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Keywords:

  • artificial vision;
  • methodology;
  • neuroprosthetics;
  • retinitis pigmentosa;
  • safety and efficacy testing;
  • subretinal implant;
  • visual acuity

Abstract

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

Background

Replacing the function of visual pathway neurons by electronic implants is a novel approach presently explored by various groups in basic research and clinical trials. The novelty raises unexplored methodological aspects of clinical trial design that may require adaptation and validation.

Methods

We present procedures of efficacy and safety testing for subretinal visual implants in humans, as developed during our pilot trial 2005 to 2009 and multi-centre clinical trial since 2010.

Results

Planning such a trial requires appropriate inclusion and exclusion criteria. For subretinal electronic visual implants, patients with photoreceptor degeneration are the target patient group, whereas presence of additional diseases affecting clear optic media or the visual pathway must be excluded. Because sham surgery is not possible, a masked study design with implant power ON versus OFF is necessary. Prior to the efficacy testing by psychophysical tests, the implant's technical characteristics have to be controlled via electroretinography (ERG). Moreover the testing methods require adaptation to the particular technology. We recommend standardised tasks first to determine the light perception thresholds, light localisation and movement detection, followed by grating acuity and vision acuity test via Landolt C rings. A laboratory setup for assessing essential activities of daily living is presented. Subjective visual experiences with the implant in a natural environment, as well as questionnaires and psychological counselling are further important aspects.

Conclusions

A clinical trial protocol for artificial vision in humans, which leads a patient from blindness to the state of very low vision is a challenge and cannot be defined completely prior to the study. Available tests of visual function may not be sufficiently suited for efficacy testing of artificial vision devices. A protocol based on experience with subretinal visual implants in 22 patients is presented that has been found adequate to monitor safety and efficacy.

The eye is the receptive organ for vision and contains several sub-specialised tissues. Fortunately, for a number of eye diseases, some of these tissues can now be replaced, for example, corneal transplants or artificial corneas, artificial lenses, endotamponade or iris prostheses. Replacing the function of neuronal tissue of the eye is currently not possible in a satisfactory manner. Depending on the particular part of the visual pathway to be replaced, there are different approaches under investigation: subretinal or subchoroidal implants, epiretinal prostheses, optic nerve cuffs or cortical visual implants.[1-6]

Our group has been developing subretinal visual implants to replace the function of degenerated photoreceptors in blind patients with hereditary retinal diseases since the mid-'90s.[7-10] Currently our subretinal implant is able to restore subjectively useful visual functions for blind patients with hereditary degenerations of the outer retina, in some patients up to measurable visual acuity with Landolt C rings, reading big letters or object recognition in daily life, recognition of facial characteristics or subjective improvement of orientation.[3, 11-15] More detailed and complete functional results beyond present short reports[3, 11-15] will be published after completion of the current multi-centre clinical trial. Before the start of our pilot human trial in 2005, testing of artificial vision in humans was a novel field. Nevertheless, a structured study procedure and the development of special function tests and methodical approaches were necessary. The novelty raised methodological aspects of efficacy and safety in a human trial that may require adaptation and validation. The methods used in the first, pilot trial have been adapted according to acquired experiences to be used in the currently running multi-centre trial (Registration Number NCT01024803 at http://www.clinicaltrials.gov).

This manuscript presents the design of our study in detail, explaining the methodological aspects of a trial with artificial vision in humans and giving suggestions for future trials of this kind.

Subretinal Visual Implant

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

The subretinal visual implant used in this study uses light-absorbing elements that can convert light signals into electrical signals. Such implants essentially replace the function of lost photoreceptors and can be applied in photoreceptor degenerations. Normal function of the remaining visual pathway is necessary.

The active subretinal implant described here consists of an array of 1,500 micro-photodiodes each of which drives an amplifier that injects currents into the bipolar cell layer via an electrode, all arranged on an area of approximately 3.0 mm × 3.0 mm with 90 μm thickness (Figure 1). In the pilot study, an additional array of 16 direct-stimulation electrodes was placed on the tip of the subretinal implant to access and test the electrical interface with the retina (Figure 1A). The electronics in visual implants require an external power supply. In the pilot trial, this was provided via a cable leading from the eye transchoroidally and transsclerally under the temporal muscle to a plug behind the ear (Figure 2A). In the current clinical trial, the power supply of the new implant (Alpha IMS, Retina Implant AG, Reutlingen, Germany, shown in Figure 1C) is wireless with subdermal and external coils (Figure 2B). A description of the surgical implantation procedure has been previously published.[16, 17]

figure

Figure 1. The subretinal implant (A) from the pilot trial, (B) from the clinical trial. The full length and detail of micro-photodiode array with 1,500 pixels are shown. In the pilot trial, 16 direct stimulation electrodes were placed on the tip of the implant foil. (C) Fundus view of the subretinal visual implant.

