Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

reduced. In later stages, when the fundus has a “scrambled-egg” appearance, the PERG and P.VEP show mild amplitude abnormalities. Thus, the EOG is very valuable when testing for this condition. Usually, it is markedly subnormal from the onset (when ERG is wholly normal), and is valuable in identifying carriers in whom it is of subnormal size.

Stargardt’s disease (STGD) is a macular dystrophy with an autosomal recessive mode of transmission. Bilateral visual loss usually occurs over a period of several months. Fundus flavimaculatus with macular involvement shows a more gradual visual loss in the second to third decade and maps to the same gene locus. These conditions display variable ERG abnormalities, loosely related to the severity of disease process and the fundal appearance. Some patients show additional marked involvement of cones, and others can show rod involvement.133 In the early stages when acuity is mildly decreased, both the flash ERG and the EOG are likely to be normal. However, the PERG and P.VEP are likely to show mild abnormalities, as they more specifically test macular pathway function. Patients with retinal flecks (26/46) had a slightly greater incidence of flash ERG abnormalities, compared with patients without flecks (20/46).206 Kretschmann et al.110 have shown that, in Stargardt’s disease, the multifocal ERG is more sensitive than the full-field flash ERG in demonstrating foveal dysfunction, at a stage before acuity or fundus signs are apparent. In advanced cases with poor acuity, the PERG is generally attenuated and P.VEP is usually attenuated and marginally delayed.131 Mutations of the ABCR gene appear to be responsible for STGD/fundus flavimaculatus, autosomal recessive RP, and cone/rod dystrophy. Interestingly, an additional locus for Leber’s amaurosis has been identified in a highly inbred family, mapping to chromosome 6, which is close to the loci for Stargardt’s disease and Northern Carolina macular dystrophy.72

Inner Retinal Dysfunction and

the “Negative” ERG

The normal bright-flash mixed rod/cone ERG has a b-wave that is 1.5- to 2-fold the size of the a-wave. When the b-wave amplitude is markedly attenuated or not detectable, the mixed ERG has a larger than average a-wave, as it is not partly reduced by the early phase of the electropositive b-wave activity. This a-wave-dominated ERG is described as a “negative” ERG

and, when associated with X-L CSNB, some authors name it Schubert–Bornschein. The negative ERG morphology indicates preserved photoreceptor activity and dysfunction of the inner retina layers, usually affecting the bipolar and Müller cells (Fig. 1-5).

The negative ERG is associated with the following clinical conditions:

•X-linked CSNB145

•X-linked retinoschisis25

•Infantile and juvenile neuronal ceroid lipofuscinosis227

•Duchenne’s muscular dystrophy39

•Early RP in a subset of RP patients41

•Bull’s eye maculopathy146

•Cone dystrophies105

Negative ERGs also occur in association with birdshot retinopathy, CRVO, and melanoma-associated retinopathy (MAR IgG circulating antibodies130). Lachapelle et al.121 reported a family in which 4 of 11 children had cone dystrophy and a negative photopic ERG, mainly ascribed to absence of OP4. In CSNB,

FIGURE 1-5. Negative ERGs: first column, from a 5-year-old patient with X-L congenital stationary night-blindness (CSNB); second column, from a 5-year-old with X-L retinoschisis; third column, normal morphology trace. It is noticeable that the CSNB patient does not appear to have any b-wave activity whereas there is some attenuated activity in the retinoschisis patient. The very poor pattern reversal VEP indicates macula pathway involvement in the patient with retinoschisis and suggests poor vision. In CSNB, the pattern reversal VEP (P.VEP) is better preserved but marginally delayed.

OP2 and OP3 are selectively abolished. Recently, Fitzgerald et al.57 described three generations of a family all of whom had nystagmus, moderate myopia, and visual developmental delay. They all produced negative ERGs but, interestingly, compared to Duchenne’s muscular dystrophy patients, there was no clinical evidence of night blindness or fundal abnormalities.

CONGENITAL STATIONARY NIGHT BLINDNESS (CSNB)

Patients with dominant CSNB (also called Nougaret type) have near-normal cone-mediated ERGs, but rod-mediated ERGs are not usually detectable. In autosomal recessive CSNB (Riggs type) without myopia and fundus albipunctatus, both rod and cone pigment take a long time to regenerate after bleaching by light. The flash ERG and EOG attain normal amplitudes only after very long periods of dark adaptation, sometimes as long as 3 h, compared with 20 min for normal rod function. This feature is distinct from that encountered in autosomal recessive Oguchi’s disease, where the rod-mediated flash ERG is of normal size and configuration for the first couple of flashes or so but then attenuates markedly. The cone ERG is normal.143

In X-linked CSNB, there is a functional deficiency affecting the ON-rod pathway. X-L CSNB is commonly associated with myopia greater than 4 diopters. The P.VEP tends to be of normal, or marginally increased latency; however, it is often smaller than average,124 which may be partly due to the nystagmus that is frequently present in these patients, although subtle abnormalities affecting the cone system have also been reported for this condition.

