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

Figure 3.1 Contrast sensitivity functions for (A) normal observer and (B) idiopathic congenital nystagmus. ( ), horizontal gratings; ( ), vertical gratings.

seen in normal subjects. A lower level of compensation was found for the meridional threshold difference.

Line and grating detection thresholds for subjects with CN are higher for targets that are vertically oriented as compared to those that are horizontally oriented.38,40,52-55 This meridional anisotropy is, in part, due to the principal axis of the IN oscillation (i.e., horizontal), together with the associated perceptual smear56,57 and the resultant meridional amblyopia.5355,58 Meridional anisotropy was also found for vernier targets,59 but the variability of the torsional eye position was not considered a factor.60

Albinos often have a VA below 20/60 and lower contrast sensitivity compared with idiopaths, principally because of the presence of foveal hypoplasia.61 Interestingly, even though albinos have poor foveal differentiation, many show foveation.62 VA and contrast sensitivity levels for the ocular-anomaly group are greatly dependent on the underlying pathological state of the eye and the duration of the form deprivation.28

Figure 3.2 The ranges for which spatial constancy was maintained for absolute and relative target motion. The targets for absolute motion were either a small local target or a large global target. The relative motion condition used a local target superimposed on a large stationary background. Feedback gain is defined as target velocity/eye velocity. A 0.0 gain indicates a case in which the observer’s eye movements are decoupled from the target motion. Feedback gains greater than or less than 0.0 decrease or increase the retinal slip motion respectively. The eye position feedback modulated local and global targets separately (absolute motion) or the local target against the stationary background (relative motion). Error bars ± SD.

Pattern contrast threshold measurements of LN and MLN subjects during monocular, binocular, and dichoptic viewing have provided information about binocular summation and suppression.63

Contour interaction or “crowding” is the term given to the adverse effect that the presence of surrounding contours have on the resolution of an acuity target. The magnitude and extent of contour interaction on letter acuity in idiopathic CN is greater than that found in normals,64,65 although this was not the case for the albino group.64 These results suggest that single-letter acuity tests may overestimate VA when compared to a traditional Snellen or a LogMAR chart.

Hyperacuity tasks include vernier and stereo detection thresholds. Both are elevated in idiopathic CN and are related to the duration of the foveation periods.59,66 The presence of the afferent defects in the albino and ocular-anomaly groups will clearly affect ocular alignment and increase the likelihood of a strabismus, thereby leading to reduced stereoacuity.28 Patients with MLN have a strong likelihood of exhibiting a strabismus and no detectable TNO stereoacuity.28,34,59,66

Motion Perception and CN

A number of studies have indicated that motion perception thresholds are raised in CN. These include absolute and relative motion,67 displacement thresholds,68 velocity estimation,69 motion discrimination,70,71 and the motion aftereffect.71 A reduced-motion sensitivity in CN does not account for spatial constancy, since the peak slow-phase velocity and the mean slow-phase velocity are both found to be greater than the absolute and relative motion threshold.67

Spatial Constancy and CN

Patients with CN rarely experience movement in their visual environment. That is, they are not usually aware of any oscillopsia and report a state of perceptual stability or spatial constancy. Nonetheless, there are occasions when perceptual stability can break down, and these events can provide clues about the underlying mechanisms responsible for spatial constancy. CN observers may experience oscillopsia when a single target is viewed against a background that has no visible structure, such as when viewing a small light in an otherwise dark room. Oscillopsia has also been reported when the CN intensity increases significantly beyond its steady-state level, such as when the subject is tired or under stress or experiencing a periodic alternating nystagmus. Patients with eccentric null zones occasionally report oscillopsia when they need to adopt or change their compensatory head posture. Additionally, oscillopsia may be induced in the laboratory when the retinal image is stabilized. This can be achieved either by using an afterimage or by optical stabilization.

A number of different mechanisms have been proposed to account for spatial constancy in CN. These include (a) reduced sensitivity to retinal-image motion, (b) adaptation to retinal-image motion,

(c) information sampled only when the eyes are moving relatively slowly during foveation periods, and (d) the use of extraretinal information to cancel the effects of the eye movements. Such extraretinal signals include efference copy (outflow), in which a copy of the CN oscillation command signal cancels the effect of subsequent retinal-image motion and proprioception.

The proposal that extraretinal cancellation (efference copy) is the primary mechanism responsible for spatial constancy has strong support from many sources.57,67,72-75 Using an electro-optical arrangement, Abadi et al.67 were able to vary the retinal-image slip feedback and thereby delineate the spatial constancy ranges for absolute and relative target motion (Fig. 3.2).