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figure

Figure 2. Placement of the power supply cable (A) in the pilot trial (2005–2009), (B) in the clinical trial (from 2010 on). The power supply was provided by a transdermal plug in the pilot trial. In the clinical trial, the transdermal power supply is based on electromagnetic induction.

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Study Design

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

Patient selection

In a relatively new field of research, the study population should be kept homogeneous and structured to achieve interpretable results. Patients with rod-cone or cone-rod degeneration, who represent the main patient group for subretinal implants, should not have additional ophthalmologic diseases. As the subretinal electronic receiver array requires a focused image, clear optic media are necessary. Also, inner retinal disease or disease of the optic nerve or central visual pathway would be a contraindication for the subretinal visual implant's successful functioning.

Because there was no pre-existing experience with a subretinal implant in humans, the quality of the chip-mediated vision to be expected prior to the pilot trial was unknown. The computations based on the spatial alignment of the micro-photodiodes and animal experiments estimated a resolution of approximately 1.0° to 0.25° visual angle or decimal acuity of 0.06 to 0.08;[4, 18-20] however, it was impossible to predict whether the chip-mediated vision would allow reading, independent orientation in space or just light perception in blind patients. Thus, low pre-implantation baseline for remaining visual function in these patients was set to allow proper assessment of chip-mediated vision. This means blindness (at least monocular), in the sense of inability to localise light and objects and lack of independent visual mobility in space. All our study subjects were completely blind (no light perception) or had only an ability to distinguish light and darkness, being unable to correctly localise a light source.

Although it is also a disease affecting the outer retina, patients with macular degeneration were not included. Despite being heavily impaired, they typically do not become blind in the sense mentioned above but suffer from a central scotoma, not necessarily losing their mobility.

Blindness as an inclusion criterion was necessary also from an ethical point of view. In a first pilot trial, the potential risk of harming patients had to be as low as possible. Also for safety reasons only one eye—the one with the least function—received the implant.

Clear optic media are important not only for a sharp image falling onto the chip, but also for the best possible vision for the surgeon implanting a new device. To avoid post-operative or age-related lens opacification, an obligatory cataract operation was included prior to the study procedures. Vitrectomy with silicone oil tamponade is a part of the implantation surgery, thus homogeneity of the vitreous can be assumed as well.

In the absence of photoreceptor input, it is still an unmet challenge to examine the function of the inner retina and of the rest of the visual pathway that at present cannot be solved with certainty. Nevertheless, there are some ways for estimating whether there is sufficient function of these systems.

The first requirement is that the subjects have a fully developed and functioning central visual pathway. This is the case if a normally functioning visual system with the ability to learn reading had been established in childhood. Congenital or early-childhood blindness are contraindications for electronic visual implants. Because the visual pathway keeps developing post-natally up to school age or early teens, our inclusion criteria allowed only subjects who were able to use some useful vision at least up to the twelfth year of life and had learned to read and to move independently.

Second, the bipolar and ganglion neurons must still be able to transmit signals to the brain. How can this be tested if there are no functioning photoreceptors to pass on the signal? After the loss of photoreceptors in retinitis pigmentosa, a slow progressive degeneration of bipolar and ganglion cells can follow,[21] although a surprisingly large population of ganglion cells and bipolar cells survives many years of complete blindness,[22] possibly by lateral signal processing in the inner retina. The central question to be answered is whether or not residual bipolar and ganglion cells are capable of properly forwarding electrical signals. Retinal excitability can be measured by means of electrically evoked phosphenes by a corneal electrode[23, 24] and such a measurement can provide valid information about the functionality of the inner retina. Recent results point to the possibility of using additional information about this functionality by pupillography, in cases where the electrically evoked phosphenes threshold cannot be determined.[25]

