Abnormal Vestibular-Ocular Reflexes in Children With Cortical Visual Impairment

To determine whether the vestibular-ocular reflexes (VORs) can be affected by central nervous system injury in children with cortical visual impairment (CVI

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Abnormal Vestibular–Ocular Reflexes in Children With Cortical Visual Impairment Sasha A. Mansukhani, MBBS, Mai-Lan Ho, MD, Michael C. Brodsky, MD Background: To determine whether the vestibular–ocular reflexes (VORs) can be affected by central nervous system injury in children with cortical visual impairment (CVI). Methods: Retrospective case series. Twenty consecutive children with CVI who presented to a pediatric ophthalmology practice over an 18-month period were included in the study. Horizontal and vertical VORs were assessed by a pediatric neuro-ophthalmologist using the standard doll’s head maneuver. MRI studies were independently reviewed by a pediatric neuroradiologist in a masked fashion. The main outcome measures were the integrity of the VORs and the presence of brainstem abnormalities on MRI. Results: VORs were found to be absent or severely impaired in 13/20 (65%) children with CVI. More surprisingly, the doll’s head maneuver failed to substantially overcome the deviated eye position in 8/13 (62%) children with conjugate gaze deviations. Reduced brainstem size and signal abnormalities were found in 4/7 children with normal VORs and in 9/13 children with abnormal VORs (P = 0.6), showing noncorrelation with the integrity of the VOR. Conclusion: VORs are commonly impaired in children with CVI. This ocular motor deficit reflects the diffuse cortical and subcortical injury that often accompanies perinatal injury to the developing brain. Consequently, these children may lack important visual compensatory mechanisms to stabilize gaze during head movements. This knowledge can help in planning visual rehabilitation. Journal of Neuro-Ophthalmology 2021;41:531–536 doi: 10.1097/WNO.0000000000000999 © 2020 by North American Neuro-Ophthalmology Society Department of Ophthalmology (SAM, MCB), Mayo Clinic, Rochester, Minnesota; Department of Neurology (MCB), Mayo Clinic, Rochester, Minnesota; Department of Radiology (MLH), Nationwide Children’s Hospital, Columbus, Ohio; and Department of Neurology (MCB), Rochester, Minnesota. Supported by Knights Templar Eye Foundation, Mounds View, TX and Mayo Foundation, Rochester, MN. The sponsor or funding organization had no role in the design or conduct of this research. The authors report no conflicts of interest. Address correspondence to Michael C. Brodsky, MD, Department of Ophthalmology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; E-mail: [e-mail]. Mansukhani et al: J Neuro-Ophthalmol 2021; 41: 531-536 C ortical visual impairment (CVI) is a devastating neurological cause of congenital blindness. Often attributed to perinatal hypoxic–ischemic injury to watershed areas within the visual cortex, associated genetic and prenatal causes are increasingly being described (1–4). MRI classically shows injury to the visual cortex with associated injury to the subcortical white matter, thalamus, basal ganglia, brainstem, and cerebellum. These secondary areas of injury can compound the visual deficit by disrupting the development of visual attention centers within the brain (5,6). In children with CVI, the ocular motor system is commonly abnormal (7,8). Although pupillary responses are generally preserved (at least at the clinical level), exotropia and horizontal conjugate gaze deviation are often present (9). A recent study has found that the vestibular–ocular reflex (VOR) may be affected in children with cerebral palsy (CP), which often occurs concurrently with CVI (10). In addition to its functional significance to the patient, impairment of VORs could provide a useful clinical assessment of associated subcortical injury involving the brainstem. To clarify this issue, we documented the horizontal and vertical VORs in a cohort of children with CVI and correlated with MRI findings. MATERIALS AND METHODS We retrospectively identified 20 consecutive patients presenting with CVI who were examined in a pediatric neuroophthalmology practice (MCB) over the 18-month period between September 2016 and March 2018. In order to be included in the study, the chart was reviewed to evaluate whether the definition of CVI was met. CVI was defined when decreased visual function was associated with neurological impairment, and MRI showed posterior visual pathway abnormalities correlating with the extent of visual impairment. Patients were excluded if ocular causes such as cataract, strabismus, optic nerve hypoplasia, or optic atrophy could entirely explain the visual deficit. Patient charts were reviewed for history and ocular and neurological 531 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution findings reported by a pediatric neuro-ophthalmologist and pediatric neurologist. The presence or absence of VORs, baseline conjugate gaze deviation, and optokinetic responses were specifically noted. The VOR was tested clinically by performing the doll’s head maneuver, which consisted of rotating the child’s head left, right, up, and down, over a 1-second period to look for a normal compensatory rotation of the eyes within the