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1.  Use of the Argus II Retinal Prosthesis to Improve Visual Guidance of Fine Hand Movements 
We studied the capabilities of the Argus II retinal prosthesis for guiding fine hand movement, and demonstrated and quantified guidance improvement when using the device over when not using the device for progressively less predictable trajectories.
A total of 21 patients with retinitis pigmentosa (RP), remaining vision no more than bare light perception, and an implanted Argus II epiretinal prostheses used a touchscreen to trace white paths on black backgrounds. Sets of paths were divided into three categories: right-angle/single-turn, mixed-angle/single-turn, and mixed-angle/two-turn. Subjects trained on paths by using prosthetic vision and auditory feedback, and then were tested without auditory feedback, with and without prosthetic vision. Custom software recorded position and timing information for any contact that subjects made with the screen. The area between the correct path and the trace, and the elapsed time to trace a path were used to evaluate subject performance.
For right-angle/single-turn sets, average tracing error was reduced by 63% and tracing time increased by 156% when using the prosthesis, relative to residual vision. With mixed-angle/single-turn sets, error was reduced by 53% and time to complete tracing increased by 184%. Prosthesis use decreased error by 38% and increased tracing time by 252% for paths that incorporated two turns.
Use of an epiretinal visual prosthesis can allow RP patients with no more than bare light perception to guide fine hand movement visually. Further, prosthetic input tends to make subjects slower when performing tracing tasks, presumably reflecting greater effort. ( number, NCT00407602.)
A total of 21 blind retinitis pigmentosa patients used retinal prostheses to visually guide their hands to trace high-contrast paths of varying complexities. Prosthesis use decreased performance error by an average of 60% and increased time to complete the task by an average of 211%. Use of an epiretinal visual prosthesis can allow RP patients with no more than bare light perception to visually guide fine hand movement. Further, prosthetic input tends to make subjects slower when performing tracing tasks, presumably reflecting greater effort.
PMCID: PMC3416020  PMID: 22661464
2.  The Detection of Motion by Blind Subjects With the Epiretinal 60-Electrode (Argus II) Retinal Prosthesis 
JAMA ophthalmology  2013;131(2):183-189.
To investigate the ability of 28 blind subjects implanted with a 60-electrode Argus II (Second Sight Medical Products Inc) retinal prosthesis system to detect the direction of a moving object.
Blind subjects (bare light perception or worse in both eyes) with retinitis pigmentosa were implanted with the Argus II prosthesis as part of a phase 1/2 feasibility study at multiple clinical sites worldwide. The experiment measured their ability to detect the direction of motion of a high-contrast moving bar on a flatscreen monitor in 3 conditions: with the prosthesis system on and a 1-to-1 mapping of spatial information, with the system off, and with the system on but with randomly scrambled spatial information.
Fifteen subjects (54%) were able to perform the task significantly better with their prosthesis system than they were with their residual vision, 2 subjects had significantly better performance with their residual vision, and no difference was found for 11 subjects. Of the 15 better-performing subjects, 11 were available for follow-up testing, and 10 of them had significantly better performance with normal rather than with scrambled spatial information.
This work demonstrates that blind subjects implanted with the Argus II retinal prosthesis were able to perform a motion detection task they could not do with their native vision, confirming that electrical stimulation of the retina provides spatial information from synchronized activation of multiple electrodes.
PMCID: PMC3924899  PMID: 23544203
3.  Preliminary 6 Month Results from the Argus™ II Epiretinal Prosthesis Feasibility Study 
Conference Proceedings  2009;2009:4566-4568.
The Argus™ II 60 channel epiretinal prosthesis has been developed in order to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. To date the device has been implanted in 21 subjects as part of a feasibility study. In 6 month post-implantation door finding and line tracking orientation and mobility testing, subjects have shown improvements of 86% and 73%, respectively, for system on vs. system off. In high-contrast Square Localization tests using a touch screen monitor 87% of tested subjects performed significantly better with the system on compared with off. These preliminary results show that the Argus II system provides some functional vision to blind subjects.
PMCID: PMC3337704  PMID: 19963839
4.  Detection, eye–hand coordination and virtual mobility performance in simulated vision for a cortical visual prosthesis device 
Journal of neural engineering  2009;6(3):035008.
In order to assess visual performance using a future cortical prosthesis device, the ability of normally sighted and low vision subjects to adapt to a dotted ‘phosphene’ image was studied. Similar studies have been conduced in the past and adaptation to phosphene maps has been shown but the phosphene maps used have been square or hexagonal in pattern. The phosphene map implemented for this testing is what is expected from a cortical implantation of the arrays of intracortical electrodes, generating multiple phosphenes. The dotted image created depends upon the surgical location of electrodes decided for implantation and the expected cortical response. The subjects under tests were required to perform tasks requiring visual inspection, eye–hand coordination and way finding. The subjects did not have any tactile feedback and the visual information provided was live dotted images captured by a camera on a head-mounted low vision enhancing system and processed through a filter generating images similar to the images we expect the blind persons to perceive. The images were locked to the subject’s gaze by means of video-based pupil tracking. In the detection and visual inspection task, the subject scanned a modified checkerboard and counted the number of square white fields on a square checkerboard, in the eye–hand coordination task, the subject placed black checkers on the white fields of the checkerboard, and in the way-finding task, the subjects maneuvered themselves through a virtual maze using a game controller. The accuracy and the time to complete the task were used as the measured outcome. As per the surgical studies by this research group, it might be possible to implant up to 650 electrodes; hence, 650 dots were used to create images and performance studied under 0% dropout (650 dots), 25% dropout (488 dots) and 50% dropout (325 dots) conditions. It was observed that all the subjects under test were able to learn the given tasks and showed improvement in performance with practice even with a dropout condition of 50% (325 dots). Hence, if a cortical prosthesis is implanted in human subjects, they might be able to perform similar tasks and with practice should be able to adapt to dotted images even with a low resolution of 325 dots of phosphene.
PMCID: PMC3902177  PMID: 19458397
5.  The Argus II epiretinal prosthesis system allows letter and word reading and long-term function in patients with profound vision loss 
Retinal prosthesis systems (RPS) are a novel treatment for profound vision loss in outer retinal dystrophies. Ideal prostheses would offer stable, long-term retinal stimulation and reproducible spatial resolution in a portable form appropriate for daily life.
We report a prospective, internally controlled, multicentre trial of the Argus II system. Twenty-eight subjects with light perception vision received a retinal implant. Controlled, closed-group, forced-choice letter identification, and, open-choice two-, three- and four-letter word identification tests were carried out.
The mean±SD percentage correct letter identification for 21 subjects tested were: letters L, T, E, J, F, H, I, U, 72.3±24.6% system on and 17.7±12.9% system off; letters A, Z, Q, V, N, W, O, C, D, M, 55.0±27.4% system on and 11.8%±10.7% system off, and letters K, R, G, X, B, Y, S, P, 51.7±28.9% system on and 15.3±7.4% system off. (p<0.001 for all groups). A subgroup of six subjects was able to consistently read letters of reduced size, the smallest measuring 0.9 cm (1.7°) at 30 cm, and four subjects correctly identify unrehearsed two-, three- and four-letter words. Average implant duration was 19.9 months.
Multiple blind subjects fitted with the Argus II system consistently identified letters and words using the device, indicating reproducible spatial resolution. This, in combination with stable, long-term function, represents significant progress in the evolution of artificial sight.
PMCID: PMC3632967  PMID: 23426738
6.  Factors Affecting Perceptual Threshold in Argus II Retinal Prosthesis Subjects 
The Argus II epiretinal prosthesis has been developed to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. Participants were surgically implanted with the system in the United States and Europe in a single arm, prospective, multicenter clinical trial. The purpose of this investigation was to determine which factors affect electrical thresholds in order to inform surgical placement of the device.