Additionally, the retinal vasculature must still allow sufficient perfusion for the inner retinal layers. We observed this in two patients of the pilot study who had considerable retinal ischemia in the region of the active microchip, when no implant-mediated visual perception was possible. Thus, a fluorescein angiographic evaluation of the retinal vasculature was made obligatory prior to inclusion in the study. Last but not least, the retinal thickness measurements by optical coherence tomography (OCT) should show neither oedema nor an extremely atrophic retina (which would suggest a profound bipolar or ganglion cell depletion). A recent subject whose retina exhibited almost no layering when imaged using spectral domain OCT had only a minimal implant-mediated perception without shape recognition or measurable acuity. Although based only on this one case, we assume that a visible layering of the inner retina in a high-resolution OCT is a good marker for its functionality. A correlation between electrical excitability of the inner retina and its thickness has been described by other research groups.[26]

Attention should also be paid to pigment clumps on the posterior pole of the eye prior to study inclusion. It is well known that the bone spicule pigment contains migrated retinal epithelium cells, with intra-retinal deposits of pigment.[21, 27] Therefore, large pigment clumps may reduce the light falling onto the chip surface, because they would be localised intra-retinally on top of the implant. Moreover, due to different adhesion properties, the clumps may present a surgical obstacle for a smooth implantation of the device in the subretinal space. Therefore, we avoided including individuals with heavily clumped pigmentation in the target area of the subretinal chip.

Our team developed and implemented a new planning procedure to include all the previously mentioned features of the retina to define the most appropriate position of the implant.[28]

In summary, we define our current most important eye-related inclusion criteria as follows:

  1. hereditary retinal degeneration of the outer retinal layers with the retinal vessels still perfused and pigment of mild to moderate density
  2. functionality of the inner retina as measured by transcorneal electrical excitability and layering visible in a spectral domain OCT
  3. no other ophthalmologic disease with relevant effects upon visual function and
  4. blindness (at least monocular) or visual functions not appropriate for navigation/orientation but a reading visual acuity in earlier life and appropriate visual functions up to 12 years of age.

In a study that involves a surgical procedure, the general health of the patient deserves special attention. The complete surgical implantation includes extraorbital cable placement and intraorbital microdevice placement, resulting in a surgery of about six to eight hours. The obligatory explantation with the device used in the pilot study because of the transdermal cable-bound power supply required another two to four hours of surgical procedure under general anaesthesia. Systemic diseases or conditions that might imply considerable risks with regard to the surgical interventions and long anaesthesia, as well as pregnancy, nursing or age below 18 and above 78 are exclusion criteria for study participation.

Last but not least, we regard the psychological precondition of the patient as well as his/her attitude to the study participation as very important. A blind or nearly blind person can find him/herself in critical psychological situations. In hereditary retinal disorders that lead to blindness mostly in the patient's middle age, the patient has experienced his/her visual impairment at young adult age with the knowledge of progression to blindness without an available treatment. Naturally, various psychological reactions can be evoked by the condition. Analogous to the grief cycle model,[29] visual loss brings stages of denial, anger, bargaining, depression and acceptance[30] as well as significant anxiety.[31] An electronic visual implant can restore only parts of the earlier visual functions and bring a blind patient to the very low or low vision range. To avoid false or unrealistic expectations concerning the benefit of study participation, disappointments or biased results, we only include blind individuals who have accepted their blindness and who have no neurological or psychiatric problems. This is ensured by a psychiatric examination as a part of the screening procedures.

Study design

The study was designed as a prospective pilot clinical study based on randomised intra-individual implants in a double-masked fashion. For better practicability, a single-masked design is used currently in the clinical trial. In our trials, each patient received an implant, while sham surgery was not performed.

Intervention takes place as an intra-individual function of activity or inactivity of the retinal implant. Implant power ‘ON’ or ‘OFF’ modality is unknown to the patient and each test is always performed under these two conditions via two consecutive tests in a randomised order.

It should be pointed out that the patient is often aware of the condition (ON or OFF) despite the masked design, as he/she is able to judge whether he/she has a perception or not. Nevertheless, we strongly recommend sticking to this study design because additional information about the state of the implant power could eventually bias the patient's performance.

Organisational aspects

In the initial pilot study with a wire-bound device, a study time of four weeks had been set, followed by explantation of the subretinal device. This time limitation was due to the transdermal cable (Figure 2A) and to safety aspects of the implant, as the reaction of the human tissue to the new technology was not known. As no side effects or serious adverse events and no infections resulted from the implant, after the eighth subject of the pilot trial, the study period was prolonged in an amendment to four months duration.

