Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Box 74.2  Genetics of retinitis pigmentosa

Nonsyndromic 65%

•Autosomal-recessive 50–60%

•Autosomal-dominant 35–40%

•X-linked 5–15%

Syndromic 30%

•Cilia syndromes

•Alstrom

•Bardet–Biedl/Meckel

•Joubert

•Senior Loken

•Usher

•Other

inheritance of BBS has also been reported. In these cases, disease is caused by mutations in two distinct BBS genes, with two mutations in one gene (which are not sufficient to cause disease alone) and a single mutation in the second.41,43 These and other recent findings have led to the suggestion that the severity of disease in ciliopathies such as BBS and RP may be due to the total mutational load on ciliary function.44 This concept is especially pertinent for RP, as it has long been recognized that the severity of disease can vary significantly among patients with RP caused by the same identified mutation.3,45 In these situations, it is likely that mutations in genes other than the identified disease gene may modify the disease severity.

Pathophysiology

Photoreceptor sensory cilia

Photoreceptor cells are sensory neurons that elaborate a highly specialized, light-sensitive organelle, the outer segment. It has recently been recognized that photoreceptor outer segments are specialized sensory cilia (Figure 74.1). This has come as part of the recognition of the importance of primary and sensory cilia in biology and disease.46 It is now evident that primary cilia are present on most cells in the human body. All cilia are composed of a microtubulebased axoneme surrounded by a distinct domain of the plasma membrane. The axonemes are derived from and anchored to the cell via basal bodies.47 These structures are typically sensory organelles, and are involved in many critical aspects of cell biology.48,49 For example, sensation of flow by primary cilia is required for maintenance of renal nephron structure and body axis determination. Recent evidence has also revealed that primary cilia play important roles in various aspects of development, such as planar cell polarity and hedgehog signaling.46,50

The sensory cilia elaborated rod and cone photoreceptors are among the largest of mammalian cilia.49,51 Like other cilia, the outer segments contain an axoneme, which begins at the basal bodies and passes through a transition zone (the so-called “connecting cilium”) and into the outer segment (Figure 74.1). The basal bodies also nucleate the ciliary

Pathophysiology

rootlet, which extends into the inner segment.51 The photoreceptor sensory cilium (PSC) complex comprises the outer segment and its cytoskeleton, including the rootlet, basal body, and axoneme (Figure 74.1). The outer-segment membrane domain of the PSC complex is highly specialized, with discs stacked in tight order at 30 per micron along the axoneme. The proteins required for phototransduction are located in or associated with these discs.

PSC dysfunction and photoreceptor cell death

The value of recognizing photoreceptor outer segments as cilia is that it connects retinal degenerative disorders such as RP to other cilia disorders. In addition, recognition of RP as a cilia disorder (ciliopathy) can also help with understanding disease pathogenesis. That is, many of the mutations identified to cause RP and related disorders exert their pathogenic effects by causing cilia dysfunction, which in turn leads to photoreceptor cell death. If the affected genes are expressed exclusively or predominantly in the retina, then nonsyndromic RP results. More widespread expression of the disease genes may result in systemic disorders reflecting the locations of gene expression.41,42

Defective signaling in photoreceptor cilia

One general mechanism by which disease-causing mutations damage photoreceptors is by causing defects in phototransduction. In a general way, this is similar to defective signaling that is thought to underlie other ciliopathies, such as polycystic kidney disease, in which cilia defects result in dysfunction of the ion channel formed by the polycystin proteins, alterations in Wnt signaling, and changes in cell cycle regulation.42

Disruption of the phototransduction cascade at any point can lead to defects in signaling, and thus in vision (Figure 74.5). Indeed, mutations in genes that encode many of the proteins involved in phototransduction have been found to cause RP and related disorders (Tables 74.2 and 74.3). For example, mutations in PDE6A and PDE6B, which encode the α- and ß-subunits of the phosphodiesterase, lead to recessive RP.52,53 They also cause photoreceptor degeneration in rd mice, rcd1 dogs.54–56 Study of these animal models shows that loss of phosphodiesterase activity leads to persistent elevation of cGMP levels, and chronically open cGMP-gated channels. It is hypothesized that the chronically open cGMPgated channels in patients and animals with PDE6A and PDE6B mutations result in metabolic overload, by demanding continuous activity of the Na+/K+-ATPase exchanger to maintain electrochemical gradients in photoreceptor cells. Mutations in rhodopsin can also disrupt phototransduction, and are a common cause of RP.3,35

