of this study and also encouraged our efforts to accomplish it. Author Contribution Statements Dr. Mariana Misawa participated in data collection, in designing the study, in the interpretation of the data, writing the manuscript, and coordinating the study. Dr. Mohab Eldeeb participated in the statistical analysis and interpretation of the results. Dr. Yulia Pyatova participated in study design, study coordination, and data collection. Dr. Michelle Markowitz screened and referred the patients to the low vision clinic, and participated in the data collection. Max Goldsmith participated in the data collection and study coordination. Dr. Samuel Markowitz participated in the design of the study, interpretation of the results and reviewing the manuscript. Dr. Monica Daibert Nido , the correspondence author, adapted biofeedback training for nystagmus in children in the low vision clinic, designed the study, collected data, did statistical analysis, interpreted the results, and wrote the manuscript. Data Availability The datasets generated during and/or analysed during the current study are available at https://docs.google.com/spreadsheets/d/1rKyFKfGkzNH-Z6fVRH7XdE2_GTEUmpTcbxvUymyMTUY/edit#gid=0 Competing interests The author(s) declare no competing interests. References Sarvananthan, N. et al. The Prevalence of Nystagmus: The Leicestershire Nystagmus Survey. Investigative Ophthalmology & Visual Science 50, 5201–5206 (2009). Abadi, R.V. (2002) ‘Motor and sensory characteristics of infantile nystagmus’, British Journal of Ophthalmology , 86(10), pp. 1152–1160. doi: 10.1136/bjo.86.10.1152 . Das, A. et al. 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(2018) ‘Neuroimaging study of Alpha and beta eeg biofeedback effects on neural networks’, Applied Psychophysiology and Biofeedback , 43(2), pp. 169–178. doi: 10.1007/s10484-018-9396-2 . Sharma, P. et al. (2000) ‘Reduction of congenital nystagmus amplitude with auditory biofeedback’, Journal of American Association for Pediatric Ophthalmology and Strabismus , 4(5), pp. 287–290. doi: 10.1067/mpa.2000.107900 . Kramer, A., Röder, B. and Bruns, P. (2020) ‘Feedback modulates audio-visual spatial recalibration’, Frontiers in Integrative Neuroscience , 13. doi: 10.3389/fnint.2019.00074 . Liu C, Yang J.(1997) Stereopsis disorders in patients with congenital nystagmus. Yan Ke Xue Bao . 13(1) pp. 1–4. Additional Declarations No competing interests reported. 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Markowitz","email":"","orcid":"","institution":"University Health Network Hospitals, University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Samuel","middleName":"N.","lastName":"Markowitz","suffix":""},{"id":313610527,"identity":"fc0d5fa7-d779-41bb-bbc0-0090b6bf51da","order_by":6,"name":"Monica Daibert Nido","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBACg+M9xh9+GBy2t2dvPvjgZ5uEvQED88PHPHi0WJ45Z3Cwp+Ixj2HPsWTD3nM2PAYMbMbGc/Bosb+Rb3CY5cxnHoMbOWrSjP/SgFp4xKT/4NFiBtLC2AbWwlbNuO0wSAubdA5eLbkbgFpuA7XkHrtNqpa8tNuyxGgBuufDYcZ/50EOMyvmbfsP0YIvxIAqCw6zth0Ha2HmbTsM8T5eLWfOFBzsBWoBBbJkL0gLMzCQ8WoBReXPNkhUQhjtzfijEgtgJk35KBgFo2AUjAIsAACTAWBoc79sTAAAAABJRU5ErkJggg==","orcid":"","institution":"University Health Network Hospitals, University of Toronto","correspondingAuthor":true,"prefix":"","firstName":"Monica","middleName":"Daibert","lastName":"Nido","suffix":""}],"badges":[],"createdAt":"2024-05-28 16:57:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4492358/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4492358/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58309998,"identity":"0f5c5515-00f2-4036-8521-720c354a64cc","added_by":"auto","created_at":"2024-06-13 19:05:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":50287,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFixation Stability pre-and-post-Biofeedback Training (BT)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4492358/v1/1e2997c43eab8e62a16749ec.jpg"},{"id":58309676,"identity":"35b1bea1-68d6-47db-9af2-e4601f84618a","added_by":"auto","created_at":"2024-06-13 18:57:45","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":165109,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBest Corrected Binocular Distance Vision, Binocular Near Vision, Reading Speed, Contrast Sensitivity, and QoL questionnaire progression\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4492358/v1/053412ce5c98497431a2c636.jpg"},{"id":58309678,"identity":"147355e9-996b-4796-94ec-9d43974bfd90","added_by":"auto","created_at":"2024-06-13 18:57:45","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":33542,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFixation Stability pre, during, and post-Biofeedback Training (BT)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4492358/v1/e1137317c4be43a9f67f9e52.jpg"},{"id":59826158,"identity":"96279418-069f-4abc-a73e-e202eb7f6754","added_by":"auto","created_at":"2024-07-08 05:55:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1152355,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4492358/v1/ca5966ca-130f-4eb1-bb5c-0a539333f886.