In the short time of four weeks, as much information as possible had to be obtained. For this reason, a high frequency of visits was established, consisting of daily clinical and functional measurements for many hours. This is feasible only with a low number of study patients and the study physicians cannot plan more than two (optimally only one) patients to be implanted and tested in parallel.

During these weeks or later months, the study team has to consider also a variety of logistic aspects. As the study population is strictly defined, patients had to be recruited from large distances. Logistics, accommodation and personal assistance for blind subjects must be available in an unfamiliar city for the study period.

Refraction correction after implantation

As mentioned above, the implantations were combined with a preceding cataract surgery and intra-operative silicone oil tamponade. The silicon oil changes the eye's refraction and pseudophakia precludes accommodation. Depending on the distance to the visual stimulus, appropriate refractive correction is necessary to guarantee a focused image on the microphotodiodes. This must be determined prior to the functional tests; however, an autorefractometer can fail in the case of highly reflective subretinal implants and also a retinoscopy over a subretinal chip can lead to irregular reflexes. Thus, a very careful retinoscopy is recommended or, if available, refraction with a manual refractometer, where the examiner can directly check the reflection image quality on the microchip.

As soon as chip-mediated vision allows the patient to see grids or optotypes, an additional subjective refraction can be performed.

Assessing the Efficacy Testing—Visual Functions

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

Principal considerations

One of the features of testing a new medical technology in humans for the first time worldwide is the insecurity about the reliability of the results. When the first pilot trial was planned to begin in 2005, virtually no recommendations for testing artificial vision were available. Thus, function testing design will necessarily undergo a development itself and consequently the study protocol cannot be defined completely prior to the study.

The quality of artificial vision must be quantifiable to allow for scientifically solid results and it also needs to be subjectively useful in life-relevant situations. Naturally, measurement of visual acuity is the most precise approach but standardised visual acuity testing cannot be applied easily in the range of very low vision. Moreover, seeing cannot be described only by visual acuity. Other aspects like visual field, interpretation of the visual input and recognition of seen objects, spatial resolution of repetitive stimuli, contrast perception or navigation as well as orientation in space need to be examined.[32]

There are some aspects of vision, such as colour vision, which cannot be achieved with the current subretinal implants. All subretinal micro-photodiodes are set to an equal spectral sensitivity, thus not allowing for distinguishing between colours. Patients describe their image perception in terms of several grey levels. Furthermore, the above-mentioned resolution limit of approximately 0.08 visual acuity cannot be exceeded. The visual field provided by the 3.0 mm by 3.0 mm area of the chip is a square of 10° by 10°, allowing for an angle of approximately 15° horizontally and vertically across the corners of the chip.

In research into artificial vision, observation and listening to the patients' descriptions are of crucial importance. We strongly recommend videotaping to recall and prove the spontaneous descriptions of the subjects confronted with the new perceptions. Video documentation provides not only a proof of results but also important additional material concerning the qualitative aspects of the artificial vision and the design of future devices. It is not to be regarded as a substitute for a patient-reported-outcome instrument but helps the study team to understand better the quality of the subjects' perceptions.

To assess vision mediated by the subretinal chip as systematically as possible, we proceed through various functional tests from the easiest to the most difficult. From a scientific as well as from a psychological point of view, this approach can reliably establish the functional outcome. It would not be reasonable to expose the subject to a more challenging test without him/her having passed an easier one before; for example, if a patient is not able to recognise light, it would not be meaningful to present Landolt C rings.

In general, time measurement for efficacy tests may be suitable for evaluation. The patients are mostly aware of the condition (power supply ON or OFF), since they can distinguish whether a visual perception is available and take more time to perform the task visually as correctly as possible in the ON condition. For this reason, the reaction time is not necessarily suitable for efficacy evaluation but rather for an intra-individual comparison of a learning effect.

