Ординатура / Офтальмология / Английские материалы / Artificial Sight Basic Research, Biomedical Engineering, and Clinical Advances_Humayun, Weiland, Chader_2007
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Clinical Study
Purpose
It is known from previous studies that visual perceptions are elicited when the retina of patients with RP is stimulated electrically. The minimum charge that must be supplied to each electrode is the perceptual threshold charge. This value may differ for individual patients. For blind human beings it may even exceed the charge capacity of modern electrode materials [19, 22]. Knowing that this value has a major influence on the design of a Retinal Implant System, IMI started an acute clinical trial to evaluate the threshold charge for patients with RP [18, 23–25].
Materials and Methods
The study performed to determine the minimal threshold currents in blind patients was designed as an open, acute, multi-center study involving the following clinical centers and investigators: Division of Ophthalmology, University Hospital Hamburg-Eppendorf, Prof. Dr. Gisbert Richard; Division of Ophthalmology, University Hospital Essen, Dr. Thomas Laube; Division of Ophthalmology, RWTH Aachen, Prof. Dr. Peter Walter; and General Hospital of the City of Vienna, Division of Ophthalmology and Optometry, Prof. Dr. Michaela Velikay-Parel.
The study was approved by the institutional review boards concerned and satisfied the requirements of Directive 93/42/EEC and the Declaration of Helsinki.
Twenty human subjects with RP were recruited. The general inclusion criteria were volunteers, aged between 18 and 79 years, suffering from RP with best corrected vision (ETDRS) of the study eye ≤ 4/200, normal hearing and linguistic understanding and good general condition. The general exclusion criteria were as follows: the study eye was the better or only eye; concomitant ophthalmologic diseases (e.g. optic nerve atrophies with the exception of those related to retinitis pigmentosa, diabetic retinopathy, glaucoma, etc.), serious general illness, cardiac pacemakers or other electronic implants, and pregnancy or breastfeeding. All subjects were briefed comprehensively about the study procedure as well as the associated risks and signed a statement of informed consent.
All participating subjects were prepared psychologically for the test. The procedure was discussed in detail and all subjects attended a special training. It was assumed that the subjects could have visual perceptions that were not caused by electrical stimulation but by the intraocular light source or mechanical irritation. Therefore, one focus of the training was to teach the subjects to distinguish true test signals from interfering signals. This training was performed with tactile signals instead of electrical stimulation signals using a hand-held device. Stimulation events consisted of three mechanical vibrations of 0.5 seconds each accompanied by a sound and spaced at 0.5 second intervals. Interfering audio signals were mixed in and the subjects had the task of detecting the true stimulation signal in a noisy environment. This training was carried out one day before the electrical stimulation of the retina.
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The intraocular electrical stimulation of the retina was carried out during regular eye surgery performed under local subconjunctival anesthesia. Four of the eye muscles were fixed (muscle fixation was not performed at one center). A pars plana vitrectomy with focus on complete removal of the vitreous was performed. Afterward, the electrodes were introduced into the eye with a specially developed device (MESE 12 system; Figure 6.8) and placed onto the macula. The “MESE 12” system is a surgical instrument for controlled positioning of a microcontact film onto the retina. It has to be held in the surgeon’s hand during the entire stimulation procedure.
Two different microcontact films were used, as shown in Figure 6.6. Electrodes with diameters of 100, 200, and 360 m were tested. Moreover, each microcontact film had one common electrode with a surface area of 0 25 mm2, positioned 5.5 mm away from the stimulation electrodes. All electrodes were made of iridium oxide.
The stimulation currents were generated by a neurostimulator, the STE10, developed by IMI. This device has 10 channels that can be programmed to generate currents between 0.5 and 380 A. It is powered by batteries and permits monitoring of the voltage of one selected electrode. The device has been successfully tested and certified according to the EN 60601-1 standard. The STE10 was connected by a cable to the MESE 12 system.
For each electrode size, five charge density levels were used (0.05, 0.1, 0.2, 0.5, and 1 mC/cm2). The pulse frequency was always 60 Hz. Anodic-first chargebalanced current pulses were used. The anodic pulse had a duration of 2 ms and the cathodic pulse had a duration of 1 ms. Between the anodic and the cathodic pulses, the electrode was open-circuited for 100 s.
To reduce the risk of mechanically damaging the retina, the subjects were not allowed to talk during the stimulation time. They responded to questions posed by the study investigator by pressing pushbuttons held in their right and left hands.
