13.1  Introduction

The basic assumption behind the development of implantable devices for retinal stimulation is that electrical stimulation of the retina may provide useful vision in patients suffering from advanced forms of degenerative diseases of the retina. Either from theoretical considerations but also from early experiments in blind human subjects one may conclude that this assumption should be correct. An early example of a human experiment was the implantation of stimulation electrodes across the visual cortex as reported by Brindley and associates. A blind RP patient reported phosphenes upon electrical stimulation of the visual cortex [1]. Dobelle and his group continued the work of Brindley and they were also able to demonstrate that blind subjects do have visual sensations when the posterior parts of the visual system are electrically stimulated [5]. The application of electrodes onto, underneath, or within the retina was limited to basic research approaches and did not extend to therapeutic efforts. Not earlier than 1991 devices and surgical techniques became available with which in patients suffering from retinitis pigmentosa (RP) experiments for retinal stimulation could be performed in the operating room without considerable risk to the patients. The rationale to do these experiments was that only data was available from retinal stimulation experiments in animals with a normal retina using preliminary electrode arrays or in tissue preparations of RCS rat retina using multielectrode array devices but not implantable electrodes. From these animal experiments only some information was known about the range of stimulation currents and about the timing of the stimulation pulses. It was not known to what extent the stimulation parameters would have to be changed to achieve visual percepts in blind humans suffering from such a disease. Three major questions should be answered by acute retinal stimulation experiments in humans.

(a) Is it possible to elicit visual percepts when stimulation pulses are emitted by electrodes placed near the degenerated retina? (b) What charge delivery is necessary to obtain such responses? (c) Is it possible to elicit several percepts when several electrodes are activated and what is the two-point discrimination? All three questions were crucial. If it was found that the energy required to obtain visual percepts in RP patients was above the maximum charge delivery capacity of the electrode material or beyond a level indicating toxic tissue reactions then it would not have been possible to further pursue these research projects. If only unpatterned chaotic percepts were registered than there would also be no chance to establish artificial vision in terms of useful vision.

13.2  General Considerations for Acute Retinal Stimulation Experiments

Acute experiments for retinal stimulation in blind humans require the possibility to measure more or less quantitatively the visual response. Objective measurements are not possible in a clinical setting because the obtained local responses are too small to detect them with surface electrodes attached to the skull, although Chen reported one blind patient in which he recorded evoked cortical potentials with scalp electrodes upon electrical stimulation of the retina with eight electrodes simultaneously and 10% above threshold [3]. Due to obvious reasons microelectrodes inserted in the visual cortex to record local field potentials or functional imaging experiments in humans were not performed in contrast to such experiments which have been reported for animal studies [9, 18].

Acute tests for electrical stimulation of the retina have to be performed under local anesthesia. Only superficial anesthesia techniques such as subconjunctival or subtenon injections are recommended because any effect of the anesthetic drug on the optic nerve must be excluded. Sedative drugs should also be avoided because the patient has to indicate the visual response either by voice but more reliable by a response interface such as a set of buttons which he is asked to press to indicate whether he sees something or not. All patient responses must be recorded using such response interfaces to correlate them afterwards with the stimulus parameters. When using single electrodes, stimulus thresholds can be recorded by a two-alternative forced choice method at several points of the retinal surface.

When using electrode arrays, stimulus threshold data can be determined for each electrode or electrode pattern. Electrode arrays could also be used to estimate if two points or lines can be differentiated by the patient when two electrodes or two clusters of electrodes are stimulated simultaneously. Information on the distance of distinguishable electrodes or angles should give some information on the possible visual acuity that can be achieved with such systems. Important aspects of the neurophysiology of the target tissue can also be investigated, such as the determination of rheobase, which is the minimum stimulus intensity necessary to elicit a response at very long stimulus durations, and chronaxie which is the stimulus duration necessary to elicit a response at twice the rheobase level of stimulus strength. These data are characteristic for certain elements of nervous tissue.

The main limitation of acute retinal stimulation experiments in humans is that the time to perform these experiments is limited. Usually 1 h of experimentation is possible. Within this time all the possible combinations of stimulus intensity and time at all electrode positions cannot be included in the experimental setup. Another limitation is that the patient’s response is not a uniform standardized yes or no. The answer sometimes also contains information on shape or color or maybe on temporal aspects of phosphenes. This information can usually not be interpreted systematically.

It should also be pointed out that acute tests for retinal stimulation have been performed in two types of patients: blind patients with RP and patients in which the eye has to be removed because of cancer. In the latter the retina itself usually was normal [12–14, 19].

and also depending on the location of the electrode. For animal experiments therefore devices were used which were placed onto the retinal surface and held here in place with heavy liquids such as Perfluorodekaline [17]. Rizzo and coworkers used gold weights to apply pressure to the devices in a series of human experiments [14].

Quantification of the precision in terms of distance between electrodes and retina or pressure between retina and electrode and the constancy of the position is difficult. Even with such tools movement of the array may occur during the experiment as mentioned by Rizzo [15]. Therefore, the conclusions drawn from such experiments should be regarded cautiously. It is important when such experiments are performed and their results interpreted that the position of the array on the retinal surface is known. Much better information could be gained with experiments where the electrode array is chronically mounted onto the retina. Weiland and coworkers found in acute retinal stimulation tests in normal eyes that lifting an epiretinal electrode more than 0.5 mm off the retina resulted in loss of the electrically evoked percept [19] (Figs. 13.2 and 13.3).

After removal of the implant the sclerotomies are closed. Clinically, the patients showed adverse events in rare cases only. As in every vitrectomy the patient should be informed that a retinal detachment may occur in up to 5% of cases, as may cataract formation or in rare cases endophthalmitis. Such adverse events may require secondary interventions.

Fig. 13.2  Left; General setup for acute experiments on retinal stimulation. Under vitrectomy conditions the stimulator (STIM) is handheld at the desired position. A light probe (LP) is also inserted to allow visualization of the stimulator position onto the retinal surface. The electrodes are connected to a power source (PS) controlled by a computer system (PC) and possibly using a multiplexer (MUX) if several electrodes are desired. The electrodes are physically isolated from the high voltage devices using stimulus isolation units (SIU). The patient’s responses are registered using response interfaces (RI) and the whole procedure is usually video documented (VD). Right; Intraoperative situation during an acute experiment for retinal stimulation – surgeon’s view, inferior retina is in the upper part of the picture. The handheld microelectrode device is placed onto the retinal centre with the active electrodes near the superior arcade