Oscillopsia: causes and management Caroline Tilikete a,b,c and Alain Vighetto a,b,c

Oscillopsia: causes and management Caroline Tilikete a,b,c and Alain Vighetto a,b,c a Hospices Civils de Lyon, Unité de Neuroophtalmologie and Service de Neurologie D, Hôpital Neurologique, Bron, b Université Claude Bernard Lyon I, Lyon and c INSERM UMR-S 864 Espace et Action, Bron, France Correspondence to Caroline Tilikete, INSERM UMR-S 864 Espace et Action, Bron F-69677, France Tel: +33 472913428; fax: +33 47291341; e-mail: caroline.tilikete@inserm.fr Current Opinion in Neurology 211, 24:38 43 Purpose of review Oscillopsia is an illusion of an unstable visual world. It is associated with poor visual acuity and is a disabling and distressing condition reported by numerous patients with neurological disorders. The goal of this study is to review the recent findings in the various pathophysiological mechanisms of oscillopsia and the potential treatments available. Recent findings Oscillopsia most often results from abnormal eye movements or from impaired vestibulo-ocular reflex. A special emphasis is provided on new hypotheses concerning the mechanisms of pendular nystagmus associated with oculopalatal tremor; on the clinical relevance of fixation instability in the diagnosis of degenerative disease; and on the causes of vestibular areflexia. Oscillopsia could also theoretically result from a deficit in mechanisms underpinning perceptual stability maintenance despite constant gaze displacement in the environment. The recent findings concerning the mechanisms and underlying neural network subserving this phenomenon of spatial constancy are developed. Summary Oscillopsia may result either from impaired ocular stability or impaired compensation or suppression of afferent visual information resulting from normal eye movements. Understanding the exact mechanisms of oscillopsia may lead to novel treatment. Keywords nystagmus, ocular fixation, spatial constancy, spatial updating, vestibulo-ocular reflex Curr Opin Neurol 24:38 43 ß 211 Wolters Kluwer Health Lippincott Williams & Wilkins 13-74 Introduction Oscillopsia is an illusion of an unstable vision, made up of the perception of to-and-fro movement of the environment. The notion of oscillopsia refers to the interaction between the physiological mechanisms resulting in movements of the eyes and those keeping a stable visual perception [1]. Stable visual perception is conditioned by two factors. First, images of the seen world projected onto the retina have to be quite fixed for stable perception of the environment. The threshold perception of retinal drift is around.1 deg/s in normal individuals [2]. Oscillopsia may then be due to ocular instability, when exceeding this threshold. Congenital nystagmus represents an exception since despite important ocular instability, patients do not describe oscillopsia. This phenomenon can be explained by an elevated detection threshold of retinal drift but recent data also suggest the role of acquired suppression of the apparent visual motion at higher-order visual cortex level [3 ]. Optimal perception of an object also needs a quite stable retinal projection, onto or close to the fovea [4]. The visual acuity rapidly declines if the displacement of the image on the retina exceeds the threshold of a few (2. 4) deg/s []. Supra-threshold ocular instability may be consequently associated with decreased visual acuity. Oscillopsia may also result from excessive motion of images on the retina due to acquired abnormal functioning of central stabilizing ocular motor systems, leading to different types of nystagmus, saccadic intrusions or from impaired visuovestibular stabilizing reflexes. It may also result from abnormal hyperactivity in the peripheral ocular motor system, such as superior oblique myokimia or in the peripheral vestibular system, such as superior canal dehiscence syndrome. In the first part of this review, we develop the recent findings about mechanisms and causes of oscillopsia due to ocular instability and their treatment. Second, whereas moving our gaze within a stable environment could induce a visual instability due to retinal drift and a spatial disorientation due to changes in visual referential, our perception remains of a perfectly stable and well oriented environment, a phenomenon called spatial constancy [6]. The central nervous system is first able to anticipate retinal drift in capturing an expectation of the visual consequences of eye movements and suppress its perception. The accompanying issue is how the brain differentiates retinal drift produced by an eye movement from those produced by object displacement 13-74 ß 211 Wolters Kluwer Health Lippincott Williams & Wilkins DOI:1.197/WCO.b13e328341e3b

