Ординатура / Офтальмология / Английские материалы / Electrodiagnosis of Retinal Disease_Miyake_2005

Representative dark-adaptation curves from a normal subject and from patients with complete and incomplete CSNB are shown in Fig. 2.58. With complete CSNB, the cone threshold is elevated above that of normal individuals,

and the “rod” threshold is the same as the cone threshold (i.e., no rod threshold). With incomplete CSNB, a rod threshold is present, although the final threshold is elevated by approximately 1.0–1.5log units above normal [2, 10].

The chief complaints at the initial visit of our 49 complete CSNB and 41 incomplete CSNB patients are listed in Table 2.1. Most of our patients had an initial complaint of blurred vision. Because of the normal fundus appearance, the correct diagnosis was not easy unless electroretinography was performed. It should be noted that only 1 of the 41 patients with

incomplete CSNB complained of night blindness. The absence of a complaint of night blindness is important because if it was not reported it we might overlook CSNB in the differential diagnosis. We may not obtain ERGs from patients complaining of decreased vision without night blindness.

Representative examples of the standard fullfield ERGs recorded from patients with both types of CSNB are compared to those with normal eyes in Fig. 2.59. The rod ERG is absent in complete CSNB; it is present but reduced in incomplete CSNB. The mixed rod–cone ERGs elicited by a single bright flash has a negative configuration with normal a-wave amplitude and reduced b-wave amplitude in both types of CSNB. The OPs are absent in the complete type but present in the incomplete type [2, 10].

The normal a-wave amplitude with reduced or absent rod ERGs suggests that both types

of CSNB have a defect not in the rod photoreceptors but in the second-order neurons or their synapses in the rod visual pathway. The defect is almost complete in complete CSNB, whereas it is incomplete in incomplete CSNB. The cone and 30-Hz flicker ERGs appear nearly normal in complete CSNB except that the a- wave of the cone ERG has a plateau-like bottom (Fig. 2.59). In contrast, the cone and 30-Hz flicker ERG are extremely reduced in incomplete CSNB, which is highly characteristic and extremely important for the differential diagnosis.

It was noted in Section 1.1.4.1 that the amplitude of the cone-mediated ERGs in normal subjects increases by 1.5–2.0 times during the course of light adaptation after sufficient dark adaptation. As shown in Fig. 2.60, this increase was seen in both types of CSNB, but the increase was exaggerated in incomplete CSNB [13]. Although the amplitudes of the 30-Hz flicker ERGs recorded after 30min of dark adaptation are small in incomplete CSNB, as

mentioned, it is markedly increased (by 4.0–5.0 times) after 10min of light adaptation. This exaggerated increase is never seen in patients with complete CSNB, but they have a normal increase in the amplitude. The mechanism of this phenomenon is still unknown, but we believe that rod–cone interactions may play an important role in creating this phenomenon (see Section 1.1.4.1).

The ERGs elicited by various intensities of dim stimuli (Fig. 2.61, top) and bright stimuli (Fig. 2.61, bottom) from a normal subject, two patients with complete CSNB, and two patients with incomplete CSNB are shown in Fig. 2.61 [14].As was shown in Section 1.1.1 for a normal subject, the cornea-negative scotopic threshold response (STR) is recorded at an intensity of

-8.2log units, and the implicit time decreases as the stimulus intensity is increased. At -5.8 log units, the b-wave becomes clearly visible for the first time, and the amplitude increases with increasing stimulus intensities (Fig. 2.61, bottom), until it saturates at -1.4log units. The a-wave begins to appear at -1.7log units and the OPs at -0.8log units.

With complete CSNB, neither the STR nor the b-wave was recorded when the stimulus intensity was low (Fig. 2.61, top). At an intermediate stimulus intensity of -4.4log units (Fig. 2.61, bottom), both the a-waves and b- waves appear, with the a-wave having a normal amplitude. The a-waves and b-waves increase with increasing stimulus intensities, but the b- wave saturates quickly, resulting in an ERG with the amplitude of the a-wave larger than that of the b-wave, a negative-type ERG. OPs are undetectable in eyes with complete CSNB.

