Report of oscillopsia in ataxia patients correlates with activity,not vestibular ocular reflex gain

Abstract

BACKGROUND:

Patients with cerebellar ataxia report oscillopsia, “bouncy vision” during activity, yet little is known how this impacts daily function. The purpose of this study was to quantify the magnitude of oscillopsia and investigate its relation to vestibulo-ocular reflex (VOR) function and daily activity in cerebellar ataxia.

METHODS:

19 patients diagnosed with cerebellar ataxia and reports of oscillopsia with activity were examined using the video head impulse test (vHIT), Oscillopsia Functional Index (OFI), and clinical gait measures. Video head impulse data was compared against 40 healthy controls.

RESULTS:

OFI scores in ataxia patients were severe and inversely correlated with gait velocity (r = –0.55, p < 0.05), but did not correlate with VOR gains. The mean VOR gain in the ataxic patients was significantly reduced and more varied compared with healthy controls. All patients had abnormal VOR gains and eye/head movement patterns in at least one semicircular canal during VHIT with passive head rotation.

CONCLUSIONS:

Patients with cerebellar ataxia and oscillopsia have impaired VOR gains, yet severity of oscillopsia and VOR gains are not correlated. Patients with cerebellar ataxia have abnormal oculomotor behavior during passive head rotation that is correlated with gait velocity, but not magnitude of oscillopsia.

Keywords

Oscillopsia cerebellar ataxia vestibular ocular reflex gaze stability gait

1 Introduction

Oscillopsia, the experience of motion of the vis-ual environment (“bouncy vision”) is commonly reported patients with cerebellar ataxia. Oscillopsia in ataxia patients may be characterized among static oculomotor abnormalities (downbeating nystagmus, opsoclonus, ocular flutter) as well as dynamic oculomotor abnormalities occurring with activity. Oscillopsia, as described in peripheral vestibular disorders, has been attributed to impairment of the vestibular ocular reflex (VOR) [1 , 13].

Patients with cerebellar ataxia are known to have abnormal oculomotor control, though only recently has such evidence included an abnormal VOR. Lee et al. reported abnormal VOR gain (eye/head velocity) among spinocerebellar ataxia type 6 (SCA 6) patients in at least one semicircular canal (SCC) in 8 of 12 patients. Additionally, they reported temporal degradation of the horizontal and anterior SCCs, but not the posterior SCC. Interestingly, anterior SCC gains were increased relative to the posterior SCC gains early in the disease. Lee et al. also reported negative correlations between VOR gain and the Scale for Assessment and Rating of Ataxia (SARA) score [17].

Bilateral VOR gain deficits among cerebellar ataxia patients was reported by Bronstein et al. 1991 [5]. Later, Migliaccio et al. [22] first described the syndrome, cerebellar ataxia with bilateral vestibulopathy (CABV), in which patients have impaired horizontal canal plane VOR, smooth pursuit and optokinetic responses, distinguishing CABV patients from patients with bilateral vestibular hypofunction (BVH). CABV was later termed CANVAS (cerebellar ataxia with neuronopathy and bilateral vestibular areflexia syndrome) when ganglion neuronopathy, was additionally described by Szumulewicz et al. [31]. CANVAS is now suspected to involve the Scarpa’s ganglion, alluding to a vestibular neuronopathy as the mechanism of bilateral vestibulo-pathy, consistent with other bulbar findings observed in CANVAS, with the exception of spared auditory function [34].

Spinocerebellar ataxia type 3 (SCA3) patients are reported to have VOR impairments in all six semicircular canal planes, with preserved saccular function [9, 10]. The role of utricular function is less reported though was impaired in SCA3 [25]. Friedreich ataxia patients are known to have abnormal VOR deficits as well as saccade and gaze fixation impairments [8].

Although there now exists evidence of VOR abnormality in patients with cerebellar ataxia, the impact of such pathophysiology on functional behavior is relatively unknown. The purpose of this study was to quantify the magnitude of oscillopsia and investigate its relation to vestibular function and daily activity in cerebellar ataxia. This paper also describes eye and head movement patterns in response to passive head impulse rotations, as well as highlights relationships between magnitude of oscillopsia symptoms, VOR gain, and activity impairments in cerebellar ataxia patients.