orbits. This test is routinely performed in all CVI patients in our pediatric neuroophthalmology clinic. A positive (normal) VOR was defined by a contraversive movement of the eyes within the orbit that maintained the position of the eyes in space. A negative VOR was defined as the absence of any contraversive movement of the eyes, causing the eyes to move in lockstep with the head. An impaired VOR was defined as a partial contraversive ocular rotational response to head rotation. When testing the VORs in children who manifested a conjugate gaze deviation of the eyes, the head was initially positioned to directionalize the eyes toward the examiner’s face so that the examiner could readily detect even small contraversive rotations of the eyes during forced head rotation. The head was then rotated toward the direction of the tonic gaze deviation to see whether the VOR could override the tonic deviation. In a child with a right horizontal conjugate gaze deviation, for example, the head was positioned maximally to the left so that the ensuing head rotation to the right could produce a contraversive VOR to the left. Because horizontal conjugate gaze deviation is frequently accompanied by an ipsiversive head turn in the setting of CVI, this maneuver required rotating the head 180° to reach the necessary starting point to accurately assess the VORs. All VOR assessments were made by a pediatric neuro-ophthalmologist (MCB). MRI were reviewed by a pediatric neuroradiologist who was masked to the VOR abnormalities. The presence, location, and characteristics of cortical, basal ganglia, and brainstem injuries were documented. The proportion of MRI brainstem, and other structure abnormalities such as cortical, subcortical and periventricular white matter, basal ganglia, thalamus, and cerebellum in children with normal and impaired VORs was compared using the Fisher exact test. The study was conducted with approval from the Institutional Review Board at the Mayo Clinic, Rochester, MN. All experiments and data collection were conducted in compliance with the Health Insurance Portability and Accountability Act. RESULTS Of the 20 children with CVI, median age was 3 years (range, 4 months to 9 years), and 14 (70%) of 20 were female. Based on the integrated review of clinical and imaging features, the etiology of CVI was hypoxic–ischemic encephalopathy in 5 (25%), intraventricular hemorrhage of 532 prematurity in 3 (15%), traumatic brain injury in 3 (15%), congenital brain abnormality in 3 (15%), seizures in 2 (10%), unknown in 2 (10%), neonatal stroke in 1 (5%), and congenital hydrocephalus in 1 (5%). CP was present in 15 (75%) of the children with dyskinetic features in 4 (27%) of these patients. Ocular and systemic features are shown in Table 1. Mild optic atrophy was present on ophthalmologic examination in 11 (55%) patients; however, there was no infantile nystagmus, suggesting that the atrophy was not the primary cause of the visual loss (11). Thirteen (65%) of 20 patients had absent or severely impaired VORs, and 6 (30%) of 20 patients had completely absent VORs in at least 1 plane. The doll’s head maneuver was unable to overcome the eye positions in 8 (62%) of 13 children with tonic gaze deviations. Thus, a compensatory ocular movement in the opposite direction of the head rotation could not be evoked in these children so that the eyes moved in lockstep with the head during the forced turn. Nine of the 13 with absent or severely impaired VORs had abnormalities of the brainstem on MRI, whereas 4 of the 7 with normal VORs (69% vs. 57%; P = 0.6) had abnormalities of the brainstem (Fig. 1). Occipital gray matter abnormalities were detectable in 14 (70%) of 20 children, whereas 18 (90%) of 20 children had subcortical and periventricular white matter signal changes including occipital lobes. Thalamic, basal ganglia, and cerebellar signal changes or atrophy were evident in 14 (70%), 12 (60%), and 2 (10%) of 20 children, respectively. There was no difference in the involvement of the following structures among children with abnormal and normal VORs: cortical (P = 0.6), subcortical and periventricular white matter (P = 1.0), basal ganglia (P = 1.0), thalamus (P = 0.3), and cerebellum (P = 1.0). Sixteen (80%) of 20 children were on seizure medication at the time of VOR testing. Of the 4 patients not on seizure medication, 2 had impaired VORs, and 1 had absent VORs. Hearing was normal in 17 (85%) of 20 children, tested by otoacoustic emission or auditory brainstem response testing. Of the 3 (15%) children with sensorineural hearing impairment, 2 had mild hearing loss, whereas 1 had severe hearing loss. DISCUSSION The finding of absent or reduced VORs in 65% of our patients is inconsistent with the antiquated notion of CVI as a selective watershed injury to the visual cortex. VORs have been demonstrated to be well developed in infants as early as 1 month of age (12,13). Animal studies and case reports in humans have shown that VORs are essentially intact after injury limited to the cortex (14–16). There has been a growing understanding that the term hypoxic– ischemic injury is just one of many potential etiologies for CVI, with others including prematurity, traumatic brain injury, and genetic disease. Indeed, MRI has expanded our understanding of CVI to comprise