Defective photoreceptor function can also result from mutations in the genes that encode the proteins which regulate the phototransduction cascade. For example, patients with mutations in the genes that encode rhodopsin kinase and arrestin have a form of congenital stationary night blindness called Oguchi disease.57,58 These mutations are thought to lead to continuous activation of phototransduction, since the negative regulators of the process are missing. It is hypothesized that the photoreceptor degeneration which occurs in these patients and animals is similar to the

Section 9  Retina

Na+

Na+

Ca2+, K+ Ca2+

Na+

Na+

hv

K+

K+

Na+ K+

A

Chapter 74  Retinitis pigmentosa and related disorders

cG cG

B

retinal degeneration that occurs in animals following continuous exposure to light. Support for this “equivalent light” hypothesis has recently been provided from studies of mice with deletions of genes that encode components of the retinoid cycle and the phototransduction cascade.59

RPE proteins/visual cycle defects

Another class of mutations that lead to defects in phototransduction are those that disrupt the recycling of the opsin chromophore from all-trans to 11-cis-retinal. This visual cycle involves reduction of all-trans-retinal to the retinol form, transport from the photoreceptor cilia to the RPE, where the 11-cis form is regenerated via a series of enzymatic reactions prior to transport back to the photoreceptor outer segments.60 The classic example of retinal degeneration caused by a visual cycle defect is mutations in the RPE65 gene, which cause LCA. The RPE65 protein has recently been identified to be the retinal isomerohydrolase.61,62 Lack of this protein leads to failure of phototransduction due to lack of 11-cis retinal. A similar situation is hypothesized to occur secondary to mutations in the LRAT gene.63 Mutations in RPE proteins can also lead to retinal degeneration via defects in phagocytosis of shed photoreceptor outer segments.64

Defective photoreceptor cilia formation

Another important cause of photoreceptor cilia dysfunction is defects in cilia structure.65 Since photoreceptor outer segments turn over every 10 days, they are susceptible to errors in formation and in maintenance.66 In the most basic form of disease in this category, photoreceptor outer segments do

588

not form. This has been observed in rhodopsin knockout mice, and is hypothesized to occur in patients with recessive RP caused by null mutations in rhodopsin.67,68 Lack of photoreceptor outer-segment formation has also been observed in mice with targeted deletion of the cone–rod homeobox (Crx) gene.69 CRX is a transcription factor which stimulates expression of photoreceptor-specific genes. Mutations in CRX cause LCA, as well as other retinal degenerations, possibly via disruption of photoreceptor outer-segment formation due to alterations in expression of photoreceptor cilia genes.70

Photoreceptor outer segments also fail to form in rds mice, which have a mutant peripherin 2 (Prph2) gene.71 Mutations in the human PRPH2 gene cause dominant retinal degenerations, including RP.72,73 As heterozygous rds mice have defects in outer-segment formation, it is hypothesized that this is also the mechanism of human disease.74 Severe defects in outer-segment formation were observed in semaphorin 4a (Sema4a) knockout mice.75 Mutations in this gene cause dominant RP, possibly by altering outer-segment organization.76

A number of proteins produced by retinal degeneration disease genes have been identified to be components of the basal body, transition zone (connecting cilium), and axoneme of photoreceptor sensory cilia. Mutations in many of these genes are thought to cause disease by resulting in production of disorganized photoreceptor outer segments. The retinitis pigmentosa 1 (RP1) protein has been observed to be part of the axoneme of photoreceptor sensory cilia.77,78 Targeted alterations in the mouse retinitis pigmentosa 1 homolog (Rp1h) gene gene also lead to production of disorganized outer segments, with failure of discs to align along

the axoneme.79 Based on these data, it is hypothesized that mutations in the human RP1 gene, which have been identified to cause dominant and recessive RP, cause disease by disruption of photoreceptor cilia structure.78 The retinitis pigmentosa GTPase regulator (RPGR) protein and its interacting protein RPGRIP1 localize to the transition zone/ connecting cilia of photoreceptor cells. Mutations in these genes cause LCA and X-linked RP. Disruption of these genes in mice also leads to production of disorganized outer segments.80,81

