Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

striking ERG finding in both CSNB1 and CSNB2 is a negative full-field ERG for the scotopic bright-flash combined rod–cone response where the a-wave is preserved and the b-wave is marked reduced but not prolonged. However, in CSNB1, the scotopic rod response is non-detectable, the scotopic oscillatory potentials are absent, and the photopic cone flash and 30-Hz responses are normal or mildly reduced. In contrast, in CSNB2, the scotopic rod response is reduced but detectable, the scotopic oscillatory potentials are present but delayed, and the photopic cone flash and 30-Hz responses are reduced. Of interest, in CSNB patients with moderate to severe myopia, generalized reduction in ERG components associated with myopia may also occur and are superimposed on the CSNB ERG.

In addition to findings on standard full-field ERG, there are several other notable differences in specialized full-field ERG responses between CSNB1 and CSNB2. In CSNB1, the photopic long-duration flash response is characterized by a normal a-wave, a reduced b-wave (ON-response) and a large d-wave (OFF-response) (Fig. 9.3) (22,23). This is similar to ERG responses of monkeys after intravitreal injection of 2- amino-4-phosphonobutyric acid, a glutamate analog, which selectively blocks signal transmission from photoreceptors to ON-bipolar cells supporting the hypothesis that dysfunction of the ON-pathway is the primary defect in CSNB1 (10). In contrast, in CSNB2, the photopic long-duration flash response is characterized by a small a-wave, a relatively large b-wave with elevated plateau (ON-response) and a small d-wave (OFF-response) (Fig. 9.3). This has some similarity to ERG responses of monkeys after intravitreal injection of kynurenic acid, a glutamate analog, which selectively blocks signal transmission from cone photoreceptors to OFF-bipolar cells supporting the hypothesis that dysfunction of the OFF-path- way may be the primary defect in CSNB2 (10). Further, in CSNB1, the scotopic threshold response (STR) is not detectable, but in CSNB2 the STR is delayed and detectable at an elevated threshold than normal (24). STR is a negative scotopic wave recorded with very dim flashes and represents the initial threshold ERG response. Scotopic threshold response

originates postsynaptic to the photoreceptors and is maximal in the region of the inner plexiform layer, and impaired STR suggests proximal retinal dysfunction especially of the rod pathway. Moreover, in CSNB1, the short wavelength sensitive cone (S-cone) full-field ERG is not detectable, but in CSNB2, the S-cone ERG response is present (25). The function of the three types of cones can be tested with ERG by using wavelength-specific (i.e., spectral) stimuli. The difference in S-cone ERG response between CSNB1 and CSNB2 has been postulated to be due to the defect of the ON-pathway in CSNB1 and its effect on the predominantly ON-nature of the S-cone pathway. However, despite a non-detectable S- cone ERG, color vision is normal in CSNB1 patients, and using blue-on-yellow perimetry, Terasaki et al. (26) showed that S-cone function CSNB1 is preserved in the foveal region but is abnormal toward the peripheral retina.

Figure 9.3 (Facing page) Photopic long-duration flash responses for complete (CSNB1) and incomplete (CSNB2) forms of X-linked recessive Schubert–Bornschein congenital stationary night blindness (CSNB). The responses suggest dysfunction of the ON-path- way is the primary defect in CSNB1 and dysfunction of the OFFpathway is the primary defect in CSNB2. The response of CSNB1 has a normal a-wave, a reduced b-wave (ON-response) and a large d-wave (OFF-response) and is similar to that of monkeys after intravitreal injection of 2-amino-4-phosphonobutyric acid (APB), a glutamate analog, which selectively blocks the synapse between photoreceptors and depolarizing ON-bipolar cells. The response of CSNB2 has a small a-wave, a relatively large b-wave with elevated plateau (ON-response) and a small d-wave (OFF-response) and is similar to that of monkeys after intravitreal injection of kynurenic acid (KYN), a glutamate analog, which selectively blocks the synapse between photoreceptors and hyperpolarizing OFF-bipolar cells. Note the rod photoreceptors contact only ON-rod bipolar cells which synapse with AII-amacrine cells. The AII-amacrine cells make large gap junction with ON-cone bipolar cells and have synapses with OFF-cone bipolar cells and OFF-ganglion cells. (From Refs. 22 and 95, with permission from the Japanese Ophthalmological Society and the American Ophthalmological Society.)

In terms of multifocal ERG, in a study of four patients with CSNB1 and without nystagmus, Kondo et al. (27) found normal amplitude but delayed first-order kernels for nearly the entire field tested. The authors postulated that the delay of first-order kernels may be related to the severe amplitude reduction of the second-order kernel.

