The Argus™ II retinal prosthesis: Factors affecting patient selection for implantation

Abstract

The Argus II epiretinal prosthesis has been developed to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. To date, the device has been implanted in multiple subjects with profound retinitis pigmentosa as part of a worldwide clinical feasibility study (clinicaltrials.gov ID: NCT00407602). The Argus II is intended to provide partial restoration of functional vision. Most subjects showed an improvement in tasks assessing orientation & mobility, spatial-motor localization, and ability of discerning the direction of motion of moving stimuli. Roughly one third of subjects experienced measurable improvement in visual acuity with the implant. Some subjects identified words with high accuracy, a result that has also been reported by the leading subretinal implant group. Perceptual threshold was correlated with electrode-retina distance, electrode-fovea distance, and light sensitivity, either as single variables or in bivariate linear regression. Taken together these three variables may be used to inform patient selection and develop algorithms for the fitting of higher-electrode count systems. Visual acuity for future generations of the Argus implant may not hit theoretical limitations until arrays hold an excess of several hundreds of electrodes. Nevertheless, preliminary safety and efficacy data are supportive of the development of higher-resolution systems that target macular placement from implant design and surgical perspectives.

Introduction

The sensation of visual perception can be elicited by the electrical stimulation at any one of multiple parts of the visual pathway. In 1929 Forester exposed the occipital pole of a subject with normal vision and was able to electrically stimulate a region to create localized percepts termed phosphenes that were spatially correlated with the visual field (Foerster, 1929). A similar experiment was repeated in 1932 by Krause and Schum in a subject that had suffered a gunshot wound in the area of the left optic nerve leaving him blind for eight years (Krause and Schum, 1931). The fact that localized phosphenes could be elicited in a subject deprived of visual stimulus for such a long period of time was significant. It was not obvious that the cortex could create the sensation of perception after a sustained period of visual deprivation. Brindley and Lewin were then the first to use multiple surface electrodes to stimulate the striate cortex (also known as primary visual cortex or V1) (Brindley and Lewin, 1968). They used an array of 80 electrodes implanted in contact with the occipital pole of the right cerebral hemisphere to elicit percepts in a 52 year-old subject blinded due to retinal detachment. Each electrode was addressed via individually connected radio receivers; specific receivers were activated by pressing a transmitting coil of an oscillator tuned to the desired frequency on the scalp. This was the design of the first chronically implanted prosthesis.

While surface stimulation provided significant initial results there were a number of drawbacks. It was found that excitation in one area could create two spatially separated phosphenes and that supratheshold excitation could create percepts that could last for up to two minutes and also cause pain due to meningeal stimulation (Brindley and Lewin, 1968). Electrodes placed closer than 2.4 mm apart created phosphenes that interacted with eachother (Karny, 1975). In the time domain there was no flicker fusion frequency (Dobelle and Mladejovsky, 1974). And, perhaps most importantly, the high thresholds limited the minimum electrode size. (1–3 mA was required for a 1 mm² surface electrode (Dobelle et al., 1976).)

More recent attempts at developing a cortical prosthesis have abandoned surface stimulation and focused on intracortical stimulation with penetrating probes (Dobelle et al., 1976; Schmidt et al., 1992; Normann et al., 1999). In one study 38 microelectrodes were implanted near the right visual cortex in a 42 year old woman who had been blind for 22 years due to glaucoma (Schmidt et al., 1996). Individual phosphenes were able to be disseminated using electrodes spaced 500 μm apart, a factor of five improvement compared with surface stimulation. An excellent experiment compared the threshold for stimulation using surface electrodes and 37.5 mm long intracortical electrodes in the same patient, and found that intracortical stimulation had a threshold 10–100 times lower than surface stimulation (Dobelle et al., 1976).

While significant advances have been made in cortical stimulation an FDA approved device is yet to be developed. This is due to the increased complexity of neural wiring in visual cortex and the dangers of surgical implantation. (In some cases, epileptic seizures have occurred during stimulation (Kotler, 2002).) Because of this electrical stimulation in retina has attracted more interest recently (Humayun et al., 1996; Chow and Peachey, 1998; Zrenner et al., 1999; Rizzo et al., 2001).

