Rod–cone dystrophies (retinitis pigmentosa)

Patients with rod–cone dystrophies, usually referred to as retinitis pigmentosa (RP)—a term no longer preferred but still widely used—often present with history of nyctalopia (night blindness) and reports of vision changes that relate to visual field loss. The history may not be clear; patients may assume that their visual function is normal, because it is “normal” for them not to be able to see in the dark. It is important to ask the patient (and family members, in some instances) questions that properly assess them for vision dysfunction. Typical fundus findings in RP include arteriolar narrowing, with or without optic nerve head pallor, and variable amounts of bone spicule–like pigment changes resulting from intraretinal pigment deposition by macrophages that migrate into the retina to process degenerating retinal cells (Fig 13-3). This form of pigment deposition within the retina occurs in regions of outer retinal atrophy (eg, following retinal detachment or inflammatory retinopathies) and is not specific to hereditary retinopathies. The peripheral retina and RPE may be atrophic even if intraretinal pigment is absent (RP sine pigmento), and the macula typically shows a loss of the foveal reflex and irregularity of the vitreoretinal interface. Autofluorescence imaging can often identify additional areas of retinal involvement that are not evident on clinical examination. Vitreous cells, CME, epiretinal membranes, optic nerve drusen, and posterior subcapsular cataracts are commonly observed in eyes with panretinal dystrophies (Fig 13-4). Eyes with rod–cone degenerations typically develop partial- to full-ring scotomas in midequatorial regions; these often expand into the periphery, leaving only a small central island of visual field (Fig 13-5).

The ERG response in eyes with rod–cone dystrophies typically shows a loss or a marked reduction in rod-derived responses, more than in cone-derived responses. Both a- and b-waves are reduced because the photoreceptors are primarily involved. The b-waves are characteristically prolonged in time as well as diminished in amplitude. Individuals with the carrier state of X-linked recessive RP often show a mild reduction or delay in b-wave responses. Eyes with postinflammatory retinopathies (eg, retinopathies resulting from rubella) often have better preservation of the ERG than eyes with comparably appearing pigmentary changes from a hereditary retinopathy. In these cases, although the rod and cone amplitudes are reduced, the implicit times are usually within normal ranges, because the remaining photoreceptors are essentially normal. In contrast, in patients with a hereditary retinopathy, the remaining photoreceptors are impaired by the genetic condition and the ERG response shows prolonged implicit times. In conventional testing of many rod–cone dystrophies, the ERG responses may initially present as undetectable or become undetectable over time. An undetectable ERG signal is not diagnostic; while it represents severe retinal dysfunction, it doesn’t necessarily correlate to the patient’s level of visual function. Unless the patient has a treatable condition, such as vitamin A deficiency or an autoimmune retinopathy, repetitive ERG testing has minimal benefit for monitoring disease progression.

Figure 13-3 Different fundus photographic appearances in retinitis pigmentosa (RP). A, Posterior fundus, showing arteriolar attenuation and a dull macula. B, Fundus with dense, peripheral intraretinal pigmentary changes. C, Fundus shows peripheral atrophy but virtually no intraretinal pigment. D, Ultra-wide-angle fundus image of a patient with RP. Extensive pigmentary abnormalities, including intraretinal pigment and retinal pigment epithelium (RPE) alterations, are visible.

(Parts A and C courtesy of Michael F. Marmor, MD; part B courtesy of Carl D. Regillo, MD; part D courtesy of Colin A. McCannel, MD.)

Figure 13-4 Spectral-domain optical coherence tomography (SD-OCT) image of the macula of an eye with RP. Both CME and epiretinal membrane are present. Intraretinal fluid is characteristically present in the inner nuclear layer. Note the absence of any outer segment signal outside of the area of the fovea, as well as the thicker-than-normal appearance of the retinal nerve fiber layer near the optic nerve head.

(Courtesy of Michael B. Gorin, MD, PhD.)

Figure 13-5 Examples of visual fields in RP, obtained with a Goldmann III-4 test object. A, Early disease: midperipheral scotomas. B, Late disease: severe loss, sparing only a central tunnel and a far-peripheral island, which may eventually disappear.

(Courtesy of Michael F. Marmor, MD.)

Sectorial RP refers to disease that involves only 1 or 2 sectors of the fundus. This condition is generally symmetric in both eyes, which helps rule out acquired damage (eg, from trauma, vascular insult, or inflammation) (Fig 13-6). Unilateral RP is extremely rare; there has only been a single reported case within a family with a germline mutation. Most cases of unexplained unilateral pigmentary retinopathy are postinflammatory or post-traumatic. Most cases of pigmented paravenous retinopathy are postinflammatory, have interocular asymmetry, and are usually nonprogressive.