With incomplete CSNB, the STR is first seen at a slightly higher threshold than in normal subjects, at -7.6log units. However, the implicit time is approximately 80ms longer than normal. A small b-wave appears at -5.8log units, as in normal subjects, with a comparable implicit time. At higher intensities, the b-wave amplitude saturates at -3.4log units and is smaller than in the normal subject. The a-wave, on the other hand, continues to increase progressively, resulting in a negative ERG. The OPs are clearly visible.

The interaction of the STR with the rod (scotopic) b-wave (bs) is interesting. Despite the subjective elevation of the rod threshold in patients with incomplete CSNB, the stimulus threshold for the b-wave may not be elevated, and the b-wave near threshold intensity may be of normal amplitude and implicit time. The STRs recorded from four normal subjects and four patients with incomplete CSNB at -6.8log units are compared with the near-threshold b-wave recorded at -5.4log units in Fig. 2.62. The negative peak of the STR and the positive peak of the b-wave have nearly the same implicit times in normal subjects, indicating that the b-wave is a summation of the positive P11 component and the negative STR. It is conceivable that when the STR is small or when its peak is greatly delayed, as in incomplete CSNB, the b-wave consists only of the positive P11 component. Thus, the b-wave amplitude may appear normal at this stimulus intensity because it does not include the negative STR component.

The fundamental differences between rod and cone connections to the bipolar cells [9] were shown previously in Fig. 1.9 in Section 1.1.3.4. The photoreceptors transmit visual information to the bipolar cells, which are the secondorder neurons. Rods contact only depolarizing (on) bipolar cells (DBCs), creating on visual pathways only. On the other hand, cones have more extensive postsynaptic connections. They synapse onto various cone bipolar cells, some of which are depolarizing cells and, like the rod DBCs, form the cone “on” pathway with a sign-inverting (-) synapse. Cones also make synapses with hyperpolarizing bipolar cells (HBCs) through sign-preserving (+) synapses in the cone “off” pathway.

These two types of synapse are each selectively sensitive to different glutamate analogs.

The sign-inverting (-) synapse can be blocked by 2-amino-4-phosphonobutyric acid (APB), and the sign-preserving (+) synapses are blocked by either +cis-2,3-piperidine dicarboxylic acid (PDA) or kynurenic acid (KYN). These drugs can preferentially block either the on or off pathways in the retina [15, 16].

Using photopic ERGs elicited by longduration square-wave stimuli,we found that the cone “on” response generated by depolarizing on bipolar cells is selectively and severely depressed in patients with complete CSNB [8]; moreover, the waveform is similar to that of monkeys after APB is injected into the vitreous to block the synapse between photoreceptors and on bipolar cells (Fig. 2.63). The off response, on the other hand, which is generated by hyperpolarizing bipolar cells, is intact in

Fig. 2.63. Comparison of photopic long-duration ERGs recorded from a monkey and a human. Left: Normal control ERG for the monkey eye and after being treated by 2-amino- 4- phosphonobutyric acid (APB). Right: ERGs recorded from a normal human control, from a patient with complete CSNB, and from a patient with incomplete CSNB. (From Miyake et al. [8], with permission)

Fig. 2.64. Photopic ERGs elicited by square wave stimuli of various durations from a normal control and a patient with complete CSNB. Thick lines underneath the responses represent the stimulus duration. (From Miyake [10])

patients with complete CSNB, leading us to hypothesize that the on function of both the rod and cone visual pathways is completely blocked in eyes with complete CSNB. The complete defect of the on pathway results in the complete night blindness detected in patients with complete CSNB because rods connect only to the on bipolar cells.

It is interesting to consider why the standard brief flash cone ERG consists of a normalappearing response despite the defects of the on component evaluated by the long-flash photopic ERG. The mechanism involved in generating this phenomenon is shown in Fig. 2.64. With long-duration stimuli, the a-waves, b- waves, and d-waves are clearly separated. As the stimulus duration is shortened, the d-wave approaches the b-wave; and when the stimulus duration is short (brief flash stimuli), the positive component of the photopic ERG consists mainly of the d-wave. Therefore even when the b-wave, a component of the on response, is absent (as in complete CSNB), the d-wave

replaces the b-wave, and a positive wave is recorded with brief-flash stimuli [10].

