Rajat N. Agrawal, MD and Mark S. Humayun, MD, PhD
Age related macular degeneration (AMD) affects a significant segment of the United States population, with some of these patients reaching a late stage of irrecoverable vision loss. Treatment options are limited for such patients at this time. But with the advent of artificial vision, there is a strong possibility that some of these patients will become likely candidates for such therapy. This article presents a broad overview and the current status of the various approaches employed for artificial vision.
Initial work in the field of artificial vision began with visual cortex stimulation. Foerster1, a German neurosurgeon, observed in his patients that electrical stimulation of the visual cortex produced a sensation of a spot of light, described as phosphene. Brindley2, and later Dobelle3, implanted cortical implants in blind patients. When stimulated, the patients noted phosphenes in different positions of the visual field. Cortical implant is a form of artificial vision that has the potential to help the largest number of blind patients, since direct stimulation of occipital cortex overrides diseases of the proximal visual pathways. Some reports of pain due to meningeal irritation and occasional focal epileptic activity following electrical stimulation have been reported from these patients.4 Current models in development include the Illinois intracortical visual prosthesis project5 and the Utah electrode array.6
The optic nerve is also being evaluated as a site for visual prosthesis. A group in Belgium has implanted one such device in a blind patient with advanced retinitis pigmentosa (RP) in 1998. This patient could perceive phosphenes on electrical stimulation in preoperative evaluation. After the implant, this patient has been able to demonstrate pattern recognition.7 The dense axonal collection in the optic nerve, however, creates difficulty in achieving focal neuronal stimulation and percepts.
Blind patients have been found to perceive electrically elicited phosphenes in response to ocular stimulation by a contact lens electrode.8 Additionally, it has been found that inner retinal layers are significantly retained compared to the outer retina in diseases such as AMD9 and RP.10 These findings led to developmental effort in artificial retinal prostheses. Some researchers, including our group, follow the epiretinal approach, where the device is implanted in front of the retina after a routine vitrectomy. The electrical stimulation in this method meets the inner retina first. The other approach of subretinal implantation utilizes the space between the neurosensory retina and the retinal pigment epithelium. The subretinal space can be accessed either through a retinotomy or through a sclero-choroidal pocket.
Epiretinal implantation allows electronics to be kept off the retinal surface and in the natural “heat-sink” of the vitreous cavity. The external device includes a video camera and power supply; the images and power are transmitted to the intraocular device by telemetry. Also, due to separation of the electronics, software control and upgrades are possible, in contrast to the subretinal device. Such epiretinal devices are in development by our group at the Doheny Eye Institute in cooperation with Second Sight Medical Products, Inc (Sylmar, CA). Other groups, including the Learning Retina Implant group in Germany11, are also working on a similar approach.
Our group (Intraocular Retinal Prosthesis Project) has successfully implanted a 16-electrode Model-1 device in six patients of advanced RP with encouraging results. These patients, with bare or no light perception pre-operatively, can distinguish direction of motion of objects and also discriminate between percepts created by different electrodes within a few days of surgery.12 These patients have a minimum of three years follow-up and there have been no adverse implant-related events or safety issues in the patients implanted so far. The next generation device (Model-2), consisting of 60 electrodes, has been given permission by the Food and Drug Administration (FDA) for clinical trials, which is expected to improve visual perception for the patient. We also hope to increase the number of electrodes in future versions to help patients regain significant visual capabilities.
The Learning Retinal Implant is made of an external Retina Encoder and an intraocular Retina Stimulator. It is affixed to the epiretinal surface and has been implanted in four blind patients with RP. According to the company press release (Intelligent Medical Implants, GmBH), these patients have shown pattern recognition.
Several groups are working on developing subretinal devices. Optobionics Corporation has developed an Artificial Silicon Retina (ASR) microphotodiode device that is powered entirely by incident light entering the eye, which in turn creates electrical impulses.13 A similar approach has been undertaken by a consortium of research universities in Germany.14 Their Microphotodiode Array (MPDA) is different than the ASR in that they have additional sources of power and are not completely dependent on incident light. A group from Harvard Medical School and Massachusetts Institute of Technology (Retinal Implant Project) is working on an ab externo approach to subretinal devices.15 Close proximity to the viable inner retinal neurons, and subsequent reduced current requirement, is a significant advantage of the subretinal approach. It also does not require any fixation methods. However, the limited space increases the chances of thermal damage.
Ten patients with advanced RP have been implanted with the ASR in a safety and feasibility trial that started in June 2000. The researchers reported subjective visual gain in all patients at six months follow-up.13 Two patients were reported to be able to preoperatively read between 0 to 25 letters of EDTRS letters in the right eye at 0.5m, while most others could not. Postoperatively, all patients reported subjective improvement in perception of brightness, contrast, color, movement, shape, resolution, and visual field size. The two patients who were able to read EDTRS letters before were now reported to read between 25 and 41 letters. Observation of retinal visual improvement was noticed in areas far from the implant site and greater than that expected from a small ASR chip implanted in the superior or superior temporal retina. These effects are being considered to be due to neurotrophic effects from the prosthesis electrical activity, mechanical injury due to implantation, or presence of chronic foreign body in the subretinal space.16 The German MPDA have implanted two patients (blind from RP) with their device in 2005; one of these devices was explanted as planned at four weeks, while the other patient decided to keep the implant.17 Electrode stimulation elicited reproducible phosphenes of well defined shape, enabling clear pattern recognition. The Retinal Implant Project device is still in development.