Oscillopsia Tilikete and Vighetto 39 within a visual scene. Furthermore, the central nervous system is able to take into account the new positions of objects relative to our body after each change in gaze position, and induce a spatially oriented and continuous visual perception of the scene. This second phenomenon is mainly dependent on a remapping process and is called spatial updating [7]. Oscillopsia could theoretically result from an impairment of spatial constancy mechanisms but clinical data in this case are scarce. In the second part of the review we develop recent findings about the mechanisms and neural network computing spatial constancy. Oscillopsia due to ocular instability Eye instability may be observed in two main conditions: impairment of an ocular motor system that serves to maintain ocular stability, leading to permanent oscillopsia, or abnormal hyperactivity in the peripheral ocular motor or vestibular system, leading to paroxysmal oscillopsia. Permanent oscillopsia due to impairment of the ocular stabilizing systems Three different ocular motor systems serve to maintain the ocular stability: the fixation system, the visuo-vestibular stabilizing system and the neural integrator. The fixation system and its deficit In fixation condition, both visual and cerebellar ocular motor feedback loops [8] help to limit the physiological ocular motor noise made up of microsaccades, microtremor and slow drifts, which themselves serve important perceptual functions [9]. Fixation also requires accurate saccade and inhibition of unwanted saccades through a frontal-basal ganglia and cerebellar network [1]. Deficit in fixation systems results in ocular instability, which mainly comprises acquired pendular nystagmus and saccadic intrusions. Acquired pendular nystagmus is encountered in a variety of clinical conditions, the two most frequent being multiple sclerosis (MS) and oculopalatal tremor (OPT), both causes differing in clinical presentation and underlying mechanism (C. Tilikete, L. Jasse, D. Pelisson, et al., in revision) (Fig. 1). In MS, abnormal delay secondary to demyelination of either visual and/or motor central feedback loops represents the main hypothesis that can also explain the rare observation of eye-position-dependent monocular pendular nystagmus in some patients [11]. OPT is a peculiar condition that develops within a few weeks or months after a single brainstem or cerebellar lesion as part of the Guillain Mollaret triangle, a pathway originating in the dentate nucleus, passing through the superior cerebellar peduncle and looping caudally through the contralateral central tegmental tract down to the inferior olivary nucleus (ION) [12,13]. It results in synchronized low-frequency tremor of eyes and palate Key points Pendular nystagmus is the most disabling abnormal eye movement, on which specific therapeutics may be tested to alleviate oscillopsia. Fine analysis of saccadic intrusions during fixation may prove their usefulness as part of a differential oculomotor profile in degenerative disorders. Vestibular areflexia results in head movementinduced oscillopsia and may be clinically evaluated in measuring dynamic visual acuity. Following two centuries of specific research, the understanding of the underlying process of spatial constancy during and after eye movements remains complex, with the more recent notion of visual attentional focus and salience maps. and/or other oro-facial motor territories. This clinical condition is associated with anatomical changes, namely a hypertrophic degeneration with demonstrated immunohistochemical changes of the ION [14], leading to T2 hypersignal on MRI [12]. The more consistent recent model of OPT suggests that disruption of inhibitory cerebellar modulation of the ION results in the development of junction between neurons, generating periodic oscillations that are transmitted to the cerebellar cortex, which in turn would give a smoothing of the output signal leading to less periodic eye movements [1 ]. Finally, two recent controlled pharmacological studies confirmed the usefulness of gabapentin and memantine in the treatment of acquired pendular nystagmus in both MS [16 ] and, surprisingly, OPT [17]. Saccadic intrusions are defined by the abnormal occurrence of saccades and may reflect a dysfunction of the steady visual fixation system involving the frontal eye field, basal ganglia, superior colliculus and cerebellum. In cerebellar dysfunction, saccadic intrusion might be explained by disinhibition of the projection site of Purkinje neurons on the fastigial nucleus [18 ]. Saccadic intrusions are frequent in parkinsonian conditions but still have to prove their usefulness as part of a differential oculomotor profile [19]. Saccadic intrusions during fixation may also help to show up infraclinical frontal dysfunction such as demonstrated recently in patients with motor neuron disease without dementia [2]. The visuo-vestibular stabilizing systems and their deficits In head/body displacement condition, the vestibular and visual ocular stabilizing systems interact to maintain the image of the visual scene steady on the retina. The vestibular system, through the vestibulo-ocular reflex (VOR), induces a compensatory ocular movement that helps to maintain the eye stable in regard to the visual scene during head displacements. The visual stabilizing systems, through the smooth pursuit and the optokinetic

4 Neuro-ophthalmology and neuro-otology Figure 1 Acquired pendular nystagmus in oculopalatal tremor and multiple sclerosis OPT 1 1 Right eye 1 1 Left eye 1 MS 1 1 1 1 1 1 1 1 s Eye position (in degrees) traces with time (in seconds) for right (left panels) and left (right panels) eye in one oculopalatal tremor (OPT) patient (upper panels) and one multiple sclerosis (MS) patient (lower panels). Dark line, horizontal position; mid-grey line, vertical position; light grey line, torsional position. reflex, induce following eye movements that maintain the images stable on the retina. Furthermore the fixation system may interact to inhibit unwanted VOR, for example during eye and head tracking of a moving object. Deficit in vestibular/visual ocular stabilizing systems may result in ocular instability due to pathological jerk nystagmus. VOR deficit, especially when bilateral, and