2 Methods

2.1 Subjects

31 patients with ataxia and reports of oscillopsia during motion were evaluated between May 2018 and March 2020. Patient diagnoses included spinocerebellar ataxia types 2, 3, 7, (confirmed via genetic testing) or cerebellar ataxia of unknown etiology with/without family history. Of the 31 patients tested, 19 patients (9 male, 10 female, age range = 24–82 years, mean age 61±15 years) were included in final data analysis. 12 subjects were excluded for reasons including severe diplopia, disconjugate eye movements, a diagnosis of Sensory Ataxia Neuropathy Dysarthria and Ophthalmoplegia SANDO (n of 1); or unconfirmed ataxia diagnoses. Of the 19 subjects, the mean age of onset for the ataxia symptoms was 51±16 years (range 14–78) and the mean disease duration was 10±7 years (range 2–27).

An index of oscillopsia severity, VOR gain, and functional measures of gait and balance were collected. In addition, the VOR gains of n = 40 healthy controls were used for comparison. This study was approved as a retrospective chart review by the Johns Hopkins Medicine Institutional Review Board.

2.2 Patient reported outcome measure

Oscillopsia Functional Index (OFI): The OFI was initially developed in patients with peripheral vestibular dysfunction (Anson et al., 2017). The 43-item questionnaire tasks patients to report their level of oscillopsia during various activities such as walking, riding in a car, or ability to recognize familiar faces. Scores range from 0–215 points, ranked from 0 (no oscillopsia symptoms) to 5 (severe oscillopsia such that the person has stopped doing the activity). A scoring option of ‘not applicable’ reflects the persons’ avoidance of a particular activity. The OFI scale has high internal consistency with excellent validity and is correlated with other oscillopsia measures (oscillopsia visual analog scale r = 0.69 p < 0.001; oscillopsia severity scale r = 0.84 p < 0.0001). The OFI is also correlated with the Activities of Balance Confidence scale (ABC, r = –0.84 p < 0.001), a subjective measure of balance confidence [23].

2.3 Vestibular-ocular function measure

Video head impulse test (VHIT): Eye and head velocity was measured during passive head impulses for each semicircular canal with the ICS Otometrics vHIT system (Natus Medical Incorporated, Taastrup, Denmark) using the standard manufacturer recommended protocol. The ICS includes a monocular video camera for recording right eye velocity at 220 frames/second and a gyroscope to detect head velocity [18, 21]. Patients were seated 1 meter from a stationary eye level visual target, in room light. A minimum of 12 passive head rotations were performed in both directions of three planes parallel with the three pairs of semicircular canals: horizontal, right anterior/left posterior (RALP) and left anterior/right posterior (LARP). VHIT traces were deleted if the eye velocity trace preceded head velocity, if evidence suggested goggle slip, or if the passive head rotation trace did not match the acceleration profile suggested by the manufacturer [20]. VOR gain was computed in the ICS system using the ratio of the area under the curve of eye velocity relative to area under the curve of head velocity (after saccade traces are removed) from onset to offset of head velocity [14].

2.4 Ataxia severity rating measures

Brief Ataxia Rating Scale-oculomotor subscore (BARS): The BARS is a clinical measure of oculomotor impairments that considers the presence/absence of spontaneous nystagmus, saccadic pursuit, gaze-evoked nystagmus, and saccadic hyper/hypometria. One-half point is scored for each of the 4 conditions, yielding a score that ranges from 0 to 2 with higher scores indicating worsening velocity of eye movement. A score of (0) is rated a normal; (0.5) mildly reduced; (1.0) moderately reduced; (1.5) severely reduced, (2) ophthalmoplegia. Scoring for hypermetria considers velocity of the saccade, when present [28].

Scale for Assessment and Rating of Ataxia (SARA) is a clinical neurological measure that ranks severity of ataxia [26]. Mean SARA scores in SCA patients have been reported as 15.9±8.5 9, range = 0–40 points, relative to healthy controls (mean 0.4±11, range 0–7.5) [27, 30].

2.5 Activity measures

Dynamic Gait Index (DGI): The Dynamic Gait Index is an 8-item functional outcome that tasks patients to perform various dynamic gait activities (i.e., walk and then turn 180°, walk and step over an obstacle). The DGI measures fall risk with scores < 19/24 points reflecting a 2.58 times greater likelihood to have fallen in the previous 6 months [32]. The DGI in cerebellar ataxia has high inter-rater reliability (ICC = 0.98), high test-retest reliability (ICC =0.98), and construct validity: (r = –0.81 SARA) [24].

Timed Up and Go (TUG): The TUG measures the duration to stand, walk 3m, and turn 180° before returning to sit. The TUG indicates fall risk when scores are > 13.5 s in older adults with vestibular disorders. The TUG has high inter and intra-rater reliability. The Timed up and Go Dual Task challenge included a cognitive challenge (TUG Cog) of counting backwards from 100 by 3s. A TUG cognitive score of > 15 seconds in elderly subjects has been used to identify individuals with increased fall risk [28].

