Which patients can benefit from a subretinal implant?
"...A subretinal chip partly takes over the function of the photoreceptors and transmits visual image information point by point in the form of electrical signals to the bipolar cells. In this way, the geometry of the object viewed is preserved in in the electronic image accordance with the retinotopy. However, this approach presumes that the rest of the retinal layers are still functional, so that the information can be successfully conducted to the visual cortex. Not only must the other neurons of the visual pathway be functional, but clear optic media are also absolutely necessary for a subretinal implant to ensure that the optical picture is free of distortion before it falls upon the chip. For that reason, in view of glaucomatous damage at the posterior pole, which is typical in retinitis pigmentosa, a cataract extraction should take place before implantation of the chip.
All of these considerations of themselves define for the most part the circle of patients who can benefit from a subretinal implant. Above all, these are patients with degenerative photoreceptors but no other eye diseases which affect the optical functions of the eye or the inner retina. In particular, glaucoma and other forms of optic neuropathy, retinal detachment, or impairment of the optic media would constitute a contraindication for the functionality of the subretinal chip. In addition, subretinal implants also are out of the question in the case of central insults and cortical blindness in general. Unfortunately it is not possible to determine in detail whether the function of the bipolar cells and the ganglion cells has remained intact when photoreceptor degeneration and severely reduced vision have possibly been present for many years.
However, certain conditions are to be regarded as criteria for exclusion: for example, optic neuropathy and additional retinal diseases may not be present, since they would prevent the implanted subretinal chip from functioning correctly. The residual composition of the inner retina can be determined through a visualization of the nerve fibre layer with modern, high-resolution OCT equipment or technologies which are routinely used in the diagnosis of glaucoma. In general, it is also possible to determine the functionality of the bipolar and ganglion cells by triggering phosphenes via corneal stimulation. This method, developed in collaboration with our clinic, reflects the ability of the bipolar and ganglion cell systems to transmit electrical stimuli as perception of phosphenes .
Last but not least, before taking a subretinal implant into consideration, a retinal fluorecein angiographic examination should also be carried out. If the vascular blood supply has practically ceased to exist, particularly that of the small vessels of the retina, and in extreme cases in the area of retinal degeneration, it is reasonable to expect that retinal ischemia has damaged the ganglion cells and that conditions for the implant described here are unfavourable. We also observed during the pilot study that when perfusion of the inner retina is lacking in the area of the microchip it is not possible to perceive the chip signals.
Another requirement is that the ability to see in earlier years of life was adequate and that development of the central nervous system, i.e. of the visual pathway, is normal. Thus amblyopia and congenital blindness are also contraindications for the use of a subretinal visual implant.
Finally, it must also be taken into consideration that the implantation procedure constitutes one of the longest surgical interventions in ophthalmology. During the operation, which lasts for hours, no form of pathology may be present which could increase the risk of a long period of general anaesthesia. In other words, systemic disorders which present a significant risk for general anaesthesia are a criterion in our studies for exclusion from implantation of the microchip.
Specifically, the implants described here were developed for retinitis pigmentosa patients and patients with other primary rod and cone degenerations. These patients are usually born with good vision and now find themselves for the most part in their most productive years of life but in the final stages of a disorder which often leads to blindness and is currently without real hope of a cure. At the onset of blindness, the bipolar cells and ganglion cells remain intact for a relatively long time. Provided that angiography shows that retinal perfusion has not been completely lost and that phosphenes can still be triggered by corneal electrostimulation, it can be assumed that the function of the two remaining inner retinal layers has been preserved. Moreover, these patients are usually in their middle years of life, meaning that major systemic diseases are likely to be rare.
Regarding the question of the stage of such disorders at which the subretinal implant is indicated, it is necessary to be aware of the functional possibilities of the subretinal chip. A surface area of 3×3 mm at the posterior pole of the eye provides a visual field of about 10° - 12°. When this image is regarded as a "picture frame" with 1,500 pixels, these pixels provide a resolution of up to 0.25° of visual angle (corresponding to a visual acuity of up to 0.08).