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Microperimetric Biofeedback Training for Children with Idiopathic Infantile Nystagmus Syndrome: a Short-and-Long Term Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInfantile idiopathic nystagmus syndrome occurs in 31% of all pediatric nystagmus cases, being the most common cause of nystagmus is oculocutaneous albinism.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Idiopathic nystagmus is almost always bilateral, conjugate, and occurs in the horizontal plane, in upgaze and downgaze, with little variability.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e As a general rule, although the visual acuity is not profoundly decreased, contrast sensitivity, stereopsis and other visual functions may be affected. Consequently, this can negatively impact quality of life (QoL).\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e In the presence of low vision or marked abnormal head posture, interventions are warranted. Current therapies include muscle surgery, the use of optical devices, oral drugs, topical drugs, and botulinum toxin injections.\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Low vision rehabilitation interventions with magnifiers may be necessary. However, distance vision is the most difficult to improve in low vision patients, requiring the use of telescopes or head worn video magnifiers.\u003c/p\u003e \u003cp\u003eCurrent therapies aim to improve oculomotor balance, so the foveation time increases. With the advent of microperimetry, which makes it possible to observe the ocular movements and train it simultaneously, the audio-luminous biofeedback training (BT) module became available.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e BT on the microperimeter has been used for twenty years in vision rehabilitation, promoting eccentric viewing deployment and improving visual functions after central vision loss.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Our research group has studied the use of BT to improve fixation stability (FS) in idiopathic nystagmus cases. We used the MAIA microperimeter to train 10 children in a prospective pilot study that compared pre-and-post-BT visual functions 1 week after training.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The study showed an improvement in distance and near vision, contrast sensitivity, reading speed, parental questionnaire of quality of life, stereopsis, and a trend for improvement in fixation stability. In this prospective pre-and-post case series we hypothesized that these improvements would be maintained for a longer period in an extended cohort. This would encourage vision rehabilitation using BT, yielding a new therapeutic option for idiopathic nystagmus syndrome cases.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eThis was a prospective case series study. Children with idiopathic nystagmus syndrome were followed for more than 8 months post-BT for visual functions and QoL, comparing pre- and post-BT on short (1 week to 1 month) and long term (8 months to 5 years). The study was approved by the University Health Network Research Ethics Board. The research followed the principles of the Declaration of Helsinki. All patients and their legal guardians signed an informed consent form and assent when pertinent. The study is registered at ClinicalTrials.gov, identifier: NCT04142307.\u003c/p\u003e \u003cp\u003eThe children were referred from the Hospital for Sick Children, Toronto, Canada for the LVR service from the University of Toronto. The inclusion criteria were idiopathic infantile nystagmus previously diagnosed accordingly by electroretinogram and other tests as needed, age 5\u0026ndash;17 years, and ability to follow the stimuli and training instructions. The exclusion criteria were the presence of other ocular diseases and secondary nystagmus.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eVisual Acuity, Contrast, Reading Speed, and Stereopsis Assessment\u003c/h2\u003e \u003cp\u003eDuring the screening and follow up visits, the patients were assessed for Binocular Best Corrected Visual Acuity (BBCVA) for distance with ETDRS charts at 4 meters, and binocular Colenbrander 100% ETDRS chart for near vision, using the best correction.\u003c/p\u003e \u003cp\u003eContrast Sensitivity was assessed with the Colenbrander 10% ETDRS chart, which is suitable for children.\u003c/p\u003e \u003cp\u003eReading speed was assessed with the Minnesota Low-Vision Reading Test (MNRead) App on the iPad using the best binocular near correction.\u003c/p\u003e \u003cp\u003eStereopsis was assessed with the Frisby Stereo Test at the maximum distance possible for the best stereoacuity.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eFixation Stability\u003c/h2\u003e \u003cp\u003eThe 20\u0026rdquo; fixation test was performed on baseline and follow up visits. Preferred retinal locus or fixation points on the microperimetry report were assessed with the MAIA microperimeter (Centervue, Padova, Italy). The fixation stability (FS) was calculated by the MAIA software using 2 different methods: 1) according to Fuji\u0026rsquo;s classification, the percentage of fixation points that fall within a 1\u0026deg; circumference radius centered on the fovea (P1), and within a 2\u0026deg; circumference radius centered on the fovea (P2); and 2) a 63% bivariate contour ellipse area (BCEA) calculated by the MAIA microperimeter.