As described above, RP occurs in the setting of other cilia disorders, including BBS, Alstrom syndrome, Joubert syndrome and Senior Loken syndrome/nephronophthisis. Many of the proteins produced by the BBS, Alstrom syndrome 1 (ALMS1), Joubert, and nephronophthisis genes have been localized to cilia and basal bodies.41,42 Animal models for several of these disorders have been generated or identified, and demonstrate that defects in or lack of these cilia proteins lead to production of disorganized photoreceptor outer segments. For example, Bbs1 M390R knockin mice and Bbs2 null mice have disorganized outer segments. Photoreceptor degeneration and defects in photoreceptor protein transport were detected in the Bbs4 knockout mice. All three mouse models also demonstrate other cilia defects, including lack of flagella on sperm.82–85

Other widely expressed proteins

In addition to the cilia proteins described above, mutations in genes that encode several other widely expressed proteins have been found to harbor mutations which cause nonsyndromic RP. Several hypotheses have been suggested to explain how the identified mutations lead to photoreceptorspecific disease. In the case of mutations in the inosine monophosphate dehydrogenase 1 (IMPDH1) gene, whose mutations cause dominant RP, it has been suggested that retina-specific disease may be related to the relatively high level of IMPDH1 protein in the retina, and unique retinal

isoforms of the protein, which may perform retina-specific function(s).86 Mutations in several components of the splice­ osome, which is responsible for splicing pre-mRNA transcripts into mature mRNAs, have also been found to cause dominant RP. These genes include pre-mRNA-processing factors 3, 8, and 31 (PRPF3, PRPF8, PRPF31) and retinitis pigmentosa 9 (RP9).87–90 It has been suggested that mutations in these RNA-splicing factors could cause RP by disrupting the splicing of retina-specific genes. Alternatively, global defects in splicing could result in retina-specific disease due to the high biosynthetic demand of photoreceptor cells.87

Programmed cell death

As for many neurodegenerative diseases, it has been suggested that programmed cell death (PCD) is the final common pathway to photoreceptor cell death in retinal degenerations. Evidence from studies of animal models indicates that at least some forms of inherited retinal degeneration photoreceptor cells die via the type of PCD called apoptosis.91–93 Apoptosis is characterized by specific morphologic changes which are generated by a cascade of biochemical events that are mediated in part by caspases.94 For several other animal models of retinal degeneration, however, it is evident that PCD occurs in a caspase-inde- pendent fashion. In these models, it appears that increased intracellular calcium levels lead to activation of calpains and cathepsins, which can be associated with a distinct form of PCD called necrosis.95,96 These findings highlight the point that the specific mechanisms by which mutations in retinal degeneration disease genes lead to PSC dysfunction and ultimately death of rods and cones remain to be defined.65,97

It is hoped that, as additional information about the mechanisms by which mutations in retinal degeneration disease genes cause photoreceptor cell death is gained from research, it will be applied to the development of therapies to prevent loss of vision from these disorders.

1.Berson EL. Retinitis pigmentosa. The Friedenwald lecture. Invest Ophthalmol Vis Sci 1993;34:1659–1676.

2.Weleber RG. Infantile and childhood retinal blindness: a molecular perspective (the Franceschetti lecture). Ophthalm Genet 2002;23:71–97.

3.Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006;368: 1795–1809.

7.Lamb TD, Pugh EN Jr. Phototransduction, dark adaptation, and rhodopsin regeneration the proctor lecture. Invest Ophthalmol Vis Sci 2006;47:5137–

5152.

8.Marmor MF, Holder GE, Seeliger MW, et al. Standard for clinical electroretinography (2004 update). Doc Ophthalmol 2004;108:107–114.

10.Berson EL. Long-term visual prognoses in patients with retinitis pigmentosa: the Ludwig von Sallmann lecture. Exp Eye Res 2007;85:7–14.

14.Stone EM. Genetic testing for inherited eye disease. Arch Ophthalmol 2007;125: 205–212.

19.Berson EL, Rosner B, Sandberg MA, et al. Vitamin A supplementation for retinitis pigmentosa. Arch Ophthalmol 1993;111: 1456–1459.