Electrode–retina and electrode–fovea distances were determined using SD-OCT and fundus photography, respectively. Perceptual threshold to electrical stimulation of electrodes was measured using custom developed software, in which current amplitude was varied until the threshold was found. Full field stimulus light threshold was measured using the Espion D-FST test. Relationships between electrical threshold and these three explanatory variables (electrode–retina distance, electrode–fovea distance, and monocular light threshold) were quantified using regression.
Regression analysis showed a significant correlation between electrical threshold and electrode–retina distance (R2 = 0.50, P = 0.0002; n = 703 electrodes). 90.3% of electrodes in contact with the macula (n = 207) elicited percepts at charge densities less than 1 mC/cm2/phase. These threshold data also correlated well with ganglion cell density profile (P = 0.03). A weaker, but still significant, inverse correlation was found between light threshold and electrical threshold (R2 < 0.52, P = 0.01). Multivariate modeling indicated that electrode–retina distance and light threshold are highly predictive of electrode threshold (R2 = 0.87; P < 0.0005).
Taken together, these results suggest that while light threshold should be used to inform patient selection, macular contact of the array is paramount.
Translational Relevance
Reported Argus II clinical study results are in good agreement with prior in vitro and in vivo studies, and support the development of higher-density systems that employ smaller diameter electrodes. ( identifier: NCT00407602)
PMCID: PMC3763895  PMID: 24049718
retinal prosthesis; retinal degeneration; retinitis pigmentosa
7.  Reading Visual Braille with a Retinal Prosthesis 
Retinal prostheses, which restore partial vision to patients blinded by outer retinal degeneration, are currently in clinical trial. The Argus II retinal prosthesis system was recently awarded CE approval for commercial use in Europe. While retinal prosthesis users have achieved remarkable visual improvement to the point of reading letters and short sentences, the reading process is still fairly cumbersome. This study investigates the possibility of using an epiretinal prosthesis to stimulate visual braille as a sensory substitution for reading written letters and words. The Argus II retinal prosthesis system, used in this study, includes a 10 × 6 electrode array implanted epiretinally, a tiny video camera mounted on a pair of glasses, and a wearable computer that processes the video and determines the stimulation current of each electrode in real time. In the braille reading system, individual letters are created by a subset of dots from a 3 by 2 array of six dots. For the visual braille experiment, a grid of six electrodes was chosen out of the 10 × 6 Argus II array. Groups of these electrodes were then directly stimulated (bypassing the camera) to create visual percepts of individual braille letters. Experiments were performed in a single subject. Single letters were stimulated in an alternative forced choice (AFC) paradigm, and short 2–4-letter words were stimulated (one letter at a time) in an open-choice reading paradigm. The subject correctly identified 89% of single letters, 80% of 2-letter, 60% of 3-letter, and 70% of 4-letter words. This work suggests that text can successfully be stimulated and read as visual braille in retinal prosthesis patients.
PMCID: PMC3504310  PMID: 23189036
retina; epiretinal prosthesis; sensory substitution; retinitis pigmentosa; blindness; perception; degeneration; sight restoration
8.  Intrastromal Corneal Ring Implants for Corneal Thinning Disorders 
Executive Summary
The purpose of this project was to determine the role of corneal implants in the management of corneal thinning disease conditions. An evidence-based review was conducted to determine the safety, effectiveness and durability of corneal implants for the management of corneal thinning disorders. The evolving directions of research in this area were also reviewed.
Subject of the Evidence-Based Analysis
The primary treatment objectives for corneal implants are to normalize corneal surface topography, improve contact lens tolerability, and restore visual acuity in order to delay or defer the need for corneal transplant. Implant placement is a minimally invasive procedure that is purported to be safe and effective. The procedure is also claimed to be adjustable, reversible, and both eyes can be treated at the same time. Further, implants do not limit the performance of subsequent surgical approaches or interfere with corneal transplant. The evidence for these claims is the focus of this review.
The specific research questions for the evidence review were as follows:
Corneal Surface Topographic Effects:
Effects on corneal surface remodelling
Impact of these changes on subsequent interventions, particularly corneal transplantation (penetrating keratoplasty [PKP])
Visual Acuity
Refractive Outcomes
Visual Quality (Symptoms): such as contrast vision or decreased visual symptoms (halos, fluctuating vision)
Contact lens tolerance
Functional visual rehabilitation and quality of life
Patient satisfaction:
Disease Process:
Impact on corneal thinning process
Effect on delaying or deferring the need for corneal transplantation
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) comprises a range of disorders involving either primary disease conditions such as keratoconus and pellucid marginal corneal degeneration or secondary iatrogenic conditions such as corneal thinning occurring after LASIK refractive surgery. The condition occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. Thinning occurs primarily in the stoma layers and is believed to be a breakdown in the collagen network. This bulging can lead to an irregular shape or astigmatism of the cornea and, because the anterior part of the cornea is largely responsible for the focusing of light on the retina, results in loss of visual acuity. This can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus (KC) is the most common form of corneal thinning disorder and is a noninflammatory chronic disease process. Although the specific causes of the biomechanical alterations that occur in KC are unknown, there is a growing body of evidence to suggest that genetic factors may play an important role. KC is a rare condition (<0.05% of the population) and is unique among chronic eye diseases as it has an early age of onset (median age of 25 years). Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. When patients can no longer tolerate contact lenses or when lenses no longer provide adequate vision, patients are referred for corneal transplant.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last three decades. Yet, despite high graft survival rates of up to 20 years, there are reasons to defer receiving transplants for as long as possible. Patients with keratoconus are generally young and life-long term graft survival would be an important consideration. The surgery itself involves lengthy time off work and there are potential complications from long term steroid use following surgery, as well as the risk of developing secondary cataracts, glaucoma etc. After transplant, recurrent KC is possible with need for subsequent intervention. Residual refractive errors and astigmatism can remain challenging after transplantation and high refractive surgery rates and re-graft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
INTACS® (Addition Technology Inc. Sunnyvale, CA, formerly KeraVision, Inc.) are the only currently licensed corneal implants in Canada. The implants are micro-thin poly methyl methacrylate crescent shaped ring segments with a circumference arc length of 150 degrees, an external diameter of 8.10 mm, an inner diameter of 6.77 mm, and a range of different thicknesses. Implants act as passive spacers and, when placed in the cornea, cause local separation of the corneal lamellae resulting in a shortening of the arc length of the anterior corneal curvature and flattening the central cornea. Increasing segment thickness results in greater lamellar separation with increased flattening of the cornea correcting for myopia by decreasing the optical power of the eye. Corneal implants also improve corneal astigmatism but the mechanism of action for this is less well understood.
Treatment with corneal implants is considered for patients who are contact lens intolerant, having adequate corneal thickness particularly around the area of the implant incision site and without central corneal scarring. Those with central corneal scarring would not benefit from implants and those without an adequate corneal thickness, particularly in the region that the implants are being inserted, would be at increased risk for corneal perforation. Patients desiring to have visual rehabilitation that does not include glasses or contact lenses would not be candidates for corneal ring implants.
Placement of the implants is an outpatient procedure with topical anesthesia generally performed by either corneal specialists or refractive surgeons. It involves creating tunnels in the corneal stroma to secure the implants either by a diamond knife or laser calibrated to an approximate depth of 70% of the cornea. Variable approaches have been employed by surgeons in selecting ring segment size, number and position. Generally, two segments of equal thickness are placed superiorly and inferiorly to manage symmetrical patterns of corneal thinning whereas one segment may be placed to manage asymmetric thinning patterns.
Following implantation, the major safety concerns are for potential adverse events including corneal perforation, infection, corneal infiltrates, corneal neovascularization, ring migration and extrusion and corneal thinning. Technical results can be unsatisfactory for several reasons. Treatment may result in an over or under-correction of refraction and may induce astigmatism or asymmetry of the cornea.