The best visual acuity achieved to date in our study was 0.021 (logMAR 1.69) , and electrophysiologic measurements in animal trials preceding the study with humans showed a resolution of 1° . These implants - at least at the current state of technology - are therefore not to be understood as offering a complete recovery of full vision but rather as an option in the final stage of photoreceptor degeneration; by restoring a certain degree of visual function they can offer better localization of objects and improved mobility. Both abilities represent important goals for visually impaired retinitis pigmentosa patients.
Blindness in the sense of loss of a central visual field, with a visual acuity of hand movements or less, are the conditions under which a subretinal implant can be useful and represent a future therapeutic option. The ability to move about in one's surroundings with some degree of independence, to orient oneself without assistance, and to identify and localize objects would be an enormous aid in daily life for patients who have lost their eyesight due to retinitis pigmentosa.
Another form of retinal degeneration with a much greater prevalence is age-related macular degeneration, above all in its "dry" form. In future, this diagnosis too would be an appropriate indication in individual cases for a subretinal implant when no other therapeutic options are available. Currently, however, no AMD patients are included in our studies. The age group of these patients, in whom polymorbidity is often a problem in such a long operation, should also be considered.
What must the patient know before implantation of a
Currently, all volunteers who receive a subretinal chip implant in our ongoing studies undergo a very thorough, individual consultation process about the possible benefits and risks, including those of the operation.
The only patients included in both our pilot study and main study have been and still are blind patients with retinitis pigmentosa or a similar form of hereditary retinal degeneration. Only one eye is used for the implant in the study.
Since the possibilities of vision with a visual implant are limited in comparison to those of natural vision, a patient who is to receive the implant should know that with the chip in its current form the maximum possible visual acuity is ca. 0.1 and the maximum possible visual field is 10° - 12°. This nevertheless represents an enormous improvement in blind patients who currently have no prognosis for therapy and are usually in perfect health otherwise. It is therefore not to be expected that activities like driving a car or riding a bicycle will again be within reach, but rather that only part of the former ability to see will again become possible and be adequate for moving about independently in unfamiliar areas, thus providing independent mobility as far as possible.
At the present technical state of the subretinal chip, all 1,500 photodiodes are identically sensitive to the wavelengths of the light spectrum. It is also for this reason that no difference in colours can be perceived with the chip, since all of the photodiodes send an identical signal for all parts of the colour spectrum. The only distinguishable factor is brightness. The patient must therefore conceive of vision with the chip as colourless or as confined to gravy tones. We found during the course of the pilot study, however, that different shades of gravy can in fact be differentiated with the subretinal chip.
Last but not least, we have observed in our studies to date that there is a difference between this "artificial" vision and that of the patient's former natural vision. Often it takes time for the patient to know which perception is the one that comes from the chip. This is due on the one hand to the fact that the electronic chip always works with a single frequency, i.e. that it "feels its way around" the world with a constant frequency (usually 1 - 20 Hz, which can be adjusted at the external power supply). At lower frequencies, this may be perceived as "blinking".
On the other hand, this artificial vision presents a rectangular segment of the world in which objects can be observed under conditions of good contrast. In contrast to the natural photoreceptors, subretinal photodiodes do not adapt to different degrees of light brightness. This adjustment to the surrounding brightness must be carried out "manually" by the patient by changing the settings of the implant to match changes in the brightness of the surroundings or the respective room. Two parameters exist for this. First, the chip's reaction to brightness ("sensitivity") can be shifted and adapted to the respective lighting conditions so that the patient always sees with optimum contrast. Secondly, the maximum electrical charge given off (i.e. the maximum brightness, or "gain" of the visual perception) can be adjusted by means of a so-called "bias" adjustment.
For both adjustments the external power supply has two control knobs, with which the patient himself can optimize his visual perception. As was to be expected, it was found that it is mostly "sensitivity" which is adjusted.