22.Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA 2006;103:3896–3901.

25.Maguire AM, Simonelli F, Pierce EA,

et al. Safety and efficacy of gene transfer

for Leber’s congenital amaurosis. N Engl J Med 2008;358:2240–2248.

34.RetNet website address. 2008. http:// www.sph.uth.tmc.edu/Retnet/.

35.Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol 2007;125:151–158.

41.Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 2006;7:125–148.

42.Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 2007;18:1855–1871.

60.Saari JC. Biochemistry of visual pigment regeneration: the Friedenwald lecture. Invest Ophthalmol Vis Sci 2000;41:337– 348.

The field of retinal prosthetics began about 20 years ago, largely because of advances in microelectronic technology1,2 which permitted the development of electronically sophisticated devices that were small enough to be implanted into the eyeball. The remarkable success of cochlear implants, which has been achieved without a large number of electrodes or very advanced electronic technology, served as a beacon for the emerging field of visual prosthetics. This chapter provides an overview of the challenges and achievements in the development of visual prostheses, which have the potential to provide vision to patients for whom there is otherwise little opportunity for significant rehabilitation. Potential sites for implementation of a visual prosthesis include the subretinal space, epiretinal surface, optic nerve, lateral geniculate nucleus (LGN), and visual cortex (Figure 75.1).

Clinical background

Blindness is one of the most common forms of disability, and in industrialized countries retinal disease accounts for the majority of blind patients. Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are the two retinal diseases causing blindness that are considered to be potentially treatable with a retinal prosthesis. There are roughly 2 million Americans with AMD, and the percentage of affected individuals is expected to increase by 50% by the year 2020.3,4 RP is the leading cause of inherited blindness in the world, affecting roughly 1.7 million patients. The cost to the US government to provide support services for the blind is enormous, reaching $4 billion annually.5

Pathology

AMD and RP cause blindness because of grossly similar pathologies (Figure 75.2), although the mechanisms of injury are different. Both diseases cause blindness because of a loss of the rods and cones (i.e., the photoreceptors),6,7 which are the only cells in the retina that can convert incoming light into neural signals that create conscious visual perception. The neural signals are propogated to retinal ganglion cells (RGC) in the inner retina, which connect the eye to the brain and remain relatively healthy in AMD and RP.7–11 A

prosthesis can potentially restore vision to patients with these diseases by providing electrical stimulation to the RGCs, which will then conduct the visual information to the brain. Diseases that damage the inner retina or optic nerve, like diabetic retinopathy and glaucoma, would not be amenable to the use of a retinal prosthesis.

The belief that there was “sparing” of RGCs was based upon the interpretation of standard histopathology of the retinas of affected patients (Figure 75.2: upper right and lower). More careful study of such retinas, however, showed the “sparing” to be relative.9–11 For RP, there is a loss of 30–70% of the RGCs; there is greater loss of RGCs in the peripheral retina, and cell loss is greatest in more advanced cases, especially in the X-linked and recessive forms of RP.10,11 The loss of RGCs is the result of anterograde transsynaptic degeneration, invasion of inwardly migrating retinal pigment epithelial cells into the blood vessels of the inner retina, and perhaps compression of axons due to altered anatomy of the inner retina.12–14 In patients with severe RP, only about 300,000 of the average 1.2 million RGCs in normally sighted humans survive. This degree of survival would still seem to be adequate to support the delivery of a substantial amount of visual information to the brain. By comparison, the auditory nerve contains roughly 30,000 cells,15 and stimulating some fraction of these cells has been sufficient to provide useful hearing for deaf patients, although admittedly the more complex visual sense will require more detailed information transfer.

Robert Marc has described in detail a predictable and orderly “reorganization” of molecules, synapses, cells, and networks in retinas following degeneration of photorecep- tors.16–19 The neural retina initially responds to loss of photoreceptors by showing subtle changes in neuronal structure, like neuronal swelling and disruption of microtubular structure (i.e., phase I changes). In phase II, there is death of photoreceptors – first rods, then cones. The loss of cones is followed by whole-scale reorganization of retinal cell layers and interconnections. Prior to their death, the metabolically stressed photoreceptors sprout neurites that extend, quite anomalously, up to the inner plexiform layer and ganglion cell layers. As the photoreceptors die, the bipolar cells retract their dendrites; the horizontal cells retract their dendrites within the outer plexiform layer while (anomalously) extending axonal processes and dendrites toward the inner plexiform layer. The Müller cells increase synthesis of their

Visual cortex

Optic nerve

Subretinal

Figure 75.1  Potential sites for implantation of a visual prosthesis.