Gait velocity: The Ten Meter Walk Test (10MWT) measures gait velocity. Patients were asked to walk 10 meters, during which their comfortable gait speed was determined, with or without an assistive device. Normal age range values are available in community dwelling adults, and not explicitly known for patients with ataxia.

2.6 Data analysis

Data was confirmed to be normally distributed per the probability density function in SPSS (SPSS version 26, Chicago, IL, USA). We conducted a two-factor ANOVA considering diagnosis (healthy, ataxic) and semicircular canal (anterior, posterior, horizontal) for comparing VOR gains. Head velocity was compared across semicircular canal planes using an ANOVA. The level of statistical significance was set at alpha p < 0.05, with post-hoc analysis completed using the Bonferroni correction at an adjusted alpha of p≤0.016. Clinical outcome measures were examined for correlation using the Pearson Product-Moment Correlation Coefficient with a significance level set at alpha p≤0.05. A multiple regression analysis was performed between the OFI and SARA scores. Z-scores were calculated in Excel (MS office, Redmond WA, USA) to examine the number of standard deviations by which the mean VOR gains in ataxic patients were above or below the mean values observed in healthy controls. VOR gains were defined as abnormal when the ataxia subjects’ VOR gain values were two standard deviations outside of the mean VOR gain values of the healthy control subjects, among each of the six semicircular canals.

3 Results

3.1 Clinical and activity measures

The severity of oscillopsia in our patient cohort (mean 68.4±28.7) was comparable to the magnitude of oscillopsia reported in bilateral vestibular hypofunction (65.9±7.7) [2] Fig. 1. In addition, greater than 1/3 of ataxia patients had abnormal oculomotor exam findings, Fig. 2.

Fig. 1

Patients with ataxia have Oscillopsia Functional Index (OFI) scores comparable to those with bilateral vestibulopathy. Mean and 1 SD of Oscillopsia Functional Index (OFI) scores in cerebellar ataxia (solid line) are similar to those reported in bilateral vestibular hypofunction (dashed line). OFI mean and 1 SD: ataxia patients (68.4±28.7) (solid line), BVH patients (65.9±7.7) (dashed line), healthy controls (12.0±1.6) (dotted line). BVH and healthy control OFI data per Anson et al., 2018 [2].

Fig. 2

Summary of percentages of abnormal oculomotor results in all 19 subjects. SN = presence of spontaneous nystagmus, GEN= presence of gaze evoked and/or direction changing nystagmus, Pursuits = impaired smooth pursuit in horizontal or vertical direction. Saccades = hypo or hypermetric saccades in horizontal or vertical direction, slow VOR sinusoidal = absence of VOR reflex upon passive head rotation in yaw plane, VOR suppression = impaired suppression of VOR reflex with fixation during yaw rotation, Clinical yaw HIT = presence of overt catch up saccade during passive head rotation in yaw plane, Yaw vHIT = impaired VOR gains with video head impulse testing of the yaw plane. Vertical vHIT = impaired VOR gains with video head impulse testing among either of the two vertical canal planes.

The balance and gait activity measures were abnormal in all categories. OFI scores were inversely correlated with gait speed (r = –0.55, p < 0.05). SARA was correlated with both the TUG (r = 0.55, p < 0.05) and TUG cog (r = 0.69, p < 0.01). DGI was inversely correlated with TUG (–0.673, p < 0.01), TUG cog (r = –0.63, p = 0.05), and BARS (r = –0.56, p < 0.05). Additionally, the clinical measures grading severity of ataxia (SARA) and oculomotor function (BARS) were also abnormal. Each measure of fall risk (DGI: 14/24 (range 6–22); TUG: 15.2 s±9.5; Gait speed: 0.9 m/s±0.3) was abnormal reflecting ataxia patients with oscillopsia symptoms are a high risk for falls, Table 1. The multiple regression analysis revealed no correlation between OFI and SARA scores (R = 0.19, p = 0.21).