The external power supply (currently about 12×5×2 cm) must always be carried on the body when vision is desired, and the external coil must be mounted behind the ear by means of a magnet so that it can supply the implant with current via electromagnetic induction. A small pouch can be used to carry the power supply. During the first weeks the patients are accompanied by a professional mobility trainer to learn the practical aspects of using the implant with the power supply, for example outdoors and away from the clinic.
a) Pilot study
The subretinal chip, with its 1,500 microphotodiodes, was implanted in 11 blind volunteers during our pilot study from 2005 to 2009. The patients were in the final stages of retinal degeneration such as retinitis pigmentosa and before inclusion in the study were capable at most of perceiving only light without corrected projection. In 5 of the 11 patients, the subretinal chip successfully mediated the perception of light sources or bright objects and even helped the patients to localize them.
Two patients achieved a visual three-dimensional resolution of up to 0.34 cycles per degree and 0.22 cycles per degree, respectively, with the chip. The best visual acuity, measured with Landolt rings, was 21/1000 (logMAR 1.69). With the help of the implant and under good contrast conditions, this patient was even able to recognize letters of the alphabet (white letters about 8×8 cm in size on a black background), to slowly read the words formed by them , and to name unfamiliar objects and shapes like dishes, tableware, bananas, etc...."
(From: Stingl K et al., Klin Monatsbl Augenheilkd, 2010; 227: 940-945)
b) Main Study
"...To date, 11 patients in the pilot study and a further nine patients in the main study have received the subretinal Alpha IMS implant of Retina Implant AG (Reutlingen, Germany). One woman patient had no visual impressions from the implant due to an intraoperative "opticus touch". Two patients in the main study subjectively found that the new visual information which they gained from the implant in everyday life was not useful, even though the visual results recorded in standardized tests with the implant were better than those provided by their own residual visual function. One woman patient has had the implant only for a relatively short time, and insufficient data are available in her case. The other five patients had good experiences with the implant in everyday life and reported that the visual information was useful. In addition, one patient in the pilot study confirmed useful results in everyday situations even though it was not possible at that time to turn on the power supply unit outside the clinic.
The period of observation for use of the implant to date has been from 2 to 12 months.
For patients who have previously had a visual acuity of only light perception at best, this constitutes an improvement of visual function in everyday life, as the following overview of patient statements about the benefits of a subretinal implant in everyday life shows. In contrast to the study's functional tests in the laboratory, their experiences were not gained under standardized conditions, and are thus not quantifiable. The results presented here are based both on study documentation with film material and on oral statements and descriptions of the study participants after they had assimilated their newly-gained visual impressions in their home surroundings, at work, and outdoors.
The objective, standardized results have already been published in part and will be published in full after the conclusion of the clinical study as a whole [5 - 8].
Use in the near vision area
Most of the experiences related here are based on visual perceptions in the near vision area. Many patients use the implant during everyday activities such as eating, working, regarding objects, or visual contact with other human beings. Examples:
- The contours of a visitor sitting on a couch are recognized, including the fact that one arm is resting on the arm of the couch.
- Persons wearing spectacles can be distinguished from persons who do not by setting a higher level of contrast or through the reflections given off by the lenses or metal frame of the spectacles, which are recognized by the microchip as a strong signal. In the process, the patients are able to recognize a brighter area around the eyes of the other person's face. Moreover, two patients were able to roughly see the facial features of their partners; they reported recognizing the mouth as well as the shadow of the nose and the shadows between the light-coloured teeth during laughter. Other patients can simply perceive only the shape of the head.
- The type of clothing can be recognized by patterns or contrasts in brightness: one patient saw a striped sweater, another was able to describe such things as a necklace or an wrist band or the shape and brightness of clothing (colour recognition is not possible, see above).
- Everyday objects like sinks, tableware on the table, parts of a meal (e.g. dark pieces of beef versus bright side-dishes, red wine vs. white wine), a banana or other fruit on the table can be visually distinguished according to shape and brightness and grasped accurately (● see Figure 1).
- At work it is possible to learn to visually distinguish staplers, the telephone and certain other office items from one another.
- Door handles, a paper notice on the door, etc. can be recognized during movement around a room.
The subretinal implant permits correct localization and grasping of a drinking glass in a restaurant.
- It is often possible to recognize the horizon and objects which stand out on the horizon due to their good contrast against the bright sky. The patients can localize large trees or buildings or even a stream which is seen from an outlook as a bright strip due to reflections from the sun.
