Ординатура / Офтальмология / Английские материалы / Electrodiagnosis of Retinal Disease_Miyake_2005

References

1.Wright WD (1952) The characteristics of the tritanopia. J Opt Soc Am 42:509–521

2.Terasaki H, Miyake Y, Awaya S, Horio N (1995) Visual functions of dominantly inherited juvenile optic atrophy. Acta Soc Ophthalmol Jpn 99:964– 971

3.Krill AE, Smith VC, Pokorny J (1970) Similarities between congenital tritan defects and dominant opticus-atrophy: coincidence or identity? J Opt Soc Am 60:1132–1139

4.Krill AE, Smith VG, Pokorny J (1971) Further studies supporting identity of congenital tritanopia

and hereditary dominant optic atrophy. Invest Ophthalmol 15:457–465

5.Miyake Y, Yagasaki K, Ichikawa H (1985) Differential diagnosis of congenital tritanopia and dominantly inherited juvenile optic atrophy. Arch Ophthalmol 103:1496–1501

6.Weitz CJ, Miyake Y, Shinzato K, Montag E, Zrenner E, Went LN, Nathans J (1992) Human tritanopia associated with two amino acid substitutions in the blue-sensitive opsin. Am J Hum Genet 50:498–507

7.Votruba M, Moore AT, Bhattacharya SS, et al. (1997) Genetic refinement of dominant optic atrophy (OPA1) locus to within in a 2 CM interval of chromosome 3q. J Med Genet 34:117–121

Some unusual forms of retinal dysfunction have been reported that involve the cone and the rod photoreceptor systems in an extraordinary way. With the rod–cone dysfunction syndrome, there is decreased sensitivity to light while at the same time its responsiveness to superthreshold light stimuli is enormously augmented [1–3].

This unusual combination is illustrated in three of our patients [4]. A 15-year-old girl (case 1), an 11-year-old girl (case 2), and a 32- year-old woman (case 3) had low visual acuity of 0.1–0.4 with moderate to high myopia from birth. The family history was negative in the three patients. Night blindness was detected by dark-adaptation curves with elevation of the final rod thresholds by 1.5–2.3log units. The visual fields were almost normal except for slight constriction with small and dim targets. The color vision was markedly abnormal, with a scotopic pattern similar to that of rod monochromats. The fundus and fluorescein angiograms are essentially normal (Fig. 2.120), except for bull’s-eye maculopathy in case 1 and slight optic atrophy in case 3. We have followed two of these patients for more than 10 years, and the clinical condition has not changed (i.e., it is stationary).

The standard full-field ERGs recorded from these three patients are shown in Fig. 2.121. Compared with the results of age-matched normal young subjects, the amplitude of the scotopic (rod) ERG was markedly reduced, and the implicit time was delayed. The photopic (cone) and 30-Hz flicker ERGs were almost undetectable. The bright-flash mixed rod–cone ERG was markedly altered; the a-wave had a

step-like configuration, the OPs were reduced, and the b-wave amplitude was supernormal.

The changes in the ERGs elicited by white flash stimuli of various intensities are shown in Fig. 2.122. Despite the undetectable b-wave recorded with dim stimuli, the b-wave became supernormal when recorded with stronger stimuli. The most remarkable aspect of this disorder is demonstrated in Fig. 2.122. The threshold, amplitude, and waveform of the flash ERGs are abnormal. The stimulus threshold is elevated by approximately 3.5log units in all patients; but as the intensity of the stimulus is increased, the responses become larger in an extraordinary fashion. When the stimulus is high, the a-wave has been almost step-like in its waveform, and its amplitude is smaller than normal. On the other hand, the b-wave is supernormal with a normal implicit time.

The ERG findings of this disorder are somewhat similar to those of the enhanced S-cone syndrome (i.e., markedly reduced or absent rod and 30-Hz flicker ERGs, supernormal b-wave, and step-like a-wave. However, the definitive differences are the markedly reduced or undetectable photopic (cone) and blue-cone ERGs.

It is possible experimentally to produce changes similar to those observed in these patients by increasing the intracellular cyclic guanosine monophosphate (cGMP) in rods in several ways. These experimental conditions produce an increase in the amplitude, prolongation in the time course, and steepening of the intensity-response curve of the rod photoreceptor responses [5].

These experimental results may provide the key to solving the unique paradox of the

elevated subjective dark-adapted thresholds associated with the supernormal responses in bright flash ERG in the dark-adapted condition. However, we have measured the cyclic

nucleotide levels in the blood and urine of these patients, and our results did not show any significant abnormality, although the values were slightly higher than normal.

References

1.Abraham FA, Sandber MA (1977) An unusual type of juvenile foveal dystrophy: electrophysiologic study. Doc Ophthalmol Pro Series 11:75–83

2.Alexander KR, Fishman GA (1984) Supernormal scotopic ERG in cone dystrophy. Br J Ophthalmol 68:69–78

3.Gouras P, Eggers HM, MacKay CJ (1983) Cone dystrophy, nyctalopia, and supernormal rod responses: a new retinal degeneration. Arch Ophthalmol 101: 718–724

4.Yagasaki K, Miyake Y, Litao RE, Ichikawa K (1986) Two cases of retinal degeneration with unusual form of electroretinogram. Doc Ophthalmol 63:73– 82

The hereditary eye diseases associated with the negative-type ERG (a-wave larger than b-wave) with normal a-wave amplitude are congenital stationary night blindness, X-linked congenital

retinoschisis, and Batten disease. Two additional conditions whose etiology is still uncertain are described in this section.