Table 1

Clinical and activity measures in ataxia patients are impaired

Clinical/Activity measures	Normative values	Patient (Mean±1SD)	Range
SARA	< 0.4	11.38±5.53	4.5–23.5
DGI	> 19/24	14.0±5.89	2–23
TUG (s)	< 11	15.18±8.9	7–37.1
Gait velocity (m/s)	1.24–1.34^*	0.97±0.35	0.25–1.49
BARS- oculomotor	0	1.2±1.0	0–2
OFI	< 12	68.4±28.7	13–116

SARA-Scale for Assessment and Rating of Ataxia, DGI –Dynamic Gait Index, TUG –Timed up and Go test. TUG cog- Timed up and Go test with a cognitive dual task. Gait velocity: ^*1.24–1.34 m/s = mean normative value in healthy community dwelling men and women respectively, ages 60–69, corresponding to the ataxia patients’ mean age [4]. BARS oculomotor- Brief Ataxia Rating Scale oculomotor sub-score, OFI –Oscillopsia Functional Index. Several functional tasks listed on the OFI were rated by patients, “not applicable”, including driving (28% responders), running (28%), needing to change a job due to symptoms (28%), or activities involving multi-task scenarios, i.e. walking while making a phone call (17%), sending a text (17%), or reading a shopping list while walking (6%).

3.2 VOR gain

The mean with two-standard deviation range of VOR gain for the healthy control subjects were: left horizontal canal (L HC) 0.75–1.11, right horizontal canal (R HC) 0.83–1.15, left anterior canal (L AC) 0.36–0.96, right anterior canal (R AC) 0.60–1.28, left posterior canal (L PC) 0.58–1.26, right posterior canal (R PC) 0.64–1.20. The percentage of ataxic patients outside of this normal range were as follows: L HC 58%, R HC 68%, L AC 37%, R AC 32%, L PC 11%, and R PC 37%. In addition, overt saccades (saccades during head motion in the direction of the VOR) were identified in 36% of patients.

VOR gain was not correlated with any clinical or activity outcome measure. Additionally, mean VOR gain differences among vertical canal planes were not correlated with OFI scores. The mean and 2SD VOR gains among the ataxic patients were significantly reduced compared with healthy controls (hSCC (0.76±0.73 vs 0.96±0.17) p < 0.001; aSCC (0.55±0.52 vs 0.80±0.32) p < 0.001; pSCC (0.61±0.41 vs 0.88±0.36) p < 0.001). The mean asymmetry of VOR gain among ataxia patients between the left and right semicircular canals was smallest in the horizontal canals (0.7% ±18.0, range 0–76.5%); and largest in the anterior semicircular canals (27.6% ±29.5, range 9.5–100%) with the posterior canals in the middle (11.5% ±6.8, range 3.8–21.7%). Passive head velocities administered were faster (p < 0.0001) for horizontal (157°/sec±24, range 130–208°/s) than vertical head rotations (anterior canals 118°/s±13, range 105–153°/s; posterior canals 118°/s±12, range 104–154°/s). The median VOR gain among healthy controls relative to ataxia patients is presented in Fig. 3.

Fig. 3

VOR gains with passive head rotation are impaired in ataxia patients versus healthy controls. The Box and whiskers plot indicate a range of VOR gain values of all 6 semicircular canal (SCC) planes using vHIT Otometrics ICS system. White boxes = 40 healthy controls. Gray boxes = 19 ataxia patients. The middle line represents the median VOR gain values, the edges of the boxes represent the median values of the 1st and 3rd quartiles. The edges of the whiskers = minimum and maximum VOR gain values. X = VOR mean gain values. Among all 19 subjects, abnormal VOR gains were observed in at least 1 SCC): Left (L), Right (R), Horizontal canal (H), Anterior canal (A), Posterior canal (P).

VOR gain values were more variable in ataxia patients than in healthy controls. The sum of variability of the VOR gains across all 6 SCCs relative to control mean VOR gains is illustrated by individual ataxia patients’ z-score, Fig. 4.

Fig. 4

VOR gains in patients were more varied than controls, reflected by the sum of Z-scores for 19 individual patients relative to VOR gain means in 40 controls. Z-score ranges: LH = –2.22–1.65, RH = –7.77–1.31, LA = –3.18–0.58, RP = –3.01–0.58, LP = –6.06–0.93, RA = –0.93–0.29. Please see figure legend from Fig. 1 for abbreviations.

Abnormal eye and head movement patterns were identified in each of the 19 patients with cerebellar ataxia. In particular, we noted four primary patterns: 1) Anti-compensatory saccades with normal, hypometric, or hypermetric VOR; 2) Hypermetric gain of the VOR; 3) Hypometric VOR responses with appropriate compensatory saccades; 4) Premature deceleration in normal and abnormal VOR gains Fig. 5.

Fig. 5

Abnormal eye patterns were identified with rapid passive head rotation in cerebellar ataxia patients and present in at least 1 semi-circular canal: A) Hypometric VOR responses with saccades, B) Hypermetric VOR, C) Anti-compensatory saccades with hypometricVOR, D) Pre-mature deceleration with abnormalVOR gains.