Postmortem anatomical studies of patients with retinitis pigmentosa (RP) (Stone et al., 1992; Santos et al., 1997) and age-related macular degeneration (AMD) (Kim et al., 2002) found that both inner retinal cells (78.4%) and ganglion cells (29.7%) may be preserved even though there is considerable photoreceptor cell death. It was first shown using corneal stimulation that a percept could be elicited in an RP patient (Potts and Inoue, 1969). This lead to further studies in which phosphenes were elicited by direct stimulation of still viable ganglion cells and indirect (presynaptic) stimulation of cells that feed into the ganglion cell layer (e.g. bipolar, amacrine, horizontal, and photoreceptor cells) (Humayun et al., 1996, 1999).

Two different approaches have been taken to retinal stimulation using an electrode array: subretinal and epiretinal (Fig. 1). The subretinal approach has been the focus of a number of groups, and targets placement of an active or passive device in between the neural retina (defined by the photoreceptor outer segments) and the blood–brain barrier of the eye (defined by the retinal pigment epithelium (RPE)-Bruch's membrane-choriocapillaris boundary). One group implanted a silicon array consisting of 5000 microelectrode-tipped microphotodiodes in the right eye of six subjects with advanced RP (Chow and Peachey, 1998; Chow et al., 2004). The aim of these implants was to convert incident photons to a stimulating pulse via the photoelectric effect with no gain supplied by external power sources. While improvements were reported in the detection of brightness, contrast, and shape, much of it was in a region distal to array placement. It was hypothesized that neurotropic factors induced by immediate response to surgical trauma or due to electrical stimulation. It was unlikely that the reported 8–12 nA pixel current over a 9 μm × 9 μm iridium electrode could have depolarized a cell. However, much was learned from the study including surgical technique of subretinal implantation, and possible sham effects due to mechanical disruption of tissue. The latter served as a precursor to an on-going study employing the release of ciliary growth neurotropic factor (CNTF) in the intraocular cavity toward prevention of photoreceptor death (clinicaltrials.gov ID: NCT00447954).

Another subretinal effort employs an active microphotodiode array (MPDA) consisting of 1500 electrodes, and a 4 × 4 array of larger 200 μm diameter electrodes used for direct stimulation (Zrenner et al., 1999; Kuttenkeuler et al., 2006) (MPDA; Retina Implant AG, Reutlingen Germany) (Fig. 2). This device has been implanted in the most human subjects to date (and followed up clinically for the longest time post-implantation) compared with other subretinal efforts, and has been shown to restore some functional vision in a portion of the implanted cohort (Zrenner et al., 2011). It's worth noting that although the aim of a subretinal implant is to excite cells earlier in the retinal pathway so as to preserve some processing (e.g., the bipolar-ganglion cell synapse), recent work has shown that in addition to cell death, degeneration results in gross anatomical remodeling and can also lead to glial sheath formation in the region between optimally placed electrodes and target neurons (Marc, 2003).

Epiretinal prostheses have a longer history of successful chronic implantation and partial restoration of visual function compared with subretinal implants. While a few groups have performed successful acute implants in humans including Intelligent Medical Implants GmbH (Bonn, Germany; n = 4 subjects, 49 electrode array implanted for 18 months; ClinicalTrials.gov ID: NCT00427180) and EPI RET (n = 6 subjects, 25 electrode array for 1 month; Clinical Trial ID DE/CA21/A07), The Argus™ I and II studies remain the only chronic trials to date. The Argus I System (Second Sight Medical Products, Inc., Sylmar CA) consists of a surgically implanted 16 channel stimulating microelectrode array, an inductive coil link used to transmit power and data to the internal portion of the implant, an external video processing unit, and a miniature camera mounted on a pair of glasses. The video camera captures a portion of the visual field and relays the information to the visual processing unit. The visual processing unit digitizes the signal in real-time, applies a series of image processing filters, down samples the image to a 4 × 4 pixilated grid, and creates a series of stimulus pulses based on pixel grayscale values and look-up tables customized for each subject. The stimulus pulses are delivered to the microelectrode array via an inductive RF coil link and the application-specific circuitry.