In general, heterozygous female carriers of X-linked CSNB are asymptomatic and have normal dark-adaptation retinal thresholds (28). Miyake and Kawase (28) found normal full-field ERG responses except for reduced oscillatory potentials with normal implicit times in X-linked CSNB female carriers. These findings were confirmed by Young et al. (13) who demonstrated that reduced oscillatory potentials were most apparent with a blue flash stimulus under scotopic condition. Reduced photopic 30-Hz flicker cone responses are also occasionally found in obligatory female CSNB carriers (29). Rarely, female CSNB carriers may manifest the disease and demonstrated typical CSNB ERG responses, presumably due to uneven X-chromosomal lyonization where disproportionate inactivation of the normal allele of the X chromosome occurs so that the abnormal allele is expressed in the retina (30). Affected homozygous females of X-linked CSNB have been reported (31).

Riggs Type

In 1956, Riggs (32) described three CSNB patients, two of whom were sisters, with detectable but markedly impaired dark-adaptation and full-field ERG responses consisting of reduced b-waves, which, in contrast to the Schubert– Bornschein type, remained positive with b-wave to a-wave amplitude ratios of greater than one. In 1969, Auerbach et al. (33) reported findings on 95 CSNB patients, 82 of whom were males, and classified 59 patients into the Schubert– Bornschein type and 36 patients into the Riggs type. Of the 36 CSNB patients with Riggs type, details of mode of inheritance were not available but most were males, and 12 of the patients were offsprings of consanguineous marriages. Taken together, this suggests that the Riggs type is likely inherited

as X-linked recessive or autosomal recessive. In the same study, the authors found that myopia and nystagmus were less common in Riggs type patients than Schubert– Bornschein type patients.

Although often mentioned as a distinct type of CSNB, the Riggs type is rare as no large series of Riggs type patients have been reported since Auerbach et al. (33) in 1969. Miyake and Kawase (28) have suggested that the scotopic b-wave ERG responses of incomplete type Schubert–Bornschein CSNB patients do not become negative until stronger stimulus intensity, and under lower stimulus intensities, incomplete type Schubert–Bornschein CSNB patients have reduced but positive b-wave ERG responses which resembles those responses described by Riggs. Therefore, at least some of the incomplete type Schubert–Bornschein CSNB patients are likely to have the same clinical entity as the Riggs type.

Autosomal Dominant CSNB

In addition to the rare autosomal dominant Schubert– Bornschein type, several other pedigrees of autosomal dominant CSNB have been described. The Nougaret type derives its name from the first recognized affected individual, Jean Nougaret (1637–1719), a butcher who lived in Vendemian in Southern France (34). Dryja et al. (35) found that affected descendants have a heterozygous missense mutation (Gly38Asp) in the gene encoding the a-subunit of rod-specific transducin, the G-protein that couples rhodopsin to cGMP-phosphodies- terase in the phototransduction cascade. Sandberg et al. (36) noted non-detectable scotopic full-field ERG responses to dim blue flash in a father and son with Nougaret CSNB, implying that the standard scotopic dim white-flash rod response may also be non-detectable. The scotopic white bright-flash combined rod–cone responses demonstrated decreased biphasic a-wave with a b-wave amplitude that was positive and at least 50% of normal indicating that the loss of rod function was not complete. The cone responses were only slightly impaired. These Nougaret CSNB ERG findings are similar to the ERGs described for the Riggs CSNB

type. The EOG light-peak to dark-tough amplitude ratios were only mildly decreased and ranged from 1.4 to 2.0 (normal 1.8). Taken together, the results suggest that these abnormalities can be simulated by light-adapting the normal retina and are compatible with the proposal that the defective rod transducin is constitutively active in darkness but produces partial desensitization of rods.

Another type of autosomal dominant CSNB was described by Rambusch in 1909 in a Danish family (37). The ancestor of the Rambusch pedigree is Niels Sorensen, a farmer who was born about 1660. Gal et al. (38) found that affected descendants have a heterozygous missense mutation (His258Asp) in the gene encoding the b-subunit of the rod cGMP phosphodiesterase. Full-field ERG responses of affected individuals of the Rambusch pedigree are similar to those of Nougaret CSNB type and resembles the ERG responses of the Riggs CSNB type. Rosenberg and colleagues (37) noted non-detectable scotopic full-field ERG responses to dim blue flash in six affected descendents indicating that the standard scotopic dim white-flash rod response may also be non-detect- able. The scotopic white bright-flash combined rod–cone responses demonstrated moderately decreased a-waves and more pronounced b-wave depressions but the b-waves were usually positive or nearly equal to the amplitudes of the a-waves. Cone responses were normal or only slightly impaired. The authors also reported one descendent who seemed to be affected in one eye only with reduced rod and cone full-field ERG responses and a normal ERG in the other eye.

Several types of autosomal dominant CSNB associated with rhodopsin mutations have been described. Dryja et al. (39) noted a heterozygous missense mutation (Ala292Glu) of the rhodopsin gene in a 34-year-old man with CSNB. The patient showed no scotopic full-field ERG rod response to dim blue flash and reduced a-wave and b-waves with shortened implicit times for the scotopic white bright-flash combined rod–cone response. The cone 30-Hz white-flash flicker response was at the low end of normal.