deficit of VOR inhibition may result in oscillopsia and impaired visual acuity during head/body displacement. New findings in acquired jerk nystagmus are reported for downbeat and primary position upbeat nystagmus. Downbeat nystagmus, which is most often increased in lateral orbital position, is thought to result from floccular dysfunction and is attributed to either vestibular [21] or smooth pursuit [22] up down asymmetry. It is, for example, a frequent finding in spinocerebellar ataxia type 6 (SCA6) [23 ]. Orbital position-independent downbeat nystagmus can be observed either in uvula/nodulus [24] or the paramedian pontomedullary region [2] lesions. Downbeat nystagmus presents a decrease in intensity during daytime [26] and in idiopathic causes has demonstrated no change over a course of up to 6 years in some patients [27]. Positional downbeat nystagmus may be a clue for the diagnosis of multiple system atrophy in Parkinson disease [28]. Downbeat nystagmus and resulting oscillopsia are responsive to clonazepam, but the usefulness of 3, 4-diaminopyridine or 4-aminopyridine has been largely demonstrated in recent studies [29,3]. Primary position upbeat nystagmus (PPUN) is an uncommon form of central nystagmus. Its clinical importance usually lies in the fact that it results from a brainstem focal lesion at either the paramedian pars of caudal medulla or the paramedian rostral pons sites [31,32]. In many cases, PPUN is dampened in prone or supine head position, mainly in lesions involving the crossing ventral tegmental tract (CVTT) at the pontine level, suggesting a role for this pathway in counteracting the effect of gravity [33]. Rare cases of PPUN have been described secondary to bilateral involvement of vertical semi-circular canals [34,3]. Gabapentin, memantine and 4-aminopyridine have also demonstrated an effect on upbeat nystagmus in single case reports [17,29]. Vestibular areflexia, particularly when bilateral, results in oscillopsia during head and body displacement, associated with postural disturbances. In these cases, the measurement of dynamic visual acuity can be interesting for the evaluation of visual functional deficit [36 38]. Vestibular areflexia may be the consequence of multiple diseases involving either the peripheral vestibular end organ or vestibular nerve, including Creutzfeldt Jakob disease [39]. Vestibular deficit seems also to be a quite frequent consequence of cochlear implants [4]. It has recently been shown to be associated frequently to polyneuropathy, which should be a prompt for systematic vestibular tests in such patients in order to orient treatment toward specific physiotherapy [41 ]. Treatment in vestibular areflexia can rely on physiotherapy to help for compensation or different types of sensory feedbacks to develop substitutions [42,43], but these approaches only address the postural deficit. Promising animal studies are actually testing vestibular implant possibilities, notably on the adaptative aspect of the vestibulo-ocular reflex [44 ]. Deficit in VOR cancellation during gaze shift along with head motion, such as seen in some cerebellar patients, may also

Oscillopsia Tilikete and Vighetto 41 result in oscillopsia and visual impairment [4]. Two mechanisms have been proposed to explain VOR cancellation: a reduction of the VOR gain or cancellation using smooth pursuit. The observations of normal VOR cancellation despite impaired smooth pursuit in some cerebellar syndromes suggests that smooth pursuit is not the sole mechanism involved [46]. The neural integrator and its deficit In eccentric eye position in the orbit, the neural integrator helps to maintain a constant innervation of extra-ocular eye muscles to avoid backward drift of the eyes [47]. A deficit in the neural integrator may result in gaze-evoked nystagmus and oscillopsia in the eccentric eye position. This nystagmus can occur after different lesions involving the brainstem and cerebellum, most often in cases of metabolic, toxic, or degenerative diseases. It is even used by the US police officers to determine alcohol intoxication, the validity of which can be contested regarding the variability of physiological gaze-evoked nystagmus in sober individuals [48 ]. Gaze-evoked nystagmus still remains an important interictal diagnostic clue in episodic ataxia [49] and a quite constant finding in SCA6 [23 ], both diseases sharing overlapping phenotypes and calcium channel dysfunction. It can exceptionally be found in discrete lesions, specifically involving the nucleus prepositus hypoglossi or the paramedian tract at medullar or ponto-medullary levels []. Paroxysmal oscillopsia due to hyperactivity in the peripheral ocular motor or vestibular system When oscillopsia occurs in paroxysmal episodes, hyperactivity in the peripheral ocular motor or the vestibular system may be searched for. (1) Superior oblique myokymia is a rare disorder characterized by episodic monocular oscillopsia, following neurogenic hyperactivity in the trochlear nerve. Microvascular compression syndrome of the IVth nerve is thought to be the main mechanism. Whereas recurrent studies emphasize the efficacy of surgery for superior oblique myokymia [1,2], medical treatments based on carbamazepine, gabapentin or propanolol demonstrate potential benefits with less secondary effects [3]. (2) Superior canal dehiscence syndrome is another condition in which transient oscillopsia is triggered by loud sounds or maneuvers raising the intracranial pressure. The topic is reviewed elsewhere in this