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe raw data points registered were collected from the MAIA for each test. The FS test represents up to 500 fixation points, as the MAIA registers the points at 25Hz.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eQuality of Life\u003c/h2\u003e \u003cp\u003eQoL was assessed with the Children\u0026rsquo;s Visual Function Questionnaire (CVFQ), version 3, 2004. Questions 2\u0026ndash;34 were suitable for and used in this study.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eBiofeedback Training Sessions\u003c/h2\u003e \u003cp\u003eOn top of the fixation test report, a fixation training target (FTT) was selected at the foveola on the MAIA screen. Only the eye with the better visual acuity or FS was delivered BT on the microperimeter.Each session included BT attempts of 20 minutes, plus resting time, that was also given on demand. In each BT session a standard LED fixation target (FT) consisting of a small red circle of 0.76\u0026deg; was presented by the microperimeter, accompanied by audio and luminous stimuli in a synchronous manner. As the nystagmus frequency increased, the audio decreased the frequency of the beep presented. The patient was guided to try to control the eye movements to instinctively make the sound on the audio feedback become more frequent until it became a continuous sound. This signaled to the patient that the best oculomotor control had been achieved, and at this moment a white dot appeared filling the interior of the circle. Altogether, this consisted of a bimodal audio-luminous stimulation. A video illustration of this method is available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://drive.google.com/file/d/1eD2tuqUX0oDnUljkEImIpUVMmKFbR-9p/view?usp=sharing\u003c/span\u003e\u003cspan address=\"https://drive.google.com/file/d/1eD2tuqUX0oDnUljkEImIpUVMmKFbR-9p/view?usp=sharing\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe BT protocol involved 4 consecutive weekly sessions of training. P1 and P2 values were collected for every training session. A follow up visit occurred 1 week to 1 month post-BT (short term follow up), and a long-term follow up visit after 8 months post-BT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePrimary and Secondary Outcomes\u003c/h2\u003e \u003cp\u003ePrimary outcome measures selected for analysis were BBCVA for distance and near, FS (P1, P2, BCEA), reading speed, contrast sensitivity, stereopsis and QoL CVFQ scores. Secondary outcomes were BT P1 and P2 performance results for each session (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcomes, Biofeedback Training, Visit Testing and Treatment Schedule\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e V1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eV2 \u0026ndash; V5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eV6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eV7\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBT sessions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 week follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLong term follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFixation Stability:\u003c/p\u003e \u003cp\u003eP1 (%fixations up to 1\u003csup\u003e0\u003c/sup\u003e from fovea)\u003c/p\u003e \u003cp\u003eP2 (%fixations up to 2\u003csup\u003e0\u003c/sup\u003e from fovea)\u003c/p\u003e \u003cp\u003eBCEA 63%\u003c/p\u003e \u003cp\u003eBBCVA distance and near\u003c/p\u003e \u003cp\u003eReading speed (MNRead App),\u003c/p\u003e \u003cp\u003eContrast sensitivity, (Colenbrander 10% chart),\u003c/p\u003e \u003cp\u003eStereopsis (Frisby Stereotest),\u003c/p\u003e \u003cp\u003eQoL parental Children\u0026rsquo;s Visual Function Questionnaire\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 weekly sessions \u0026minus;\u0026thinsp;20 min\u003c/p\u003e \u003cp\u003eMAIA Microperimeter\u003c/p\u003e \u003cp\u003eTrained retinal locus (TRL) \u0026rarr; foveal fixation\u003c/p\u003e \u003cp\u003eMonocular - better BCEA\u003c/p\u003e \u003cp\u003eP1 (%fixations up to 1\u003csup\u003e0\u003c/sup\u003e from fovea)\u003c/p\u003e \u003cp\u003eP2 (%fixations up to 2\u003csup\u003e0\u003c/sup\u003e from fovea)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll baseline tests\u0026nbsp;repeated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAll baseline tests repeated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData analysis was based on descriptive statistics that include frequency distributions, a measure of central tendency (mean) and a measure of dispersion (standard deviation). Statistical comparison between the measures was made by t-tests. ANOVA repeated measures test was used for comparisons. Differences were considered statistically significant at a p-value of less than 0.05. Correlation coefficient, confidence interval at 95%, and Cohen\u0026rsquo;s d coefficient were calculated for the variables.