Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

in other macular dystrophies, and the reason for this is unclear (Fig. 10.4) (51).

Noble and Carr (52) found impaired full-field ERG in 27% and reduced EOG responses in 20% in a study of 30 patients with Stargardt macular dystrophy. Itabashi et al. (53) as well as Starvou et al. (54) noted that ERG and EOG abnormalities were common in patients with macular atrophy and diffuse retinal flecks. More recently, using standardized full-field ERG, Lois et al. (51) classified 63 study patients with Stargardt disease into three groups based on full-field ERG responses. Of the total 63 patients, 68% had normal scotopic and photopic full-field ERG amplitudes (group 1), 14% had normal scotopic rod ERG amplitude but reduced photopic cone flash and 30-Hz flicker responses (group 2), and 16% had both reduced scotopic rod and photopic cone responses (group 3) (Fig. 10.4). Using this scheme, only 1 of the 63 patients was not classifiable. Considerable overlap of clinical attributes was noted among the three groups. However, group 1 patients tended to have better visual acuity and more restricted distribution of retinal flecks and atrophy, whereas those in group 3 had the worse visual acuity and consistently demonstrated macular atrophy with more widespread flecks. Pattern ERG and focal foveal ERG were abolished in all patients tested from all three groups even when visual acuity was still good, consistent with similar pattern ERG findings reported earlier by Stavrov et al. (54). Of the patients tested with EOG, 10%, 57%, and 80% in groups 1, 2, and 3, respectively, had impaired EOG light-peak to dark-trough amplitude ratios reflecting, in part, the full-field ERG impairment.

When patients with Stargardt disease are classified by retinal appearance into Stargardt macular dystrophy or fundus flavimaculatus, the prevalence of ERG and EOG abnormalities reported for each clinical subtype is highly variable mostly because of variable expressivity of the disease, differences in recording methodology, and differences in classification criteria (53–59). For instance, Aaberg (55) found impaired scotopic and photopic full-field ERG responses in 24 patients with Stargardt macular dystrophy to be 46%

and 71%, respectively, compared with 44% and 56% for 16 patients classified as fundus flavimaculatus. In contrast, Moloney et al. (59) noted impaired scotopic and photopic full-field ERG responses in 20 patients with Stargardt macular dystrophy to be only 20% and 20%, respectively, compared with only 39% and 21% for 28 patients with fundus flavimaculatus. However, prevalence of EOG abnormalities was similar between the two studies with Aaberg finding reduced EOG light-peak to dark-trough amplitude ratios of 44% and 83% for Stargardt macular dystrophy and fundus flavimaculatus patients, respectively, and Moloney demonstrating similar prevalence of 45% and 61%, respectively. In terms of other reports, Lachepalle et al. (58) noted greater full-field ERG impairment in six fundus flavimaculatus patients compared to nine Stargardt macular dystrophy patients. Klein and Krill (57) found impaired full-field ERG in 83% of their 24 fundus flavimaculatus patients but most of the ERG tests were performed with only 17 min of dark adaptation.

In terms of multifocal ERG, Kretschmann et al. (60) found that 96% of 51 Stargardt patients had markedly reduced or non-detectable macular ERG responses with the area of macular dysfunction usually larger than expected from visual acuity and retinal appearance. Toward more peripheral areas, ERG responses of Stargardt patients approach those of normal, and implicit times are not markedly delayed. Finally, VEP findings in Stargardt disease are rarely reported but are likely to parallel retinal function and show impairment especially in light of impaired pattern ERG and macular dysfunction.