Progression of the corneal cone with corneal opacities is also invariably an indication for progression to corneal transplant. Other reasons for treatment failure or patient dissatisfaction include foreign body sensation, unsatisfactory visual quality with symptoms such as double vision, fluctuating vision, poor night vision or visual side effects related to ring edge or induced or unresolved astigmatism.
Evidence-Based Analysis Methods
The literature search strategy employed keywords and subject headings to capture the concepts of 1) intrastromal corneal rings and 2) corneal diseases, with a focus on keratoconus, astigmatism, and corneal ectasia. The initial search was run on April 17, 2008, and a final search was run on March 6, 2009 in the following databases: Ovid MEDLINE (1996 to February Week 4 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 10), OVID Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2000 and April 17, 2008. The resulting citations were downloaded into Reference Manager, v.11 (ISI Researchsoft, Thomson Scientific, U.S.A), and duplicates were removed. The Web sites of several other health technology agencies were also reviewed including the Canadian Agency for Drugs and Technologies in Health (CADTH), ECRI, and the United Kingdom National Institute for Clinical Excellence (NICE). The bibliographies of relevant articles were scanned.
Inclusion Criteria
English language reports and human studies
Any corneal thinning disorder
Reports with corneal implants used alone or in conjunction with other interventions
Original reports with defined study methodology
Reports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, vision quality of life or patient satisfaction
Case reports or case series for complications and adverse events
Exclusion Criteria
Non-systematic reviews, letters, comments and editorials
Reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
Reports not involving corneal thinning disorders and an intervention with corneal implants
Summary of Findings
In the MAS evidence review on intrastromal corneal ring implants, 66 reports were identified on the use of implants for management of corneal thinning disorders. Reports varied according to their primary clinical indication, type of corneal implant, and whether or not secondary procedures were used in conjunction with the implants. Implants were reported to manage post LASIK thinning and/or uncorrected refractive error and were also reported as an adjunctive intervention both during and after corneal transplant to manage recurrent thinning and/or uncorrected refractive error.
Ten pre-post cohort longitudinal follow-up studies were identified examining the safety and effectiveness of INTAC corneal implants in patients with keratoconus. Five additional cohort studies were identified using the Ferrara implant for keratoconus management but because this corneal implant is not licensed in Canada these studies were not reviewed.
The cohorts implanted with INTACS involved 608 keratoconus patients (754 eyes) followed for 1, 2 or 3 years. Three of the reports involved ≥ 2 years of follow-up with the longest having 5-year follow-up data for a small number of patients. Four of the INTAC cohort studies involved 50 or more patients; the largest involved 255 patients. Inclusion criteria for the studies were consistent and included patients who were contact lens intolerant, had adequate corneal thickness, particularly around the area of the implant incision site, and without central corneal scarring. Disease severity, thinning pattern, and corneal cone protrusions all varied and generally required different treatment approaches involving defined segment sizes and locations.
A wide range of outcome measures were reported in the cohort studies. High levels of technical success or ability to place INTAC segments were reported. Technically related complications were often delayed and generally reported as segment migration attributable to early experience. Overall, complications were infrequently reported and largely involved minor reversible events without clinical sequelae.
The outcomes reported across studies involved statistically significant and clinically relevant improvements in corneal topography, refraction and visual acuity, for both uncorrected and best-corrected visual acuity. Patients’ vision was usually restored to within normal functioning levels and for those not achieving satisfactory correction, insertion of intraocular lenses was reported in case studies to result in additional gains in visual acuity. Vision loss (infrequently reported) was usually reversed by implant exchange or removal. The primary effects of INTACS on corneal surface remodelling were consistent with secondary improvements in refractive error and visual acuity. The improvements in visual acuity and refractive error noted at 6 months were maintained at 1 and 2-year follow-up
Improvements in visual acuity and refractive error following insertion of INTACS, however, were not noted for all patients. Although improvements were not found to vary across age groups there were differences across stages of disease. Several reports suggested that improvements in visual acuity and refractive outcomes may not be as large or predictable in more advanced stages of KC. Some studies have suggested that the effects of INTACs were much greater in flattening the corneal surface than in correcting astigmatism. However, these studies involved small numbers of high risk patients in advanced stages of KC and conclusions made from this group are limited.
INTACS were used for other indications other than primary KC. The results of implant insertion on corneal topography, refraction, and visual acuity in post-LASIK thinning cases were similar to those reported for KC. The evidence for this indication, however, only involved case reports and small case series. INTACS were also successfully used to treat recurrent KC after corneal transplant but this was based on only a single case report. Corneal implants were compared to corneal transplantation but these studies were not randomized and based on small numbers of selected patients.
The foremost limitation of the evidence base is the basic study design in the reports that involved longitudinal follow-up only for the treated group; there were no randomized trials. Follow-up in the trials (although at prescribed intervals) often had incomplete accounts of losses at follow-up and estimates of change were often not reported or based on group differences. Second, although standardized outcome measures were reported, contact lens tolerance (a key treatment objective) was infrequently specified. A third general limitation was the lack of reporting of patients’ satisfaction with their vision quality or functional vision. Outcome measures for vision quality and impact on patient quality of life were available but rarely reported and have been noted to be a limitation in ophthalmological literature in general. Fourth, the longitudinal cohort studies have not followed patients long enough to evaluate the impact of implants on the underlying disease process (follow-up beyond 3 years is limited). Additionally, only a few of these studies directly examined corneal thinning in follow-up. The overall quality of evidence determined using the GRADE hierarchy of evidence was moderate.
There is some evidence in these studies to support the claim that corneal implants do not interfere with, or increase the difficultly of, subsequent corneal transplant, at least for those performed shortly after INTAC placement. Although it’s uncertain for how long implants can delay the need for a corneal transplant, given that patients with KC are often young (in their twenties and thirties), delaying transplant for any number of years may still be a valuable consideration.
The clinical indications for corneal implants have evolved from management of myopia in normal eyes to the management of corneal thinning disorders such as KC and thinning occurring after refractive surgery. Despite the limited evidence base for corneal implants, which consists solely of longitudinal follow-up studies, they appear to be a valuable clinical tool for improving vision in patients with corneal thinning. For patients unable to achieve functional vision, corneal implants achieved statistically significant and clinically relevant improvements in corneal topography, refraction, and visual acuity, providing a useful alternative to corneal transplant. Implants may also have a rescue function, treating corneal thinning occurring after refractive surgery in normal eyes, or managing refractive errors following corneal transplant. The treatment offers several advantages in that it’s an outpatient based procedure, is associated with minimal risk, and has high technical success rates. Both eyes can be treated at once and the treatment is adjustable and reversible. The implants can be removed or exchanged to improve vision without limiting subsequent interventions, particularly corneal transplant.
Better reporting on vision quality, functional vision and patient satisfaction, however, would improve evaluation of the impact of these devices. Information on the durability of the implants’ treatment effects and their affects on underlying disease processes is limited. This information is becoming more important as alternative treatment strategies, such as collagen cross-linking aimed at strengthening the underlying corneal tissue, are emerging and which might prove to be more effective or increase the effectiveness of the implants, particularly in advances stages of corneal thinning.
Ontario Health System Considerations
At present there are approximately 70 ophthalmologists in Canada who’ve had training with corneal implants; 30 of these practice in Ontario. Industry currently sponsors the training, proctoring and support for the procedure. The cost of the implant device ranges from $950 to $1200 (CAD) and costs for instrumentation range from $20,000 to $30,000 (CAD) (a one time capital expenditure). There is no physician services fee code for corneal implants in Ontario but assuming that they are no higher than those for a corneal transplant, the estimated surgical costs would be $914.32(CAD) An estimated average cost per patient, based on device costs and surgical fees, for treatment is $1,964 (CAD) (range $1,814 to $2,114) per eye. There have also been no out of province treatment requests. In Ontario the treatment is currently being offered in private clinics and an increasing number of ophthalmologists are being certified in the technique by the manufacturer.
