Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

the electrophysiologist is helpful so that useful recordings are obtained. For example, in fundus albipunctatus, rod ERG responses increase with prolonged dark adaptation, and if this diagnosis is suspected, prolonged dark-adapted ERG responses are required.

Because the clinical indications of when to perform a diagnostic test are determined by numerous factors, a list of conditions for which visual electrophysiologic tests would be of clinical value is difficult to generate. Nevertheless, consensus regarding the key diagnostic value of electrophysiologic testing exists in many conditions including achromatopsia, Leber congenital amaurosis, cone dystrophy, X-linked retinoschisis, enhanced S cone syndrome, and thioridazine toxicity.

DISEASE CLASSIFICATION

Traditionally, many disorders are defined by clinical features. For instance, numerous retinal conditions are defined or grouped mostly on the basis of retinal appearance. However, recent advances in the understanding of basic disease mechanisms have caused disease classification to evolve.

A case in point is the retinal dystrophies. Rapid advances in molecular genetics have identified alterations of specific genes that are responsible for many of the hereditary retinal conditions. These advances have led to accurate molecular diagnosis, even during the early stages of the disease and have improved understanding of the underlying disease mechanism. The genotypes for the hereditary retinal degenerations are numerous and diverse, and the fundamental biochemical aberrations which produce these disorders are correspondingly complex. In addition, the expressivity or manifestation of a particular hereditary disorder is often variable even for affected persons with identical disease-causing genotype in the same family. Because these disorders have been classified traditionally on basis of clinical findings, that is, expressivity, a great deal of disparity between traditional disease classification and genetic categorization has emerged.

For example, genetic mutations associated with a clinical diagnosis of retinitis pigmentosa are found on numerous genes including genes encoding rhodopsin, peripherin, cGMP phosphodiesterase, and retinal pigment epithelium protein RPE65. Conversely, a specific disease-causing peripherin gene mutation within a single family may produce different phenotypes compatible with clinical diagnoses of not only retinitis pigmentosa but also macular pattern dystrophy and adult-onset vitelliform macular dystrophy.

No doubt, with further advances in the future, the classification of diseases will become more rooted in physiologic mechanisms. Nevertheless, both clinical classification and physiologic classification have a role in the management of patients. Clinical classification helps to categorize patients on the basis of clinical features, and physiologic classification, such as genotypic classification as in the case of retinal dystrophies, identifies the pathophysiologic origin of the condition.

Enhanced S cone syndrome

Goldmann–Favre syndrome

Dominant late-onset retinal degeneration

Cone–rod dystrophy

Alstro¨m syndrome

RETINITIS PIGMENTOSA (ROD–CONE DYSTROPHY)

Retinitis pigmentosa (RP) refers to a large group of genetically heterogeneous disorders characterized by early rod photoreceptor dysfunction and progressive rod and cone dysfunction. The prominent retinal pigmentary changes, which occurs in most but not all patients with RP led Donders to use the term ‘‘retinita pigmentosa’’ in 1857. Pigmentary retinal degenerations associated with systemic findings such as Refsum syndrome, Bardet–Biedl syndrome, Bassen– Kornsweig syndrome, and neuronal ceroid lipofuscinosis (Batten disease) have occasionally been clumped under the broad category of RP or secondary RP. However, to avoid confusion, ‘‘retinitis pigmentosa’’ is recommended to be reserved only for primary rod–cone photoreceptor dystrophies and not as a synonym for pigmentary retinal degeneration (1).

