Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

Age-related macular degeneration

Macular degeneration—autosomal dominant, recessive

Central serous chorioretinopathy

Doyne honeycomb retinal dystrophy=malattia leventinese

Stargardt macular dystrophy—fundus flavimaculatus

Best vitelliform macular dystrophy

Cone dystrophy

Central cone dystrophy (occult macular dystrophy)

Peripheral cone dystrophy

Cone dystrophy with supernormal and delayed rod ERG (supernormal and delayed rod ERG syndrome)

Sorsby fundus dystrophy

Pattern dystrophy

X-linked retinochisis

Central areolar choroidal dystrophy

North Carolina macular dystrophy (central areolar pigment epithelial dystrophy)

Progressive bifocal chorioretinal atrophy

Fenestrated sheen macular dystrophy

Familial internal limiting membrane dystrophy

AGE-RELATED MACULAR DEGENERATION

Age-related macular degeneration (AMD), also known as agerelated maculopathy or senile macular degeneration, is one of the leading causes of blindness. Age-related macular degeneration usually affects persons over age 50 years and the incidence increases with age. Age-related macular degeneration is more prevalent among Caucasians than among blacks. Both environmental and genetic factors are involved in the pathogenesis of AMD. Clinical features include macular drusen, pigmentary changes, and geographic atrophy of the retinal pigment epithelium and choriocapillaris. In addition, the disease may progress with further loss of central vision from neovascular maculopathy characterized by choroidal neovascularization, serous or hemorrhagic detachment of the sensory retina or pigment epithelium, lipid exudates, and

subretinal and fibrovascular proliferation with scar formation. The diagnosis of AMD is based on clinical examination with the aid of angiography to assess neovascularization. Treatments include high-dose oral antioxidant, vitamin, and mineral supplementation, focal laser photocoagulation, and photodynamic therapy involving systemic administration of a photosensitizing drug followed by nonthermal laser application.

Electrophysiologic tests are not routinely performed clinically in the setting AMD. Focal macular ERG or multifocal ERG may be helpful to detect macular dysfunction when signs of AMD are mild and not readily apparent or when decrease in visual acuity is out of proportion to retinal appearance and angiographic findings. Because AMD is primarily a macular disease, full-field ERG, EOG, and dark adaptation are generally normal after taking into account the effects of aging (1–3). Mild impaired EOG and full-field ERG in AMD have also been described and are more pronounced in those with greater area of retinal destruction (4,5). In one report, the photopic 30-Hz full-field ERG cone response was found to be reduced in patients with AMD compared to control subjects suggesting extra-foveal involvement at least in some patients (6). Slow rate of dark adaptation and abnormal color matching may occur in eyes whose fellow eye has exudative AMD (7).

Focal macular ERG and multifocal ERG are useful objective measures of macular dysfunction in AMD (Fig. 10.1) (8–13). Reduced foveal ERG amplitude and prolonged latency are found in pre-AMD or early AMD eyes as well as their asymptomatic fellow eyes (13,14). Both focal macular ERG and multifocal ERG have been used as an outcome measure in clinical treatment trials for AMD (15,16). Pattern ERG may also serve as an objective measure of macular function in AMD (8).

MACULAR DEGENERATION—AUTOSOMAL

DOMINANT, RECESSIVE

Aside from AMD, distinct autosomal dominant or recessive forms of macular degeneration are recognized. Compared to

Figure 10.1 Multifocal ERG of a normal subject and a patient with dry AMD. The first-order trace arrays of the right eyes are shown. Note the impaired responses centrally caused by geographic atrophy of the retina.

patients with AMD, these affected patients are generally younger and demonstrate clinical and genetic heterogeneity. For instance, while several mutations of the peripherin=RDS gene are associated with autosomal dominant retinitis pigmentosa, some genotypes (Arg172Trp, Tyr258Stop, Gly167Asp) cause macular dystrophy. Likewise, mutations of the human retinal fascin gene (FSCN2) cause retinitis pigmentosa (RP) or macular degeneration. In patients with autosomal dominant macular degeneration, the full-field ERG cone responses range from normal to reduced and delayed while the rod responses are normal or near normal (17–19).