Pedigrees of autosomal dominant Stargardt-like macular dystrophy are rarely found with genetic linkage to 6q14 and 13q34 (61,62). The clinical features of 6q14 dominant Stargardt disease include a well circumscribed, homogenous macular atrophy of the retinal pigment epithelium and choriocapillaris with surrounding yellow fleck-like lesions and temporal pallor of the optic nerve head (63). Full-field ERG for 6q14 Stargardt’s disease may be normal or show prolonged b-wave implicit times (61,63). Of interest, fundus

(67). Although visual prognosis is generally favorable, only 20% of Best disease patients older than age 40 have a visual acuity of 20=40 or better in at least one eye (68). Histopathology in early stages of Best disease reveals generalized abnormality of the retinal pigment epithelium with pigmented lipofuscin accumulation as well as lipofuscin within macrophages in the subretinal space and the choroid (69). In more advanced cases, finely granular material is deposited in the inner segments of the degenerating photoreceptors in addition to the retinal pigment epithelial abnormalities (70).

Best vitelliform macular dystrophy is caused by mutations of the gene designated as VMD2 located on chromosome 11 (11q13) (71). The gene encodes a 585-amino-acid protein known as bestrophin which is selectively expressed in the retinal pigment epithelium. Numerous mutations of the VMD2 are found in association with Best disease indicating genetic heterogeneity, and genetic findings suggest that a small fraction of patients with clinical diagnosis of AMD and adult-onset foveomacular vitelliform dystrophy may actually have a late-onset variant of Best disease (72–74).

The diagnosis of Best vitelliform macular dystrophy is based on a combination of clinical features, family history, electrophysiologic testing, and genetic analysis. Electrooculogram is a key diagnostic test and shows marked impairment early even when retinal lesions are not yet visible (75). The EOG light-peak to dark-trough amplitude ratios are typically less than 1.4 (normal 1.8), reflecting generalized dysfunction of the retinal pigment epithelium (75–80). However, there is no direct correlation between the degree of EOG impairment and visual acuity. Clinical full-field ERG is normal in Best disease so that in contrast to most retinal dystrophies where EOG reductions parallel ERG impairment, Best disease is one of few diseases with a distinct pattern of a normal full-field ERG with a markedly impaired EOG (Fig. 10.6). Although a diagnosis of Best disease may be obvious in a young patient with an ‘‘egg-yolk-like’’ foveal lesion and a positive family history, EOG testing is helpful in confirming the diagnosis. In older patients with atrophic foveal lesions, who are suspected of having Best disease, a combination of full-field

Figure 10.6 Full-field ERG responses and EOG results from a 31- year-old man with Best vitelliform macular dystrophy (fundus appearance shown in Fig. 10.5; left). Note the normal full-field ERG and the strikingly reduced EOG.

ERG and EOG testing will help to confirm Best disease as well as to exclude other retinal dystrophies. Further, reduced EOG amplitude ratios are found in Best dystrophy family members who harbor a VMD2 mutation but have no maculopathy (81).

In general, other electrophysiologic findings in Best disease show retinal pigment epithelium dysfunction as well as localized retinal dysfunction at the macula. Despite normal full-field ERG in Best disease, the full-field ERG c-wave, a measure of retinal pigment epithelium function and not usually assessed in clinical recordings, is reduced in Best disease (82). Focal macular ERG with flicker stimuli is impaired indicating localized retinal dysfunction (83). Likewise, multifocal ERG first-order amplitudes are significantly reduced with normal or slightly increased implicit times for the central and pericentral responses (84,85). Of interest, Weleber (86) noted that despite a dramatically impaired clinical EOG which measures EOG slow oscillation, the EOG fast oscillation, which is not

cone dystrophy are extremely diverse. For example, pedigrees of autosomal dominant forms of cone dystrophy are associated with several genotypes including mutation of the guanylate cyclase activator-1A and mutation mapped to the general area of the recoverin gene. Mutations at codon 172 in the peripherin=RDS gene may also produce a macular dystrophy with primary cone dysfunction and preserved peripheral rod function (89,90). In rare cone dystrophy patients, a green- ish-golden tapetal-like sheen of the retina has been observed which returns to normal after several hours of dark adaptation; this Mizuo–Nakamura phenomenon is most commonly encountered with Oguchi disease (91).

