Ординатура / Офтальмология / Английские материалы / Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus_Leigh, Devereaux_2008

retinal loci upon which each flash falls,31 and it occurs because saccadic suppression is not absolute. Thus, the sequence of retinal images of the flashing light is seen distributed across space.

In normal individuals, this may be nothing more than a curiosity. However, individuals with INS (unless they have a purely pendular waveform) or FMNS are making saccades—fast phases or braking saccades—at a rate of several per second. They are therefore far more likely to see rapidly flickering displays multiply across their visual field. This phenomenon was noted in response to our oscillopsia questionnaire6 and is commented upon in nystagmus online discussion boards in regard to car taillights, displays on clock radios, and scrolling text displays. Control subjects making saccades to and from the LED saw a string of lights or a stationary light, depending on whether it flickered or not. When individuals with INS and FMNS were presented with either static or flickering LEDs, those with nystagmus saw the flickering light as either moving or multiple images more often than they did the stationary light. It was not possible in our experiment to relate perceptions to the nystagmus waveforms present at that time. We would anticipate that large, fast phases would be more often associated with multiple images than would small, braking saccades. In the meantime, as LEDs are used in increasingly wide applications because of their longevity, low energy consumption, and flexibility of placement, individuals with nystagmus will be confronted with this problem.

A similar perceptual problem has arisen with the use of digital light-processor video projectors, in which an array of digital micromirrors produces a grayscale image by varying the percentage of time during which the mirrors direct light toward the lens. Color is added by placing a rapidly spinning color wheel in the light path, presenting sequences of individual primary colors so rapidly that they are seen as integrated, unless the viewer makes a saccade across the screen. Some individuals may see rainbow fringes around objects in the projected image, for the same reasons as flickering LEDs are seen across the retina. It has recently been reported that this is a particular problem for individuals with INS.32

As the preceding section illustrates, advances in technology may create unanticipated problems for specific populations, making previously straightforward tasks quite difficult. Even something as simple as reading the destination sign on a streetcar may suddenly become a problem when a printed cloth roll is replaced with a scrolling LED display. More generally, we have found that specific features of the visual environment, such as high contrast between a small light and a dim background or rapid flicker, can disturb the visual perception of individuals with infantile forms of nystagmus and disrupt a normally accurate internal

representation of their surroundings. These disruptions occur without any corresponding change in the nature of their nystagmus. As we shall see, perception may also be affected when the nystagmus waveform itself changes due to external or internal influences.

INTERNAL INFLUENCES ON INS AND FMNS

So far we have examined how particular aspects of the visual environment can affect the way individuals with infantile forms of nystagmus perceive their environment. Changes in the environment do not alter the waveforms of the nystagmus as the individual’s perceptions change. We will now look at how internal factors influence the oscillation itself and, in many cases, perception.

In one sense, the importance of internal factors to INS seems to be widely known—many descriptions of the condition discuss how stress, fatigue, illness, or, most commonly, the “effort to see” lead to an exacerbation of the condition. Certainly individuals with INS often describe instances where something of interest becomes difficult to see. What is remarkable, however, is that until recently there was almost no published research that attempted to manipulate any of these internal variables in order to observe the effects on an individual’s nystagmus waveforms or visual perception.

Visual Effort

Although an increase in visual effort is almost always given as one of the key features of INS, until recently the only demonstration of this in print was one figure in a study by Abadi et al.33 One of the most basic ways to eliminate “effort to see” would be to turn out all the lights. But this tactic fails to consider the human ability to attempt to see an imaginary object, as in the instance of monocular individuals’ nystagmus spontaneously reversing in darkness, but with direction reversible by act of will.34,35

Sometimes total darkness is not necessary for voluntary effort to change a nystagmus waveform. Figure 4.2 illustrates the nystagmus of a young woman with a microophthalmic right eye, resulting in a coarse left-beating manifest latent nystagmus, which was present as long as she was actively trying to see. When simply passively fixating in dim light, however, her nystagmus underwent a transition through a dual-jerk waveform to an asymmetrical pendular INS waveform. When she resumed active viewing, there was a brief delay before the jerk waveform returned, during which she was aware of better vision. The subject was thus left in the unfortunate position of having a visually preferable waveform only when she was not trying to actively use vision.