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwenty five patients with idiopathic nystagmus were included in the study. 25 patients completed the short term visit (1 week to 1 month after ) and 22 patients completed the long term follow up visit (more than 8 months after BT).\u003c/p\u003e\n\u003cp\u003eThe average age of the patients was 9.3 \u0026plusmn; 2.3 years, 60% were male, and 40% trained the right eye. 22 of the patients were tested after 1.6 \u0026plusmn; 1.3 years from BT sessions, ranging from 8 months to 5 years post-BT (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Baseline Demographic Characteristics IINS\u003c/strong\u003e\u003c/p\u003e\n\u003ctable width=\"377\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"247\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"131\"\u003e\n\u003cp\u003eTotal (N = 25 patients)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"247\"\u003e\n\u003cp\u003eAge (years), Mean \u0026plusmn; SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"131\"\u003e\n\u003cp\u003e9.3 \u0026plusmn; 2.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"247\"\u003e\n\u003cp\u003eMale N (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"131\"\u003e\n\u003cp\u003e15 (60.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"247\"\u003e\n\u003cp\u003eRight eye, N (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"131\"\u003e\n\u003cp\u003e10 (40.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"247\"\u003e\n\u003cp\u003eFollow-up period (years, Mean \u0026plusmn; SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"131\"\u003e\n\u003cp\u003e1.6 \u0026plusmn; 1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFor most variables, on short-and-long-term, the Cohen\u0026rsquo;s d coefficient showed a medium size effect, and the correlation coefficient showed a strong or very strong association. These and the confidence intervals were also shown on tables 3 and table 4. Figures 1 and Figure 2 illustrate the progression of the variables.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Size effect, Confidence Interval, Correlation Coefficient, and P Values for Pre-and- Long Term Post-BT\u003c/strong\u003e\u003c/p\u003e\n\u003ctable width=\"626\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eCohen\u0026rsquo;s d\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003eSize effect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eCI 95%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eCor coefficient\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eCorrelation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eFS BCEA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.59\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-2.69, 13.40\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.91\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eFS P1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e-0.69\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-29.77,-1.72\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.37\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eFS P2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.60\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-20.07,-2.08\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.69\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eStrong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eDistance Vision Long Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e23\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.66\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.08,0.14\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.93\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eNear Vision Long Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e23\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.7\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.03,0.15\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.49\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eReading Speed Long Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.52\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-37,-8.9\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.82\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eCVFQ QoL Long Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.49\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eSmall\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-2.3,-0.43\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.82\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eContrast\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e1.02\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003eLarge\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e0,0.05\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.58\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Size effect, Confidence