issue [4]. Oscillopsia in the context of impaired spatial constancy Spatial constancy processes anticipate and compensate for the two sensory consequences of gaze displacement, namely an oppositely directed retinal drift and a change in the relationship between retinal and spatial (or patientcentered) coordinates of the visual scene (spatial updating). The process of spatial constancy during eye movements It has been commonly thought for two centuries (see review in []) that the perception of a stable world during voluntary eye movement is achieved by subtracting a reference signal of the ongoing eye movement, that is the efference copy of the motor command, from the retinal motion signal induced by the eye movement. In this compensation theory, if the two signals cancel each other, stable visual objects will be perceived as nonmoving. The compensation theory could indeed explain the perceptual stability in the case of smooth pursuit. However, in normal individuals, a small illusory movement of the visual background can be perceived during smooth pursuit, known as Filehne illusion [6]. This illusion arises because the two signals would cancel only partially. However, the size of this phenomenon is too small to endanger our concept of visual stability. By modifying the background motion during pursuit of a small target in humans, one can demonstrate an inherent plasticity of the reference signal [6]. The experimental setup may be adapted to monkeys who have learned to provide a different motor response according to their perceived rightward vs. leftward background motion [7 ]. Combining those psychophysics experiments with neurophysiological recording of neurons helps to determine the underlying neuronal network subserving aspects of spatial constancy, including mainly the visual posterior sylvian area, just adjacent to the parieto-insular vestibular cortex (PIVC) [6]. In humans, the neural network would involve cerebellar crus I, supplementary eye field and PIVC [8]. The efference copy theory has, however, been challenged, and different or combining theories have recently emerged [9,6]. The major criticism is that efference copy is too slow, and its gain too low to support a perceptual compensation for saccades [9]. First, the term of reference signal would be a better way to implement the multiple neural signals that can be used to predict the sensory consequences of voluntary eye movements. In addition, suppression of perception of background motion during saccade may also involve a visual masking mechanism, which seems to be the dominant mechanism for normal high contrast environment (see review in [61]). The process of spatial updating Humans are constantly moving and this self-motion causes the visual representations of these stationary objects to move across our retinas [62]. If visual perception were based solely on the forward processing of sensory information, the position of objects in the world

42 Neuro-ophthalmology and neuro-otology would appear to shift with each eye movement. In reality, our perception is that objects in the world remain stationary. This reflects the fact that we use an internal representation of the visual world that is actively constructed and spatially updated to account for our eye movements. The reference signal used to compensate retinal drift during eye movement could also be used for spatial updating. However, this does not explain why in certain circumstances prominent objects may be perceived as unstable meanwhile the global background keeps stability (see review in [9]). More recent data indeed showed that neurons in the lateral intraparietal cortex (LIP) and several other cortical and subcortical areas may anticipate the perceptual consequence of the ongoing saccade, using remapping of objects in our visual environment [63]. In this way, we are able to keep track of position of relevant objects in the outside world [62]. Furthermore, different data suggest that LIP is providing a salience map of the visual scene, that allows shifting of visual attentional focus toward prominent objects that become saccade goals [64,6]. Consistency between the salience map and the eye movement made to acquire a salient target seems to be one of the fundamental requirements for keeping spatial constancy following saccades. Conclusion Oscillopsia is an illusion of an unstable vision, made up of the perception of to-and-fro movement of the environment. It may result either from impaired eye stability or impaired anticipation and compensation for the sensory consequences of gaze displacement, namely spatial constancy. Eye instability may be observed in either deficit of an ocular motor system that serves to maintain ocular stability or hyperactivity in the peripheral ocular motor or vestibular system. Spatial constancy involves anticipation and compensation of either the oppositely directed retinal drift during eye movement or the change in the relationship between retinal and spatial coordinates of the visual scene after eye movements. Acknowledgement The work was supported by Projet de Recherche Clinique des Hospices Civils de Lyon Grant n8 HCL/P/26.432/2. We do not disclose conflict of interest. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 9 91). 1 Tilikete C, Pisella L, Pelisson D, Vighetto A. Oscillopsia: pathophysiological mechanisms and treatment. Rev Neurol (Paris) 27; 163:421 439. 2 Murakami I. Correlations between fixation stability and visual motion sensitivity. 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