Figure 6.8. MESE 12 system with integrated microcontact film.
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Threshold determinations were carried out using three consecutive current pulse trains. Each pulse train had a duration of 0.5 s. Consisting of 30 pulses thereby allowing a synchronous triggering of 30 ganglion cell spikes. Synchronously with each electric pulse train, a sound was presented to the subject to indicate the stimulation process. This method allowed the subjects to discriminate visual perceptions generated by true electric stimulation from visual perceptions produced by other sources. As indicated above, the subjects were trained to react only to visual sensations in combination with a sound.
A computer with special software was used as a control and data log system. The computer was equipped with an interface card for recording of electrode voltages and subject answers. All data was continuously logged in a file for subsequent analysis. For immediate analysis, the data was presented on a display. The computer also performed speech synthesis for the subject’s answers.
The threshold determinations provided information on the minimum charge necessary to elicit a visual perception by electrical stimulation of the retina. We defined the perceptual threshold as the lowest charge applied to the retina that reliably evoked a visual perception for a given electrode. Every threshold determination consisted of two parts. In the first part, the threshold was determined; in the second part, the threshold was verified. The verification was realized by applying stimulation currents slightly above the determined threshold mixed with randomly inserted “placebo” stimulations. For placebo stimulations no electric current was used but only a sound was presented to indicate stimulation. The verification was deemed successful if no more than 2 errors out of 10 events (5 stimulations and 5 placebos) occurred.
The threshold determinations always began with stimulation at the lowest intensity level (Figure 6.9). After each stimulation event, the subject was asked
Figure 6.9. Hypothetical sequence of a threshold determination. 0 = Subject answers “No,” 1 = Subject answers “Yes.” In the example shown, the threshold was found at intensity level 4.
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if he or she had seen something while hearing the sound. If the subject answered with “no,” the current was increased. If the subject answered with “yes,” the stimulation event was repeated with the same current. If the subject answered a second time with “yes,” the current was decreased until the answer was “no.” After that, the current was increased again and the tests were repeated until the subject answered “yes” twice in a row in response to the same stimulation current.
The entire stimulation procedures were carried out within a maximum time of 45 minutes. At the end of the tests, the subjects’ eyes were examined for possible damage. The surgical openings were then closed and the subjects were treated according to the hospital’s usual standard of care. Immediately after the operation, the subjects were asked to briefly describe their visual sensations; a detailed interview was conducted approximately one hour after stimulation. The subjects were followed up by performing ophthalmologic examinations one day, one week, and three months, respectively, after surgery.
Results
Twenty subjects were tested during the time period between October 2003 and July 2004. The follow-up examinations were completed in October 2004. One subject had no perception after electrical stimulation. Four subjects reported visual perception but it was not possible to verify their thresholds. All other subjects had perceptions with verified threshold measurements.
Within the limited time of maximum 45 minutes, approximately 6 threshold measurements were possible; the exact number is determined by the surgeon after evaluating the patient’s condition. According to the definition of the threshold, the lowest value was taken into account for the analysis. For the 15 subjects with verified threshold measurements, the mean threshold after taking into account all used electrode diameters using single and multiple electrodes was 191.5 nC with a standard deviation of 189.7 nC. The minimal threshold was 20 nC measured in a late stage RP patient who had a visual acuity of light localization.
In the standardized postoperative interview the subjects reported light perception of different shapes, colors, and brightness. If the subjects reported more than one type of object, every type of object was given the same weighting in the analysis performed for the individual subject. For the overall analysis every subject had the same weighting.
The perceptions of the subjects covered a wide spectrum. The subjects described the sensations as little stars, points, circles, triangles, rectangles, a half moon, a solar eclipse, a hash (pound) symbol, etc. even if only one electrode was activated.
The sizes of the objects are shown in Figure 6.10. To describe the size of the objects, the subjects had to imagine that the objects were at a distance of 1 m. One subject was not able to imagine the object at this distance; this subject
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Figure 6.10. Size of perceived objects (imagined at a distance of 1 meter).
perceived the object immediately in the eye. Based on the description and the gestures of the subject, the interviewer assumed that the size at a distance of 1 m was about as large as an apple. Most of the subjects had perceptions in the size of a coin or the head of a match.
It has to be mentioned that the object characteristics described in the postoperative interview provide an idea of the overall impression of the subjects. This includes stimulation at threshold level and also stimulation above threshold. The stimulation above threshold may be significant as only five intensity levels from 20 to 380 nC were used. Between one level and the next, the intensity is approximately doubled.