Sieving et al. (40) reported a rhodopsin mutation (Gly90Asp) in a 22 member kindred with autosomal dominant

CSNB. All seven affected individuals had no scotopic full-field ERG rod response to dim blue flash. The cone flash and 30-Hz flicker responses were normal in all but one person. The results of the scotopic white bright-flash combined rod–cone response were not reported.

Another rhodopsin mutation (Thr94Ile) associated with autosomal dominant CSNB was described by al-Jandal et al. (41) in an Irish family. All affected persons had no scotopic full-field ERG rod responses. The scotopic white bright-flash combined rod–cone responses showed moderately reduced a- waves and markedly reduced b-waves that were severe enough to produce a negative b-wave but the b-wave implicit time was shorter than normal. However, the negative ERG in this case differs from Schubert–Bornschein CSNB types in that the a-wave in the latter is near normal rather than reduced. Other ERG features of this rhodopsin phenotype include well-preserved oscillatory potentials and normal photopic flash and 30-Hz flicker cone responses. The authors hypothesized that constitutive activation of transducin by the altered rhodopsin may be the mechanism of this type of autosomal dominant CSNB.

Other CSNB Types

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Affected patients with Aland Island eye disease may have

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similar ERG findings as incomplete CSNB. Aland Island eye disease is X-linked recessive and was described by Forsius and Eriksson in 1964 (42). Clinical features include ocular albinism, myopia, and nystagmus. Genetic changes asso-

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ciated with both Aland Island eye disease and incomplete CSNB are located in the same region of the X chromosome, and the question of whether the two disorders are one and the same has been raised (43).

Barnes et al. (44) described a distinctive form of CSNB with cone ON-pathway dysfunction in a 30-year-old man whose mother had retinitis pigmentosa. In this case, the scotopic rod full-field response was non-detectable and the scotopic combined rod–cone response had markedly reduced a-wave with a severely diminished negative b-wave.

EOG and VEP in CSNB

While the full-field ERG is a key diagnostic test in CSNB, EOG and VEP have no proven diagnostic value in CSNB. Of interest, the EOG light-peak to dark-trough amplitude ratio in CSNB may be normal or reduced (45–47). In terms of VEP, Tremblay et al. (48) found crossed visual evoked potential asymmetry in patients with CSNB2 indicating excessive decussation of retinal ganglion cell fibers at the optic chiasm. This finding not only implies impaired binocularity in CSNB2 but also demonstrates that this finding which is also found in albinism is not to be considered as pathognomonic for albinism.

Fundus Albipunctatus

Fundus albipunctatus is a rare autosomal recessive disorder characterized by impaired night vision and numerous small discrete white-yellow retinal lesions scattered throughout the retina except the fovea. This disorder is caused by mutations in the RDH5 gene (chromosome 12q13–14) which encodes the enzyme 11-cis retinol dehydrogenase (49). The enzyme expressed in the retinal pigment epithelium has an important role in the synthesis of rhodopsin by catalyzing the conversion of 11-cis retinol to 11-cis retinal with cofactor NADþ. Missense mutations (e.g., homozygous Gly238Trp, compound heterozygous Gly238Trp and Ser73Phe) of the RDH5 gene are associated with fundus albipunctatus. In addition, a homozygous one base deletion with four base insertion (1085delC=insGAAG) in the RDH5 gene may be the cause of fundus albipunctatus in most Japanese patients (50). The resulting defect in the enzyme 11-cis retinol dehydrogenase produces a prolonged regenerative cycle of visual pigment (51).

Because impaired night vision is congenital, affected persons may or may not be symptomatic. However, the numerous small discrete white-yellow retinal lesions are easily recognized on routine ophthalmic examination (Fig. 9.4). Visual acuity and fields are normal but are reduced if tested with dim stimulus. The retinal lesions evolve in appearance from

Figure 9.4 Small discrete white-yellow retinal lesions in a patient with fundus albipunctatus. The lesions spare the fovea and are scattered throughout the retina. (From Ref. 96.) (Refer to the color insert.)

flecks in childhood to permanent punctate dots that increase in number over years (52). The optic nerve heads are normal, and there are no apparent abnormality of the retinal vessels.

Although Marmor (52) found that long-term follow-up of patients with fundus albipunctatus showed no progression of dysfunction, Nakazawa et al. (53) have demonstrated that progressive cone dystrophy is frequently observed in elderly patients with fundus albipunctatus. Of the 12 patients with fundus albipunctatus and RDH5 gene mutations studied by Nakazawa, six had progressive cone dystrophy which was most frequently seen in patients over age 40. In another study of 21 patients with fundus albipunctatus, 10 patients had macular dystrophy (54). Therefore, approximately 50% of patients with fundus albipunctatus are likely to have macular dystrophy.

Dark adaptometry or full-field ERG or both are extremely helpful if not essential in the clinical diagnosis of fundus albipunctatus and in differentiating this disorder form other more progressive retinal white dot disorders such as retinitis punctata albescens. Dark adaptometry shows prolonged cone and rod adaptation with delayed cone–rod transition but