Low-vision test battery

As the very first functional test, a battery of tests targeted to the range of very low vision[32, 33] (basic assessment of light and motion or BaLM) was applied since the pilot trial. This test battery was developed as a quantitative measure of visual functions in the low-vision range.[33] All subtests of the battery are designed as two-, four- or eight-alternative forced-choice tests on a screen, the first one is a go-no go task. Neutral density filters are used to modify luminance (Figure 3).

figure

Figure 3. (A) Projector-screen setting for the low-vision test battery. The patient's eye is approximately at 60 cm from the screen. Neutral density filters can be applied in front of the projector to control the luminance of the stimuli. The patient responds by pressing keyboard buttons under his/her right hand. In the basic assessment of light and motion (BaLM) test battery, the following screens are presented: (B) a full-field flash for the ‘Light’ and ‘Time’ subtests, (C) a white wedge for the ‘Location’ subtest and (D) a moving random dot pattern or (A) hexagons for the ‘Motion’ subtest.

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The first test of the battery is the ‘light subtest’ measuring the threshold luminance. The patient responds by pressing keys whether he has seen a full-field flash on the screen (Figure 3B) or not. In the ‘time subtest’ the subject has to distinguish a one-flash from a two-flash situation (200 ms interval) presented in suprathreshold luminance. The ‘location subtest’ measures light source localisation: a black screen with a white spot in the middle is shown, onto it a white wedge appears, pointing in one of four directions (Figure 3C). The patient's task is to determine the direction of the wedge. The ‘motion subtest’ tests movement perception: a pattern of randomly arranged hexagons or dots (Figures 3A and 3D) moves in one of four or eight directions. The patient's task is to recognise the direction. The dot pattern (size and distance of the dots can be modified) has turned out to be more easily distinguishable than a hexagonal pattern and thus more suitable for movement detection.

In the ‘light subtest’ as well as the ‘time subtest’ the patient has to decide from two responses (go-no go test or a two-alternative forced choice test). The task is repeated several times per subtest (for example, twelve times), according to the psychophysical function 75 per cent or more correct responses is required for passing the test. ‘Location’ and ‘motion detection’ are designed as four or eight alternatives forced-choice tests, here 62.2 and 56.25 per cent, respectively, of correct responses are required for a positive result. In each run, the number of correct responses and average time is recorded by the software. If results are obtained repeatedly, for example during several trial and follow-up visits, learning curves for each subtest can be established as well.

In the course of the trial, the time subtest did not turn out to be useful for the following reason. The subretinal implant always samples an input for 1.0 to 4.0 ms (adjustable) with a repetition frequency of 5 Hz, resulting in short pulses of electrical activity (for example, 1 ms) alternating with non-active intervals of 199 ms, which causes a slightly ‘flickering’ perception. The comfortable frequency differs between subjects. Although five Hertz are used mostly, some patients prefer lower frequencies to achieve stable perception; others prefer seven or 10 Hz to minimise the flickering aspect of the image. A time interval of 200 ms cannot be distinguished reliably with an implant driven with five Hertz or less. Even with higher frequencies, this time resolution can lead to incorrect answers as image-capture by the chip can fall in between the presentation flashes. Different interstimulus intervals for different patients or a too long interval between stimuli when measuring time resolution would not allow for meaningful scientific results. For this reason, we currently do not include this subtest in determining the device's efficacy. Concerning the temporal aspects, we rely on the spatio-temporal ‘motion detection sub-test’ that is closer to real-life conditions than a double full-field flash.

Grating acuity (spatial resolution)

Semi-automated assessment of grating acuity[30] (basic grating acuity or BaGA) is applied. Measuring grating acuity is very valuable in devices for artificial vision. Visual acuity and grating visual acuity are different concepts but both describe the best possible spatial resolution, the former locally, the latter more globally. The grating acuity test assesses the best resolution in terms of spatial frequencies over larger areas of visual fields, while the visual acuity test measures the spatial resolution of a single item projected on a small retinal area. In amblyopia for example, the grating visual acuity is higher than the visual acuity measured with optotypes.[34]

The BaGA test is built as a two or four alternatives forced-choice test, where a black-and-white striped pattern in horizontal, 45°, vertical or 135° direction is presented in spatial frequencies of 0.1, 0.33, 1.0 and 3.3 cycles per degree (cpd). Additionally, striped patterns of 0.4 cpd, 0.5 cpd et cetera can be shown manually from a PowerPoint-based presentation. The best resolution grating acuity is documented for every visit or test run. A ratio of 1:5 for the white/black stripe thickness turned out most acceptable for the patients in this test. Possibly due to scatter or due to missing or incomplete lateral inhibition in the retinal network, the white line's image may be perceived to be broader than it is. Since for the resolution calculation the width of the whole period is used, the ratio should not bias the results.