The patient described here, as well as one described by Shawkat et al.,35 showed both INS and FMNS waveforms. The switching between them in darkness emphasizes once again the linkage that must exist at some level between these two ocular motor instabilities, even though they remain separate entities. In the patient described here, visual effort itself was the trigger that caused the switch between the two.

This effect, however, is not usually ascribed to visual effort. Generally, a vicious cycle is described in which the effort to see something at the limit of resolution causes an exacerbation of nystagmus, which makes the object of regard harder to see, thus provoking more effort, and so on. Somewhat surprisingly, although this concept agrees with anecdotal descriptions of how INS affected the vision of individuals with the condition, experimental examination of this phenomenon was lacking. We therefore undertook what we expected to be a straightforward demonstration of how this occurred.

Landolt C’s of varying sizes and orientations were presented to 14 INS patients, who had to identify their orientations in a four-alternative forced-choice paradigm.36 We analyzed their nystagmus waveforms for the duration of foveation periods and expected to find that, while their nystagmus remained stable during viewing of easy-to-read optotypes, it would deteriorate rapidly when the targets became harder to resolve. What we found, however, was completely unexpected (Fig. 4.3). Based on the numerous comments regarding the exacerbation of nystagmus with visual effort, we expected to see a well-defined relationship between Landolt C size and foveation duration, with the effort needed to see the smaller optotypes leading to a clear decline in foveation. Instead, there appeared to be no systematic relationship between the ease with which a target could be identified and the nystagmus waveform, even though the subjects were encouraged to try and

see letter sizes that were at the very limit of their previously measured visual acuity.

In trying to explain why anecdote and experiment were so different, we examined the subjects’ comments about their participation in the research study. One observation made repeatedly was that they did not really care how they did in the laboratory, as there was no particular motivation to perform well. In contrast, when trying to pass a driver’s license vision test or get through school examinations, visual performance was of considerable personal importance and, under these conditions, they found their nystagmus, and consequently their vision, worsening. Given that motivation has been shown to modulate neural activity in a number of areas in the basal ganglia and cerebral cortex,37-40

Figure 4.3 Percentage of time spent foveating versus optotype size for idiopathic congenital nystagmus patients. Note the unexpected absence of a relationship between the variables. Source: Tkalcevic L, Abel LA. The effects of increased visual task demand on foveation in congenital nystagmus. Vision Res. 2005;45:1139–1146.

plausible substrates exist whereby this internal state could influence ocular motor behavior. What is needed is to evaluate patients’ nystagmus during tasks that provide some sort of motivation to maximize visual performance, possibly by using some sort of reward/ penalty manipulation.41,42

Stress

Along with visual effort, stress is often mentioned as an exacerbating factor in INS, but formal studies have been lacking. One possible example of the influence of stress or anxiety on a patient’s nystagmus waveform, and thereby perception, was the case of a young woman with known INS who developed oscillopsia in her early teenage years.5 Eye movement recordings revealed typical CN waveforms, and discussion with the patient revealed considerable concern about the impact that her eye movements had on her appearance. Reassurance about the inconspicuous nature of her nystagmus was accompanied by a reduction in its clinical appearance. Analysis of her eye movement recordings showed an increase in foveation duration, which was associated with the disappearance of oscillopsia. Even when her nystagmus was at its worst, it never departed from typical waveforms, which in most patients do not lead to oscillopsia. Hence we argued that, for some individuals, compensatory mechanisms to suppress oscillopsia operate over fixed limits. If these limits are exceeded, oscillopsia results.

