Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

large b-wave on rod response to the scotopic dim flash, (2) a normal or increased a-wave with a delayed but above normal b-wave for the scotopic bright-flash combined rod–cone response, (3) reduced oscillatory potentials, and (4) reduced and delayed cone flash and flicker responses (Fig. 10.10). These clinical ERG findings are explained in part by a delayed rod response that is reduced for very dim flash stimulus but increases above normal for brighter flashes (Fig. 10.11).

A defect of the cGMP cascade of photoreceptors was initially proposed as a mechanism of this disorder and was supported by experiments that showed similar changes in the rod ERG in a cat eye treated with a phosphodiesterase inhibitor to elevate cGMP (107). However, the cGMP hypothesis predicts abnormalities of the scotopic bright-flash roddominant a-wave response which have not been consistent noted in this disorder. More recently, Hood et al. (108) studied five affected patients extensively with specialized ERG techniques that included a rod phototransduction activation model, a rod deactivation paradigm, cone ‘‘on’’ and ‘‘off’’ component recordings, and a cone photoreceptor activation model (see Chapter 6). The results indicated that delays in the rod and cone b-waves were not due to the speed or amplification of the phototransduction process and the sites of disease action are beyond the photoreceptor outer segment and involve a delay in the activation of internuclear layer activity. These findings make a defect in the cGMP cascade of the photoreceptor unlikely although a cGMP abnormality beyond the photoreceptor outer segments cannot be completely excluded.

SORSBY FUNDUS DYSTROPHY

In the 1940s, Sorsby described a rare autosomal dominant retinal dystrophy characterized by macular drusen-like deposits, edema, hemorrhages, exudates, and choroidal neovascular membrane followed by macular atrophy with retinal pigment proliferation (109). Other names for the same disorder include pseudoinflammatory macular dystrophy, dominantly inherited disciform macular dystrophy, and hereditary

Figure 10.10 Full-field ERG responses from a patient with cone dystrophy with supernormal and delayed rod ERG (supernormal and delayed rod ERG syndrome). Note the characteristic delayed but large b-wave for the scotopic rod and rod–cone responses. The oscillatory potentials are reduced, and the cone flash and flicker responses are reduced and delayed.

hemorrhagic macular dystrophy. In 1994, Weber et al. (110) discovered that Sorsby fundus dystrophy resulted from mutations of the gene encoding tissue inhibitor of metallo- proetinase-3 (TIMP-3). TIMP-3 is expressed in the retinal

Figure 10.11 Full-field ERG scotopic intensity response series of a patient with supernormal and delayed rod ERG syndrome, whose standard ERG responses are shown in Fig. 10.10. The scotopic ERG responses are reduced compared to normal for very dim flash stimuli. With brighter flashes, the b-wave amplitudes increase above normal but are delayed.

pigment epithelium and the endothelial cells of the choriocapillaris, and its primary roles involve maintaining homeostasis of extracellular matrix and inhibiting angiogenesis (111– 113). Histopathologically, eyes with Sorsby fundus dystrophy show deposit within the Bruch’s membrane, loss of the outer retinal layers, discontinuous retinal pigment epithelium, and atrophy of the choriocapillaris (114).

Patients with Sorsby fundus dystrophy usually develop night blindness followed by central visual loss between the second and fifth decades of life (115). Bilateral central visual loss due to progressive hemorrhagic macular degeneration occurs simultaneously in both eyes in some patients but

decreased central vision in the second eye occasionally may not become noticeable for up to 10 years. Despite the fact that the number of TIMP-3 genotypes associated with Sorsby fundus dystrophy is relatively small, variable intrafamilial expressivity is common (116,117). Several authors have documented abnormal impaired dark adaptation in Sorsby fundus dystrophy (115,118,119). The dark adaptation threshold curves in Sorsby fundus dystrophy and vitamin A deficiency are similar and are prolonged with delayed initial cone dark adaptation followed by a marked prolongation of early rod adaptation (‘‘rod plateaux’’) but normal final rod threshold is eventually reached (118). Jacobson et al. (120) have shown that high oral vitamin A supplementation of 50,000 IU daily will dramatically alleviate blindness in patients with Sorsby fundus dystrophy. These findings indicate a chronic deprivation vitamin A of the photoreceptors due in part to a thickened Bruch’s membrane between the photoreceptors and its blood supply.

The diagnosis of Sorsby fundus dystrophy is based on clinical findings, family history, and genetic analysis. Older Sorsby patients with late-onset of visual symptoms may be misdiagnosed as having AMD. However, Sorsby fundus dystrophy is very rare, and TIMP-3 mutations are generally not found in patients with age-related maculopathy (121). Electrophysiologic tests are helpful in assessing retinal dysfunction.