Miyake et al.145 have subdivided X-linked CSNB into two types: complete CSNB and incomplete CSNB. Patients with incomplete CSNB show a small positive rod ERG to dim flash, negative bright-flash mixed rod/cone ERG, delayed but intact rod-mediated oscillatory potentials (OPs), nondetectable photopic OPs, and attenuated cone and flicker ERGs. Indeed, cone function appears to be more deleteriously affected than in complete CSNB.144,219 OPs 2 and 3 are commonly not detectable in patients with complete CSNB.121 Complete CSNB is characterized by near-normal cone ERGs, but negative brightflash ERGs and very attenuated negative rod ERGs have been recorded.122

These CSNB subtypes have a different genetic basis. Incomplete CSNB has been linked with mutations affecting specific

calcium channel alpha-1 subunit (CACNA1F) in a retina.24,151 Complete CSNB is related to mutations involving nyctalopin and is postulated to disrupt development of retinal bipolar connections.17 Incomplete CSNB and Aland Island eye disease lie within the same gene interval, Xp11.23–p11.22, and there is a suggestion that the two conditions are allelic.89

X-LINKED RETINOSCHISIS

X-linked juvenile retinoschisis is a vitreoretinal disorder in which there is vitreous degeneration and a separation within the retinal nerve fiber layer. Both central and peripheral fundal areas are affected. Radial (cartwheel-like) folds consisting of perifoveal microcysts with radiate plications of overlying internal limiting membrane are commonly seen around the fovea. The cysts tend to coalesce with time, followed by pigmentation and atrophy. Mechanical separation of the inner layer affects retinal function and leads to selective attenuation of the b-wave. X-linked retinoschisis patients usually show a negative ERG to a bright flash and attenuated rodand cone-mediated ERGs. Interocular ERG and VEP are not uncommon. P.VEPs are frequently delayed, depending on the fovea involvement. Bradshaw et al.25 reported considerable heterogeneity of ERG response without clinical, age, or genetic correlates in 19 patients. They suggest retinal function is relatively stable throughout life, and found abnormal a-waves suggesting some receptor involvement as well. Sieving et al.192 have cautioned that it is possible to have a normal flash ERG in the presence of known X-L juvenile retinoschisis mutation, XLRS1 Arg213Trp. They report a grandfather and grandson, each showing characteristic fundoscopic macular changes, but a negative ERG was recorded from the grandfather. The grandson produced normal ERGs. Retinoschisis with both clinical and electrophysiological features can occur in females.

DUCHENNE’S MUSCULAR DYSTROPHY

The majority (65%–100%) of patients with Duchenne’s muscular dystrophy and Becker muscular dystrophy (the milder form of Duchenne’s) can produce a negative ERG for bright flash stimulation delivered under scotopic condition and markedly attenuated or nondetectable rod-mediated ERGs.39 Interestingly, there is no effect on dark adaptation, suggesting the defect relates to truncation or absence of retinal glia dystrophin affecting ERG generation but not the direct neural pathway.100 The presence of

increased macular pigmentation and normal photopic ERGs distinguished in patients with Duchenne’s muscular dystrophy mutations separates them from other X-linked retinal disorders with negative-shaped ERGs (e.g., iCSNB).58,194 The authors have not found any ERG abnormalities in patients with merosinpositive or -negative congenital muscular dystrophy.

NEURONAL CEROID LIPOFUSCINOSIS

(NCL OR BATTEN’S DISEASE)

All four childhood-onset forms of Batten’s disease are inherited by autosomal recessive transmission and are associated with retinal degeneration, severe visual failure, and nondetectable flash ERG at advanced stages. However, in early stages of both infantile and juvenile Batten’s disease, patients can have negative ERGs before the ERG becomes finally extinguished.227 In both conditions, the flash VEP is commonly not detectable. In late infantile Batten’s Disease, the “flash VEP” is reported to be markedly enlarged, from 12 to 20 times larger than normal.83 However, this response may not be true occipital VEP, as each flash elicits what appears to be “epileptic-like” activity with different morphology and distribution to a normal VEP (analogous to the very large myoclonic response following somatosensory stimulation).116 In the early stages, the cone b-waves are severely attenuated and markedly increased in b-wave latency. The rod responses are mildly abnormal, but more preserved than in infantile NCL or juvenile NCL. In Kuf’s disease, the adult form of Batten’s disease, the flash ERG and VEP are normal.227

Vitreoretinal Disorders

X-linked retinoschisis is characteristically associated with a negative ERG and has been discussed previously.