When evaluating suspected panretinal dystrophy in a patient with a negative family history (sporadic retinal dystrophy), it is important to consider acquired causes of retinal degeneration that can mimic hereditary conditions, including previous bilateral ophthalmic artery occlusions, diffuse uveitis, infections (eg, syphilis), paraneoplastic syndromes, and retinal drug toxicity. Syndromic forms of pigmentary retinopathy associated with metabolic or other organ system disease must also be considered (see Chapter 14). Age of onset, pattern of progression, interocular asymmetry, and comorbidities and exposures can help to distinguish these conditions.

Figure 13-6 Color fundus photographs of delimited forms of inherited retinal dystrophies. Note the sharp demarcation between the areas of degeneration and other regions of the fundus that appear quite healthy. It is important to assess interocular symmetry and the pattern of cell damage to consider acquired forms of retinopathy (such as pigmented paravenous retinopathy). A, Fundus with degenerative changes near the arcades. B, Fundus with sectorial RP (between arrows), showing vascular narrowing and spicules only in the inferonasal quadrant.

(Courtesy of Michael F. Marmor, MD.)

• Gregory-Evans K, Pennesi ME, Weleber RG. Retinitis pigmentosa and allied disorders. In: Schachat AP, Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P, eds. Ryan’s Retina. Vol 2. 6th ed. Philadelphia: Elsevier/Saunders; 2018:861–935.

Management Nutritional supplements have been advocated as therapy for RP. One large study reported that high daily doses of vitamin A palmitate (15,000 IU/day) can slow the decline in ERG response and visual fields in eyes with RP by approximately 20% per year. A slight benefit from omega-3 and omega-6 fatty-acid supplementation has also been reported. The modest benefit of high-dose vitamin A supplementation must be weighed against the risks of long-term liver toxicity, vitamin A-related intracranial hypertension, and teratogenicity.

Excessive light exposure may play a role in retinal degenerations caused by rhodopsin mutations and/or genes that contribute to lipofuscin accumulation, such as ABCA4. Recommendations for patients to employ UV-absorbing sunglasses and brimmed hats for protection from high levels of light exposure seem prudent, despite the absence of direct evidence of benefit.

Efforts to restore at least some vision in patients rendered completely blind from RP include the use of electronic chips that interface with the remaining retina tissue. One such device, the Argus II Retinal Prosthesis System (Second Sight Medical Products, Sylmar, California), is now commercially available, and others are in development.

• Makiyama Y, Oishi A, Otani A, et al. Prevalence and spatial distribution of cystoid spaces in retinitis pigmentosa: investigation with spectral domain optical coherence tomography. Retina. 2014;34(5):981–988.

• Salvatore S, Fishman GA, Genead MA. Treatment of cystic macular lesions in hereditary retinal dystrophies. Surv Ophthalmol. 2013;58(6):560–584.

Cone and cone–rod dystrophies

Patients with cone dystrophy present with progressive loss of visual acuity and color discrimination, often accompanied by hemeralopia (day blindness) and photophobia (discomfort and/or pain in the presence of normal levels of light). Onset of symptoms typically occurs in the teenage years or later adulthood. Ophthalmoscopy may be normal early in the course of the disease. Because of this, patients with cone dystrophies may be suspected of malingering. In other patients, ophthalmoscopy may reveal the typical symmetric bull’s-eye pattern of macular atrophy (Fig 13-7), or more severe atrophy, such as demarcated circular macular lesions. Mild to severe temporal optic atrophy and tapetal retinal reflexes (with a glistening greenish or golden sheen) may also be present. Unlike macular dystrophies, the cone dystrophies are more associated with color discrimination symptoms and photophobia, and as such, they must be differentiated from color vision defects (see Chapter 12).

Figure 13-7 Color fundus photograph of cone dystrophy, showing the bull’s-eye pattern of central atrophy.

When cone dystrophy is suspected, a full-field ERG is the appropriate test. Cone dystrophies are diagnosed when ERG results indicate an abnormal or undetectable photopic ERG response and a normal or near-normal rod-isolated ERG response. When present, the cone flicker ERG response is almost invariably delayed, in keeping with generalized cone-system dysfunction. Peripheral visual fields may remain normal. The cone dystrophies are progressive and are a heterogeneous group of hereditary diseases with more than 25 identified causative genes. In some patients, secondary rod photoreceptor involvement develops in later life, leading to overlap between progressive cone dystrophies and cone–rod dystrophies.