KC is a rare disease and not all of these patients would be eligible candidates for treatment with corneal implants. Based on published population rates of KC occurrence, it can be expected that there is a prevalent population of approximately 6,545 patients and an incident population of 240 newly diagnosed cases per year. Given this small number of potential cases, the use of corneal implants would not be expected to have much impact on the Ontario healthcare system. The potential impact on the provincial budget for managing the incident population, assuming the most conservative scenario (i.e., all are eligible and all receive bilateral implants) ranges from $923 thousand to $1.1 million (CAD). This estimate would vary based on a variety of criteria including eligibility, unilateral or bilateral interventions, re-interventions, capacity and uptake
Keratoconus, corneal implants, corneal topography, corneal transplant, visual acuity, refractive error
PMCID: PMC3385416  PMID: 23074513
9.  Intraocular retinal prosthesis. 
PURPOSE: An electronic implant that can bypass the damaged photoreceptors and electrically stimulate the remaining retinal neurons to restore useful vision has been proposed. A number of key questions remain to make this approach feasible. The goal of this thesis is to address the following 2 specific null hypotheses: (1) Stimulus parameters make no difference in the electrically elicited retinal responses. (2) Just as we have millions of photoreceptors, so it will take a device that can generate millions of pixels/light points to create useful vision. METHODS: For electrophysiologic experiments, 2 different setups were used. In the first setup, charge-balanced pulses were delivered to the retinal surface via electrodes inserted through an open sky approach in normal or blind retinal degenerate (rd) mice. In the second setup, the rabbit retina was removed under red light conditions from an enucleated eye and then maintained in a chamber while being superfused with oxygenated, heated Ames media. In both setups, stimulating electrodes and recording electrodes were positioned on the retinal surface to evaluate the effect of varying stimulation parameters on the orthodromic retinal responses (i.e., recording electrode placed between stimulating electrodes and optic nerve head). For psychophysical experiments, visual images were divided into pixels of light that could be projected in a pattern on the retina in up to 8 sighted volunteers. Subjects were asked to perform various tasks ranging from reading and face recognition to various activities of daily living. RESULTS: Electrophysiologic experiments: In a normal mouse, a single cycle of a 1-kHz sine wave was significantly more efficient than a 1-kHz square wave (P < .05), but no such difference was noted in either of the 8- or 16-week-old rd mouse groups (8-week-old, P = .426; 16-week-old, P = .078). Charge threshold was significantly higher in 16-week-old rd mouse versus both 8-week-old rd and normal mouse for every stimulus duration (P < .05). In all groups, short duration pulses (40, 80, and 120 microseconds) were more efficient in terms of total charge (the product of pulse amplitude and pulse duration) than longer (500 and 1,000 microseconds) pulses (P < .05). In all groups, applying a pulse train did not lead to more efficient charge usage (P < .05). Psychophysical experiments: In high-contrast tests, facial recognition rates of over 75% were achieved for all subjects with dot sizes of up to 31.5 minutes of arc when using a 25 x 25 grid with 4.5 arc minute gaps, a 30% dropout rate, and 6 gray levels. Even with a 4 x 4 array of pixels, some subjects were able to accurately describe 2 of the objects. Subjects who were able to read the 4-pixel letter height sentences (on the 6 x 10 and 16 x 16 array) seemed to have a good scanning technique. Scanning at the proper velocity tends to bring out more contrast in the lettering. The reading speed for the 72-point font is a bit slower than for the next smaller font. This may be due to the limited number of letters (3) visible in the window with this large font. CONCLUSIONS: Specific parameters needed to stimulate the retina were identified. Delineating the optimum parameters will decrease the current requirements. Psychophysical tests show that with limited pixels and image processing, useful vision is possible. Both these findings should greatly simplify the engineering of an electronic retinal prosthesis.
PMCID: PMC1359018  PMID: 11797315
10.  Interim Results from the International Trial of Second Sight’s Visual Prosthesis 
Ophthalmology  2012;119(4):779-788.
This study evaluates the Argus™ II Retinal Prosthesis System in blind subjects with severe outer retinal degeneration.
The study design is a single arm, prospective, multicenter clinical trial.
Thirty subjects were enrolled in the United States and Europe between 6 June 2007 and 11 August 2009. All subjects were followed for a minimum of six months and up to 2.7 years.
The electronic stimulator and antenna of the implant was sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array was then tacked to the epiretinal surface.
Main Outcome Measures
The primary safety endpoint for the trial was the number, severity, and relation of adverse events. Principal performance endpoints were assessments of visual function as well as performance on orientation and mobility tasks.
Subjects performed statistically better with system ON vs. OFF in the following tasks: object localization (96% of subjects); motion discrimination (57%); and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects’ mean performance on Orientation and Mobility tasks was significantly better when the System was ON vs. OFF.
Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was successfully treated in all subjects except in one which required explantation of the device without further complications.
The long-term safety results of Second Sight’s retinal prosthesis system are acceptable and the majority of subjects with profound visual loss perform better on visual tasks with system than without.
PMCID: PMC3319859  PMID: 22244176
11.  Comparison of range-of-motion and variability in upper body movements between transradial prosthesis users and able-bodied controls when executing goal-oriented tasks 
Current upper limb prostheses do not replace the active degrees-of-freedom distal to the elbow inherent to intact physiology. Limited evidence suggests that transradial prosthesis users demonstrate shoulder and trunk movements to compensate for these missing volitional degrees-of-freedom. The purpose of this study was to enhance understanding of the effects of prosthesis use on motor performance by comparing the movement quality of upper body kinematics between transradial prosthesis users and able-bodied controls when executing goal-oriented tasks that reflect activities of daily living.
Upper body kinematics were collected on six able-bodied controls and seven myoelectric transradial prosthesis users during execution of goal-oriented tasks. Range-of-motion, absolute kinematic variability (standard deviation), and kinematic repeatability (adjusted coefficient-of-multiple-determination) were quantified for trunk motion in three planes, shoulder flexion/extension, shoulder ab/adduction, and elbow flexion/extension across five trials per task. Linear mixed models analysis assessed between-group differences and correlation analysis evaluated association between prosthesis experience and kinematic repeatability.
Across tasks, prosthesis users demonstrated increased trunk motion in all three planes and shoulder abduction compared to controls (p ≤ 0.004). Absolute kinematic variability was greater for prosthesis users for all degrees-of-freedom irrespective of task, but was significant only for degrees-of-freedom that demonstrated increased range-of-motion (p ≤ 0.003). For degrees-of-freedom that did not display increased absolute variability for prosthesis users, able-bodied kinematics were characterized by significantly greater repeatability (p ≤ 0.015). Prosthesis experience had a strong positive relationship with average kinematic repeatability (r = 0.790, p = 0.034).
The use of shoulder and trunk movements by prosthesis users as compensatory motions to execute goal-oriented tasks demonstrates the flexibility and adaptability of the motor system. Increased variability in movement suggests that prosthesis users do not converge on a defined motor strategy to the same degree as able-bodied individuals. Kinematic repeatability may increase with prosthesis experience, or encourage continued device use, and future work is warranted to explore these relationships. As compensatory dynamics may be necessary to improve functionality of transradial prostheses, users may benefit from dedicated training that encourages optimization of these dynamics to facilitate execution of daily living activity, and fosters adaptable but reliable motor strategies.