Full-field ERG is a key diagnostic test in cone dystrophy and demonstrates diffuse cone dysfunction (Fig. 10.8) (6,92– 95). Both interfamilial and intrafamilial variability of clinical features and ERG responses is common (96,97). In general, the standard full-field ERG responses in cone dystrophy are as follows: (1) scotopic rod flash response—normal in early disease and may become impaired in advanced disease, (2) scotopic combined rod–cone bright flash response—mildly to moderately reduced a-wave and b-wave with variable prolongation, (3) oscillatory potentials—reduced, (4) photopic cone flash response—moderately to markedly reduced and prolonged, and (5) photopic cone flicker response—moderately to markedly reduced and prolonged. Because the ERG rod response may be impaired in advanced cases of cone dystrophy, differentiation of such patients from patients with cone–rod dystrophy may be difficult. The reduction of ERG in cone dystrophy correlates with visual field defects and with reduced EOG light rise so reduced EOG is common (93). Further, dark adaptation in cone dystrophy shows abnormal cone adaptation but the final rod sensitivity is normal or only mildly reduced. Of interest, Kellner and Foerster (98) reported two patients with cone dystrophy, who had negative full-field photopic cone flash responses with the a-wave being larger than the b-wave. One of the two patients also had a negative scotopic bright-flash combined rod–cone response. The authors concluded additional inner retinal transmission defects in the cone pathway can occur in cone dystrophy.

Figure 10.8 Full-field ERG responses from a patient with cone dystrophy. The cone flash and 30-Hz flicker responses are reduced and delayed. The ERG responses of cone dystrophy are similar to incomplete rod monochromatism (autosomal recessive achromatopsia), but the conditions are distinguishable by clinical history and findings.

CENTRAL CONE DYSTROPHY (OCCULT

MACULAR DYSTROPHY)

Central cone dystrophy, also called ‘‘occult macular dystrophy’’, is an autosomal dominant or sporadic disorder characterized by progressive bilateral decrease in visual acuity with normal retinal appearance, normal fluorescein angiography, normal EOG, normal full-field ERG, and decreased focal macular ERG response (99–101). The disorder appears to produce impairment of either only the macular cone system or macular cone and rod systems without any other visible abnormality (101). The diagnosis is made by excluding other macular disorders, and reduced macular function is detect-

PERIPHERAL CONE DYSTROPHY

Progressive peripheral cone dysfunction with normal central cone function has rarely been reported. Noble et al. (103) documented a 22-year-old man with 20=20 vision and normal Hardy–Rand–Rittler (HRR) and Ishihara color plate testing, who had normal full-field ERG scotopic responses but absent photopic responses. Pearlman et al. (104) in a report of a family with dominant cone dystrophy found an 18-year-old affected man who had 20=20 vision, red–green defect on Hardy–Rand–Rittler color plate testing, and absent full-field photopic flicker ERG response. Kondo et al. (105) reported three patients who had visual acuity ranging from 20=16 to 20=100. The full-field ERG rod responses were normal and the cone responses were significantly reduced. The focal macular cone ERG responses were well preserved in all the three patients, and multifocal ERG in two of the patients showed relatively preserved central responses with decreased responses peripherally. Taken together, these case reports indicate that in progressive cone dysfunction, the peripheral cones may be more affected than central cones in rare cases.

CONE DYSTROPHY WITH SUPERNORMAL AND DELAYED ROD ERG (SUPERNORMAL AND DELAYED ROD ERG SYNDROME)

In 1983, Gouras et al. (106) described two siblings with an unusual retinal dystrophy characterized by decreased visual acuity, decreased color vision, and diminished ERG cone response with supernormal but delayed rod response. Since the initial report, a number of other mostly sporadic or autosomal recessive cases have been documented. Common features of this rare but distinct disorder include onset of loss of central vision within the first two decades of life with variable progression, variable nyctalopia, and pigmentary disturbance of the macula which may be granular, atrophic or bull’s-eye-like. Under standardized clinical ERG conditions, the specific findings include: (1) a delayed but