Similar to patients with cone dystrophies, patients with cone–rod dystrophies typically present with reduced central visual acuities and symptoms of dyschromatopsia and photophobia. On visual field testing, some patients show a tight ring or central scotoma within the central 20° or 30° of the visual field. Ophthalmoscopy may initially be normal; later, it may demonstrate intraretinal pigment in areas of retinal atrophy in the fundus periphery, and patients may report progressive night blindness. The diagnostic hallmark of a cone– rod dystrophy is that the cone-derived full-field ERG responses are more abnormal than the rod ERG responses.

Leber congenital amaurosis

The early-onset retinal dystrophies are collectively termed Leber congenital amaurosis (LCA) (also see BCSC Section 6, Pediatric Ophthalmology and Strabismus, Chapter 25). LCA is characterized by severely reduced vision from birth, usually associated with wandering nystagmus. Infants exhibit limited to absolutely no visual responses, and visual acuities tend to range between 20/200 to no light perception (NLP). Some infants with LCA rub or poke their eyes (the oculodigital reflex) to create visual stimulation, as do other infants with poor vision.

In the early stages, obvious fundus changes are rare, and molecular genetic testing offers the best method of distinguishing stationary and progressive hereditary retinopathies. In addition, because there are both syndromic and nonsyndromic forms of LCA, a molecular genetic diagnosis can help identify potential systemic features that warrant medical management. Some forms of LCA involve developmental defects, while others appear to represent degenerations of normally formed retina. Postinfectious etiologies should be considered based on clinical history and clinical findings. Central macular atrophic lesions (sometimes incorrectly referred to as macular colobomas) are often seen in eyes with LCA, in addition to early-onset cataracts and keratoconus in older children. Most children with nonsyndromic LCA have normal intelligence, and some of the observed psychomotor impairment may be secondary to sensory deprivation.

The ERG response is typically minimal or undetectable, but ERG testing is not able to establish whether the condition is stationary (congenital stationary night blindness [CSNB] or achromatopsia) or progressive (rod–cone dystrophy or cone–rod dystrophy). OCT can help identify whether the failure of foveal maturation that is associated with ocular albinism and is also detected in dystrophy-related macular edema is present.

Currently, 3 autosomal dominant and 18 recessive mutations that cause LCA have been identified. There is some overlap in the genes responsible for LCA and those that cause later-onset retinal dystrophies (both rod–cone and cone–rod). One form of LCA bearing a mutation in RPE65 has been treated successfully by gene therapy in clinical trials using an adeno-associated virus. In 2018, the FDA issued the first approval for a gene therapy, Luxturna, for the treatment of this condition in individuals aged 1 year or older.

Enhanced S-cone disease

The most prominent features of enhanced S-cone (or blue-cone; “S” refers to short wave-length) disease (ESCD), also known as Goldmann-Favre syndrome, include night blindness, increased sensitivity to blue light, pigmentary retinal degeneration, an optically empty vitreous, hyperopia, pathognomonic ERG abnormalities, and varying degrees of peripheral to midperipheral visual field loss (Fig 13-8). The posterior pole may show round, yellow, sheenlike lesions along the arcades, accompanied by areas of diffuse degeneration. Deep nummular pigmentary deposition is usually observed at the level of the RPE around the vascular arcades. Macular (and sometimes peripheral) schisis may be present, overlapping the phenotype of X-linked retinoschisis. The ERG response includes no detectable dimflash, rod-specific signal; delayed and simplified responses to a brighter flash that have the same waveform under both dark-adapted and light-adapted conditions; and a flicker ERG response of lower amplitude than that of the single-flash photopic a-wave.

In eyes with ESCD there is an overabundance of blue cones, a reduced number of red and green cones, and few, if any, functional rods. This condition is unique in that it is both a developmental and degenerative photoreceptor retinopathy. ESCD is autosomal recessive and results from homozygous or compound heterozygous mutations in NR2E3.

Figure 13-8 Clinical characteristics of enhanced S-cone disease (ESCD). In the early stages, the fundus may be normal. In older subjects, the fundus usually shows 360° nummular pigmentary changes outside the vascular arcades at the level of the RPE (A–C). The macula may show changes resulting from schisis or nonspecific pigment epithelial changes (C). The autofluorescence is variable (D–F). There may be hyperautofluorescence within the arcades that either spares or involves the foveal region. SD-OCT imaging of the macula may be normal (G) or show schitic and/or cystoid changes (H) or outer retinal abnormalities (I).

(Used with permission from Vincent A, Robson AG, Holder GE. Pathognomonic (diagnostic) ERGs. A review and update. Retina. 2013;33(1):5–12.)

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.