Retinitis pigmentosa affects approximately 1 in 3000– 4500 persons of the general population (2). Symptoms and clinical findings in RP patients are variable, even among patients with the same genotype and within the same family. Night vision impairment, peripheral vision loss, and light sensitivity generally begin insidiously between the second and fifth decades of life (3). Visual acuity and macular function are usually relatively spared until late in the disease. Diffuse or patchy areas of retinal atrophy with vascular attenuation and pigmentary clumping (bone spicules) are typically evident initially in the mid-periphery regions of the retina producing a ring-shaped scotoma surrounding fixation on visual field testing (Fig. 8.1). In some cases, the inferior mid-peripheral regions of the retina may be preferentially involved in early disease. With time, progressive diffuse

Figure 8.1 Top: Diffuse retinal atrophy, vascular attenuation, and pigmentary clumping in a patient with advanced RP. Bottom: Cystoid macular edema may occur in RP and was present in this patient as demonstrated by optic coherence tomography. (Refer to the color insert.)

retinal degeneration occurs. Other ocular findings of RP include optic nerve atrophy, atrophic macular lesions, cystoid macular edema, vitreous syneresis with vitreous cells, and posterior subcapsular cataracts (3,4).

Autosomal recessive, autosomal dominant, and X-linked recessive forms of RP are all found. Approximately 50% of RP patients have no family history of RP and have sporadic or isolated RP. The hereditary pattern in sporadic RP patients is presumably mostly autosomal recessive implying that this mode of inheritance is the most common (2). X-linked recessive forms of RP are the least common and are generally more severe. Advances in molecular genetics have helped to determine the specific hereditary pattern as well as the fundamental biochemical defect in RP patients.

The genotypes of RP are extremely numerous and complex. Mutations on at least 40 genes are associated with the RP phenotype. Identification of RP genotypes suggests that several biochemical mechanisms may produce the RP phenotype including defects involving the renewal and shedding of photoreceptor outer segments, the visual transduction cascade, and retinol (vitamin A) metabolism (5). For example, mutations of the rhodopsin gene account for less than 25% of all autosomal dominant RP, but at least 90 different point mutations of the rhodopsin gene are associated with RP. On the other hand, mutations of the peripherin=RDS gene are associated not only with autosomal dominant RP but also with pattern dystrophy and fundus flavimaculatus (6). Examples of autosomal recessive RP genotypes include mutations of the cGMP phosphodiesterase genes, a-subunit cGMP-gated channel gene, the retinal pigment epithelium protein RPE65 gene, and the arrestin gene. Further, defects in the RP GTPase regulator (RPGR) gene account for 20–30% of X-linked recessive RP.

Full-Field ERG Findings in RP

Full-field ERG responses are reduced in early stages of RP even when symptoms and clinical findings are mild; therefore, ERG testing is helpful in diagnosing or confirming RP (7,8). For those patients with detectable ERG responses, ERG testing serves as an objective measure of retinal function, which may be used to follow the degree of progression. Among RP patients ERG responses are variable, and this variability may occur among affected persons of the same family. In general, patients with early stages of RP have reduced and prolonged rod ERG responses and near normal or slightly reduced cone responses which may or may not be prolonged (Fig. 8.2) (9). With further progression of the disease, the rod and cone ERG responses diminish, prolong, and become non-detectable (Fig. 8.2). In RP patients with moderate to severe disease, the full-field ERG responses are likely to be very small or non-detectable. In some patients with mild disease, referred to as ‘‘delimited’’ or ‘‘self-limited’’

Figure 8.2 Examples of full-field ERG responses in RP. Both rod and cone responses are impaired early in RP with a preferential impairment of rod responses. In more advanced cases, the responses are non-detectable except for residual cone flicker responses. Very rarely, a ‘‘negative ERG’’ may occur where a selective reduction of the b-wave produces a b-wave to a-wave amplitude ratio of less than 1 in the scotopic bright-flash combined rod–cone response.

disease, the ERG responses are substantial and the prognosis more favorable (8,10,11). Patients with normal or mildly delayed photopic cone response implicit times are also more likely to have better prognosis (12).