The 4 × 4 electrode arrays of 260–520 μm diameter platinum discs were implanted in six blind subjects (Humayun et al., 2003, 2005). The implant allowed for the subjects to discern ambient light and simple shapes. Visual psychophysics in sighted subjects suggested that a more densely packed electrode array with smaller sites could increase resolution by targeting fewer cells. One study created pixelated images that would correspond to 4 × 4, 6 × 10, and 16 × 16 electrode arrays and used sighted subjects to show that a 16 × 16 array might allow patients to read 36 font type (Hayes et al., 2003). Using a similar vision simulator, another study showed subjects could to navigate through a maze with obstacles using a 25 × 25 array of pixels representing a visual field (Cha et al., 1992). Though these were promising results, they are also representative of a large number of investigations of simulated prosthetic vision in normally sighted subjects. Prior to a larger chronic study from which to draw comparison with the relevance of the results with those anticipated in implanted blind subjects remained an open question. The effects of cortical dormancy and retinal degeneration on stimulus threshold and system performance could only be assessed after prosthesis development and regulatory approval (Marc et al., 2003). The first generation Argus I study provided initial support of studies in sighted subjects, and showed the ability of an epiretinal prosthesis in providing spatial information from multiple electrodes. Though a significant improvement in grating visual acuity was only reported in a lone subject, a cleverly designed control in which mapping between points in the visual field and their corresponding retinal locations (i.e. receptive fields of those points in space) were randomly scrambled, supported the case for development of future generation implants (Caspi et al., 2009).

The next generation higher density electrode prosthesis followed: The Argus™ II System. Excluding the camera and processing unit, the Argus II consists of a fully intraocular implant employing a 6 × 10 array of electrodes. Surgical implantation also uses a less invasive, shorter procedure: a pars plana approach followed by a vitrectomy, and placement of the array on the epiretinal surface. Of the 32 subjects implanted in the trial, it has been shown that the Argus II system performs best in those with some spatial vision (Ahuja, 2010), and that these subjects can perform better with the system on compared with off in door-finding and line-tracking orientation and mobility tests (Humayun et al., 2009b), and in spatial-motor object localization (McMahon et al., 2009; Ahuja et al., 2011) and direction of motion tests (Dorn et al., 2012). Recent findings even indicate the ability of some subjects to read high-contrast large font letters and words (da Cruz et al., 2010) (Movie File 1). In this paper we will restrict our investigation primarily to this clinical study since it consists of the largest blind cohort implanted to date with a single system using the same design specifications³ and stimulus parameters.⁴ Based on the work of several investigators in the field, we argue that with progress in device design, surgical placement of the implant, and safety profile (Dagnelie et al., 2010), the implantation of higher-resolution prostheses is justified.

The following is the supplementary data related to this article:

. An example of a blind subjected implanted with the Argus II System correctly identifying letters in a high-contrast closed-set test. The camera's field of view and individual electrode inputs are observed on the laptop screen on the bottom right of the movie. (Movie courtesy of Second Sight Medical Products.).

We also present a broad view of electrophysiological observations collected during this trial, including regression models for factors affecting stimulus thresholds. We believe discussion of how different electrophysiological observations made in in vitro and in vivo animal studies are consistent with results observed in patient testing will add credence to the utility of such experiments with regard to system design. The authors hope to show that strong regression results between these factors and perceptual threshold will allow for decreased system fitting times, an especially critical criteria for future higher electrode count implants.

Though this is the most comprehensive study of an approved therapeutic for retinal blindness to date, the field of vision restoration is still in its infancy with regard clinical translation. The Discussion and Implications on Vision Restoration section will investigate the possibilities for advancement in the field of device-based prosthetics, as well as compare inherent strengths and weaknesses with more recent approaches at halting or reversing disease progression such as gene and stem cell based approaches.