A Japanese group uses another approach to retinal stimulation by placing electrodes in the suprachoroidal space.18 This group has tested the device in animal studies and has yet to begin clinical trials. The electrodes are possibly less invasive to the retinal tissue and the surgical intervention appears less complicated, although choroidal bleeding could be an issue. Also, there will be need for higher threshold currents, since the electrodes will be further away from the target neurons.19
Other approaches to artificial vision include neurotransmitter based stimulation under control of an implanted device20 and directed neuronal growth onto a microfluidic stimulating device.21 These devices are probably still some years away from patient trials.
Why is RP the focus of most clinical trials? AMD significantly affects the macula, usually with an intact peripheral field of vision. Potential complications of the implant surgery include retinal detachment (as with any vitrectomy), which might lead to reduction of visual field. Since current devices do not yet have long term follow-up, it would be inadvisable to recruit AMD patients at this time, as compared to patients with advanced stages of RP, where both visual acuity and visual field are already severely affected.
Although many advances have been made in the field of artificial vision, with encouraging results from clinical trials so far, the reality of a commercially available device is still a few years away. Future clinical trials are eagerly awaited.
- Foerster O. Beitrage zur pathophysiologie der sehbahn und der spehsphare. J Psychol Neurol 1929;39:435-63
- Brindley G, Rushton D. Implanted stimulators of the visual cortex as visual prosthetic devices. Trans. Am. Acad.Ophthalmol. Otolaryngol. 1974;78:OP741–45
- Dobelle WH, Mladejovsky MG, Girvin JP. Artificial vision for the blind: Electrical stimulation of visual cortex offers hope for a functional prosthesis. Science 1974;183(123):440–44
- Margalit E, Maia M, Weiland JD, Greenberg RJ, Fujii GY, Torres G, et al. Retinal prosthesis for the blind. Surv Ophthalmol 2002;47:335-56
- Troyk P, Bak M, Berg J, Bradley D, Cogan S, Erickson R, et al. A model for intracortical visual prosthesis research. Artif Organs 2003; 27:1005-15.
- Maynard EM, Nordhausen CT, Normann RA. The Utah intracortical electrode array: a recording structure for potential brain-computer interfaces. Electroencephalogr Clin Neurophysiol 1997;102:228-39
- Veraart C, Wanet-Defalque MC, Gerard B, Vanlierde A, Delbeke J. Pattern recognition with the optic nerve visual prosthesis. Artif Organs 2003;27:996-1004.
- Potts AM, Inoue J: The electrically evoked response of the visual system (EER) III. Further consideration to the origin of the EER. Invest Ophthalmol 1970;9:814–9.
- Kim S, Sadda S, Pearlman J, Humayun MS, de Juan E Jr, et al. Morphometric analysis of the macula in eyes with disciform age-related macular degeneration. Retina 2002;22(4):471–77
- Santos A, Humayun MS, de Juan EJ, Greenburg RJ, Marsh MJ, et al. Preservation of the inner retina in retinitis pigmentosa. A morphometric analysis. Arch. Ophthalmol. 1997;115(4):511–15
- Eckmiller RE. Learning retina implants with epiretinal contacts. Ophthalmic Res 1997;29:281-9
- Humayun MS, Weiland JD, Fujii GY, Greenberg R, Williamson R, Little J, et al. Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res 2003;43:2573-81
- Chow AY, Chow VY, Packo KH, Pollack JS, Peyman GA, Schuchard R. The artificial silicon retina microchip for the treatment of vision loss from retinitis pigmentosa. Arch Ophthalmol 2004;122:460-9
- Zrenner E, Stett A, Weiss S, et al: Can subretinal microphotodiodes successfully replace degenerated photoreceptors? Vision Res 1999;39:2555–67
- Jenson RJ, Rizzo JF 3rd. Thresholds for activation of rabbit retinal ganglion cells with a subretinal electrode. Exp Eye Res. 2006 Aug;83(2):367-73
- Pardue MT, Phillips MJ, Yin H, Fernandes A, Cheng Y, Chow AY, Ball SL. Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats. J Neural Eng. 2005 Mar;2(1):S39-47
- Zrenner E, Besch D, Bartz-Schmidt KU,Gekeler F, Gaber VP, Kuttenkeuler C, Sachs H, Sailer H, Wilhelm B, Wilke R.Subretinal chronic multi-electrode arrays implanted in blind patients. IOVS 2006;47: ARVO E-Abstract 1538
- Sakaguchi H, Fujikado T, Fang X, Kanda H, Osanai M, et al. Transretinal electrical stimulation with a suprachoroidal multichannel electrode in rabbit eyes. Jpn. J. Ophthalmol. 2004;48(3):256–61
- Weiland JD, Liu W, Humayun MS. Retinal prosthesis. Annu Rev Biomed Eng. 2005;7:361-401
- Iezzi R, Safadi M, Miller J, McAllister JP Jr, Auner G, Abrams GW. Feasibility of retinal and cortical prosthesis based upon spatiotemporally controlled release of L-glutamatese. Invest. Ophthalmol.Vis.Sci. 2001;42:S815 (Abstr.)
- Peterman MC, Mehenti NZ, Bilbao KV, Lee CJ, Leng T, et al. The artificial synapse chip: a flexible retinal interface based on directed retinal cell growth and neurotransmitter stimulation. Artif. Organs 2003;27(11):975–85
Ingrid U. Scott,
MD, MPH, Editor
Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine