Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

isopters. Further, in a study of 601 RP patients, Sandberg et al. (27) noted that significant correlations between Goldmann V4e isopter equivalent diameter and full-field ERG amplitude were generally higher for the photopic 30-Hz cone flicker response than the photopic cone flash response. The correlations were also higher for patients with dominant or recessive RP than for patients with X-linked RP, most likely because X-linked RP patients generally have smaller ERG amplitudes.

ERG Response and Functional Disability in RP

Studies indicate that visual acuity and visual field measures are better correlates of difficulty with daily activities than ERG parameters. Szlyk et al. (30) administered questionnaires to 160 patients with RP and seven patients with Usher syndrome type 2 and found that perceived difficulty in performing common tasks such as mobility, driving, negotiating steps, eating meals, and activities involving central vision is strongly related to level of visual acuity and visual fields. Although some ERG amplitude measures did correlate with difficulty with some self-reported activities, overall, the ERG amplitude measures showed the least relationship with patients’ self reports. In another study, the same research group evaluated driving performance in RP patients by selfreported accident frequency and by performance on an interactive driving simulator (31). Visual field loss was found to be a primary correlate of automotive accidents in individuals with RP.

Use of ERG in Clinical Treatment Trial of RP

Favorable ERG outcomes in clinical treatment trials of RP have not necessarily been associated with better visual function outcomes. Using narrow-band filtering of the 30-Hz cone response in a randomized trial, Berson et al. (17) found that, compared to the placebo group, RP patients treated with oral 15,000 I.U. vitamin A palmitate daily had a slower rate of decline in 30-Hz cone response and those treated with oral vitamin E of 400 I.U. daily had a faster rate of decline. However, no significant differences in change of visual acuity or

visual field were noted among the patient groups. In a randomized clinical trial of patients with X-linked RP receiving either supplemental docosahexaenoic acid (DHA) or placebo, Hoffman et al. (32) noted that DHA supplementation significantly reduced rod ERG function loss in patients aged <12 years and preserved cone ERG function in patients12 years, but neither visual acuity nor visual fields showed any significant change compared to the placebo group.

Unilateral RP

Although RP is usually a bilateral condition, patients with unilateral RP are occasionally encountered. The criteria for the diagnosis of unilateral RP are: (1) retinal, functional, and ERG changes consistent with RP in the affected eye; (2) normal function and normal ERG and EOG in the fellow eye; (3) exclusion of inflammatory, infectious, vascular, and traumatic causes of the retinopathy in the affected eye; (4) a sufficient period of observation to exclude a delayed onset of RP in the unaffected eye (33). Acquired disorders that may produce unilateral retinal pigmentary degeneration include ophthalmic artery occlusion, inflammatory retinopathies from syphilis, rubeola, onchocerciasis, and diffuse unilateral subacute neuroretinitis, and traumatic retinal injuries (34–37). Serial ERG and EOG testing of both eyes over time is helpful to determine that the ‘‘good’’ eye is normal and to exclude the possibility of subsequent development of bilateral asymmetric RP (37–39). Based on these criteria, true unilateral RP is rare, and most RP patients with unilateral symptoms have asymmetric disease (Fig. 8.3). Further, the lack of positive family history in virtually all unilateral RP patients implies that this disorder is acquired or recessively inherited.

Sector RP

Sector RP occurs when retinal atrophy, attenuated retinal vessels, and bone-spicule-like pigmentary clumping are localized to one or two quadrants of the retina. This rare disorder is typically bilateral, often autosomal dominant, and generally mildly progressive (40–44). However, some

Figure 8.3 Full-field ERG responses and retinal appearance of a 52-year-old man with asymmetric RP. Visual acuity was 20=20 in each eye. Goldmann visual fields showed marked constriction in the right eye and mild constriction in the left eye. Top: The ERG responses were asymmetric with non-detectable responses in the right eye and impaired responses in the left eye. Bottom: Retinal atrophy and pigmentary clumping were present in both eyes with the left eye having less vascular attenuation.

cases of presumptive ‘‘sector’’ RP may represent early stages of widespread RP. In sector RP, rod and cone full-field ERG responses are reduced, but the implicit times are normal (43,44). Although the ERG responses are somewhat proportional to the extent of visible retinal involvement, perimetric visual thresholds, dark adaptometry, ERG, and EOG studies have also revealed dysfunction of the normal-appearing areas of the retina (41,42,44). This has led Krill and Archer to suggest that ‘‘asymmetrical’’ rather than ‘‘sector’’ RP better describes this condition.

ERG in X-Linked RP Carriers

Heterozygous female carriers of X-linked RP show a broad spectrum of clinical features ranging from normal retinal appearance to widespread retinal degeneration, presumably due to lyonization, the degree of whether the normal or the abnormal X chromosome is inactivated (45–48). Full-field ERG responses in X-linked RP carriers correlate with the extent of retinal findings, and ERG responses and prognosis are more favorable for those carriers with normal retinal appearance or tapetal-like retinal reflex only (49,50). Impaired full-field ERG responses may be demonstrated in 50–96% of X-linked RP carriers (47,51,52). In general, both the cone and rod responses are reduced in carriers, and the a-wave is reduced but not prolonged and the b-wave is both reduced and prolonged (53). The most consistent fullfield ERG abnormality in X-linked RP carriers is likely delay in cone b-wave implicit times (54,55). Retinal examination combined with full-field ERG can lead to the identification of virtually all X-linked RP carriers (47). Multifocal ERG demonstrates patchy areas of retinal dyfunction in most X-linked RP carriers, and this mosaic pattern of dysfunction may be observed even in the absence of any visible retinal and full-field ERG abnormalities (56,57).

Negative ERG in RP

A negative ERG where a selective reduction of the b-wave produces a b-wave to a-wave amplitude ratio of less than 1 in the scotopic bright-flash combined rod–cone full-field ERG response is rarely found in RP (Fig. 8.2). Cideciyan and Jacobson (58) examined seven patients who had typical clinical features of RP with negative ERG pattern and found that the derived PII component of the rod ERG was abnormally reduced relative to the PIII component. Many of the patients also had a disproportionate reduction of the ON ERG component as compared to the OFF component. Photopic oscillatory potentials were also reduced and delayed or not detectable. Taken together, these findings indicate that in this rare subset of RP patients, dysfunction occurs not only

at the level of the photoreceptor outer segment but also at or proximal to the photoreceptor terminal region.

Low Frequency Damped ERG Wavelets in RP

Low frequency damped wavelet is a very rare full-field ERG finding noted in patients with early stages of RP (59). A series of 3–5 wavelets with reducing frequency and a period of 25–37 ms are observed in the scotopic bright-flash combined rod–cone response and the photopic cone flash response. Other ERG features in these patients include a non-detectable rod response and an increased b-wave to a-wave ratio for the photopic cone flash response presumably due to contribution of the first wavelet of the low frequency wavelets to the b-wave. Because the rod ERG responses are non-detectable, the low frequency damped wavelets are presumably cone-dri- ven and may be due to a reverberating of the OFF-pathway. The wavelets diminish over time as the disease progresses.

Multifocal ERG in RP

In general, multifocal ERG assesses cone function, because recording of multifocal rod ERG is difficult due to poor sig- nal-to-noise ratio produced by the need for blank frames and the slower recovery of the rods to successive stimulation (60). Multifocal ERG studies indicate decreased amplitudes and increase implicit times especially eccentric to the fovea in RP patients (61,62). Loss of amplitude of a multifocal ERG test area is not a good predictor of visual sensitivity obtained with Humphrey visual field, but delayed timing of the test area appears to be an early indicator of local retinal damage to the cone system (61).

VEP in RP

In general, VEP responses in RP are impaired due to retinal dysfunction. However, several studies have noted detectable VEP responses in RP patients (63–66). For instance, Jacobson et al. (63) performed flash VEP in the dark-adapted and light-adapted states in 50 RP patients and found all but one

of the patients had a detectable VEP responses. Detectable VEP was present in some patients with non-detectable ERG responses, and the authors concluded VEP may be a useful objective measure in assessing patients with residual central visual fields only.

LEBER CONGENITAL AMAUROSIS

Leber congenital amaurosis (LCA), described by Leber (67) in 1869, refers to a group of genetically heterogeneous autosomal recessive retinal dystrophies characterized by severe visual impairment noted within a few months after birth, infantile nystagmus, and the subsequent development of pigmentary retinal degeneration. However, at the time of diagnosis in infancy, the retinal appearance may be normal or demonstrate macular dysplasia or coloboma. Other associated features of LCA include hyperopia, keratoconus, cataracts, mental retardation, cystic renal disease, skeletal disorders, and hydrocephalus (68,69).

Leber congenital amaurosis is associated with several genetic loci (70). LCA1 is caused by mutations of the gene encoding retinal guanylate cyclase (GUCY2D) on chromosome 17p (71). LCA2 is due to mutations of the RPE65 (retinal pigment epithelium-specific 65-kD protein) gene on chromosome 1 (72). LCA3 is mapped to chromosome 14q. LCA4 is produced by mutations of the AIPL1 (arylhydrocarbon interacting protein-like 1) gene on chromosome 17p (73). LCA5 is mapped to chromosome 6q. LCA6 is associated with mutations of the RPGR-interacting (RPGRIP1) protein. Genetic loci of other forms of LCA include the photoreceptor-specific homeo box gene CRX on chromosome 19 and the Crumbs homolog 1 gene (74).

In infants with congenital blindness, full-field ERG is the key test for determining retinal dysfunction and the diagnosis of LCA. Several studies have demonstrated nondetectable rod and cone full-field ERG responses in most patients with LCA with a few having detectable but severely reduced and attenuated responses (69,75–79). Patients with

LCA associated with heterozygous compound RPE 65 mutations (LCA2) have non-detectable rod ERG response and residual cone ERG response and may retain some useful visual function at age 10 (77). Full-field cone ERG impairment with mild cone–rod dysfunction is found in some carrier parents of patients with LCA associated with GUCY2D mutation consistent with the higher expression of GUCY2D in cone as compared to rod photoreceptors (80).

A non-detectable ERG in blind children with pigmentary retinopathy is not specific for LCA, and systemic diseases such as infantile Refsum disease, Zellweger syndrome, neuronal ceroid lipofuscinosis should be considered (76). Further, rare patients with autosomal recessive congenital stationary night blindness may have nystagmus, notable visual impairment in infancy, and reduced ERG and may be misdiagnosed as having LCA (81).

Despite mostly non-detectable full-field ERG responses, flash VEP responses are detectable in many infants and children with LCA (76,82). One hypothesis of this phenomenon is that the sensitivity of the VEP is higher in lower stimulus luminance due to the magnification of the foveal contribution (83).

USHER SYNDROME

Usher syndrome refers to a genetically heterogeneous group of autosomal recessive disorders characterized by sensorineural hearing loss and progressive retinal pigmentary degeneration. Usher syndrome, described in the 1800s, is named after Charles Usher, a British ophthalmologist of the early 1900s. Usher syndrome is classified into three main types, all of which are associated with early onset of progressive pigmentary retinopathy and marked reduction of fullfield ERG responses. Patients with type I Usher syndrome have severe congenital deafness and vestibular dysfunction, patients with type II Usher syndrome have less profound congenital hearing loss and normal vestibular function, and patients with type III Usher syndrome have congenital near normal hearing with progressive hearing loss. Therefore,

hearing testing with audiometry is valuable in differentiating types of Usher syndrome (84).

Usher syndrome is extremely heterogeneous with numerous genetic subtypes. Type I Usher syndrome is associated with at least five genetic loci located on chromosomes 14 q (type 1A), 11q (type 1B), 11p (type 1C), 10q (type 1D), and 21q (type 1E). Type 1B accounts for about 75% of patients with type 1 Usher syndrome and is caused by mutations of the gene encoding myosin VIIA, a cytoskeletal protein (85). Abnormal myosin VIIA results in abnormal organization of microtubules of photoreceptor cells and degeneration of organ of Corti. Type II Usher syndrome is associated with at least three genetic located on chromosomes 1q (type IIA), 3p (type IIB), and 5q (type IIC). Type IIA accounts to about 90% patients with type 1I Usher syndrome and is caused by mutations of the gene designated as usherin (86). Type III Usher syndrome is the least common type but more common in Finnish families and is associated with mutations of the USH3A gene on chromosome 3q.

Ocular findings and degree of visual impairment are variable in Usher syndrome even patients with similar genetypes (87). Ocular symptoms and signs of Usher syndrome are similar to severe, early-onset RP. Night vision impairment, peripheral vision loss, and light sensitivity generally begin insidiously by the second decade of life. Visual acuity and macular function are relatively more preserved early in the disease. Retinal atrophy with vascular attenuation and pigmentary clumping (bone spicules) develop, and with progression, optic nerve atrophy, atrophic macular lesions, cystoid macular edema, vitreous syneresis with mild vitritis, and posterior subcapsular cataracts ccour.

Full-field ERG responses in Usher syndrome are severely reduced even in early disease with greater impairment of rod response than cone response. With disease progression, fullfield ERG responses become non-detectable. Patients with type I Usher syndrome generally have earlier onset and more severe progressive retinopathy compared with type II patients. At any given age, visual acuity, visual field area, and ERG responses are likely to be more impaired in type I

patients than type II patients (88,89). Likewise, the prevalence of atrophic or cystic foveal lesions is greater in type I patients (90). However, considerable overlap of the degree of impairment of these clinical parameters occurs between type I and type II; this makes typing Usher patients difficult on ophthalmologic grounds (89). Further, Bharadwaj et al. (91) have shown that visual acuity, visual field area, and ERG responses are not significantly different between type IB and other type I patients. Of interest, Seeliger et al. (92) found similar first-order multifocal ERG amplitude reduction among patients with RP, type I Usher syndrome, and type II Usher syndrome, but patients with type I Usher syndrome had only slightly delayed implicit times in the periphery of the 30 tested area compared to more delayed implicit times for patients with RP and type II Usher syndrome.

Full-field ERG is an important diagnostic test in combination with an ophthalmologic examination to screen for Usher syndrome in children with profound, preverbal sensorineural hearing loss (93). Although the prevalence of Usher syndrome in the United States has been estimated at 4.4 per 100,000, up to 6% of hearing-impaired children have Usher syndrome (94).

Heterozygous carriers of Usher syndrome have mild hearing loss and tend to have mildly reduced light-peak to dark-trough EOG amplitude ratios, but these findings are not sensitive or specific enough for reliable detection of carriers (95–97).

BARDET–BIEDL SYNDROME

Bardet–Biedl syndrome (BBS), described by Bardet in 1920 and Biedl in 1922, is a rare autosomal recessive disorder characterized by obesity, mild mental retardation, severe progressive pigmentary retinopathy, polydactyly, and hypogonadism (98,99). Other common clinical features of BBS include renal abnormalities and diabetes mellitus (100). Bardet–Biedl syndrome (BBS) is a genetically heterogeneous disorder associated with several genetic loci including chromosomes 11q (BBS1), 16q (BBS2), 3p (BBS3), 15q (BBS4),