GCL

GCL

INL

ONL

RPE

Figure 75.2  Photomicrographs of normal retina (upper left) with its normal complement of three cellular layers, and two retinas with degeneration of the photoreceptors (upper right and lower). Upper right: histology of the retina from a human with age-related macular degeneration. Lower: histology from the nasal foveal region from a human patient with retinitis pigmentosa. Both of the degenerated retinas show a dramatic loss of photoreceptors from the normal 6+ layers of cells that are present in the central retina of humans (compare appearance at red arrows in the normal versus diseased retinas). Both degenerated retinas also show a moderate presence of many cell bodies in the retinal ganglion cell layer (yellow arrows). Most of the neurons in this layer send axons to form the optic nerve.

intermediate filament proteins and extend processes beneath the retina that form a dense fibrotic layer within the subretinal space,16,17 which would presumably complicate attempts to stimulate the surviving cells of the outer retina from the subretinal space.

In phase 3, the reorganizing retina displays widespread sprouting of new neurites, migration of neurons into ectopic

Pathology

Figure 75.3  Retinal histology obtained by fusion of computational molecular phenotyping data sets with conventional electron microscopy showing GABAergic amacrine cells forming multiple, focal microneuromas (circled). Each microneuroma receives processes from nearby amacrine cells that appear to have migrated distally in the retina. (Reproduced with permission from Jones BW, Marc RE. Retinal remodeling during retinal degeneration. Exp Eye Res 2005;81:123–137.)

locations, development of new and aberrant synapses, creation of reciprocal synapses, “synaptic microneuromas” (Figure 75.3), and widespread death of all neuronal cell types in the retina.

Furthermore, the degeneration of photoreceptors alters the physiology of the surviving RGCs, which develop an increased spontaneous firing rate.20 The increased spontaneous activity might produce “noise” within the signal transduction pathway, which could complicate the attempt to create a useful visual image. As such, a new body of research is being pursued within the field of retinal prosthetics to define the response properties of degenerating retinas, with special emphasis on the response characteristics of retinal neurons following electrical stimulation.21–27

More specific rationale for treatment of retinal blindness with a retinal prosthesis

Guidelines for considering the use of a retinal prosthesis should require that a patient had normal vision at some point in life. This provides assurance that the complex series of interconnections between the photoreceptors and the primary visual cortex had at one time been properly established.

RP is widely considered to be the primary target for a retinal prosthesis because affected patients often become more severely blind than patients with AMD. Thus, the Food and Drug Administration would almost certainly require a greater demonstration of safety and efficacy for any proposal to use a retinal prosthesis for AMD, since these patients generally have better vision and therefore would be taking a greater risk than patients with RP.

The hope that vision with spatial detail can be achieved is based upon the presence of a predictable topographic order along the afferent visual pathway between the photoreceptors and the visual cortex. It therefore seems reasonable to assume that direct electrical stimulation of bipolar cells or RGCs (but not their overlying axons) might generate percepts at locations within the visual field similar to those which would have been obtained by photic stimulation in

Box 75.1  Conceptual foundation for development

of retinal prosthesis

the same area (Box 75.1). Indeed, human patients who have been severely blind for decades from RP have seen photopsias of varying degrees of detail (and more, see below) following electrical stimulation of the retina by numerous groups.28–34

More detailed considerations of prosthetic intervention in AMD

Visual loss with AMD is limited to central vision, and although patients can be significantly handicapped for tasks like reading, retention of peripheral vision provides them with some degree of independence. A prosthesis for patients with AMD would only be helpful if it could improve central vision, which is a much more demanding goal than helping patients with RP by providing relatively coarse visual input to help with navigation.