For RP patients with detectable full-field ERG responses, the average yearly loss of 30-Hz cone flicker response amplitude ranges from 10% to 17%. However, because of considerable individual variation, these population ERG results should be applied with caution in predicting ERG declines in individual patients. Further, fluctuation in ERG responses due to normal re-test variations need to be considered in determining progression. Impaired 30-Hz cone flicker response in RP is likely due to a sensitivity change at the

photoreceptor and a delay in the response of the inner retina (13,14). In a 4-year study of 67 RP patients with detectable rod and cone full-field ERG responses by Birch et al. (15), the percentages of RP patients with a decline in ERG amplitudes were 64% and 60% for rod and cone responses, respectively, and the mean annual increase in rod ERG threshold was 28% per year (0.14 log unit) compared to 13% per year (0.06 log unit) for cone ERG threshold. In the same study, RP patients, on the average, lost 13.3% of the remaining 30-Hz cone flicker ERG response amplitude per year. These results are comparable to those of a previous 3-year study by Berson et al. (16), where 94 RP patients with detectable cone but not necessarily detectable rod full-field ERG demonstrated an average annual of decline of 17.1% of 30-Hz cone response amplitude. In a subsequent randomized clinical trial by Berson et al. (17), the average annual decline of 30-Hz cone flicker ERG response amplitude was 10% for untreated RP patients.

Prior to genetic advances in RP, the classification of RP was based on hereditary pattern as well as clinical and ERG findings. Discrimination among dominant, autosomal recessive, and X-linked RP is not possible based on ERG responses (11,18). Massof and Finkelstein (19) identified two types of autosomal dominant RP based on measures of rod sensitivity relative to cone sensitivity. One category of patients was characterized by an early diffuse loss of rod sensitivity and later loss of cone sensitivity while the other category had regional and combined loss of rod and cone sensitivity. Subsequently, other subgroups of dominant RP patients were also identified who did not fit into this classification scheme (20). Fishman et al. (10) classified dominant RP patients based on clinical and ERG criteria: type 1—diffuse retinopathy with non-detectable ERG; type 2—preferential inferior retinal involvement with marked loss in ERG rod response with prolonged cone implicit times; type 3—same as type 2 but with normal cone implicit times; and type 4—‘‘delimited’’ form with mild disease with substantial cone and rod ERG amplitudes and normal implicit times.

Narrow-Band Filtering of Low-Amplitude Cone

ERG in RP

In patients with advanced RP and full-field ERG responses that are very small, computer averaging alone or in combination with a narrow-band electronic filter may allow the measurement of 30-Hz cone responses of less than 1 mV (21). Averaging hundreds of 30-Hz cone responses smooths out and reduces the effect of random background electrical noise. Further, a narrow-band electronic filter with bandpass of 29–31 Hz and a center frequency of 30 Hz alters the recorded signal so that only the 30-Hz recorded signals are preserved. This technique increases the signal-to-noise ratio for responses that are predominantly sinusoidal at the 30-Hz frequency, but those signals that are outside the range of the narrow-band filter will be lost, potentially altering the amplitude of the response. Andre´asson et al. (21) found that narrow-band filtering reduces the computer-averaged amplitude by an average of 7%, but this reduction in amplitude was independent of the size of the unbandpassed response. Critics of narrow-band filtering point out that because of the nature of the narrow-band filter, the small processed signals (<0.5 mV) obtained in patients with advanced disease will resemble 30-Hz sinusoidal waves regardless of whether the signals are generated by retinal activity or by background noise.

Correlation of ERG and Visual Fields in RP

Correlations between full-field ERG amplitudes and visual field areas in RP patients have been demonstrated by several studies (22–28). Because of individual variations, correlations between ERG and visual field in individual patients are not always precise (29). Fahle et al. (23) showed significant relationships between all parameters of the full-field ERG and visual field diameters obtained by the Goldmann and Tu¨ binger perimeters with regression coefficients ranging from 0.4 to 0.67. Iannaccone et al. (25) noted significant correlations between the scotopic bright-flash b-wave amplitude and Goldmann areas obtained by the I4e, III4e, V4e