CENTRAL SEROUS CHORIORETINOPATHY

Central serous chorioretinopathy is a disorder characterized by focal retinal detachment of the macula with focal accumulation of serous fluid between the photoreceptor layer and the retinal pigment epithelium. The focal retinal detachment may be preceded or overlying a smaller retinal pigment epithelium detachment, which is a separation between the retinal pigment epithelium and Bruch’s membrane. Fluorescein angiography typically shows focal leakage of fluid at the retinal

pigment epithelium into the retinal detachment. Other names for the same disorder include central serous retinopathy and idiopathic central serous chorioretinopathy. Symptoms are usually unilateral and include metamorphopsia, micropsia, and a relative central scotoma. Over weeks to months, the retinal detachment resolves and visual function improves but recurrences are not uncommon. Despite the fact that the symptoms are often unilateral, some retinal pigment epithelium changes are also often seen in the contralateral eye. Pathogenesis is unknown but is more likely to involve broad dysfunction of the retinal pigment epithelium transport system rather than just a focal source of retinal pigment epithelium leakage. The condition affects young or middle-aged adults with men more frequently affected than women. Recent stress and type A personality may be associated with the disorder.

The diagnosis of central serous chorioretinopathy is usually made on the basis of characteristic clinical features and fluorescein angiographic findings. Focal macular ERG or multifocal ERG may be helpful as a measure of retinal function. As expected, focal macular ERG responses are impaired in central serous chorioretinopathy (20–23). Miyake et al. (21) performed focal macular ERG using a 10 size stimulus on 24 patients and found that the a-waves and b-waves were reduced and prolonged in the affected eye as compared to the fellow eye during the active as well as the recovering phases of the disease. B-wave and oscillatory potentials were significantly more deteriorated than a-wave, and the investigators theorized that the disorder may involve functional disturbances in the inner retinal layer as well as the photoreceptors. Using multifocal ERG, Marmor and Tan (20) showed broad retinal function disturbance involving both the affected and unaffected eyes in patients with central serous chorioretinopathy (Fig. 10.2). Furthermore, multifocal ERG impairment was found in areas beyond the zone of the retinal detachment. Although multifocal ERG response amplitudes increased modestly after recovery from the disease, the amplitudes remained statistically subnormal throughout the posterior pole of both eyes (22). These

Figure 10.2 Multifocal ERG first-order trace arrays of a 39-year- old woman with central serous chorioretinopathy. For reference, the trace array of a normal subject is shown in Fig. 10.1. Despite unilateral clinical involvement, the multifocal ERG is impaired in the affected eye as well as the unaffected eye. (From Ref. 20 with permission from the American Medical Association.)

investigators concluded that subretinal fluid retention in the disorder is secondary to diffuse pathologic changes in the choroid or retinal pigment epithelium or both, and that multifocal ERG in time may prove to be useful in assessing the degree of susceptibility to central serous chorioretinopathy attacks.

Of interest, patients with resolved central serous chorioretinopathy and those with mild optic neuritis may both report a similar history of a period of visual impairment followed by visual improvement. If the retinal and optic nerve head findings are minimal, the two conditions may be difficult to differentiate, and in such cases, focal macular ERG or multifocal ERG may be helpful to determine the presence of macular dysfunction.

Conventional full-field ERG is typically normal or minimally affected in central serous chorioretinopathy, because a focal macular lesion is unlikely to produce any appreciable reduction of panretinal ERG response. Therefore, the clinical role of full-field ERG in central serous chorioretinopathy is limited except in rare cases. For example, full-field ERG may be of value in a patient with macular pigmentary changes, who cannot provide an accurate ocular history. In such a case, the differential diagnosis may include resolved bilateral central serous chorioretinopathy and cone

dystrophy, and full-field ERG may be of value because fullfield ERG can detect generalized cone dysfunction due to cone dystrophy.