The same rationale of relative preservation of RGCs for use of a retinal prosthesis has been offered for AMD as for RP, although the story is more complex. In the aging retina, photoreceptor loss begins in the parafoveal region (initially inferiorly) and is dominated by loss of rods. Early on, this cell loss can occur without RPE abnormalities, although in many cases RPE abnormalities, mostly drusen, are evident and constitute perhaps the most important clinical signs of dry AMD.35,36 For wet AMD, the pathology is much more severe, with marked loss of photoreceptors and moderately severe (50% loss) of RGCs overlying the areas of photoreceptor degeneration, although, in some cases, the inner retina can be relatively spared.37 For dry AMD, these surviving photoreceptors also may not have normal synaptic connections38; and unlike RP, there is only scant physiological

evidence that RGCs can be stimulated to produce vision in patients with AMD.39 There are also a number of other anatomical features of the central macula that will likely complicate efforts to obtain vision in the range of 20/400 or better for patients with AMD. First, the anticipation that patients might see a geometrically similar (pattern to the stimulus) pattern is confounded by the fact that the RGCs are stacked upon one another within the parafovea. Thus, there may be a lack of topographical order for the centralmost RGCs such that adjacent RGCs might not correspond to adjacent points in the visual field.40

For patients with wet AMD, the scarring that follows the hemorrhages can severely distort the retinal contour (Figure 75.4), which to some extent would complicate surgical positioning or attachment of the prosthesis to the inner retinal surface.41 As such, the anatomy of each patient with AMD will have to be considered individually, and it must be assumed that some severely blind patients with AMD will not be good candidates for a prosthesis.

Etiology of outer retinal degenerations

The etiologies of AMD and RP are discussed in Chapters 68, 69, and 74.

Management

Attempts to assist patients with AMD or RP have included use of optical and electro-optical devices, such as telescopes, closed-circuit monitors and mobility training, primarily to learn how to use a cane for walking. These strategies can be beneficial but are limited in the functional gains that can be made. Newer rehabilitation strategies are also being explored, including sensory substitution; transplantation of stem cells, embryonic, or adult cells; and molecular genetic approaches, which may offer the best long-term treatment option. A prosthesis also has the significant advantage that restoration of function could be achieved by stimulation of nerve fibers that had been properly established during development – no new connections would have to be developed, as would be the case for transplanted cells.

The relative merits and disadvantages of various alternative strategies that could potentially be used in lieu of a retinal prosthesis are briefly compared below.

Sensory substitution

In sensory substitution therapy, a sensory modality is used to provide spatial information about the environment that cannot be appreciated by the compromised visual system. A customized device captures visual information and relays it to a nonvisual sense, like the tactile or the auditory system, to provide input about the spatial detail of the patient’s local environment. The late Paul Bach-y-Rita, a pioneer in this field, advocated the introduction of visual information (captured with a camera) through tactile input to the skin or tongue. His subjects were (to some extent) able to recreate an impression of their environment, experience a sense of

objects in space, and perform “eye”–hand coordination tasks.42

A more recent device uses a camera to capture visual images, which are then electronically modified (by configuring the loudness, frequency, and inter-ear disparity) to provide a “soundscape” that represents the visual landscape.43 Some completely blind patients have navigated through unfamiliar environments and even found their way through a maze on a computer screen using only the auditory cues provided by this vOICe device (Figure 75.5 and Box 75.2).

Gene therapy

The efforts to treat blindness by transferring healthy genes to repair genetic mutations achieved a major milestone in 2001 when Acland et al44 demonstrated that blind dogs (suffering from a retinal disease caused by the same mutation that causes Leber congenital amaurosis in humans) were able to regain lost sight. Within 3 months, the dogs were able to navigate within a dimly lit room.44 More recently, modifications of their packaging techniques have produced a 90% reduction of the amplitude of nystagmus.45 Additional studies on blind large animals46,47 and rodent models of retinal degeneration have provided substantial evidence that gene replacement therapy, or gene silencing therapy, represents a scientifically sound strategy potentially to treat certain forms of retinal blindness.48–50 Gene therapy trials to treat early-onset retinal degeneration have taken place in the USA and England, and have shown modest but encouraging visual results.51

Transplantation

Human transplantation studies, following earlier animal studies,52–54 have been performed using RPE, retinal neurons,

Figure 75.5  The vOICe system allows a visually impaired person to “see” by using the ears for visual input. Software that can be run by laptop computer carried in a backpack translates images captured by a video camera into sounds that the brain can use to create crude mental renderings.

partial-thickness sections of retina, and stem cells. These studies have ranged from a single patient to 56 patients, and most report relatively short follow-up of the patients. Generally, the transplants have been well tolerated and immune rejections and surgical complications have been uncommon.