A wide range of full-field ERG and EOG results ranging from normal to severely abnormal has been reported in patients with Sorsby fundus dystrophy due in part to differences in test methodology as well as to differences in disease severity and expressivity of the patients studied. Because rod dark adaptation is prolonged in Sorsby fundus dystrophy, a prolonged dark adaptation of 50–70 min may be helpful before scotopic ERG recordings. Full-field ERG and EOG responses are generally normal or only mildly impaired in patients with early stages of the disorder (122–124). In addition, Sieving noted normal standardized full-field ERG responses in seven affected members with age range of 35 and 64 years in a family with Sorsby fundus dystrophy from a Ser-181-Cys

TIMP-3 mutation. However, Clarke et al. (125) noted significantly reduced but not prolonged rod and cone full-field ERG responses in four of five Sorsby patients and reduced N30=P50 and P50=N95 amplitudes of the pattern ERG in three of the five patients. Further, Lip et al. (126) performed serial full-field ERG and EOG in a Sorsby patient over a period of 24 years and documented reduced ERG responses, especially the scotopic combined rod–cone response, corresponding to the onset of symptoms; a subsequent standardized full-field showed markedly reduced scotopic rod response with photopic cone flash and flicker responses at the low end of normal. In the same patient, the EOG light-peak to dark-trough amplitude ratio deteriorated to a subnormal level years before any symptoms or clinical evidence of the disease. Likewise, reduced EOG responses in Sorsby patients have also been reported by other authors (115,123,127) Lastly, although not extensively studied, multifocal ERG may be helpful to detect focal macular dysfunction in Sorsby patients, and the VEP is likely reduced in those with notable macular dysfunction.

PATTERN DYSTROPHY

Pattern dystrophy is a descriptive designation of a group of heterogeneous macular disorders characterized by retinal pigment epithelial changes of the macula ranging from pigmentary mottling to patterns of pigmentary clumping (128). Descriptive morphologic subtypes include reticular dystrophy, (129) fundus pulverulentus (130), butterfly dystrophy (131), and macroreticular dystrophy (132). Autosomal dominant inheritance is most common but autosomal recessive cases may occur. Clinical features include gradual progressive loss of central vision with visual acuity typically ranging from 20=20 to 20=70 accompanied by the development of patterns of macular pigmentary alteration. Prognosis is generally favorable, and some older patients with pattern dystrophy are likely to be diagnosed with AMD (133). Expressivity is highly variable and different morphologic subtypes are found

even within the same family (134–136). Rarely, different morphologic macular lesions may occur in the same person. For instance, a patient with vitelliform macular dystrophy in one eye and butterfly-shaped pigment dystrophy in the other eye has been reported (137).

Several mutations of the peripherin=RDS gene are associated with autosomal dominant pattern dystrophy (138,139). For example, butterfly-shaped pigment macular dystrophy has been found to be associated with a point mutation in codon 167 in one family and a two base pair deletion in another family (140,141). Further, point mutations at codon 172 of the perihperin=RDS gene are associated with progressive macular atrophy (89,90). Of interest, in a family with a deletion of codon 153 or 154 of the perihperin=RDS gene, Weleber et al. (64) documented wide phenotypic variations including RP, pattern dystrophy, and fundus flavimaculatus. Pattern dystrophy is also associated with a subtype of maternally inherited diabetes and deafness (MIDD) that cosegregates with a mutation of mitochondrial DNA—substitution of guanine for adenine at position 3242 of leucine transfer RNA (142).

Electrophysiologic testing is helpful to distinguish pattern dystrophy from other disorders such as cone dystrophy and cone–rod dystrophy. Full-field ERG is generally normal or only mildly impaired in pattern dystrophy; in contrast, the EOG light-rise to dark-trough amplitude ratio is usually reduced but not always abnormal (134,136,143–148). Central retinal dysfunction can be detected by focal ERG or multifocal ERG. Pattern ERG and pattern VEP are corresponding impaired depending on the disease severity.

X-LINKED RETINOSCHISIS

X-linked retinoschisis is an inherited disorder of retinal development characterized by splitting or schisis of the retinal nerve fiber layer at the macula. X-linked retinoschisis is unrelated to and differs from acquired retinoschsis where the schisis occurs in the middle layers of the sensory retina. In young

affected male patients, a cartwheel-shaped cystic formation at the fovea is frequently seen, which progresses to blunted foveal reflex or pigmentary atrophy in older patients. Over 50% of affected persons will develop peripheral retinoschisis, most commonly in the inferotemporal quadrant. Decrease of visual acuity begins in the first decade of life with variable progression. Visual acuity is usually decreased to between 20=50 to 20=100, ranging from 20=20 to light perception (149). Prognosis is generally good, but further deterioration of vision from macular atrophy occurs in the fourth and fifth decades of life. In addition, serious sight-threatening complications such as vitreous hemorrhage and retinal detachment occur in approximately 20% of patients (150). Of interest, a golden fundus light reflex that simulating Mizuo phenomenon of Oguchi disease may occur rarely in X-linked retinoschisis patients and may disappear after surgical removal of the posterior vitreous surface (151,152).