Landolt C visual acuity test

After spatial resolution is successfully established, a standardised visual acuity test is performed. For this step, the Freiburg Acuity and Contrast Test (FrACT)[35] with its Landolt C rings in contrast reversal mode (white on black) can be used and was included in the study protocol since the pilot trial. This test provides reproducible quantitative measurements of visual acuity in patients with low vision.[35, 36] The Landolt C is the most standardised optotype, whereas contrast reversal is advantageous for reading ability in the low-vision range but also for vision with an electronic implant. White-on-black patterns keep the surroundings of the visual target silent, while the black-on-white target suffers from ‘bleeding in’ activity of the white background.

The FrACT thresholding algorithm is based on a psychometric function with a constant slope on a logarithmic scale, adapting the size of the presented optotype on the correctness of previous responses; however, there can be a problem if a patient with limited visual field is doing this test, as in the case of the subretinal implant. If the optotype increases, it may exceed the size of the visual field and its visibility gets worse, resulting in incorrect responses. This causes the automatic test to present even bigger optotypes and leads to failure in the testing procedure, although the patient may have been able to correctly identify smaller optotypes. In many patients a manual presentation of 12 contrast-reversed, standardised Landolt C rings for each gap size in four possible gap directions, as in a clinical setting, was advantageous and is encouraged for the efficacy evaluation.

Activities of daily living

Visual acuity is only one of many aspects of vision. For a blind patient localisation of objects and orientation in an unfamiliar environment are extremely important functions. To meet these expectations is one of the most important demands for the future development of electronic visual implants. These expectations, although of utmost significance for the patient, are difficult to quantify scientifically and are prone to both patient and examiner bias. In addition, at the beginning of our pilot trial in 2005, there were no standardised tests available for activities of daily living (ADL) or orientation validated for use in visual implant studies.

Influence due to bias was meant to be overcome by a double-masked design. We developed a standardised approach to compare two conditions, namely, with implant power on versus off as described above, concerning detection, identification and localisation of objects of daily living and eye-hand co-ordination.[32]

One way to test activities of daily living is to involve a professional mobility trainer, who performed such tests in the pilot trial. The mobility trainer documents the correctness of the activities of daily living task results and rates the correct or incorrect performance by a score based on his professional experience with blind people (for example, on a subjective analogue scale).

A more objective way is to evaluate the tests based on patients' correct answers documented as scores: the numbers of correctly identified, described and localised objects represent the scores.

In our setup, activities of daily living are mimicked by table scenery in the laboratory. The setting is meant to provide an optimal contrast, using white homogeneous objects on a black table, or as in the pilot study, also placing pieces of fruit on a white table. In particular, in the first part of activities of daily living, the subjects are shown four geometric shapes out of square, triangle, circle, rectangular, ring and semicircle (Figure 4A). The patient is not aware of the actual number of objects placed in front of him/her. The professional mobility trainer asks the patient to say how many pieces he can identify, describe the objects he can see (shape/object recognition) and to localise them. The answers of correctly identified, recognised and localised objects are documented as a score of zero to four for each of these three questions; for example, if the patient as shown in Figure 4A reports ‘I can see three shapes; a circle (points toward the crescent), a triangle (points towards the triangle) and a square (points towards the square)’, the documented scores are identification 3, recognition 2 and localisation 3.

figure

Figure 4. The standardised ‘Activities of daily living’ test. (A) Geometric shapes of equal area. (B) Table objects. The subject has to identify, describe and localise the objects while sitting at the table. (C) Test of eye-hand co-ordination. The patient is given a chess piece, which he/she should hold by its neck. The patient is asked to place the chess piece into the area of a white square after localising it visually, without touching the table.

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Second, a table setting is presented (Figure 4B), where a big white plate in the middle is obligatory and known to the patient. Around the plate, additional tableware is placed using small plates, cups and cutlery of homogenous white colour. Again, recognition, description and localisation are asked and documented as a score of zero to four in an analogue way. The awareness of the white plate may give the patient some hints about the kind of objects he/she should search for, although the examiner does not explicitly encourage the subject to search for tableware. This may be a bias in the results on one side but on the other side in daily life we usually have a context for our visual search. For example, sitting at a table in a restaurant, there are objects you expect to see, like tableware or food, while other objects for example, from bureau tables would not be expected. In this way, the task may be more comparable to a daily life situation.