Interval, Correlation Coefficient, and P Values for \u003c/strong\u003e\u003cstrong\u003ePre-and-Short Term Post-BT\u003c/strong\u003e\u003c/p\u003e\n\u003ctable width=\"626\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003eCohen\u0026rsquo; d\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"122\"\u003e\n\u003cp\u003eSize effect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eCI 95%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eCor coefficient\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eCorrelation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eDistance Vision Short Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e25\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"122\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.05,0.11\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.93\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eNear Vision Short Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e25\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.67\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"122\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.04,0.13\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.74\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eStrong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eReading Speed Short Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.55\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"122\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-36.07,-12.18\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.85\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eCVFQ QoL Short Term\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.49\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"122\"\u003e\n\u003cp\u003e\u003cstrong\u003eSmall\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e-2.25,-0.41\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.83\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eVery Strong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"93\"\u003e\n\u003cp\u003e\u003cstrong\u003eContrast\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"44\"\u003e\n\u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.82\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"122\"\u003e\n\u003cp\u003e\u003cstrong\u003eLarge\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.05,0.15\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.73\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003eStrong\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"64\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1: Fixation Stability pre-and-post-Biofeedback Training (BT) \u003c/strong\u003e\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFigure 2: Best Corrected Binocular Distance Vision, Binocular Near Vision, Reading Speed, Contrast Sensitivity, and QoL questionnaire progression\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTraining Performance\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe training performance analysis across the sessions showed that P2 was significantly higher during the second session compared to the first , from 57.4 \u0026plusmn; 23% to 63.3 \u0026plusmn; 21.5% (R=0.85, p=0.01), P1 and P2 were significantly higher on the third training session compared to the first session, from 28.3\u0026plusmn;16.9% to 34.1\u0026plusmn;17.2% for P1 (R=0,80, p=0.009), and 57.4 \u0026plusmn;2 3% to 65.8\u0026plusmn;16.3% for P2 (R=0.71, p=0.013). There was no significant difference from the fourth to the first training sessions for P1 but a trend for P2, from 57.4 \u0026plusmn; 23% to 64.6 \u0026plusmn; 18.7% (R=0.56, p=0.07). ANOVA showed a significant improvement in the performance for P2 overall, F (3,100)= 3.0, p=0.03.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFixation Stability\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the FS measures, we verified a low percentage capture of fixation points by the MAIA compared to the total 500 points expected for normal cases. This can be explained as idiopathic nystagmus may have a speed of 25.3 degrees/second on average, and the MAIA registration reaches 20 degrees in diameter, which could have not being enough to capture all eye movements.\u003cstrong\u003e\u003csup\u003e20\u003c/sup\u003e\u003c/strong\u003e Therefore, we excluded from the FS analysis the cases who had registered less than 34 points on the 20\u0026rdquo; fixation test. This criteria was based on the observation of the points on the MAIA reports. Twelve patients could be measured for FS on baseline and post-BT (short/ long term, the best take was always considered). Using Fuji\u0026rsquo;s classification, P1 improved significantly from 41.1 \u0026plusmn; 18.6% to 56.9 \u0026plusmn; 20.6% on long term follow up (p=0.03) and P2 improved from 70.7 \u0026plusmn;18.6 to 81.8 \u0026plusmn; 17.5% (p= 0.02). For 11 cases, BCEA improved from 9.6 \u0026plusmn; 11.8 to 4.2 \u0026plusmn; 4.9\u003csup\u003e02\u003c/sup\u003e , CI 95% (0.91-9.69).