Box 75.2  Approaches to treatment of age-related macular degeneration (AMD) and retinitis pigmentosa (RP)

Many studies have reported improvement in visual acuity in some patients, occasionally up to four lines on a Snellen chart. In general, patients with wet AMD generally fared worse than dry AMD or RP patients, and worse pretreatment vision correlated with decreased chance of benefit from transplantation.54–63

Neurotrophic factors

Ciliary neurotrophic factor (CNTF), a chemical which may be released normally by the RPE in response to cellular injury, has demonstrated significant retinal protection in animal models of RP where a delay in photoreceptor cell loss and enhancement of RPE survival in a rat model were demonstrated.64,65 A company called Neurotech USA has created an encapsulated vehicle containing RPE cells that have been modified using viral vectors to secrete CNTF continuously.66 Neurotech has conducted a phase I trial on 10 RP patients, 7 of whom demonstrated improved visual acuity, which was maintained in 3 patients 6 months after the removal of implant. However, one patient suffered a complete choroidal detachment.67 Other neurotrophic factors, like brain-derived neurotrophic factor and nerve growth factor, have also shown some neuroprotective benefit in animal experiments68 and may be other options for future human tests.

What is a visual prosthesis?

A retinal prosthesis is a complex device that functions by:

(1) capturing visual images; (2) communicating the images to electronic components that interface with the retina; and

(3) selectively delivering electrical pulses to the retina to create vision (Figure 75.6). The neurons can also be stimulated by some nonelectrical means using neurotransmitters or cations.69–72 Although such nonelectrical strategies offer

Figure 75.6  Minimally invasive, subretinal prosthetic system designed, built, and tested by the Boston Retinal Implant Project. (A and B) An illustration of our device, as seen from the front of a patient (A) and in a sagittal projection of the eye (B). The visual image is obtained by an external camera on a pair of spectacles and is translated into an electromagnetic signal that is transmitted wirelessly to the implanted components of the device, which are sutured to the sclera. Electrical power is also transmitted similarly from the primary to the secondary coil. The sagittal view reveals that only the electrode array (arrow) penetrates the wall of the eye. (C) An illustration of our first-generation device that we have used for animal tests. The secondary coils for power and data transmission (shown on the right) and the integrated circuit and discrete electronic components (shown on the left) are all mounted on a flexible, polyimide substrate. Only the stimulating electrode array (red arrow) enters the eye, where it is positioned within the subretinal space. Calibration bar (lower left).

the potential for being less toxic to the host tissue, development lags substantially behind the efforts to use electrical stimulation.

Attempts to develop visual cortical prostheses began in the 1970s,73,74 and have been advanced by Drs. Normann (University of Utah) and separately by Philip Troyk (Illinois Institute of Technology).75 Advancements in microtechnology roughly 20 years ago allowed our group and another at Duke University to begin efforts to develop a retinal prosthesis. Since then, the field has enjoyed enormous growth and now includes 22 retinal prosthetic research groups in six countries. There is not yet enough evidence to know which approach(es) might be preferable, and it is possible different diseases might be treated differently.

Comparison of different types of visual prosthetic devices

Each of the locations being considered as a site for a visual prosthesis (Figure 75.1) has certain advantages and disadvantages, and each approach has merit (Box 75.3). In general,

Box 75.3  Potential sites for implantable visual

prostheses

the more central the placement of a prosthesis, the greater the range of diseases it can treat. For instance, a retinal prosthesis could not be used to treat glaucomatous blindness (because of damage to the optic nerve), but a LGN or cortical approach could potentially provide some vision. By comparison, the convoluted topography of the visual cortex and the need for a substantial neurosurgical procedure to implant a cortical device impose challenges on the widespread use of visual cortical prosthetic devices (Figure 75.1). On the other hand, the eye is prone to develop chronic inflammations whereas the brain seems to respond fairly indolently to long-term implantation of foreign material.76,77 A cuff electrode array can be easily placed around the optic nerve in the orbit, but in this location the nerve is invested by all three meningeal sheaths and requires greater charge density for stimulation. Conversely, placing electrodes on the meninges-free, intracranial part of the optic nerve would require a large craniotomy. At the level of the LGN, it would be very challenging to implant a large number (i.e., hundreds) of electrodes that might ultimately be needed to create spatially detailed vision there.78 The recent use of small craniotomies for placement of deep brain implants in the treatment of patients with Parkinson’s and other neurological diseases has been well tolerated, and it is possible that some similar technique can be adapted for visual cortical implants in the future. Each potential site for a visual prosthesis has its advantages and drawbacks.