Thereafter, eye-hand co-ordination is tested. For example, the examiner can ask the patient to move and position some of the objects after their identification, recognition and localisation;[32] however, a more specific test for the visual eye-hand co-ordination seems to be necessary to obtain comparable results. As blind patients are used to grasping objects rather slowly, using their tactile perception in localisation and grasping, the eye-hand co-ordination can be partly biased even with some degree of regained visual function. Such bias could be overcome for example, by using a chess piece, which the patient holds on its neck and has to put onto/into another object placed on the table that he had localised visually without touching the actual table area (Figure 4C). The correct performance is then documented, if the chess piece is placed in the requested area.

The second part of the laboratory version of the activities of daily living tasks in the pilot trial was devoted to outdoor scenarios. The ultimate goal of an electronic visual implant in daily life is to provide orientation ability in unfamiliar surroundings. Classic mobility tests with the patient moving freely could not be performed in the pilot trial, as the wire-bound implant could only be activated in the hospital setting in contrast to the presently ongoing trial with wireless implants. We tested this in the pilot trial by means of a series of images presented on a two by two metre projection screen depicting street scenes viewed from various angles (for example crosswalk, traffic lights, dust bin, barrier on pedestrian path).[32] The subject was asked to describe the image. Additionally, the time necessary for the task solution was documented. Again, these tasks were performed by the independent professional low-vision mobility trainer with implant-power switched on and off in a double-masked manner with the performance being scored afterwards by both the specialist and the subject.

In the current clinical trial the patients are allowed to use the visual implant outside the clinic, such as outdoors, at their homes, workplaces or on the street. In the first days, they are accompanied by the mobility trainer, later they use the implant on their own. They are instructed to adjust the parameters of brightness and contrast (adjustable on the power supply box) to achieve optimal visual information. During the study visits, the mobility trainer documents the performance and experiences of the subject in a normal environment in a written study report. At home, patients use a dictaphone or writing software to document their visual experiences. In this way, the most significant activities of daily living can be improved by implant-mediated visual functions. These activities cannot be scored or evaluated scientifically but provide very important information on the question of subjective benefit for the patient and what characteristics of objects can be used best, for example, shiny borders of cars, streetlamps et cetera.

Assessing Safety—Clinical Examinations

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

Ophthalmologic safety endpoints

Regular slitlamp and fundus examinations by an ophthalmologist are necessary during the study period. In a four-week trial, as in the beginning of the pilot trial, daily slitlamp examination and funduscopy were performed with careful inspection of the implant itself, the subretinal cable, vessels, especially those above the implant and their relation to the implant position, search for small bleedings, development of pigments and deposits, as well as nerve fibre and optic disc evaluation. With study duration prolonged to four months, at least weekly ophthalmologic examinations after the first week are recommended. In a trial where no explantation is foreseen, as in the current one, co-operation with the patient's primary ophthalmologist is important for following check-ups.

To monitor the retinal situation above the implant, OCT and fluorescein angiography of the retinal vessels are necessary at regular intervals. At the beginning, an OCT was performed at least weekly and fluorescein angiography approximately once per month. According to the schedule of trial visits, currently we perform these examinations once per month in the first three months, then during every study visit at three-month intervals. Special attention is paid to development of oedema, changes at the borders of the implant and macula, vessel dilatations such as microaneurysms, vascular drop outs, neovascularisation and retinal position in relation to the chip surface.

Last but not least, post-operative ocular motility needs to be observed because the power supply cable is placed in the orbit and may restrict motility. These examinations are currently performed at a similar interval as the fluorescein angiography and documented photographically for nine gaze directions.

General safety aspects

Due to the long period under general anaesthesia necessary for the surgical study procedures, the novelty of the implant and the potential risk of infection around the retroauricular transdermal cable entrance in the pilot trial, checking for general diseases is necessary before and during study participation. Vital signs and laboratory diagnostics were also included in the study protocol, obligatory prior to the implantation, as well as the explantation in the pilot trial and daily in the first days after the surgery.