\u003c/p\u003e\n\u003cp\u003eFigure 3 shows the fixation test (20\u0026rdquo;) from a baseline visit compared to 1 week post-BT and also the report for a BT session, showing how BT increased the fixation stability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3: Fixation Stability pre, during, and post-Biofeedback Training (BT) \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis figure shows how the BT is done and its effect on FS. On the left, the fixation stability is represented through the BCEA 63% (inner ellipse) and 96% (outer ellipse). Each point in green in the graph represents one attempt of fixation.The instability of the fixation is shown by the wideness of the ellipses on the Fixation 20\u0026rdquo; pre-BT test. At the center, the fixation points fall closer to the center, the point that was set for the training. P1 is represented by the green circle, P2 by the yellow circle, showing BT performance. On the right, the spontaneous fixation stability post-BT improved visibly, shown by a smaller BCEA 63% and 95% areas.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDistance and Near Vision\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBBCVA improved from 0.38\u0026plusmn;0.18 logMAR to 0.29\u0026plusmn;0.18 logMAR in the short-term, and to 0.26\u0026plusmn;0.18 logMAR in the long-term (F(2,66)=36.54, p\u0026lt;0.001). Short-term was significantly better than baseline (p\u0026lt;0.001), and long-term was better than baseline (p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eNear vision improved from 0.09\u0026plusmn;0.15 log MAR to 0.004\u0026plusmn;0.1 logMAR on short-term, and to 0.008\u0026plusmn;0.07 logMAR on long-term (F (2,66)=10.07, p=0.002). Short-term was significantly better than baseline (p\u0026lt;0.001) and long-term was better than baseline (p=0.003).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eContrast Sensitivity\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContrast sensitivity improved significantly from 0.15 \u0026plusmn; 0.16 log units to 0.04 \u0026plusmn; 0.1 log units in the short term, and further to 0.02\u0026plusmn;0.08 log units in the long term (F(2,63=18.99, p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eReading Speed\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReading speed improved from 84.7 \u0026plusmn;42.6 to 108.8\u0026plusmn;43.9 on short term and to 109\u0026plusmn;44.2 words/minute (wpm) on long term post-BT (F2,45=11.09, p\u0026lt;0.001). Short term was better than baseline (p\u0026lt;0.001) and long term was better than baseline (p=0.003).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStereopsis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStereopsis did not improve in the short term or long term.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eQuality of life\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParental quality of life questionnaire total score improved from 25.9 \u0026plusmn; 2.9 to 27.32 \u0026plusmn; 2.7 on short term and to 27.3 \u0026plusmn; 2.7 on long term post-BT (F(2,42)=9.68, p\u0026lt;0.001). Short term was better than baseline (p=0.007) and long term was better than baseline (p=0.007). Enjoying traveling with the family, improvement in fine near vision tasks such as drawing, painting and reading books are a few examples disclosing the relevance of the BT therapy for these patients. Reports from our patients and their families are found on the media: https://toronto.ctvnews.ca/video/c2856897-new-therapy-gives-4-year-old-new-outlook-on-life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSide Effects\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo side effects occurred, besides variable tiredness and eye dryness during the training sessions. After BT sessions, in many cases, nystagmus intensity reduction was visible when the patient attempted fixation and if told to remember the BT acoustic signal. This better control also occurred naturally during conversations, playing video games or improving psychological behaviour, as related by the parents. Impressively, some cases who did not fulfill the criteria for driving in Ontario, Canada, improved to the eligible level and were allowed to drive safely.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study we present BT as a new non-invasive therapy, with no side effects, showing a significant improvement in visual functions and quality of life in patients with idiopathic infantile nystagmus syndrome, confirming our last studies.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The benefits from BT continued up to 5 years after BT. The last recent advance in the treatment of nystagmus was the use of topical brinzolamide in adults. However, it entails side effects and has to be used continuously to keep its benefits.\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDifferently from central vision loss, BT for idiopathic nystagmus trains the fixation at the fovea, and needs no relocation because the retina is intact. Its mechanisms of action remain not fully understood, but involve brain plasticity.