The brightness of the perceived objects is shown in Figure 6.11. Most of the subjects had perceptions with brightnesses comparable to a candle or a light bulb. Objects with very low brightness and extremely bright objects were rare. One subject saw dark shadows instead of light. The threshold of this subject was extremely low and stimulation was not applied significantly above threshold. It is unclear whether the subject would perceive brighter objects if larger stimulation currents were applied.
Objects appeared in a wide range of colors (Figure 6.12). The predominant colors were white, yellow, and blue (see Figure 6.12). Red and green were rare. The perception “black” was reported by the subject who saw shadows instead of light. In general, one perceived object has one color. Different objects perceived by the same subject can have different colors. One subject saw an object that was filled with a mosaic of different colors.
The subjects were asked to categorize the sharpness of the perceived objects. The results are shown in Figure 6.13. It can be seen that most objects were seen sharply and clearly.
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Figure 6.11. Brightness of perceived objects.
The subjects were asked whether their visual experience had been pleasant, unpleasant, or painful. Almost all subjects described the objects perceived during the threshold measurement as pleasant. Only two of the subjects said the perceived objects were neither pleasant nor unpleasant or painful.
Except for a peripheral retinal detachment in one subject, there were no significant complications or adverse events during the three-month follow-up period. The detached retina was subsequently reattached.
Figure 6.12. Color of perceived objects.
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Figure 6.13. Sharpness of perceived objects.
Conclusions
Clinical trials have demonstrated, in a limited number of patients, that it is possible to elicit visual perceptions by electrical stimulation of the retina using the epiretinal approach [3, 4, 18, 19, 22, 23, 26, 27].
The collected data show that functional electrical stimulation of the retina is possible in patients with retinitis pigmentosa, i.e. in totally blind persons. The perceptions described by the subjects were typically small and are useful for a chronic retinal implant. The measurement of thresholds showed a mean threshold of 191.5 nC with a significant standard deviation of 189.7 nC. Given the requirement of an electrochemical biocompatible charge limit of 1 mC/cm2 and an electrode diameter of 360 m, 19 out of 20 subjects experienced visual perception evoked by electrical stimulation.
The perception of the majority of subjects in the acute clinical trial carried out with RP patients has proven to be valuable for the realization of a chronic retina implant.
Acknowledgment. This work is supported by IMI Intelligent Medical Implants, Bonn, Germany, and by the European Community (Healthy Aims Project, Contract No. 001837).
References
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7
Challenges in Realizing a Chronic High-Resolution Retinal Prosthesis
Wentai Liu1, Mohanasankar Sivaprakasam1, Guoxing Wang1, Mingcui
Zhou1, James D. Weiland2, and Mark S. Humayun2
1Department of Electrical Engineering, University of California
2Department of Ophthalmology, University of Southern California
Introduction
Electrical stimulation has been proposed by several research works as a means of restoring vision in blind patients whose vision is impaired due to retinitis pigmentosa (RP) and age-related macular degeneration (AMD). RP affects the rods (used in night vision) first and then the cones (used in ambient daylight levels). AMD results from abnormal aging of the retinal pigment epithelium and retina. Persons with AMD will start to have distorted vision and eventually lose most of the vision in the central 30 . RP is a collective name for a number of genetic defects that result in photoreceptor loss. In both diseases, the vision is impaired due to the damage to the photoreceptors that convert photons to neural signals [1]. Post-mortem evaluations of retina with RP or AMD have shown that a large number of cells remain healthy in the inner retina compared to the outer retina [2]. Further, electrical stimulation of humans with RP and AMD results in the perception of light; so the neural cells can be activated, providing the hope of restoring lost vision in blind persons [3]. A chronic implant with 16 electrode sites on the retina in three blind patients has yielded promising results [4]. After being implanted with the prosthetic device, the patients were able to detect motion of a white bar (up, down, left, or right), detect a rectangular object, count objects, discriminate the orientation of two white bars in an ‘L’ configuration as to where the corner of the L was positioned, and discriminate between a dessert plate, a coffee cup, and a plastic knife [5]. The success rate of these simple visual tasks differed between subjects and the difference is attributed possibly to the age and the number of years of blindness. The results of acute and chronic studies have encouraged several research and development efforts for realizing chronically implantable, high-resolution retinal prostheses [6].
One implementation of such a retinal prosthesis is shown in Figure 7.1. An external camera, which preferably can be worn on the glasses, captures the image in the field of vision of the patient. This image is processed through
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