MANIFEST LATENT NYSTAGMUS

MLN may be divided into four distinct categories,34 which are distinguished by the fixation characteristics seen during binocular and monocular viewing. Type 1 MLN represents the absolute case in which the eyes are stable during binocular viewing but oscillate in a manner consistent with MLN when either eye is covered. In the past, this MLN type was referred to as LN. In type 2 MLN, horizontal conjugate saccadic intrusions are seen during binocular viewing, whereas type 3 MLN exhibits a torsional nystagmus. As in type 1 MLN, subjects with type 2 and type 3 MLN always display conjugate horizontal jerk MLN oscillations during monocular viewing. Patients with type 4 MLN exhibit decelerating or linear slow-phase jerk MLN waveforms during both binocular and monocular viewing.

All four types of MLN are visually driven by and greatly dependent on the patient’s state of attention.31,34 Extensions of the slow phase have been reported after prolonged monocular occlusion and during periods of low attention. In addition, the removal or reduction of visual feedback tends to delay the fast phase and reduce mean slow-phase velocity, thereby reducing the number of fast phases.34,76,77

In 1999, a unique case was reported in which an adult patient with a horizontal left-beating MLN converted to a right-beating CN on covering the patient’s only seeing (left) eye.76 Removal of the visual feedback in the left eye (i.e., darkness or stabilizing the retinal image) resulted in the oscillation changing from an MLN to CN. The MLN slow phase also changed to a grossly extended slow phase during periods of visual disengagement.

The vast majority of individuals with MLN have squints.28,30-34 Since MLN occurs frequently in individuals who have early-onset bilateral or unilateral vision loss, it has been proposed that a disturbance in egocentric localization may be partly responsible for these oscillations.63 Further evidence for this proposal is found in studies on infantile cataracts, where the presence of an MLN appeared to be linked to the emergence of a squint.20-22,24,28

MLN offers a unique opportunity to investigate oculomotor behavior at the same time as perceptual behavior, since the direction of the fast phase of the jerk nystagmus indicates the viewing eye. Recently, Abadi and Theodorou simultaneously recorded eye movements of patients with MLN as they viewed rival stimuli.78 A method of constant stimuli was used to determine the manner in which the pattern alternations were influenced by attentional modulations for a number of cuing paradigms. The subjective percept correlated with the direction of the

fast phase, and the rate of alternation was found to be less frequent compared with the normal controls. Cue position, type, and duration correlated with the MLN beat direction.

EARLY VISUAL LOSS AND

FIXATION STABILITY

number of albinos has been carried out by measuring contrast-detection thresholds when a small, discrete light source was directed at the inferior iris.89 These measurements have led to the prescription of specific pigmented contact lenses to reduce the intraocular light scatter and thereby improve contrast sensitivity.

Albinism

Albinism represents a heterogeneous group of inherited disorders of pigmentation and is characterized by a cluster of ocular features including IN, foveal hypoplasia, and strabismus.61,79 The presence of IN and the lack of a normally differentiated fovea are primarily responsible for the commonly found low VA.28,39,47,61,79-84 The range and type of waveforms seen in albinos do not differ significantly from those in nonalbinos with IN, but albinos do exhibit a greater prevalence of periodic alternating nystagmus (i.e., a dynamic null)28,85 and an exceptionally high incidence of squint.28,47,61,82-84 VA is generally much worse as compared with the idiopaths.28

On occasion, individuals can exhibit the phenotype of albinism without a detectable nystagmus.79,83,84,86,87 Recently, Timms et al.86 reported that a non-nystag- mus albino group exhibited frequent macrosaccadic intrusions (amplitude range 0.25° to 4.25°), about twice the mean amplitude found in a random normal population.12 The size of the intrusions found in the albino group was highly correlated with the velocities of steady drifts during fixation, but not with VA.

As albinos do not have a differentiated fovea, Abadi and Pascal88 investigated incremental light detection thresholds across the central visual field to determine whether albinos had a modified retinal sensitivity profile. Using a Goldman perimeter and the simultaneous recording of the eye movements in order to trigger target presentation during the foveation interval, they found a great deal of foveal heterogeneity. They also found that, on occasion, the sensitivity profiles reached near-normal levels. This finding further supported a previous study that used fundus videoing to show that albinos can regularly image the target of interest at the retinal location judged to be consistent with the normal anatomical position of the fovea.62

One clinical manifestation of the lack of ocular pigment is the existence of iris trans-illumination, and many albinos experience discomfort and disability even under exposure to quite modest light. This is particularly the case for types 1 and 2 oculocutaneous albinos (OCA); type 1 OCA designates tyro- sinase-negative OCA, and type 2 tyrosinase-positive OCA. Quantification of the intraocular scatter in a

Infantile Cataracts

The magnitude and severity of infantile cataracts varies enormously.90 Recently, Abadi et al.24 examined how the severity and duration of this early-onset form of deprivation affected eye alignment and ocular stability. Thirty-three patients (ranging in age from 1 week to 12.8 years) were examined before and after surgery, over periods of up to 61 months. Of the 23 patients with severe opacities, 9 underwent surgery within eight weeks of birth, and 10 had surgery after eight weeks. Of the 9 patients who underwent early surgery (≤8 weeks postnatally), 2 displayed a preoperative nystagmus. However, 8 of the 9 (89%) exhibited a nystagmus between 10 and 39 months postoperatively. In the late surgery group (≥8 weeks postnatally), 8 of the 13 (62%) exhibited a nystagmus. The most commonly found nystagmus by far was an MLN, making up a combined total for the early and late surgery groups of 75% of all recorded nystagmus types.