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e BT for Nystagmus was described as early as 1980 used in other instruments,\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e and since 2018 our team has studied BT on the microperimeter. Microperimeters may be superior to the former BT methods due to its bimodal stimulation, that amplifies multisensory plasticity, and also the recalibration of spatial awareness between vision and audition in sub-cortical (superior colliculus and pulvinar controlling covert attention) and cortical areas (hMT+/V5).\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe performance during the training was progressively better across the visits, markedly on session 3 compared to session 1. There was a trend for P2 to improve in the fourth session, which is justifiable, since P2 requires less control of the fixation than P1. As the performance was not better for P1 on the last session, we believe that the brain memory for the fixation oculomotor control was not totally consolidated after four sessions, therefore, there could be room for further improvement.\u003c/p\u003e \u003cp\u003eFS BCEA 63% was significantly better post-BT when reliable. Fuji\u0026rsquo;s classification, the percentage of fixation points within 1\u003csup\u003e0\u003c/sup\u003e (P1) and 2\u003csup\u003e0\u003c/sup\u003e (P2) radius from the fovea during 20\u0026rdquo;confirmed this improvement. In our observations, nystagmoid movements frequently fell out of the MAIA\u0026rsquo;s capacity, so it was not possible to measure the FS in 52% of the cases. For the 48% cases measured,the FS improvement suggested better oculomotor control after BT. The literature has also reported significant BCEA improvement post-BT in many different studies.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBBCVA and contrast sensitivity, two correlated variables, were positively impacted by BT. Distance vision improvement is a challenge in low vision rehabilitation, since magnification with telescopes or bioptics reduces the visual fields. Indeed, some patients who had low vision before BT did not have it anymore after training. Patients and parents manifested great satisfaction during the sessions and follow up. The improvement of a single ETDRS line for visual acuity may be the difference for being eligible for a driver\u0026rsquo;s license, psychological comfort for social conversations, reading menus in restaurants, and can never be overemphasized. Driving eligibility in Ontario, Canada, was achieved by some patients from our study when they reached adolescence. These patients would not be able to drive following the expected visual development for the age without BT.\u003c/p\u003e \u003cp\u003eReading speed and near vision critical print size were positively impacted by BT in our study, showing a significant improvement post-BT. Indeed, a reference to better school performance was frequent post- therapy, and some patients who needed to use bifocals as a magnification for near vision did not need them after training.\u003c/p\u003e \u003cp\u003eStereopsis showed a significant improvement in our last study with 10 patients, but was not better on the present cohort post-BT. This may be explained by the fact that, in nystagmus, visual acuity is not related to stereopsis on a linear correlation.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eQoL CVFQ scores increased significantly after BT. In our last study, it showed improvement in all its subsections, including personality and visual competence. We had many examples of this in this study, including one child who improved her behavior drastically post-BT.\u003c/p\u003e \u003cp\u003eThe BT protocol used was feasible for application in a clinical setup, although it requires specialized staff training. The BT is a non harmful, inexpensive and non-surgical therapy. BT can be repeated as needed, and we hypothesize that the repetition of the sessions can achieve higher results based on the training performance progression.\u003c/p\u003e \u003cp\u003eBT effects were maintained after the sessions. After researching in Cochran, PubMed, and Google Scholar databases, we could not find a study that reported the long term results for BT in children with nystagmus. Unlike brinzolamide therapy, that has to be used three times a day continuously, BT benefits persist after only 4 sessions. Following validation with larger studies, BT could provide a novel and long lasting visual rehabilitation option for patients with idiopathic nystagmus.\u003c/p\u003e \u003cp\u003eA limitation of this study was the lack of a Nystagmus Acuity Function (NAFX) to measure the nystagmus amplitude and frequency. Another limitation of this study was the absence of a control group, which should be done on the next study as a randomized controlled clinical trial. Therefore, the continuation of this research is mandatory.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the efforts of Luminita Tarita-Nistor, PhD and scientist in Low Vision Rehabilitation affiliated to the Krembil Institute, University Health Network, who cooperated with the revision and statistics of this study and also encouraged our efforts to accomplish it.