4 Discussion

Our data reveal patients with ataxia and reports of oscillopsia have a significantly abnormal VOR gain that correlates with impaired gait velocity and increased fall risk. However, the magnitude of oscillopsia did not correlate with VOR gain. To our knowledge, no other authors have correlated oscillopsia and activity with VOR gain in patients with cerebellar ataxia. VOR gain and report of oscillopsia has been examined in vestibular hypofunction, interestingly - with similar results. McGath et al. [19] reported no correlation of oscillopsia symptoms in patients with caloric reduction or impaired VOR with low frequency sinusoidal rotation tests. Bhansali et al. characterized oscillopsia in patients with loss of vestibular function and revealed a poor relationship between oscillopsia and dynamic visual acuity or whole-body rotation testing [3]. Grunfeld et al. [12] reported subjects with bilateral vestibular hypofunction and a perception of having little control over their health had worse oscillopsia handicap scores than those BVH subjects with a greater internal sense of control of their pathology. In addition, the velocity of retinal slip speed was negatively correlated with oscillopsia handicap score implying that patients with BVH and the largest magnitude retinal slip were least affected by oscillopsia. Conversely, Anson et al. reported worse oscillopsia visual analog scale (oVAS) scores as VOR gain was reduced (inverse correlation) in BVH [1].

The fall risk scores we report are consistent with pre-intervention activity impairments reported among cerebellar ataxia patients who participated in a home exercise program study [16]. The clinical, and activity measures among our cerebellar ataxia patients were all impaired relative to normative values and were not correlated with VOR gain.

We did not investigate cerebellar ataxia patients with known impaired static oculomotor fixation, such as downbeating nystagmus (DBN), who also experienced oscillopsia. One patient with SCA 8 reporting oscillopsia was assessed yet excluded from the analysis as this individual’s oculomotor symptoms were related to DBN and diplopia rather than head motion-induced oscillopsia. In this patient’s case, VOR gains were normal and the DBN and oscillopsia symptoms significantly improved in response to the potassium channel blocker, 4 amino-pyridine. Of interest however, Helmchen et al. reported that postural control can be maintained in people with downbeating nystagmus, thus oscillopsia during walking cannot solely account for the gait disorder of patients with DBN [15].

Another significant observation of this study was various abnormal eye movement patterns in response to passive head rotation in patients with cerebellar ataxia, likely reflecting unique degenerative processes of the cerebellum. Eye movement patterns associated with central VOR impairments have been reviewed by Halmagyi et al. [14]. Choi et al. reviewed abnormal eye movement patterns in ataxia and reported the presence of a hyperactive VOR gain with corrective saccades in the opposite direction, hypoactive gains in horizontal planes (unilaterally and or bilaterally), as well as the presence of cross coupled vertical corrective saccades in response to horizontal head rotations [6, 7].

The role of efference copy as a mechanism to reduce oscillopsia during active head rotations has not been investigated in patients with cerebellar ataxia. However, we may expect that oscillopsia during active (self-generated) head rotations may not be reduced given internal models of predictive control are typically impaired in cerebellar ataxia [33].

4.1 Limitations

While oscillopsia symptoms, measured via OFI scores, were correlated with activity measures, limb ataxia symptoms may have been a confounding variable of the OFI total score, although our multiple regression analysis revealed no correlation between OFI and SARA scores. We did not examine for eye rotations outside of the primary axis of head rotation, thus cannot speak to the whether the axis of eye rotation was impaired. Additionally, we did not evaluate eye movement patterns over multiple time points, nor explore possible evidence of anticipatory eye movements.

5 Conclusion

Oscillopsia during head motion among cerebellar ataxia patients correlates with gait velocity, but not VOR gain. VOR gains in the ataxia patients were significantly reduced and variable relative to healthy controls. Abnormal VOR gains and eye/head movement patterns were present in at least one semicircular canal for all patients, during VHIT with passive head rotation. Future research to improve our understanding of the magnitude of oscillopsia symptoms and neurophysiology during activity is warranted to improve treatment outcomes and quality of life among patients with ataxia.

5.1 Ethics Statement

Retrospective clinical data collection of the ataxia patients was approved by the Johns Hopkins Medicine Institutional Review Board, IRB00138970. Prospective healthy control data was collected with the support from the Department of Defense under the Neurosensory and Rehabilitation Research Award Program (W81XWH-15-1-0442) and approved by the Johns Hopkins Institutional Review Board, IRB00059430.

Footnotes

Acknowledgments

The authors wish to thank the Johns Hopkins Ataxia Center patients, Clinic Director, Liana Rosenthal, MD, PhD, as well as the healthy control volunteers.

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