What has been achieved to date?

What has been achieved to date?

The following is a brief discussion of the results of testing for each type of visual prosthetic device. An example of some psychophysical tests used by one group to test patients who have received a retinal prosthesis is shown in Figure 75.7. At the end, a summary of results across all of these studies will be provided.

Visual cortical prosthesis

Brindley produced crude perceptions by implanting an electronically primitive device into the visual cortex of a patient who was completely blind from glaucoma.73,79 Later, Dobelle and Mladejovsky74 showed that multiple phosphenes could be perceived simultaneously following stimulation of multiple cortical electrodes, and that there was a perceptual alignment of the phosphenes that roughly correlated with the spatial organization of the visual cortex.79 These experiments were conducted by delivering stimulation to the surface of the cortex, which required high charge levels and produced only coarse two-point discrimination of phosphenes. In efforts to address these shortcomings, Hambrecht’s group (at the National Institutes of Health) reported the perception in a patient of multiple phosphenes that formed a straight line.80 Normann and colleagues (University of Utah) worked toward improving electrode design and techniques for surgical implantation of their device in the brain,81,82 and this has contributed significantly to the development of a motor prosthesis that has recently shown promising results in paralyzed patients.83–85 Phil Troyk and coworkers at the Illinois Institute of Technology have implanted 128 electrodes into the visual cortex of monkeys and have demonstrated the ability of the monkeys to learn to direct their eyes accurately toward specific points in space in relation to which electrodes were driven.86 Interestingly, there was a “learning effect” such that the psychophysical performance of the monkeys was initially quite poor but then after some months improved substantially over a very short period of time.

Retinal and optic nerve prostheses

The following is a brief summary of all projects that have performed psychophysical experiments after chronic implantation of a prosthetic device in humans (Box 75.4). In general, none of the retinal groups has yet published the results of a large number of psychophysical experiments with multiple trials and statistics of accuracy and reproducibility. In part, some of the lack of information may be related to the fact that the more recent (and potentially better-performing) devices have been implanted only recently. The fact that some of these data are considered proprietary by some companies is also limiting the flow of results in scientific journals. This review is at best an approximation of the results that can be gleaned from published results, scientific presentations, or information available on the official websites of some of these companies. Without a similar degree of published information from each company, it is possible that the following summary inaccurately portrays the achievements of some groups. Any such seeming biases are unintentional.

Box 75.4  Results of chronic human implantation of

retinal prostheses

of information has been published at this time are briefly discussed below.

The most fundamental achievement of these studies is the determination of psychophysical threshold. These thresholds have varied widely but tend to be in the range of 1–3 mC/cm2 range, which is near or above the acceptable safe charge limits for the metal electrodes that were used.31,87,88 Some thresholds, especially after long-term implantation, have been substantially below 1 mC/cm2, which is a more encouraging number for chronic stimulation.31,89 In general, the psychophysical thresholds have been at least four times higher for patients with RP compared to normally sighted patients,90,91 and, as described above, this may partly be the result of pathology that develops in degenerated retinas, among other factors. Thus far, the only strategy to reduce electrical stimulation thresholds in degenerate retinas has been achieved by infusion of CNTF into the vitreous cavity of rats.71

Retinal prosthesis

Five companies (two from the USA, three from Germany) have performed chronic implants of retinal prosthetic devices in humans. Three of the groups have used an epiretinal approach, the other two a subretinal approach. The results of four of the companies for which the most amount

596

Optobionics

The first to perform chronic human testing was Optobionics (Wheaton, IL), which implanted a photodiode array into the eyes of 12 RP patients. This device was designed to operate only from the power of incident light reaching the retina, and this was widely considered to be insufficient to drive