PMCID: PMC4164738  PMID: 25192744
Upper limb; Transradial amputation; Kinematics; Trunk; Prosthesis
12.  Static and dynamic posture control in postlingual cochlear implanted patients: effects of dual-tasking, visual and auditory inputs suppression 
Posture control is based on central integration of multisensory inputs, and on internal representation of body orientation in space. This multisensory feedback regulates posture control and continuously updates the internal model of body's position which in turn forwards motor commands adapted to the environmental context and constraints. The peripheral localization of the vestibular system, close to the cochlea, makes vestibular damage possible following cochlear implant (CI) surgery. Impaired vestibular function in CI patients, if any, may have a strong impact on posture stability. The simple postural task of quiet standing is generally paired with cognitive activity in most day life conditions, leading therefore to competition for attentional resources in dual-tasking, and increased risk of fall particularly in patients with impaired vestibular function. This study was aimed at evaluating the effects of postlingual cochlear implantation on posture control in adult deaf patients. Possible impairment of vestibular function was assessed by comparing the postural performance of patients to that of age-matched healthy subjects during a simple postural task performed in static (stable platform) and dynamic (platform in translation) conditions, and during dual-tasking with a visual or auditory memory task. Postural tests were done in eyes open (EO) and eyes closed (EC) conditions, with the CI activated (ON) or not (OFF). Results showed that the postural performance of the CI patients strongly differed from the controls, mainly in the EC condition. The CI patients showed significantly reduced limits of stability and increased postural instability in static conditions. In dynamic conditions, they spent considerably more energy to maintain equilibrium, and their head was stabilized neither in space nor on trunk: they behaved dynamically without vision like an inverted pendulum while the controls showed a whole body rigidification strategy. Hearing (prosthesis on) as well as dual-tasking did not really improve the dynamic postural performance of the CI patients. We conclude that CI patients become strongly visual dependent mainly in challenging postural conditions, a result they have to be awarded of particularly when getting older.
PMCID: PMC3893730  PMID: 24474907
posture control; cochlear implanted patients; dual-tasking; visual input; auditory input
13.  Impaired navigation skills in patients with psychological distress and chronic peripheral vestibular hypofunction without vertigo 
Few studies have focused on the role of the vestibular system for navigation and spatial memory functions in humans, with controversial results. Since most experimental settings were based on magnetic resonance imaging volumetry of the hippocampus and virtual navigation task on a PC, aim of this study was to investigate whether a well-compensated unilateral peripheral vestibular hypofunction in humans could interfere with navigation tasks while walking on memorized routes. A series of 50 unilateral labyrinthine-defective patients, without vertigo at the time of examination, and 50 controls were invited to visually memorize 3 different routes (a triangle, a circle and a square) on a grey carpet and then to walk along them clockwise and counter-clockwise (mental map navigation) with eyes closed. The same test was then repeated with eyes open (actual navigation) and a second time with eyes closed (mental navigation). Execution time was recorded in each test. In the same session, working spatial memory was assessed by the Corsi block test and all subjects completed the Symptom Check List (SCL-90) to assess depression and anxiety levels. Results showed that labyrinthine-defective patients presented higher levels of anxiety and depression and performed the Corsi block test with more difficulties than controls. All differences reached statistically significant level (p < 0.05). Moreover, patients needed more time than controls in the first and third navigation tasks (eyes closed). No difference was observed between clockwise and counter-clockwise walking, on all routes, either in patients or controls. Patients showed a greater improvement in the third navigation task, with respect to the first test, than controls, with no side-effect in relation to labyrinthine hypofunction. These data demonstrate that walking along memorized routes without vision is impaired by peripheral vestibular damage even if vestibular compensation prevents patients from suffering from vertigo and balance disturbances. This impairment could be due to a permanent deficit of visuo-spatial short-term memory as suggested by the Corsi block test results even if a residual sensori-motor impairment and/or an interference of psychological distress could not be excluded.
PMCID: PMC2640064  PMID: 18533551
Vestibular disorder; Spatial memory; Visuo-spatial short-term memory; Memorized routes; Navigation; Anxiety
14.  Electrically Elicited Visual Evoked Potentials in Argus II Retinal Implant Wearers 
We characterized electrically elicited visual evoked potentials (eVEPs) in Argus II retinal implant wearers.
eVEPs were recorded in four subjects, and analyzed by determining amplitude and latency of the first two positive peaks (P1 and P2). Subjects provided subjective feedback by rating the brightness and size of the phosphenes. We established eVEP input–output relationships, eVEP variability between and within subjects, the effect of stimulating different areas of the retina, and the maximal pulse rate to record eVEPs reliably.
eVEP waveforms had low signal-to-noise ratios, requiring long recording times and substantial signal processing. Waveforms varied between subjects, but showed good reproducibility and consistent parameter dependence within subjects. P2 amplitude overall was the most robust outcome measure and proved an accurate indicator of subjective threshold. Peak latencies showed small within-subject variability, yet their correlation with stimulus level and subjective rating were more variable than that of peak amplitudes. Pulse rates of up to 2/3 Hz resulted in reliable eVEP recordings. Perceived phosphene brightness declined over time, as reflected in P1 amplitude, but not in P2 amplitude or peak latencies. Stimulating-electrode location significantly affected P1 and P2 amplitude and latency, but not subjective percepts.
While recording times and signal processing are more demanding than for standard visually evoked potential (VEP) recordings, the eVEP has proven to be a reliable tool to verify retinal implant functionality. eVEPs correlated with various stimulus parameters and with perceptual ratings. In view of these findings, eVEPs may become an important tool in functional investigations of retinal prostheses. ( number NCT00407602.)
Dutch Abstract
We characterized electrically elicited visual evoked potentials (eVEPs) in Argus II retinal implant wearers. eVEPs were correlated significantly with stimulus level and subjective percept. We conclude that eVEPs may become an important tool for intraoperative monitoring and rehabilitation purposes.
PMCID: PMC3676187  PMID: 23611993
retinal implant; visual evoked potential; visual prosthesis; psychophysics
15.  Initiation and Stability of Pursuit Eye Movements in Simulated Retinal Prosthesis at Different Implant Locations 
To assess the possible effects of retinal prosthesisimplant location on the initiation and stability of pursuit eye movements.
Six normally sighted subjects visually tracked a horizontally moving target in natural vision and in simulated prosthetic vision. Subjects were instructed to press a key when the target jumped. Prosthetic vision was simulated with a 10 × 10 array of 1° diameter phosphenes. Three implant locations in the retina were simulated: macular, 8° superior, and 8° nasal. Target motion had two speeds: 4°/s and 8°/s. Eye movement latency, horizontal stability, and vertical stability were assessed. Key-press behaviors responding to target jump were analyzed to evaluate functional eye movements.
Compared with natural vision, horizontal eye position with respect to target position was less stable in simulated prosthetic vision at macular, superior, and nasal implant locations, in ascending order of the degree of instability. Vertical eye position with respect to target position in simulated prosthetic vision with the superior implant location was less stable in tracking slow target motion than fast. Eye movement latency in simulated prosthetic vision was longer than in natural vision. Key-press performance was impaired in simulated prosthetic vision.
Pursuit eye movements in prosthetic vision, compared to natural vision, are significantly slower in initiation and less smooth in motion. They seem, however, still functional, even if the prosthesis is implanted in the peripheral retina. A superior implant locus may help the prosthesis wearer better control horizontal eye movements, which are more frequently used in the activities of daily living.
PMCID: PMC2677095  PMID: 18539937
16.  The Argus II prosthesis facilitates reaching and grasping tasks: a case series 
BMC Ophthalmology  2014;14:71.
To evaluate the reach-to-grasp performance of patients fitted with an epiretinal artifical retina device.
This was a hospital-based case series consisting of six patients fitted with the Argus II (Second Sight Medical Products Inc, California, USA) retinal prosthesis. Participants were asked to reach out and pick up a high-contrast cuboid object with the prosthesis in the ‘On’, ‘Off’ or ‘Scrambled’ setting presented in a randomised order. The ‘Scrambled’ setting consisted of a random, scattered signal presented to the prosthesis. The session was repeated after a 4–6 week period. Hand movements were measured using motion detection cameras. The number of successful object grasps was calculated.