Although we inferred that stress was causing this patient’s nystagmus exacerbation and consequent oscillopsia, we did not monitor any of the accepted physiological indicators used to indicate the experience of stress, such as blood pressure, heart rate, or galvanic skin response.43 To properly examine the influence of stress on nystagmus, the employment of these measures and the recording of eye movement during tasks involving variable degrees of stress is essential. Such measures have been widely used and can provide a useful correlate of any changes in the nystagmus waveform. Under stressful conditions, we would not generally expect INS patients to develop oscillopsia, but we might expect a deterioration in foveation and a concomitant reduction in visual acu- ity.16,44-48 In daily life, separating the effects of stress from those of motivation could be difficult, as the act of trying to achieve a highly desired goal (e.g., getting a driver’s license) could be a potent stressor.

Attention

Although attention in various forms is a ubiquitous topic of study by psychologists, cognitive scientists, and physiologists, its formal conceptualization is often

credited to William James,49 who said, “Every one knows what attention is. It is the taking possession by the mind, in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought …. It implies withdrawal from some things in order to deal effectively with others, and is a condition which has a real opposite in the confused, dazed, scatterbrained state which in French is called distraction, and Zerstreutheit in German.” Many studies focus on the differences between “bottom-up” attention, elicited by some novel stimulus in the external environment, and “top-down” attention, directed toward some object by a conscious act of will, and on how these may be affected by age or disease.50-55 Less often quoted but germane to a discussion of nystagmus is the following statement by James:

We all know this latter state, even in its extreme degree. Most people probably fall several times a day into a fit of something like this: The eyes are fixed on vacancy, the sounds of the world melt into confused unity, the attention is dispersed so that the whole body is felt, as it were, at once, and the foreground of consciousness is filled, if by anything, by a sort of solemn sense of surrender to the empty passing of time. In the dim background of our mind we know meanwhile what we ought to be doing: getting up, dressing ourselves, answering the person who has spoken to us, trying to make the next step in our reasoning.

When considering modulating influences on nystagmus, it becomes apparent that top-down, volitionally directed attention cannot entirely be separated from visual effort. The act of scrutinizing a target requires it to be the object of attention. However, in assessing nystagmus, simple point targets such as LEDs or spots on a computer monitor are generally used. Sustaining attention on these targets for long periods of time is problematic, since they are of no inherent interest. When attention is disengaged from these targets, either by explicitly engaging subjects in a nonvisual task56 or when focus is lost in the way described previously by James, FMNS slow phases have been shown to continue for longer-than-usual periods of time, interrupted less frequently by corrective fast phases. These socalled extended slow phases may also be seen in INS when attention to the fixation target lapses (Fig. 4.4). This phenomenon, in which nystagmus spontaneously changes as engagement with the fixation target is lost, is a particular problem when assessing congenital forms of periodic alternating nystagmus. Shallo-Hoff- mann et al.57 attempted to control for this by having patients listen to stories during the recording session. While this was an improvement over simply assuming that an LED in a dark room would maintain its interest

Figure 4.4 Examples of extended slow phases from approximately 204 to 207 seconds into recording; the slow phases were presumably caused by loss of attention.

for, say, 10 minutes, it is also possible that stories chosen for their neutral tone could also come to be ignored; anyone who has nodded off in a lecture can confirm that the simple presence of auditory and visual stimuli is insufficient to ensure sustained attention.

Most studies that have quantitatively examined INS and FMNS have used simple targets, to avoid variations in visual engagement, and selected relatively brief segments of data generated during a period in which it was inferred that subjects were actively fixating. Recently, however, several studies have appeared that dispensed with this approach and instead applied wavelet13 and nonlinear dynamic12 analysis techniques to entire recording sessions of several minutes’ duration. They argued that selection of brief portions of data in order to assess a new therapy16 could not be justified. This point was strongly argued by authors from the two sets of studies.14,15 It seems clear, however, that analyzing a long recording that included lapses of attention and reductions in arousal would yield results that were not representative of nystagmus behavior during times of active visual processing or even sustained arousal.