GOLDMANN FAVRE SYNDROME

This syndrome is an autosomal recessive condition that may present in the second and third decade. The flash ERGs are markedly attenuated, the EOG is subnormal, and flash VEPs are attenuated and degraded. It has been suggested that the rare “enhanced S-cone sensitivity” (ESCS) syndrome may fall within the spectrum of Goldmann Favre syndrome, as the retinal appearance is similar with yellowish retinal pigment epithelial lesions in the region of the retinal vascular arcades.138 ESCS is

characterized by night blindness and cystoid maculopathy, and both scotopic and photopic ERGs are of similar morphology characterized by a large slow response.138 ESCS is thought to be caused by a mutation of the nuclear receptor gene NR2E3 that drives pluripotent cells into S-cones.77

WAGNER’S VITREORETINAL DEGENERATION AND

EROSIVE VITREORETINOPATHY

These diseases are both allelic autosomal dominant conditions manifesting as atrophy of the RPE, with choroidal and lenticular changes that distinguish them from Stickler’s syndrome. Patients have poor night vision and attenuated ERGs.

STICKLER’S SYNDROME

This syndrome is a dominantly inherited disorder of collagen connective tissue causing an abnormal vitreous, myopia, variable orofacial abnormality, deafness, and arthropathy. Almost two-thirds of the families affected by Stickler’s syndrome have mutations in type 2 procollagen (COL2A1).199 COL2A1 is present in the vitreous. The flash ERG changes appear to be directly proportional to the extent of retinal detachment and myopic fundal changes.

DIAGNOSTIC APPLICATIONS OF PERG

The combination of flash ERG and P.VEP can indicate if the macular pathway is compromised. The PERG can further help to distinguish macular retinal dysfunction from postretinal macula pathway dysfunction. PERGs are most frequently used to investigate possible early maculopathies (e.g., Stargardt’s). The P50 component is expected to be attenuated in these circumstances. Attenuation of the P50 component is also reported in diabetes, central serous retinopathy, and age-related maculopathy, whereas the N95 reflects more proximal retina and is abnormal in optic nerve dysfunction51,90 (e.g., optic neuritis, optic nerve compression, and optic atrophy associated with Leber’s optic neuropathy) linked with 11778 mutations and with dominant optic atrophy linked with OPA1 locus 3q abnormalities. These abnormalities can be present before clinical signs are evident.90 Usually, the ratio N95/P50 amplitude is greater than 1.

DIAGNOSTIC APPLICATIONS OF EOG

A main indication for an EOG in young children is to investigate the possibility of Best’s disease maculopathy. Here the ERG is likely to be normal, but the EOG will be conspicuously abnormal. This picture contrasts with established Stargardt’s disease, RP, and myopic choroidal degeneration, in which both the EOG and ERG are abnormal. If there is severe RPE photoreceptor dysfunction, then the EOG can be too small to record eye movements. Recently, Arden and Wolf10 have described how alcohol directly affects the RPE to elicit the same voltage changes as produced by light. In patients with RP, both light rise and alcohol rise are diminished, suggesting that secondary abnormalities of RPE function have occurred in these RP patients.

DIAGNOSTIC APPLICATIONS OF VEP

It is worth briefly stressing again that there are overwhelming advantages, particularly in pediatric practice, to record both the ERG and VEP together in diseases that affect the retina or ocular structures anterior to the retina. By these means, it is possible to gauge deleterious involvement of macular and extramacular areas and to obtain an indication of the quality of macular pathway function, including acuity levels. The pattern VEP indicates the functioning of the postretinal macula pathway and optic nerve. Thus, the presence of a pattern VEP with an attenuated ERG indicates relative preservation of the macula region.

Ocular Opacities

Bright flashes usually penetrate all but the densest ocular opacities, and flash VEPs and ERGs are particularly valuable when ocular opacities prevent adequate ophthalmoscopic visualization of the perimacular fundus.223,228

CORNEAL OPACITY

Mucopolysaccharidoses and homocystinuria are associated with corneal opacification. The flash ERG can help in gauging the degree of retinal dysfunction, often before retinal pigmentary changes are apparent, and the VEP (particularly those to pattern