The number of successful grasps was greater with the prosthesis in the ‘On’ setting (visit 1: median [interquartile range] percentage success: ‘Off’ = 0 [0 to 50]%, ‘On’ = 69 [67 to 95]%, ‘Scrambled’ = 59 [42 to 95]%; Friedman Chi-squared test statistic 6.5, p = 0.04; visit 2 median [IQR] percentage success: ‘Off’ = 0 [0 to 25]%, ‘On’ = 69 [53 to 100]%, ‘Scrambled’ = 28 [13 to 63]%; Friedman Chi-squared test statistic 8.4, p = 0.02).
The use of an electronic retinal prosthesis facilitates reach-and-grasp performance. Further work should explore how performance can be improved with targeted rehabilitation.
PMCID: PMC4039311  PMID: 24885164
Retinal prosthesis; Functional vision; Reach and grasp
17.  Frequency and Amplitude Modulation Have Different Effects on the Percepts Elicited by Retinal Stimulation 
To restore functional form vision, epiretinal prostheses have been implanted in blind human subjects to electrically elicit percepts. These findings suggest that frequency modulation may be the best way to produce percepts that range widely in brightness while minimizing loss of spatial resolution.
In an effort to restore functional form vision, epiretinal prostheses that elicit percepts by directly stimulating remaining retinal circuitry were implanted in human subjects with advanced retinitis pigmentosa RP). In this study, manipulating pulse train frequency and amplitude had different effects on the size and brightness of phosphene appearance.
Experiments were performed on a single subject with severe RP (implanted with a 16-channel epiretinal prosthesis in 2004) on nine individual electrodes. Psychophysical techniques were used to measure both the brightness and size of phosphenes when the biphasic pulse train was varied by either modulating the current amplitude (with constant frequency) or the stimulating frequency (with constant current amplitude).
Increasing stimulation frequency always increased brightness, while having a smaller effect on the size of elicited phosphenes. In contrast, increasing stimulation amplitude generally increased both the size and brightness of phosphenes. These experimental findings can be explained by using a simple computational model based on previous psychophysical work and the expected spatial spread of current from a disc electrode.
Given that amplitude and frequency have separable effects on percept size, these findings suggest that frequency modulation improves the encoding of a wide range of brightness levels without a loss of spatial resolution. Future retinal prosthesis designs could benefit from having the flexibility to manipulate pulse train amplitude and frequency independently ( number, NCT00279500).
PMCID: PMC3292357  PMID: 22110084
18.  Optical Coherence Tomography for Age-Related Macular Degeneration and Diabetic Macular Edema 
Executive Summary
The purpose of this evidence-based review was to examine the effectiveness and cost-effectiveness of spectral-domain (SD) optical coherence tomography (OCT) in the diagnosis and monitoring of patients with retinal disease, specifically age-related macular degeneration (AMD) and diabetic macular edema (DME). Specifically, the research question addressed was:
What is the sensitivity and specificity of spectral domain OCT relative to the gold standard?
Clinical Need: Target Population and Condition
The incidence of blindness has been increasing worldwide. In Canada, vision loss in those 65 years of age and older is primarily due to AMD, while loss of vision in those 18 years of age and older is mainly due to DME. Both of these conditions are diseases of the retina, which is located at the back of the eye. At the center of the retina is the macula, a 5 mm region that is responsible for what we see in front of us, our ability to detect colour, and fine detail. Damage to the macula gives rise to vision loss, but early detection of asymptomatic disease may lead to the prevention or slowing of the vision loss process.
There are two main types of AMD, ‘dry’ and ‘wet’. Dry AMD is the more prevalent of the two, accounting for approximately 85% of cases and characterized by small deposits of extracellular material called “drusen” that build up in Bruch’s membrane of the eye. Central vision loss is gradual with blurring and eventual colour fading. Wet AMD is a less prevalent condition (15% of all AMD cases) but it accounts for 90% of severe cases. It’s characterized by the appearance of retinal fluid with vision loss due to abnormal blood vessels/leakage within weeks to months of diagnosis. In 2003, the Canadian National Institute for the Blind (CNIB) prevalence estimate for AMD was 1 million Canadians, including approximately 400,000 affected Ontarians. The incidence in 2003 was estimated to be 78,000 new cases in Canada, with approximately one-third of these cases arising in Ontario (n=26,000). Over the next 25 years, the number of new cases is expected to triple.
DME is caused by complications of diabetes mellitus, both Type 1 and Type 2. It is estimated that 1-in-4 persons with diabetes has this condition, though it occurs more frequently among those with type 2 diabetes. The condition is characterized by a swelling of the retina caused by leakage of blood vessels at the back of the eye. In early stages of the disease, vision may still be normal but it can degrade rapidly in later stages. In 2003, the CNIB prevalence estimate for DME was 0.5 million Canadians, with approximately 200,000 Ontarians affected. The incidence of DME is more difficult to ascertain; however, based on an annual incidence rate of 0.8% (for those 20 years of age or older) and the assumption that 1-in-4 persons with diabetes is affected, the incidence of DME in Ontario is estimated to be 21,000 new cases per year.
Optical Coherence Tomography
Prior to the availability of OCT, the standard of care in the diagnosis and/or monitoring of retinal disease was serial testing with fluorescein angiography (FA), biomicroscopy (BM), and stereo-fundus photography (SFP). Each of these is a qualitative measure of disease based on subjective evaluations that are largely dependent on physician expertise. OCT is the first quantitative visual test available for the diagnosis of eye disease. As such, it is allows for a more objective evaluation of the presence/absence of retinal disease and it is the only test that provides a measure of retinal thickness. The technology was developed at the Michigan Institute of Technology (MIT) in 1991 as a real-time imaging modality and is considered comparable to histology. It’s a light-wave based technology producing cross-sectional images with scan rates and resolution parameters that have greatly improved over the last 10 years. It’s also a non-invasive, non-contact visual test that requires just 3 to 5 minutes to assess both eyes.
There are two main types of OCT system, both licensed by Health Canada as class II devices. The original patent was based on a time domain (TD) system (available from 1995) that had an image rate of 100 to 400 scans per second and provided information for a limited view of the retina with a resolution in the range of 10 to 20 μm. The newer system, spectral domain (SD) OCT, has been available since 2006. Improvements with this system include (i) a faster scan speed of approximately 27,000 scans per second; (ii) the ability to scan larger areas of the retina by taking six scans radially-oriented 30 degrees from each other; (iii) increased resolution at 5μm; and (iv) ‘real-time registration,’ which was not previously available with TD.
The increased scan speed of SD systems enables the collection of additional real-time information on larger regions of the retina, thus, reducing the reliance on assumptions required for retinal thickness and volume estimates based on software algorithms. The faster scan speed also eliminates image distortion arising from patient movement (not previously possible with TD), while the improvement in resolution allows for clearer and more distinguishable retinal layers with the possibility of detecting earlier signs of disease. Real-time registration is a new feature of SD that enables the identification of specific anatomical locations on the retina, against which subsequent tests can be evaluated. This is of particular importance in the monitoring of patients. In the evaluation of treatment effects, for example, this enables the same anatomic retinal location to be identified at each visit.
Literature Search
A literature search was performed on February 13, 2009 using Ovid MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 2003 to February 2009. The subject headings and keywords searched included AMD, DME, and OCT (the detailed search strategy can be viewed in Appendix 1). Excluded were case reports, comments, editorials, non-systematic reviews, and letters. Abstacts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In total, 542 articles were included for review.
English-language articles and health technology assessments.
RCTs and observational studies of OCT and AMD or DME.
Studies focusing on either diagnosis or monitoring of disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies of pediatric populations.