The disorder is caused by mutations of the X-linked retinoschisis gene, XLRS1, which encodes a protein expressed in rod and cone photoreceptor cells but not in the inner retina (153). The protein sequence contains a highly conserved discoidin domain that is implicated in phospholipid binding and cellular adhesion. Missense genetic mutations are not distributed randomly but are clustered in the discoidin domain. However, despite the genetic findings, histologic studies have suggested that the defect is located in Mu¨ ller cells (154).

The full-field ERG is a key diagnostic test in X-linked retinoschisis because the ERG has characteristic findings and fluorescein angiography is often normal. The most striking ERG finding is a selective impairment of the b-wave responses presumably due to functional deficit of the inner retinal layers (155–157). However, mild impairment of the a-wave also occurs implying some photoreceptor dysfunction (158). On standard full-field ERG, patients with X-linked retinoschisis are typically found to have impaired scotopic rod response and a selective reduced and prolonged b-wave for the scotopic combined rod–cone response such that the b- to a-wave amplitude ratio is less than 1.0 and a ‘‘negative

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ERG and VEP may show abnormalities presumably secondary to retinal dysfunction. With time, in addition to macular pigmentary atrophy, some patients may develop a diffuse pigmentary retinal degeneration with atrophy and pigment clumping that may simulate RP. At this stage, marked impairment of the ERG a-wave and b-wave may occur along with reduced EOG ratio. Of note, aside from genetic analysis, no clinical, electrophysiologic, or psychophysical abnormalities are found consistently in heterozygous carriers of X-linked retinoschisis (161).

Results form specialized ERG techniques indicate that there is a considerable impairment of the ON-bipolar cell pathway in X-linked retinoschisis. Shinoda et al. (162) using long-duration ERG light stimulus assessed the ONand OFF-responses of the photopic ERG and demonstrated considerable impairment of the ON-pathway in 11 patients with XLRS1 genetic mutations. No significant correlation was found between the ERG responses and the locus of the mutation, and the authors postulated that the defect of the on-responses is due to ON-bipolar cell dysfunction or possibly secondary to Mu¨ ller cell abnormality. In addition, Alexander et al. (163) studied the photopic cone ERG response of patients with X-linked retinoschisis with various flicker frequencies and found that the amplitudes of the ERG response were significantly reduced for frequencies of 32 Hz or higher. The impaired response at higher flicker frequencies stems in part from a predominant attenuation of the ON-bipolar cell contribution to the flicker ERG.

The multifocal ERG responses are more impaired in the central than peripheral retina in X-linked retinoschisis (164,165). Multiple areas of reduced amplitude may be present with significant reduction at the fovea (165). Delayed first-order responses and reduced second-order responses are found across the entire field suggesting a widespread dysfunction of the cone system (164).

The occurrence of foveal retinoschisis without X-linked pedigree is occasionally encountered. Such patients have disorders that are genetically distinct from X-linked

retinoschisis. For example, Lewis et al. (166) reported three female patients with familial foveal retinoschisis with mildly impaired ERG responses without a selective impairment of the b-wave. Noble et al. (167) noted foveal retinoschisis associated with rod–cone dystrophy in a brother and sister born of a consanguinous marriage. Shimazaki and Matsubashi (168) reported a mother and daughter with presumably dominant retinoschisis with a selective impairment of the b-wave and a ‘‘negative’’ ERG pattern. In another report, peripheral retinoschsis without foveal retinoschisis was found in a father and daughter with mildly impaired ERG responses without a selective impairment of the b-wave (169).

CENTRAL AREOLAR CHOROIDAL DYSTROPHY

Central areolar choroidal dystrophy refers to a heterogeneous group of disorders that is autosomal dominant or autosomal recessive and characterized by progressive loss of central vision associated with the development of a demarcated area of macular retinal and choroidal atrophy (170,171). Central areolar choroidal dystrophy has been associated with mutations of the peripherin=RDS gene (172). In addition, Lotery et al. (173,174) examined a large 3 generation kindred with autosomal dominant central areolar choroidal dystrophy and established linkage of the disease in this family to chromosome 17p. Clinical features include decreased color vision and decreased visual acuity with central visual field defect corresponding to the area of the atrophic lesion. Dark adaptation is either normal or near normal.

The diagnosis is based on clinical features, and a positive family history is helpful for autosomal dominant cases. In general, full-field ERG responses in patients with central areolar choroidal dystrophy demonstrate normal or near normal responses except for mildly impaired photopic cone responses (175–177). Progressive loss of cone b-wave amplitude parallels disease progression (178). However, in some cases of central areolar choroidal dystrophy, generalized