Changes in Visual Status

The frequency with which changes in nystagmus patients’ clinical condition lead to exacerbations of their nystagmus or even a loss of perceptual stability is not known. At its simplest, the increase in nystagmus intensity that is seen when one eye of someone with FMNS is occluded could be considered an example of this. The change from a manifest latent to a latent nystagmus under these circumstances can even lead to

oscillopsia when the better-seeing eye of a child with this condition and amblyopia is patched.58 Interestingly, under these circumstances, adaptation eventually occurs, with a concomitant disappearance of oscillopsia. More recently, Hertle et al.17 found that a change in strabismus angle or loss of visual function in patients with INS could lead to an exacerbation of nystagmus and onset of oscillopsia in adult patients. Quantitative analysis of their nystagmus waveforms showed relatively low periods of foveation. When treatment addressed the problems and their exacerbations, foveation improved and oscillopsia was reduced or eliminated. Like the patient for whom anxiety over her nystagmus led to lower foveation and onset of oscillopsia,5 it appears that both the FMNS and INS patients have oscillopsia-suppression mechanisms that are limited in the range of retinal slip over which they can successfully operate. Why this is only true for a subset of such patients remains an unresolved question.

SUMMARY

Although much has been learned, particularly over the last few decades, about the behavior and visual consequences of infantile forms of nystagmus, and though comprehensive models of its origin have begun to appear,59 our understanding remains incomplete. The phenomena reviewed in this chapter indicate that although the mechanisms that give rise to the oscillations themselves may be centred in the brainstem, they are under the influence of other regions of the central nervous system, apparently including cortical and subcortical regions that underlie such higher cognitive functions as top-down allocation of attention and limbic system processes such as the stress response. Perception in some—but not all—patients with these conditions is susceptible to destabilization when their ocular oscillations worsen under the influence of the processes discussed here. Perception may also become unstable when nystagmus remains unchanged but specific changes take place in visual stimuli. These exogenous and endogenous causes of oscillopsia also remain to be adequately modeled. It is hoped that experimental examination of these influences will contribute to both the comprehensive modeling of nystagmus mechanisms and the evaluation and treatment of patients with this disorder.

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ABSTRACT

Perceptual fading (PF) is a phenomenon in which a target in the visual field fades from view after a certain fading time (FT). PF is reset by microsaccadic eye movements; however, PF has not been investigated during nonfixation eye movements. We compared PF during voluntary eye movements in healthy volunteers and in patients with involuntary eye oscillations caused by nystagmus. Twelve healthy volunteers performed a PF task consisting of following an oscillating fixation cross moving with either a sine wave (pursuit task) or a square wave (saccadic task) profile while viewing a static peripheral spot of low contrast (1.5x threshold). This was compared to FT during a static fixation cross with peripheral spot moving and also when both were moving. FT was also compared in 4 volunteers with nystagmus. During pursuit, FT was significantly longer for the static cross + moving target condition compared to the moving cross + static target (p = 0.04) and moving cross + moving target (p = 0.001). In contrast, during the saccadic trial, FT was similar for static cross + moving target and moving cross + static target tasks, but both were lower than the moving cross + moving target task. FT was more strongly correlated to retinal speed of the PF target during square wave than during sine wave tasks. FT was correlated to foveation in the four subjects with nystagmus. We describe the PF during voluntary eye movements when stimuli are applied at low contrast. Fading time was not

simply related to retinal velocity of the target but also to efferent information. Interestingly, patients with involuntary eye movements could also fill in targets, although responses were more variable than in healthy volunteers.

Interest in the role of involuntary fixational eye movements for counteracting neural adaptation has recently been revived in studies by Martinez-Conde et al.1,2 They found an association between probability, rate, and magnitude of microsaccades made during fixation and perceptual fading (PF) and reappearing of a target in the peripheral vision. Although the simplest forms of PF could be explained by neural adaptation in the retina, several lines of evidence suggest that PF is an active cortical process in which the perceptual image is represented at a neural level. For example, several animal studies have shown responses in visual cortical neurons during PF of an artificial scotoma3 and perceptual completion across the blind spot.4,5 Also, PF appears to occur separately for visual features such as texture and color, and visual information is never completely suppressed, even after an image has faded completely from consciousness.6