Studies on OCT as a screening tool.
Studies that did not assess comparative effectiveness of OCT with a referent, as specified below in “Comparisons of Interest”.
Outcomes of Interest
Studies of sensitivity, specificity.
Comparisons of Interest
Evidence exists for the following comparisons of interest:
OCT compared with the reference “fluorescein angiography” for AMD.
OCT compared with the reference “biomicroscopy” or “stereo or fundus photography” for DME.
Summary of Existing Evidence
No evidence for the accuracy of SD OCT compared to either FA, BM or SFP was published between January 2006 to February 2009; however, two technology assessments were found, one from Alberta and the other from Germany, both of which contain evidence for TD OCT. Although these HTAs included eight studies each, only one study from each report was specific to this review. Additionally, one systematic review was identified for OCT and DME. It is these three articles, all pertaining to time and not spectral domain OCT, as well as comments from experts in the field of OCT and retinal disease, that comprise the evidence contained in this review.
Upon further assessment and consultations with experts in the methodology of clinical test evaluation, it was concluded that these comparators could not be used as references in the evaluation of OCT. The main conclusion was that, without a third test as an arbiter, it is not possible to directly compare the sensitivity and specificity of OCT relative to either FA for AMD and stereo- or fundus – photography for DME. Therefore, in the absence of published evidence, it was deemed appropriate to consult a panel of experts for their views and opinions on the validity of OCT and its utility in clinical settings. This panel consisted of four clinicians with expertise in AMD and/or DME and OCT, as well as a medical biophysicist with scientific expertise in ocular technologies. This is considered level 5 evidence, but in the absence of an appropriate comparator for further evaluation of OCT, this may be the highest level of evidence possible.
Summary of Findings
The conclusions for SD OCT based on Level 5 evidence, or expert consultation, are as follows:
OCT is considered an essential part of the diagnosis and follow-up of patients with DME and AMD.
OCT is adjunctive to FA for both AMD and DME but should decrease utilization of FA as a monitoring modality.
OCT will result in a decline in the use of BM in the monitoring of patients with DME, given its increased accuracy and consistency.
OCT is diffusing rapidly and the technology is changing. Since FA is still considered pivotal in the diagnosis and treatment of AMD and DME, and there is no common outcome against which to compare these technologies, it is unlikely that RCT evidence of efficacy for OCT will ever be forthcoming.
In addition to the accuracy of OCT in the detection of disease, assessment of the clinical utility of this technology included a rapid review of treatment effects for AMD and DME. The treatment of choice for AMD is Lucentis®, with or without Avastin® and photodynamic therapy. For DME the treatment of choice is laser photocoagulation, which may be replaced with Lucentis® injections (Expert consultation). The evidence, as presented in systematic reviews and other health technology assessments, indicates that there are effective treatments available for both AMD and DME.
Considerations for the Ontario Health System
OCT testing is presently an uninsured service in Ontario with patients paying approximately $150 out-of-pocket per test. Several provinces do provide funding for this procedure, including British Columbia, Alberta, Saskatchewan, Newfoundland, Nova Scotia, Prince Edward Island, and the Yukon Territory. Provinces that do not provide such funding are Quebec, Manitoba and New Brunswick.
The demand for OCT is expected to increase with aging of the population.
PMCID: PMC3377511  PMID: 23074517
19.  The cost-effectiveness of the Argus II retinal prosthesis in Retinitis Pigmentosa patients 
BMC Ophthalmology  2014;14:49.
Retinitis Pigmentosa (RP) is a hereditary genetic disease causing bilateral retinal degeneration. RP is a leading cause of blindness resulting in incurable visual impairment and drastic reduction in the Quality of life of the patients. Second Sight Medical Products Inc. developed Argus II, a retinal prosthesis system for treating RP. Argus II is the world’s first ever-commercial implant intended to restore some vision in the blind patients. The objective of this study was to assess the cost-effectiveness of the Argus® II Retinal Prosthesis System (Argus II) in Retinitis Pigmentosa (RP) patients.
A multi -state transition Markov model was developed to determine the cost-effectiveness of Argus II versus usual care in RP from the perspective of healthcare payer. A hypothetical cohort of 1000 RP patients aged 46 years followed up over a (lifetime) 25-year time horizon. Health outcomes were expressed as quality adjusted life years (QALYs) and direct healthcare costs expressed in 2012 €. Results are reported as incremental cost per ratios (ICERs) with outcomes and costs discounted at an annual rate of 3.5%.
The ICER for Argus II was €14,603/QALY. Taking into account the uncertainty in model inputs the ICER was €14,482/QALY in the probabilistic analysis. In the scenarios of an assumption of no reduction on cost across model visual acuity states or a model time horizon as short as 10 years the ICER increased to €31,890/QALY and €49,769/QALY respectively.
This economic evaluation shows that Argus II is a cost-effective intervention compared to usual care of the RP patients. The lifetime analysis ICER for Argus II falls below the published societal willingness to pay of EuroZone countries.
PMCID: PMC3990272  PMID: 24731533
Retinitis Pigmentosa; Retinal prosthesis; Cost-effectiveness analysis; Decision analytic modelling
20.  System training and assessment in simultaneous proportional myoelectric prosthesis control 
Pattern recognition control of prosthetic hands take inputs from one or more myoelectric sensors and controls one or more degrees of freedom. However, most systems created allow only sequential control of one motion class at a time. Additionally, only recently have researchers demonstrated proportional myoelectric control in such systems, an option that is believed to make fine control easier for the user. Recent developments suggest improved reliability if the user follows a so-called prosthesis guided training (PGT) scheme.
In this study, a system for simultaneous proportional myoelectric control has been developed for a hand prosthesis with two motor functions (hand open/close, and wrist pro-/supination). The prosthesis has been used with a prosthesis socket equivalent designed for normally-limbed subjects. An extended version of PGT was developed for use with proportional control. The control system’s performance was tested for two subjects in the Clothespin Relocation Task and the Southampton Hand Assessment Procedure (SHAP). Simultaneous proportional control was compared with three other control strategies implemented on the same prosthesis: mutex proportional control (the same system but with simultaneous control disabled), mutex on-off control, and a more traditional, sequential proportional control system with co-contractions for state switching.
The practical tests indicate that the simultaneous proportional control strategy and the two mutex-based pattern recognition strategies performed equally well, and superiorly to the more traditional sequential strategy according to the chosen outcome measures.
This is the first simultaneous proportional myoelectric control system demonstrated on a prosthesis affixed to the forearm of a subject. The study illustrates that PGT is a promising system training method for proportional control. Due to the limited number of subjects in this study, no definite conclusions can be drawn.
PMCID: PMC4041142  PMID: 24775602
Electromyography; Estimation; Myoelectric control; Proportional control; Prosthesis guided training; Prosthetics; Prosthetic hand
21.  Spatial working memory for locations specified by vision and audition: Testing the amodality hypothesis 
Spatial working memory can maintain representations from vision, hearing, and touch, representations referred to here as spatial images. The present experiment addressed whether spatial images from vision and hearing that are simultaneously present within working memory retain modality-specific tags or are amodal. Observers were presented with short sequences of targets varying in angular direction, with the targets in a given sequence being all auditory, all visual, or a sequential mixture of the two. On two thirds of the trials, one of the locations was repeated, and observers had to respond as quickly as possible when detecting this repetition. Ancillary detection and localization tasks confirmed that the visual and auditory targets were perceptually comparable. Response latencies in the working memory task showed small but reliable costs in performance on trials involving a sequential mixture of auditory and visual targets, as compared with trials of pure vision or pure audition. These deficits were statistically reliable only for trials on which the modalities of the matching location switched from the penultimate to the final target in the sequence, indicating a switching cost. The switching cost for the pair in immediate succession means that the spatial images representing the target locations retain features of the visual or auditory representations from which they were derived. However, there was no reliable evidence of a performance cost for mixed modalities in the matching pair when the second of the two did not immediately follow the first, suggesting that more enduring spatial images in working memory may be amodal.