a more global injury to Mansukhani et al: J Neuro-Ophthalmol 2021; 41: 531-536 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Historical, demographic, and clinical characteristics of 20 children diagnosed with CVI Age/Sex 9 y, M History and Systemic Features Preterm (32 wks), Lennox– Gastaut syndrome, developmental delay, and chromosome 22q11.2 duplication 4 y, F Preterm (36 wks), neonatal stroke, and seizures 3 y, M Full term, seizures, developmental delay, and phenotypically Cornelia de Lange syndrome 5 y, F Full term, congenital hydrocephalus due to aqueductal stenosis, seizures, developmental delay, and excess chromosomal homozygosity on microarray; probable AR congenital hydrocephalus 2 y, M Preterm (34 wks), intraventricular hemorrhage, development delay, and West syndrome 18 m, M Full term, developmental delay, and lissencephaly (LIS1 mutation c.430C.T) 3 y, F Full term, seizures, and traumatic brain injury from car accident at 1 mo age 7 y, F Full term, infantile spasm (CDKL5 mutation), and developmental delay 4 y, F Full term, right spastic hemiparesis, seizures, developmental delay, and nonaccidental head injury at 3 mo 8 y, F Full term, hypoxic-ischemic encephalopathy, neonatal seizures, and developmental delay 7 y, F Full term, seizures, developmental delay, and traumatic brain injury at 3 mo of age 7 m, M Full term, seizures, microcephaly, developmental delay, and congenital cortical malformations OKN Pupillary Response Strab Tonic Hor Gaze Tonic Vert Gaze Optic Atrophy VOR Hor VOR Vert + Brisk XT Right No Present Impaired Impaired 2 Brisk ET Right Down Present Absent Absent + Brisk 2 No No Present Impaired Impaired 2 Brisk XT No Down Absent Absent Absent + Brisk ET No Down Present Present Present + Brisk XT No No Absent Present Present + Brisk ET Right No Present Impaired Impaired 2 Brisk XT No No Absent Present Present + Brisk ET Right Down Present Impaired Impaired 2 Brisk ET No No Present Present Present + Brisk 2 Left Down Absent Impaired Impaired 2 Sluggish XT No Up Absent Absent Absent Mansukhani et al: J Neuro-Ophthalmol 2021; 41: 531-536 533 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Age/Sex 3 y, F 2 y, F 4 y, F 4 m, F 2 y, M 8 y, F 2 y, F 8 m, F History and Systemic Features Full term, seizures, neonatal encephalopathy of unclear etiology, and developmental delay Full term, seizures, developmental delay, and neonatal anoxic encephalopathy Full term, neonatal encephalopathy, developmental delay, and Lennox–Gastaut syndrome (ADCY5 variant of unknown significance) Preterm (36 wks), seizures, congenital cortical malformation, and maternal methamphetamine use Preterm (34 wks) and developmental delay Full term, seizures, developmental delay, and hypoxic ischemic encephalopathy Full term and developmental delay (DDX3X mutation c.1438A.G). Full term, seizures, developmental delay and hypoxic ischemic encephalopathy OKN Pupillary Response Strab Tonic Hor Gaze Tonic Vert Gaze Optic Atrophy VOR Hor VOR Vert + Brisk XT Left No Present Impaired Impaired + Sluggish 2 Left No Present Present Absent 2 Sluggish XT No No Absent Present Present 2 Sluggish XT Left No Absent Present Present 2 Sluggish ET No Up Absent Absent Present + Sluggish XT No Down Present Absent + Brisk XT No No Absent Impaired Unable to move the head Impaired + Brisk XT Left No Present Present Present AR, autosomal recessive; CVI, cortical visual impairment; ET, esotropia; Hor, Horizontal; OKN, optokinetic nystagmus; Strab, Strabismus; Vert, Vertical; VOR, vestibulo ocular reflex; XT, exotropia. the developing brain. Depending on the severity, duration, and timing of injury, associated involvement of the subcortical structures including thalami, cerebellum, and brainstem have been described (17–20) and contribute to the overlap of CVI with CP (21). Abnormal ocular alignment and eye movements have been described in patients with CVI and CP (7,9,10,22). A previous study performed in 14 children with severe dyskinetic CP found that this subtype is often associated with dyskinetic eye movements, which can result in overestimation of the degree of CVI. In a previous study, children with perinatal cortical visual loss display a horizontal conjugate gaze deviation of their eyes to 1 side (9). They attributed this finding to asymmetric injury to conjugate gaze centers within the cerebral hemispheres. We have since observed that this horizontal conjugate gaze deviation is accompanied by an ipsiversive tonic head turn, which effectively directs gaze back behind the head. This finding differentiates CVI from other common causes of head turns such as 534 incomitant strabismus or infantile nystagmus, wherein the head turn is contraversive to the tonic gaze deviation. Our finding that this horizontal conjugate gaze deviation could not be reversed with the doll’s head maneuver in most patients indicates the presence of direct injury to the prenuclear VOR pathways within the brainstem. This central vestibular etiology is supported by the finding that most patients in our study had normal auditory function tests. The common usage of antiepileptic medications may have also diminished the VOR responses in some cases (23). Perinatal cortical visual injury has been shown to produce some degree of transsynaptic degeneration of pupillary pathways (24). Transsynaptic