Visual evoked potential has no established clinical role in central serous chorioretinopathy. Prolonged VEP responses occur in central serous chorioretinopathy and are secondary to the retinal macular dysfunction (24). Since VEP impairment also occurs in patients with optic neuritis, VEP is not helpful in differentiating patients with resolved optic neuritis from central serous chorioretinopathy (25). Sherman et al. (26) recorded pattern-reversal VEP in 10 patients with central serous chorioretinopathy and found that, during the acute stage, 90% of the patients had significant VEP delays in the affected eye while only 30% had significant reduction in amplitude. Six of the 10 patients were re-evaluated after resolution of the disease, and in all six patients, the VEP delays returned to normal. The authors concluded that a VEP delay in isolation of other tests should not be used in the differentiating macular from optic nerve disease.

Lastly, pattern ERG findings were reported on two patients who had systemic lupus erythematosus and associated macular findings that were similar to central serous chorioretinopathy (27). However, the clinical usefulness of pattern ERG in central serous chorioretinopathy is not clear especially in light of the usefulness of focal ERG and multifocal ERG.

DOYNE HONEYCOMB RETINAL

DYSTROPHY=MALATTIA LEVENTINESE

In 1899, Doyne (28) described an autosomal dominant disorder characterized by small round drusen-like yellow–white spots at the macula, which were nearly confluent with a honeycomb-like appearance. In 1925, Vogt (29) reported a similar autosomal dominant condition (malattia Leventinese) found in the Leventine valley in Switzerland. Subsequently, Stone et al. (30) discovered that a mutation (Arg345Trp) in the gene EFEMP1 (epithelial growth factor-containing

fibrillin-like extracellular matrix protein 1) is the cause of this single disorder. Affected persons with malattia Leventinese=Doyne honeycomb retinal dystrophy usually have visual acuity ranging from 20=20 to 20=100, and subretinal neovascular membrane may rarely occur. The condition may be misdiagnosed as AMD in same cases. Full-field ERG and EOG are generally normal or mildly impaired (31,32). Pattern ERG is usually impaired with reduced P50 and N95 but P50 latency is unaffected (32). Focal and multifocal ERG show near normal to reduced macular responses (31,32). Dark adaptation is prolonged over macular deposits but are normal elsewhere (32).

STARGARDT MACULAR DYSTROPHY—

FUNDUS FLAVIMACULATUS

In 1909, Stargardt (33) reported several patients, including siblings, with macular and white fleck-like retinal lesions. The disorder that became known as Stargardt macular dystrophy is an autosomal recessive disorder characterized by bilateral retinal atrophic-appearing foveal lesions and variable number of scattered yellow–white fleck-like lesions. In 1963, Franceschetti (34) used the term ‘‘fundus flavimaculatus’’ for patients with extensive retinal fleck-like lesions with or without a foveal lesion. This attempt to classify patients into two distinct genetic disorders based on retinal appearance alone was not successful because of overlapping clinical and genetic findings between Stargardt macular dystrophy and fundus flavimaculatus. For instance, the degree of macular atrophy and distribution of flecks change over time in many patients. In addition, intrafamilial variation of the disease is common, and within the same family, some siblings can have primarily macular disease while others have only peripheral flecks (35,36). However, the use of Stargardt macular dystrophy and fundus flavimaculatus as distinct clinical phenotypes is still employed by some investigators for describing the natural history and estimating visual prognosis of this condition.