PMCID: PMC3482114  PMID: 22552825
22.  Adaptive Changes in Early and Late Blind: A fMRI Study of Braille Reading 
Journal of neurophysiology  2002;87(1):589-607.
Braille reading depends on remarkable adaptations that connect the somatosensory system to language. We hypothesized that the pattern of cortical activations in blind individuals reading Braille would reflect these adaptations. Activations in visual (occipital-temporal), frontal-language, and somatosensory cortex in blind individuals reading Braille were examined for evidence of differences relative to previously reported studies of sighted subjects reading print or receiving tactile stimulation. Nine congenitally blind and seven late-onset blind subjects were studied with fMRI as they covertly performed verb generation in response to reading Braille embossed nouns. The control task was reading the nonlexical Braille string “######”. This study emphasized image analysis in individual subjects rather than pooled data. Group differences were examined by comparing magnitudes and spatial extent of activated regions first determined to be significant using the general linear model. The major adaptive change was robust activation of visual cortex despite the complete absence of vision in all subjects. This included foci in peri-calcarine, lingual, cuneus and fusiform cortex, and in the lateral and superior occipital gyri encompassing primary (V1), secondary (V2), and higher tier (VP, V4v, LO and possibly V3A) visual areas previously identified in sighted subjects. Subjects who never had vision differed from late blind subjects in showing even greater activity in occipital-temporal cortex, provisionally corresponding to V5/MT and V8. In addition, the early blind had stronger activation of occipital cortex located contralateral to the hand used for reading Braille. Responses in frontal and parietal cortex were nearly identical in both subject groups. There was no evidence of modifications in frontal cortex language areas (inferior frontal gyrus and dorsolateral prefrontal cortex). Surprisingly, there was also no evidence of an adaptive expansion of the somatosensory or primary motor cortex dedicated to the Braille reading finger(s). Lack of evidence for an expected enlargement of the somatosensory representation may have resulted from balanced tactile stimulation and gross motor demands during Braille reading of nouns and the control fields. Extensive engagement of visual cortex without vision is discussed in reference to the special demands of Braille reading. It is argued that these responses may represent critical language processing mechanisms normally present in visual cortex.
PMCID: PMC3684969  PMID: 11784773
23.  Spatial and temporal characteristics of V1 microstimulation during chronic implantation of a microelectrode array in a behaving macaque 
Journal of neural engineering  2012;9(6):065003.
It has been hypothesized that a vision prosthesis capable of evoking useful visual percepts can be based upon electrically stimulating the primary visual cortex (V1) of a blind human subject via penetrating microelectrode arrays. As a continuation of earlier work, we examined several spatial and temporal characteristics of V1 microstimulation.
An array of 100 penetrating microelectrodes was chronically implanted in V1 of a behaving macaque monkey. Microstimulation thresholds were measured using a two-alternative forced choice detection task. Relative locations of electrically-evoked percepts were measured using a memory saccade-to-target task.
Main results
The principal finding was that two years after implantation we were able to evoke behavioural responses to electric stimulation across the spatial extent of the array using groups of contiguous electrodes. Consistent responses to stimulation were evoked at an average threshold current per electrode of 204 ± 49 µA (mean ± std) for groups of four electrodes and 91 ± 25 µA for groups of nine electrodes. Saccades to electrically-evoked percepts using groups of nine electrodes showed that the animal could discriminate spatially distinct percepts with groups having an average separation of 1.6 ± 0.3 mm (mean ± std) in cortex and 1.0 ± 0.2 degrees in visual space.
These results demonstrate chronic perceptual functionality and provide evidence for the feasibility of a cortically-based vision prosthesis for the blind using penetrating microelectrodes.
PMCID: PMC3521049  PMID: 23186948
24.  Is DOPA-Responsive Hypokinesia Responsible for Bimanual Coordination Deficits in Parkinson’s Disease? 
Bradykinesia is a well-documented DOPA-responsive clinical feature of Parkinson’s disease (PD). While amplitude deficits (hypokinesia) are a key component of this slowness, it is important to consider how dopamine influences both the amplitude (hypokinesia) and frequency components of bradykinesia when a bimanually coordinated movement is required. Based on the notion that the basal ganglia are associated with sensory deficits, the influence of dopaminergic replacement on sensory feedback conditions during bimanual coordination was also evaluated. Bimanual movements were examined in PD and healthy comparisons in an unconstrained three-dimensional coordination task. PD were tested “off” (overnight withdrawal of dopaminergic treatment) and “on” (peak dose of dopaminergic treatment), while the healthy group was evaluated for practice effects across two sessions. Required cycle frequency (increased within each trial from 0.75 to 2 Hz), type of visual feedback (no vision, normal vision, and augmented vision), and coordination pattern (symmetrical in-phase and non-symmetrical anti-phase) were all manipulated. Overall, coordination (mean accuracy and standard deviation of relative phase) and amplitude deficits during bimanual coordination were confirmed in PD participants. In addition, significant correlations were identified between severity of motor symptoms as well as bradykinesia to greater coordination deficits (accuracy and stability) in PD “off” group. However, even though amplitude deficits (hypokinesia) improved with dopaminergic replacement, it did not improve bimanual coordination performance (accuracy or stability) in PD patients from “off” to “on.” Interestingly, while coordination performance in both groups suffered in the augmented vision condition, the amplitude of the more affected limb of PD was notably influenced. It can be concluded that DOPA-responsive hypokinesia contributes to, but is not directly responsible for bimanual coordination impairments in PD. It is likely that bimanual coordination deficits in PD are caused by the combination of dopaminergic system dysfunction as well as other neural impairments that may be DOPA-resistant or related to non-dopaminergic pathways.
PMCID: PMC3715734  PMID: 23882254
bimanual coordination; motor control disorders; dopamine; bradykinesia; hypokinesia; Parkinson’s disease
Journal of neural engineering  2014;11(4):046012.
In clinical trials, retinitis pigmentosa (RP) patients implanted with a retinal prosthetic device show enhanced spatial vision, including the ability to read large text and navigate. New prosthetics aim to increase spatial resolution by decreasing pixel/electrode size and limiting current spread. To examine spatial resolution of a new prosthetic design, we characterized and compared two photovoltaic array (PVA) designs and their interaction with the retina after subretinal implantation in transgenic S334ter line 3 rats (Tg S334ter-3).
PVAs were implanted subretinally at two stages of degeneration and assessed in vivo using extracellular recordings in the superior colliculus (SC). Several aspects of this interaction were evaluated by varying duration, irradiance and position of a near infrared (NIR) laser focused on the PVA. These characteristics included: activation threshold, response linearity, SC signal topography and spatial localization. The major design difference between the two PVA designs is the inclusion of local current returns in the newer design.
Main Results
When tested in vivo, PVA-evoked response thresholds were independent of pixel/electrode size, but differ between the new and old PVA designs. Response thresholds were independent of implantation age and duration (≤ 7.5 months). For both prosthesis designs, threshold intensities were within established safety limits. PVA-evoked responses require inner retina synaptic transmission and do not directly activate retinal ganglion cells (RGCs). The new PVA design evokes local retinal activation, which is not found with the older PVA design that lacks local current returns.
Our study provides in vivo evidence that prosthetics make functional contacts with the inner nuclear layer at several stages of degeneration. The new PVA design enhances local activation within the retina and SC. Together these results predict that the new design can potentially harness the inherent processing within the retina and is likely to produce higher spatial resolution in patients.
PMCID: PMC4128185  PMID: 24940618
retina; prosthesis; photovoltaic; retinitis pigmentosa; artificial vision

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