With incomplete CSNB, on the other hand, the story is more complex, with both subnormal on and off responses. We hypothesized that the on and off systems are incompletely disturbed at the level of the bipolar cells in patients with incomplete CSNB [10]. This hypothesis was confirmed by the standard full-field ERGs recorded from the monkey’s eye after being treated by neurotransmitter blocking agents [10]. The technique of full-field ERGs recording from monkeys under the same conditions as human patients is shown in Fig. 2.65. The ERGs recorded after the on synapses were completely blocked by APB are identical to those recorded from complete CSNB patients (Fig. 2.66A). After the monkey eye was treated with low levels of APB and PDA to block both the on and off synapses incompletely, the shape of the full-field ERG is similar to that for incomplete CSNB (Fig. 2.66B)

The S-cone ERGs are markedly different in the two types of CSNB because the S-cones connect only to the on bipolar cells, whereas ML-cones connect to both on and off bipolar cells [17]. Thus, the full-field S-cone ERG is undetectable in complete CSNB [18, 19], which is reasonable, but it is relatively well preserved in cases of incomplete CSNB [19] (Fig. 2.67). The wellpreserved S-cone ERG for incomplete CSNB is diagnostically important because the full-field ERGs of incomplete CSNB are similar to those of X-linked congenital retinoschisis. However, the S-cone ERGs from patients with X-linked congenital retinoschisis are selectively absent (see Fig. 2.37 in Section 2.8.3.1). This functional difference is important for determining the pathogenesis of these two disorders.

With complete CSNB, it is somewhat curious that despite the fact that S-cone ERGs are undetectable, subjective color vision is essentially

normal [18]. The blue-on-yellow perimetric findings in five patients with complete CSNB and four patients with incomplete CSNB are shown in Fig. 2.68. The blue sensitivity is nearly normal in patients with incomplete CSNB [10] but is severely depressed in patients with complete CSNB. However, the blue sensitivity is well preserved in the central 10° to 15° in complete CSNB [20]. These findings solve the riddle of the discrepancy between the undetectable fullfield S-cone ERGs and normal color vision in patients with complete CSNB because psychophysically determined color vision is influenced mainly by the central visual field. In addition, these findings lead us to believe that the macula of complete CSNB patients may have a unique pathology that is different from that in other parts of the retina. This topic is discussed in the following section.

As mentioned, the blue sensitivity is preserved only in the macula in patients with complete CSNB, suggesting that the on function is preserved only in the macula. This is supported by the results of full-field ERGs and focal macular ERGs elicited by long-duration stimuli. A comparison of full-field, long-duration photopic ERGs and focal macular ERGs recorded from a normal subject and from a patient with complete CSNB are shown in Fig. 2.69 [10]. The full-field ERG recorded from the patient with complete CSNB has a hyperpolarizing pattern (large a-waves and d-waves and almost undetectable b-waves), whereas the focal macular ERG has a large b-wave-like positive deflection with delayed implicit time. These findings suggest that some of the on function is pre- served—but only in the macula in complete CSNB, as was shown by preservation of the psychophysically determined blue sensitivity (see Fig. 2.68). Although the properties of this positive deflection in the macula have still not

been determined, the pathophysiology of the macula may be different from that of other retinal areas in complete CSNB.

Because the pathogenesis of complete CSNB is most likely due mainly to complete blockage of signal transmission between the photoreceptors and the on bipolar cells, it was interesting to study the focal retinal responses using multifocal ERG techniques [21]. The amplitudes of the first-order kernel of the multifocal ERGs in patients with complete CSNB are normal, but the implicit times are delayed over nearly the entire field (Fig. 2.70). There is no central depression. The second-order kernel, which is involved in adaptive mechanisms of the retina to repeated flashes and contains a large contribution from the neural cells in the proximal layers of the retina, is selectively reduced. The delay of the implicit times of the first-order kernel may be related to the severe reduction in the amplitude of the second-order kernel (Fig. 2.70).