- On the street it is possible to recognize parked cars by their metallic reflections or the edges of a sidewalk when contrast is good. It is also possible for most patients to recognize the windows of a house as rectangles.
- One patient is able to see street lights in the evening as lights and to recognize the path followed by the street by seeing how they stand in a row.
- When sitting in the garden, a woman patient can recognize her sunshade and a sunflower stem. Another patient can spot the trash barrel on his balcony.
- When observing people who are some distance away, provided that contrast is good, smaller and larger persons can be distinguished from one another and the contours of colleagues can be recognized during a meeting at work.
- One patient reported that he was able to recognize the dark, rectangular carpet on the floor of the neighbouring room when looking through its open door and was able to sense a human shape bent over a laptop computer.
Perception of movement
The possibility of perceiving movement in observed objects is very important for visual orientation. It can be demonstrated that this is possible with the subretinal chip by using a standardized test with dot patterns which move in four directions on a screen. For the patient himself, however, it is more meaningful if he can have such perceptions in real life.
- One patient is able to see automobiles on the street in the evening because of their moving headlights; he can also correctly track a bus when it moves and stops at the crossing (as reported by the persons with normal vision who accompany him).
- It is important for improved hand-eye coordination to see movements of one's own hands or those of others with good contrast and to follow the movements of the fingers; some of the patients are quite successful at this.
- One patient was able, according to the reports of the mobility trainer, to correctly observe outdoors how a white goose was swimming in a straight line on a dark pond.
Investigation of the safety of the implants is an important goal of the current clinical study. Up to now, no long-term results are available for a period of several years; the longest period of use of the implant has been one year. Most of the potential risks of this surgical intervention lie in the relatively long duration of the operation, which can last for more than six hours under general anaesthesia. Postoperatively a temporary rise in IOP may occur, along with retinal haemorrhaging in the area of the implant or smaller retinal tears. These, however, can be adequately tamponaded with silicone oil. Serious complications like retinal detachment or endophthalmitis have not been observed to date either in the pilot study or in the main study which is currently underway.
The results reported above show that a subretinal implant in everyday life can provide useful visual information, and that this can serve the patients as important information. When the patients are asked how much this so-called "artificial vision" with the subretinal chip differs from the normal vision which they experienced earlier in life, the astonishing answer is: "relatively little". Apart from the lack of colours, the limited visual acuity, and the mild blinking of the images (the implant functions at a certain frequency), it is very much like normal vision. It could be described as a black-and-white, somewhat blurred vision with a reduced number of contrast levels in a concentrically limited visual field.
Not all patients profit to the same extent: two of the 9 patients were able to recognize only images with a refresh rate of 1-2 Hz instead of the typical 5-7 Hz. This limited the benefits and might also have been due to longer retinal refresh periods after electrical stimulation, due to the individual degeneration process. After a study of further patients in the present multicentre study has been completed, a comprehensive report on long-term results and the different individual visual performance results will be published.
It is natural that the patients also rely on context: the woman patient described above knows that she has ordered a beer in a restaurant; when her implant is turned on, however, she is able to locate and grasp the glass quickly. The patient described above hears the honking of the geese outdoors, but with the chip he can also observe their direction of movement. Much the same is true in the evening regarding street traffic: the bus is audible, but it is easier to recognize where it is coming from and where it is going when the chip is turned on than with the sense of hearing alone.
The patients perceive the fact that they can follow objects directly with their eyes as very positive. The Alpha-IMS implant represents the world's only approach in a clinical study in which a light-sensitive "camera chip" with 1,500 pixels is located directly in the eye and not in a camera housing on a spectacle frame. The localization of objects afforded by eye movements with this approach is perceived as enormously important. In contrast to this, patients with an implant which uses an externally mounted camera can recognize and localize objects only by means of "scanning" movements.
A blind patient learns to use all of his remaining senses to orient himself. For most of our patients, however, the visual impressions mediated by the chip provided an additional benefit for localizing objects, orienting themselves in rooms, and communicating with other persons....."
(From: Stingl K et al., Der Ophthalmologe, 2012;109:136-141)
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