The microsaccades, drift, and tremor that occur during fixation eye movements are involuntary and unconscious, yet little is known about the influence of voluntary eye movements, such as smooth pursuit and saccades, on PF. Voluntary eye movements influence visual perception in a number of ways. During smooth pursuit, pursuit suppression occurs to reduce the optokinesis that should result from global motion that

occurs on the retina when tracking a target.7 With the often large and rapid changes in retinal image that occur during saccadic eye movements, saccadic suppression reduces the effects of motion.8 Also, efference copy is used to generate a stable world view from rapidly changing images that fall on the retina.9 To investigate these effects, we have compared PF during voluntary saccadic eye movements and smooth pursuit to tasks that generate similar target motion on the retina when the eyes are fixating. As soon as an image of a target in the peripheral field begins to move on the retina it becomes more salient, as neural adaptation is opposed. Since PF is related to the salience of visual stimuli,10 we have applied visual targets at low contrast levels, using a method to measure the contrast increment detection threshold.

We have also investigated PF in patients with large involuntary eye movements caused by congenital idiopathic nystagmus. Since the intensity of nystagmus varies at different eccentricities of gaze, we have been able to compare the FT when patients are fixating different eccentricities with velocity of eye movements.

METHODS

Twelve healthy volunteers and 4 patients with nystagmus participated in the study. A staircase method was used to measure the contrast detection threshold for each individual. Each of the 12 healthy volunteers performed seven PF trials (shown in Table 5.1), which were pseudo-randomly applied to nasal or upper visual field (1.5x threshold, 20° eccentricity, six repeats). An infrared video pupil tracker (250 Hz) was used to record horizontal and vertical gaze position at the same time. For testing FT of the 4 nystagmus patients, the fixation cross appeared in one of five positions (−20°, −10°, 0, 10°, and 20°), and the PF target was always placed 20° above the fixation cross (repeated

Table 5.1 Combinations of Movements Applied to the Fixation Cross and PF Spot

PF, perceptual fading.

five times). For each trial, the intensity of the nystagmus (amplitude × frequency) and the expanded nystagmus acuity function were calculated.11

RESULTS

Figure 5.1 shows a representative example of FTs recorded in a healthy volunteer. Analysis of median FTs of all healthy volunteers during the sine wave movements (Fig. 5.1A) showed that FT was significantly longer for +st •sin than for +sin •st (p = 0.048) or +sin •sin (p = 0.006). In comparison, during the square wave movements (Fig. 5.1B), FTs were longest for the +sq •sq trial (p = 0.02 for +sq •st versus +sq •sq). An analysis of the velocity of the target on the retina during each task found little difference between the image movement during the three sine tasks (p = 0.92), whereas image movement was greatest during the +sq •sq for the square wave trials (p < 0.0001). FT was more strongly correlated to retinal speed of the PF target during square wave (r = 0.10, p = 0.39) than sine wave tasks (r = 0.32, p = 0.007).

Volunteers with nystagmus could also successfully fill in peripheral targets. However, the correlation between fading time and foveation (r = 0.32, p = 0.17)

Figure 5.1 Fading times recorded for a healthy volunteer when targets were located along the horizontal (H) or vertical (V) meridian. Movement of the perceptual fading target or fixation cross are shown along the x-axis.

was stronger than for fading time and velocity (r = 0.68, p = 0.0009).

DISCUSSION

We describe PF during voluntary smooth pursuit and saccadic tasks in healthy volunteers, as well as during the involuntary eye movements made by patients with nystagmus, but only when stimuli are of sufficiently low salience. In healthy volunteers, fading time is not simply related to retinal velocity of the target but also appears to be influenced by efferent output. For example, FT during pursuit took less time than when targets moved with equivalent motion during fixation. Correlation between FT and velocity of the eyes was also poor during pursuit tasks. Patients with involuntary eye movements could also fill in targets, although their responses were more variable than those of healthy volunteers. The responses were more strongly correlated to foveation than to velocity, possibly because of reduced visibility of targets during faster eye movements. The influence of the efferent signal in PF implies a role in post-retinal processing of afferent information in the perceived salience to the stimuli.

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