degeneration of subcortical pathways could exert a similar effect on the vestibular–ocular pathways. For example, a recent study found that slow pupillary light responses were associated with periventricular leukomalacia in premature infants at risk of developing CP (21) and attributed this pupillary dysfunction to diffuse disruption of the cortical–subcortical Mansukhani et al: J Neuro-Ophthalmol 2021; 41: 531-536 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. A. Axial T2-weighted image shows signal hyperintensity (arrows) and volume loss within the dorsal pons. B. Axial T2weighted image shows signal hyperintensity (arrows) and volume loss within the midbrain. connectivity (25). Drawing a parallel with the vestibular system, several recent animal studies have demonstrated “top-down” modulation of the VOR (26). These studies describe a network extending from the parietotemporal, retroinsular, and the prefrontal cortex directly to the vestibular nuclei complex, suggesting a link between cortical and vestibular function. In humans, there are clinical reports of cortical lesions leading to asymmetric or abnormal VORs (27,28). Although injury to this cortico–vestibular modulation could explain the VOR dysfunction in some of our patients, particularly those with unremarkable brainstem morphology on MRI, cortical injury alone would not produce complete obliteration of VORs as observed in some of our patients. A recent study of children with CP found intact VORs at low frequency but impaired VORs at higher frequency of head turns along with other evidence of impaired vestibular and balance abilities (10). They hypothesized that children with CP have intact peripheral vestibular systems but have central vestibular pathology. Similarly in patients with CVI, although cortical injury may have been contributory, central vestibular dysfunction is most likely responsible for impaired VORs. There are significant limitations to this study. The study was retrospective with utilization of routine MRI protocols, which are of 4–5 mm slice thickness and, therefore, less sensitive to minor structural brain abnormalities in infants. Utilization of advanced MR sequences including highresolution anatomic imaging, diffusion tensor imaging for Mansukhani et al: J Neuro-Ophthalmol 2021; 41: 531-536 white matter microstructure, arterial spin labeling for cerebral perfusion, and/or spectroscopy for metabolism could conceivably enhance the detection of injury to prenuclear ocular motor structures. Other limitations include the small cohort of patients, the clinical variability in terms of age at presentation and neuroimaging acquisition, and the absence of precise VOR quantification using eye tracking systems under conditions of low and high-frequency head rotation. Although this was a small cohort, the absence of VORs in many children clearly demonstrated that the vestibular– ocular system can be severely affected in children with CVI. Although 16 children were on antiepileptic medications, which can reduce VOR responses, they are unlikely to completely abolish VORs, and impaired VORs were also found in 3 children not taking antiepileptic medications. All patients were from a tertiary clinic and a single center and are subject to selection bias. Finally, because of difficulties quantifying vision due to age and behavioral limitations, we were unable to assess whether the presence of VOR impairment correlates with more severe degrees of CVI. Despite these limitations, however, the clinical limitations of this study are significant for children with CVI. For example, it has been estimated that blur caused by retinalimage slip moving as slow as 1°/second has about the same effect on acuity as 3 diopters of myopia (29). Disruptions in head stability during locomotion (possibly even when stationary if poor neck muscle control) in children with CVI can have exponential effects of degradation of vision in the 535 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution setting of impaired VORs. This study provides preliminary data useful in planning a prospective and quantitative study to address the clinical impact of this ocular motor deficit. Our finding that the VORs are frequently absent or impaired in children with CVI reinforces the global nature of perinatal brain injury (30). More importantly, it demonstrates that some patients with CVI may lack important visual compensatory mechanisms to stabilize gaze during head movements. Finally, VOR impairment may potentially enable some children with CVI and impaired gaze control to use head movements to redirect their gaze to objects of interest. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. A. Mansukhani, M. L. Ho, and M. C. Brodsky; b. Acquisition of data: S. A. Mansukhani, M. L. Ho, and M. C. Brodsky; c. Analysis and interpretation of data: S. A. Mansukhani, M. L. Ho, and M. C. Brodsky. Category 2: a. Drafting the manuscript: S. A. Mansukhani, M. L. Ho, and M. C. Brodsky; b. Revising it for intellectual content: S. A. Mansukhani, M. L. Ho, and M. C. Brodsky. Category 3: a. Final approval of the completed manuscript: S. A. Mansukhani, M. L. Ho, and M. C. Brodsky. REFERENCES 1. Bosch DG, Boonstra FN, Reijnders MR, Pfundt R, Cremers FP, de Vries BB. 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