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution Statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDr. Mariana Misawa\u003c/strong\u003e participated in data collection, in designing the study, in the interpretation of the data, writing the manuscript, and coordinating the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDr. Mohab Eldeeb\u003c/strong\u003e participated in the statistical analysis and interpretation of the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDr. Yulia Pyatova\u003c/strong\u003e participated in \u0026nbsp;study design, study coordination, and data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDr. Michelle Markowitz\u0026nbsp;\u003c/strong\u003escreened and referred the patients to the low vision clinic, and participated in the data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMax Goldsmith\u003c/strong\u003e participated in the data collection and study coordination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDr. Samuel Markowitz\u003c/strong\u003e participated in the design of the study, interpretation of the results and reviewing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDr. Monica Daibert Nido\u003c/strong\u003e, the correspondence author, \u0026nbsp;adapted biofeedback training for nystagmus in children in the low vision clinic, designed the study, collected data, did statistical analysis, interpreted the results, and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available at https://docs.google.com/spreadsheets/d/1rKyFKfGkzNH-Z6fVRH7XdE2_GTEUmpTcbxvUymyMTUY/edit#gid=0\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSarvananthan, N. \u003cem\u003eet al.\u003c/em\u003e The Prevalence of Nystagmus: The Leicestershire Nystagmus Survey. \u003cem\u003eInvestigative Ophthalmology \u0026amp; Visual Science\u003c/em\u003e 50, 5201\u0026ndash;5206 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbadi, R.V. 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(2020) \u0026lsquo;Feedback modulates audio-visual spatial recalibration\u0026rsquo;, \u003cem\u003eFrontiers in Integrative Neuroscience\u003c/em\u003e, 13. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fnint.2019.00074\u003c/span\u003e\u003cspan address=\"10.3389/fnint.2019.00074\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu C, Yang J.(1997) Stereopsis disorders in patients with congenital nystagmus. \u003cem\u003eYan Ke Xue Bao\u003c/em\u003e. 13(1) pp. 1\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"nystagmus, biofeedback, quality of life, low vision, vision rehabilitation, microperimeter","lastPublishedDoi":"10.21203/rs.3.rs-4492358/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4492358/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMicroperimetric Biofeedback training (BT), a new vision rehabilitation therapy, was used to improve fixation stability, visual functions, and parental quality of life questionnaire (QoL) in children with idiopathic infantile nystagmus. The patients were followed for short and long term. 25 cases (9.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 years old) trained on the MAIA microperimeter for 80 minutes delivered within 4 weekly sessions. They were followed for the short (1 week to 1 month) and long term (22 patients, from 8 months, up to 5 years). Binocular distance and near vision, fixation stability (FS), reading speed, contrast sensitivity, and QoL showed a significant improvement post-BT on short and long term. Stereopsis did not improve. Distance and near vision improved 1 ETDRS line, contrast improved 2 lines on 10% contrast Colenbrander Test, reading speed improved 22 words/minute, and QoL 1.3 points. FS could be measured in 48% of the cases, and improved 38%. BT had a significant long lasting positive effect on visual functions and QoL in children with idiopathic nystagmus. This research suggests that, as a low cost-benefit therapy, BT may become a new therapeutic option for these cases.\u003c/p\u003e","manuscriptTitle":"Microperimetric Biofeedback Training for Children with Idiopathic Infantile Nystagmus Syndrome: a Short-and-Long Term Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 18:57:40","doi":"10.21203/rs.3.rs-4492358/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"96d5e7ac-8c84-42c5-add3-f08043e0bb3d","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":33159428,"name":"Biological sciences/Neuroscience"},{"id":33159429,"name":"Biological sciences/Psychology"},{"id":33159430,"name":"Health sciences/Diseases"},{"id":33159431,"name":"Health sciences/Health care"},{"id":33159432,"name":"Health sciences/Medical research"},{"id":33159433,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2024-07-08T05:47:08+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-13 18:57:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4492358","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4492358","identity":"rs-4492358","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}