Emmetropization

A notable feature of the refractive state of individuals with IN is that they have a higher incidence of large refractive errors and, in particular, a greater-than-nor- mal incidence of high-spectacle astigmatism.91,92 The astigmatism is corneal in origin (anterior) and predominantly “with the rule.” The distributions of refractive errors for the idiopath and albino groups exhibit no significant kurtosis, unlike those in the normal adolescent and adult population, and suggest that the presence of the nystagmus may interfere with normal refractive development.92 Such a failure to regulate refractive development (i.e., emmetropize) is not an unusual occurrence in systems that have experienced early form deprivation.93,94

CONCLUSION

Normal fixation control has a defined operating range beyond which spatial and temporal vision are affected. Sensitivity losses in idiopathic CN are minimized when long foveation periods, with little variability, coincide with a functional fovea. VA is further undermined by the afferent sensory defects found in albinism and in

individuals who experience early form deprivation. To date, the vast majority of psychophysical studies have been carried out on adults, since the participants are required to cooperate and understand the instructions. The potential VA of an infant is notoriously difficult to predict, due in part to the likely modifications of the waveform26,95,96 and/or the affect of any attendant afferent defect. Moreover, difficulties often remain in correlating preferential looking, single and line optotype, and visually evoked potential procedures.97 Recently, studies have been carried out that establish useful objective VA predictors,48,50,98 which, together with electro-diagnostic techniques, may assist the scientist, clinician, and patient.

ACKNOWLEDGMENT Over the years I have had the very good fortune to work closely with many colleagues, and I would like to thank Anne Bjerre, David Broomhead, Richard Clement, Christine Dickinson, Jo Forster, Emma Gowen, Gemma Hocking, Ellen Lee, Chris Lloyd, Mark Lomas, Mark Muldoon, Eric Papas, Eve Pascal, Columba Scallan, Nana Theodorou, Jon Whittle, Ralph Worfolk, and, of course, all of our subjects, who have contributed so much time, fun, and enthusiasm to our pursuit of knowledge.

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ABSTRACT

Infantile nystagmus syndrome (INS) is a disorder that is influenced by a range of both internal and external factors, more so than many other disturbances of vision. Manipulation of stimulus characteristics such as contrast have been shown to provoke oscillopsia—a perception of environmental motion often said to be absent in INS. Rapidly flickering stimuli can also lead to multiply perceived images. Some internal factors, such as variability with gaze position, have been well documented. Others, such as exacerbation with visual effort, are widely described but have rarely been formally studied. In one study that did examine this, the expected relationship was not found, but subjects’ comments suggested that an absence of motivation may have been contributory. Although case reports have shown that stress or anxiety can exacerbate INS and provoke oscillopsia, systematic studies have been lacking. Similarly, changes in visual function or ocular alignment in adulthood may decrease foveation and elicit oscillopsia in nystagmus patients who were previously free of this symptom. Future models of INS should incorporate modulatory inputs from the limbic system that represent motivational or stress-related influences, as well as limits on the functioning of the mechanisms that compensate for retinal-image motion and thus suppress oscillopsia.

Infantile nystagmus syndrome (INS)1 is a relatively common ocular motor disorder that presents early in life.

Its consequences for vision depend first on whether there are concurrent sensory abnormalities present, such as albinism, congenital cataract, or aniridia, as there are in the majority of cases.2-4 A defective sensory pathway will impose a limitation upon visual acuity above and beyond any that arises from the oscillation of the eyes. However, the nystagmus itself also affects visual perception, and its effects vary. The factors that influence this variability—both internal to the individual with nystagmus and external, or found in the surrounding visual environment—are the focus of this chapter. The variability of these factors distinguishes INS from other forms of visual impairment, which are either stable (e.g., amblyopia post-childhood) or deteriorate inexorably over a period of time (e.g., retinitis pigmentosa). Absence of oscillopsia is a commonly noted diagnostic criterion for INS. However, it is not always absent.4-6 Such exceptions to the rule can tell us something interesting about the phenomenon; it is significant that the breakdown in perceptual stability is sometimes a function of the visual environment and sometimes a function of the nystagmus waveform.