Stargardt macular dystrophy or fundus flavimaculatus affects about 1 in 10,000 people. The atrophic macular lesion may have a ‘‘beaten metal’’ appearance, and the shapes of the fleck-like lesions may be linear, ovoid, or pisciform (fishtaillike). Visible retinal lesions develop in affected persons during the first two decades of life with corresponding moderate to severe progressive deterioration in visual acuity. Visual acuity impairment is variable but usually results in 20=200 vision in 90% of patients over time (37). In the 1970s, and 1980s, diffuse blockage of choroidal filling on fluorescein angiography, the so-called ‘‘choroidal silence’’ or ‘‘dark choroids,’’ due in part to the accumulation of lipofuscin-like material in the retinal pigment epithelium was recognized as a feature of Stargardt macular dystrophy (Fig. 10.3) (38–40). The retinal fleck-like lesions was noted to correspond to hypertrophic retinal pigment epithelial cells with extensive accumulation of lipofuscin-like material (39). Despite evidence of widespread accumulation of lipofuscin-like material in the retinal pigment epithelium, peripheral vision is usually relatively well preserved in the disorder.

In 1997, mutations of a gene on chromosome 1, which encodes for a member of the ATP-binding cassette (ABCR)

Figure 10.3 Left: Fundus appearance of a patient with Stargardt macular dystrophy. Note the macular fleck-like lesions. Right: Fluorescein angiography showing numerous retinal fleck-like lesions and diffuse blockage of choroidal filling (‘‘choroidal silence’’) due in part to the accumulation of lipofuscin-like material in the retinal pigment epithelium. (From Ref. 202.) (Refer to the color insert.)

transporter proteins, were found in patients with Stargardt macular dystrophy and those with fundus flavimaculatus (41). This ATP-binding transporter protein was subsequently designated as ABCA4. The ABCA4 protein is expressed in the outer segments of both rod and cone photoreceptors and is thought to transport vitamin A derivatives across intracellular membranes (42,43). The ABCA4 gene is unusual in many respects when compared to genes of other recessive diseases. First, the gene exhibits a wide degree of sequence variation such that the majority of the unaffected, general population is not homozygous for the consensus ABCR4 sequence (44). Second, in contrast to other autosomal recessive disorders, most affected individuals with disease-causing ABCA4 genotypes are not homozygous but heterozygous and carries at least two variants of the ABCA4 gene (44,45). Third, because of the large number of sequence variations observed in the ABCA4 gene with many possible heterozygous diseasecausing genotypes, identifying plausible disease-causing genotypes is difficult in some patients with Stargardt disease. Of interest, clinical as well as electrophysiologic manifestations are variable in Stargardt patients with specific identifiable disease-causing sequence changes in the ABCA4 gene (46). In addition, ABCA4 mutations have also been found in patients with clinical features of cone–rod dystrophy and RP (47,48).

The diagnosis of Stargardt macular dystrophy is based on clinical findings and the presence of choroidal blockage on fluorescein angiography with the support of genetic findings when possible. Electrophysiologic tests may aid in detecting retinal dysfunction and assessing disease progression.

In general, full-field ERG responses are within the normal range in most patients with Stargardt macular dystrophy, but the full-field ERG responses are variable among patients and may demonstrate impaired cone responses as well as impaired rod and cone responses especially in those with more widespread retinal atrophy and fleck-like lesions (Fig. 10.4). Numerous investigators have demonstrated prolonged rod dark adaptation in Stargardt patients, and at least 45 min of dark adaptation are recommended before scotopic

Figure 10.4 Variability of full-field ERG responses in Stargardt macular dystrophy. The full-field ERG responses range from normal to considerablc impairment of both cone and rod responses. The pattern ERG is primarily a measure of retinal ganglion cell function and is preferentially affected in macular conditions and is often non-detectable in Stargardt macular dystrophy. (From Ref. 51 with permission from the American Medical Association.)

ERG recordings (49,50). The EOG light-peak to dark-trough amplitude ratios in Stargardt disease may be normal but tend to be reduced in many patients with numerous fleck-like lesions and reduced full-field ERG. By far, the most consistent electrophysiologic abnormalities in Stargardt disease are the focal, multifocal, and pattern ERG responses. The focal and multifocal ERGs show markedly diminished or non-detectable foveal response in almost all patients even in those with good visual acuity, and the pattern ERG response, a measure of ganglion cell activity, is also severely reduced or abolished in almost all patients regardless of visual acuity. This striking, consistent pattern ERG reduction is rather unusual