The relatively long ocular surgery leads to lid swelling, lid haematoma and conjunctival reddening in most patients. In the first post-operative period the ocular surface may not be recovered enough to test visual functions, for example, due to lid swelling, post-operative conjunctival irritation et cetera. It is recommended to devote the first seven to 14 post-operative days to regular checking of the eye and general health and to begin measuring the chip-mediated functions no earlier than seven days after surgery. With longer trial duration, as in the later pilot and current clinical trial, a longer post-operative recovery period of 14 days seems to be advantageous in most patients. It also turned out that long-duration surgery, which is unusual in ophthalmology, can lead to transient focal pressure on extremity nerves with transient post-surgical palsy. Therefore, training of ophthalmological personnel for extremity positioning routines for up to six or even eight hours of surgery is recommended.

Testing Microchip Function

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

The microchip's electrodes emit short current pulses at the working frequency (usually 5 Hz). The amplitude of the current at each electrode depends on the local luminance falling on the respective microphotodiode of the autonomous pixel. By means of ERG recording in front of a steady full-field illumination, the size of the current amplitude can be measured for various levels of luminance. This allows determining the light-input versus current-output functions that are important for adjusting the microchip's sensitivity and gain to the luminance condition for every function test mentioned.

Psychological Counselling

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

Patient well-being in the trial is an important issue and therefore, we contacted patient organisations for advice and close communication. They recommended carefully considering the emotional and psychological side of a pilot trial testing artificial vision.

As described earlier, we only include blind individuals who have accepted their blindness. A progressive disease with blindness in a person's most productive age can lead to various psychological reactions. After inclusion and implantation, regular psychological counselling is offered by a specialist in psychiatry to provide expert support in case of stress reactions. In the pilot trial, we also used the BSI (Brief Symptom Inventory) as an instrument that evaluates psychological distress and psychiatric disorders.[37, 38]

Conclusion

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

To perform a clinical trial with a new medical device in humans is a challenge. It can only be done after extensive preclinical testing in vitro and in animals. This phase took us 10 years (1995 to 2005). Many scientific as well as logistic and financing aspects had to be considered in advance, without having any empirical comparison with other results of the newly introduced device, except for animal studies.[20] In this paper, we present a study design for testing subretinal visual implants that have been implanted in 11 subjects of a human pilot trial in 2005 to 2009 and in a further clinical trial using a new generation of the subretinal implant starting 2010 with a further 11 patients. The results to date have proven that an active subretinal microchip can restore useful visual functions for blind patients with hereditary retinal degenerations.[3, 11-15] Overall, the study design presented here can be recommended for further testing of electronic visual implants. Still, the ongoing clinical trial is a constant process of learning of the technology as well as its methodological and medical aspects.

Grants and Financial Assistance

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

The pilot and clinical trial were supported by BMBF Grants 01KP0401 and 315113, the Kerstan Foundation and Retina Implant AG. Funds were also received from Bernstein Center for Computational Neuroscience, Tuebingen (BMBF; FKZ: 01GQ1002).

Conflicts of Interests

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References

Katarina Stingl is employed by the University of Tübingen with funds provided by Retina Implant AG, Reutlingen for the clinical trial, travel support.

Michael Bach received consultant fees from Retinal Implant AG, Reutlingen for the development of BaLM and BaGA.

Anna Bruckmann and Robert Wilke are employed by the University of Tübingen with funds provided by Retina Implant AG, Reutlingen for the pilot trial.

Eberhart Zrenner is employed by the University of Tübingen and owns stock in Retina Implant AG, Reutlingen, is a paid consultant, holder of patents as inventor/developer and receives travel support from Retina Implant AG, Reutlingen.

Florian Gekeler owns stock in Retina Implant AG, Reutlingen and is a paid consultant.

Gernot Hörtdörfer is a free lancing mobility trainer and has co-operated in a clinical trial financed by Retina Implant AG, Reutlingen.

Angelika Braun and Udo Greppmaier are employees of Retina Implant AG, Reutlingen.

Tobias Peters and Barbara Wilhelm are CRO of the trial on behalf of Retina Implant AG, Reutlingen.

References

  1. Top of page
  2. Abstract
  3. Subretinal Visual Implant
  4. Study Design
  5. Assessing the Efficacy Testing—Visual Functions
  6. Assessing Safety—Clinical Examinations
  7. Testing Microchip Function
  8. Psychological Counselling
  9. Conclusion
  10. Grants and Financial Assistance
  11. Conflicts of Interests
  12. References
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