In 1989 we reported four male patients [1] who had bull’s-eye maculopathy and an otherwise normal fundus except for a dark choroid seen on fluorescein angiography in one patient (Fig. 2.123). The bright flash, mixed rod–cone ERG in the dark was made up of a normal a-wave but the b-wave that was reduced and smaller than the a-wave (Fig. 2.124). The full-field rod ERGs were moderately reduced, and the cone and 30Hz flicker ERGs were relatively well preserved (Fig. 2.125). Other findings common to all four patients were moderately low visual acuity (normal visual acuity initially), mild to moderate color vision deficiency, normal peripheral visual fields, normal EOGs, near-emmetropia, and appearance predominantly in men.

Recently, molecular genetic examinations were performed in all patients, and one patient (case 2) had a novel missense mutation, Ala101Pro (c.301G to C) in the XLRS1 gene, which was identified from his genomic DNA. He was thus diagnosed as having X-linked retinoschisis. Although bull’s-eye maculopathy is rarely associated with X-linked retinoschisis, we should consider the possibility of this disorder when bull’s-eye maculopathy is associated with negative ERGs. We could not find any mutation in the other patients. Case 1 showed a dark choroid,which is often seen with Stargardt disease, but no mutation of the gene associated with Stargardt disease was detected.

Fig. 2.123. Fluorescein angiograms of four patients with bull’s-eye maculopathy and negative ERGs. Case 1 shows a dark choroid. Case 4 was diagnosed as having X-linked congenital retinoschisis by molecular genetic examinations. (From Miyake et al. [1], with permission)

Fig. 2.124. Mixed rod–cone ERGs elicited by a bright flash recorded from a normal control and the four patients whose fluorescein angiograms are shown in Fig. 2.123. (From Miyake et al. [1], with permission)

Earlier investigators reported that negative ERGs were rarely associated with optic nerve atrophy because patients with the inherited forms of optic atrophy had been reported to have normal ERG findings [2]. The optic atrophy was assumed to occur from transsynaptic degeneration of the bipolar cells.

In 1992, in collaboration with Richard Weleber of Portland, Oregon, we found that the affected members of two families with presumably autosomal dominant optic atrophy also had negative-type ERGs (Fig. 2.126) [3]. They had poor central vision, and the decrease occurred during the second to third decade of life. Ophthalmological examinations showed that the affected members had visual acuities of 1.0–0.4, defective color vision, mild to moderate myopia, and pericentral or centrocecal scotomas. Optic atrophy was found in four of the five patients (Fig. 2.127). The age of the affected members ranged from 21 to 56 years (mean 42 years).

The amplitude of the a-wave of the full-field ERGs (Fig. 2.128) and the scotopic rod–cone ERGs were normal, but the amplitude of the b- wave was markedly reduced. The amplitudes of the rod responses were moderately reduced but with normal implicit times. The amplitudes of the b-wave of the photopic ERGs varied from normal to mildly reduced, and the implicit times were normal. The amplitudes of 30-Hz flicker ERGs were normal.

The moderately low visual acuity of these patients may be caused by optic atrophy or some macular problem. The essentially normal focal macular ERGs suggest that the low visual acuity is caused by optic nerve dysfunction. Because negative ERGs are not seen with other familial optic atrophies, we concluded that this disease, with an association of optic atrophy and abnormal negative ERGs, represented a new genetic disorder.

References

1.Miyake Y, Shiroyama N, Horiguchi M, Saito A, Yagasaki K (1989) Bull’s eye maculopathy and negative ERG. Retina 9:210–215

2.Yagasaki K, Miyake Y, Awaya S, Ichikawa H (1986) ERG (electroretinogram) in hereditary optic atrophy. Acta Soc Ophthalmol Jpn 90:124–130

Fig. 2.128. Full-field ERGs recorded from a normal control and three patients (cases 1, 2, and 3) examined in Nagoya, Japan (A); and two patients (cases 4 and 5), a patient with complete CSNB, and a normal control examined in Portland, Oregon, USA (B). A Rod ERGs are subnormal, and mixed rod–cone (bright white) ERGs have the shape of the negativetype ERG. The OPs are reduced. The cone and 30-Hz flicker ERGs are normal. B The blue light was scotopically balanced with the red light for production of equal-amplitude rod responses. Note that the rod b-waves responses to dim white light and dim blue light were subnormal for both patients and nearly undetectable for the patient with complete CSNB. The cone-mediated ERGs were normal. (From Weleber and Miyake [2])

3.Weleber RG, Miyake Y (1992) Familial optic atrophy with negative electroretinograms. Arch Ophthalmol 110:640–645