The other benign form of nystagmus with onset in infancy is manifest latent nystagmus, which has recently been relabeled fusion maldevelopment nystagmus syndrome (FMNS), to acknowledge that a lack of sensory fusion is essential for the development of this condition.1 In many ways this form of nystagmus is simpler than INS—there is little variability of waveform and a more predictable variation with gaze angle.7-10 The two forms may also coexist in the same patient.9,11 Perception in this form of nystagmus can be affected by changes in ocular alignment or degree of binocular input.

The influences upon perception and upon the nystagmus itself are important for several reasons. From the perspective of the individual with nystagmus, a vision impairment that varies with circumstance may not be understood by teachers or employers. Frustration may ensue when print of a particular size can be seen clearly when idly viewing a sign but blurs into illegibility when applying for a driver’s license. From the perspective of the researcher, it is important that putative mechanisms for these influences be incorporated into any comprehensive model of INS. In particular, changes with arousal level or emotional state suggest inputs from areas of the brain that are not usually incorporated into ocular motor models. Variability arising from changes in the internal state may present problems in a clinical assessment or therapeutic evaluation. In some instances, the dividing line between actual treatment and placebo effect may be blurred.5 There is ongoing debate with regard to the aspects and time span of assessment and the degree to which internal influences should be taken into account.12-16 Also, if changes in a patient’s clinical status occur—for example, in ocular alignment or visual function17—the mechanisms that maintain perceptual stability in the face of the ocular oscillations may not be able to compensate and therefore may impact the stability of the subject. This chapter examines the influences—both external and internal—upon perception.

EXTERNAL FACTORS

INFLUENCING INS AND FMNS

Contrast

At first, it would seem unlikely that varying brightness or contrast of the visual environment should affect whether it is perceived as stable. Regardless of its characteristics, the image moves uniformly across the retina. However, anecdotal reports that objects seen at night or in poor lighting appeared to move prompted us to examine this pheno menon.6 Perhaps because it is so often asserted that individuals with INS do not experience oscillopsia, this was the first time that the phenomenon was examined using normal viewing conditions (i.e., without stabilizing all or part of the retinal image).18,19 A bright, central-fixation light-emitting diode (LED) presented in an otherwise dark room was viewed against a series of backgrounds that varied in brightness, contrast, and size. We anticipated that some subjects would experience oscillopsia, and they did. However, in most instances the oscillopsia was spatially inhomogeneous (i.e., only part of the visual stimulus was seen to move). As seen in Figure 4.1, this was most often the case when the LED was seen against a dim background. The background was more frequently

seen as moving when it was dim; the “LED only moving” percept was also most common with the dimmest background. Because most reports of occasional oscillopsia in the literature4,5,17,20 involve exacerbations of the patient’s customary level of nystagmus, we examined whether perception of oscillopsia was associated with poorer foveation; it was not.

Although some individual reports of oscillopsia described mouse pointers shimmering against a static screen, the mechanisms underlying the inhomogeneous perception of a uniformly moving stimulus are not immediately apparent. To identify them conclusively we would have to know what mechanisms are used in the suppression of oscillopsia. Although a range of explanations have been offered,18,19,21-29 the most widely supported is that an efference copy signal is subtracted from the cortical representation of the moving visual image, thus stabilizing it perceptually.19,29 It seems implausible that this efference copy signal would be subtracted inhomogeneously from the retinal slip signal, so some other explanation would seem to be necessary. If dim regions generated a weaker retinal slip signal by virtue of their lower luminance, then uniform subtraction of the compensatory efference copy signal would yield a similarly varied difference signal. Another possibility is that neural conduction velocities from retina to cortex vary with the brightness of the stimulus.30 In this case, subtracting the efferent motion signal could not be uniformly compensatory. This explanation seems the most parsimonious.

It is still unknown why sometimes the fixation light and sometimes the background appears stable. A light moving against a static background would be most consistent with daily experience. Encountering the opposite situation would be unlikely in normal life. The results are confounded, however, by the fact that that the bright fixation light was also the focus of the subjects’ attention in the preceding experiments. It is unknown how a bright but extrafoveal stimulus would be perceived. It may be that once attention (and fixation) is withdrawn from the bright light, it is seen to behave in the same fashion as its dimmer surroundings.

Flicker

Modern display technologies have made flickering stimuli a part of daily life in industrial societies. LEDbased displays, such as clock radios, car taillights, or commercial signage, generally flicker at a rate of several hundred to several thousand Hz to avoid overheating. This is usually so far above the flicker-fusion frequency that we are unaware of it. However, if such displays are viewed in otherwise dark surroundings and a saccade is made across them, a string of lights is seen during the saccade. This arises from the different