VEP visual acuity in children with cortical visual impairment

Given improvements in neonatal care and the increased survival rates of infants born pre-term, Cortical Visual Impairment (CVI) is now the leading cause of visual impairment (VI) in the developed world. In this study, Step VEPS, transient VEPS and Vernier Sweep VEPs all demonstrated unbiased relationships with Preferential looking (PL) cards over the whole range of Visual Acuity (VA) in children with CVI, allowing equations for clinical use to be derived. The results also suggested that a slower, vernier steady-state stimulus of 80% contrast and presented with the Step VEP algorithm could further improve VA agreement with PL and optimise developmental sensitivity.

An eye tracking device has proved very useful in the clinical assessment of this cohort. It is also now known that children can have good VA and CVI, and that sweep VEPS can highlight higher processing deficits. As well as negative findings, compensatory neuroplasticity is thought to occur during maturation and it is now realistic to study this mechanism, and other age-related changes across VI with functional tests and neuroimaging (including VEPS). A cross-sectional study of adults would highlight CVI’s ultimate functional limitations.

Cerebral Visual Impairment and Cortical Visual Impairment (CVI) are slightly different terms for pre-perinatal hypoxic damage to the post-chiasmal visual pathway causing a reduction in Visual Acuity (VA) and other functions [1,2]. Terminology in the literature has been governed by geography [3] and the work that the scientific researcher is exposed to. Given improvements in neonatal care and the increased survival rates of infants born pre-term, CVI is now the leading cause of visual impairment in the developed world [4]; in 2000, 197 diagnoses of CVI were made among 483 children born with Severe Visual Impairment (SVI) in the UK [5].

Table 1 ranks the visual manifestations of CVI according to prevalence; the majority of patients have impaired visual perception, reduced VA, altered smooth pursuit, strabismus, and nystagmus. In Cerebral Palsy (CP), the proximity of lesions to the motor pathways (i.e. periventricular leukomalacia) to the visual pathways means that CP and CVI often co-occur [6]. In children with CP, the severity of Visual Impairment (VI) and motor deficits (MD) tends to correlate [7], and vision is known to improve with age given maturation of the visual system and adaptive neuroplasticity [8].

MD can make any assessment difficult [9,10] and solutions proposed for directing VEP stimuli onto the retina given poor VA [11] are highly relevant. Projection of the stimulus onto three walls of a room may also help, however, ISCEV field size requirements would be exceeded [12,13]. Historically, t-VEPS were used to test children and other challenging cohorts such as those with CVI, and extrapolation of the spatial frequency-amplitude function was used to establish a threshold [14]. However, given its apparent ability to provide complete VA assessment of all patients, the sweep VEP dominated the academic literature from the mid-eighties, with different tests emerging after the Millenium [15]. Equations were derived to express Step VEP VA in terms of subjective VA in a broad Neuro-Ophthalmological cohort [11] and optically degraded normal adults [16], providing a metric that was easy for all clinicians to interpret. Publication of this methodology meant that similar formulae could be calculated by workers using commercial VEP systems.

A recent systematic review [17-19] presented results from just four studies of VA in CVI where both sweep VEPs and PL were measured successfully, and these results will be considered alongside locally collected data using t-VEPs and Step VEPs. The aim of the study is to investigate the relationship between VEP and subjective VA in children with CVI.

Prospective patients referred to a pediatric neuro-ophthalmological clinic had VA assessed with Preferential Looking cards and either t-VEPs or Step VEPs. The VA comparison of PL and Step VEPs in the whole cohort using has been published previously [11]. However, further consideration of the complete clinical work-up allowed a small proportion of these children to be sub-categorized as having CVI. The uniqueness of this study, enabled by the technical development of the Step VEP, meant that a-priori power calculations for the comparisons was not possible. An equivalent group of children receiving t-VEPs were also identified [15] and this thesis also provides details of the stimulation and recording parameters of VEPs, which met with contemporaneous ISCEV technical standards [20]. Children wore any prescribed refractive correction for all modalities of assessment. Separate analyses were performed on successful pairs of t-VEPs and PL, Step VEPS and PL, and sweep VEP vs PL from the work of Good, et al. [19], Lim, et al. [20] and Watson, et al. [21].

The agreement and relationship between methods were investigated using Bland-Altman Analysis (BA-A) [22] and regression, according to our published methodology [16]. If BA-A revealed an absence of bias in the agreement between tests across all VA, then the relationship was expressed using a regression equation.

31 children successfully underwent Step VEPs and PL and had a mean age of 2.8 years (SD 3.20) and a mean VA of 0.70 LogMAR (0.51). 19 children successfully underwent t-VEPs and PL and had a mean age of 2.47 years (4.20), with a mean VA of 1.08 LogMAR (0.58). While the ages are matched, the difference in VA is both clinically and statistically significant (0.38 poorer for the t-VEP group). WHO definitions of visual impairment (Table 2) place the t-VEP and Step VEP groups in the ‘severe’ and ‘moderate’ categories respectively.

The key parameters of BA-A and regression analyses are given in Table 3 and exclude the data of two patients in the Step VEP group that were classed as outliers. This does not prevent the resulting equations being applicable to all children with CVI completing the test. BA-A revealed that no bias was present across the range of VA for either group in this study and so regression equations were derived (Table 4). A post-hoc power calculation demonstrated that these analyses have 100% power. Bias was also absent in the vernier sweep VEP data of Watson, et al. [21] allowing an additional equation was derived. All these equations required a constant term to fulfil the mathematical requirement of homoscedasticity [23].

The first finding is that CVI with VA in WHO’s ‘Moderate Visual Impairment’ category is just as common as ‘Severe Visual Impairment’. Moreover, two recent publications [24,25] found near normal VA alongside higher processing deficits and a diagnosis of CVI.

Adequate BA-A test statistics for Step VEPS and the Vernier sweep VEPs of Watson, et al. [21] suggest the vernier offset stimulus, and the real-time analysis and presentation are more suited to these children than swept vertical sine-wave gratings. The longer trajectory to maturation for vernier than sinusoidal grating sweep VEP VA (four years vs one year) [26] contributes to the explanation. Incidentally, this duration is doubled for psychophysical VA employing static versions of the same stimuli [27] emphasizing the effect of temporal modulation. The normal maturation of Step VEP VA has yet to be studied, but we do know that suprathreshold pattern-onset VEPs show latency [28] and morphological changes [29] into adulthood.

The relatively large test statistics for the t-VEP stimulus in this study reflect consistent results between patients, suggesting that a slower stimulus rate is suited to children with CVI. These consistently good agreements between tVEPS and PL parallels larger step VEPS studies in adults [16] and pediatric patients [11]. Also, a recent sweep VEP study [30] used a slower reversal rate for grating VA and contrast sensitivity measurement in this cohort.

Low luminance has now been proven to work well in sweep VEP VA assessment of CVI [31] but technical nuances require expert ophthalmological and scientific input at all times. In the 2012 Smith-Kettlewell study [30], the electrophysiological contrast sensitivity function has a larger dynamic range across patient ability than the spatial-frequency amplitude function, making it distinctively useful in monitoring individual progression over time. Performing VEPs at the peak of an individual contrast sensitivity function (typically 80%) may improve SNR (Gordon Dutton personal communication) and make the test more sensitive to anatomical and physiological development.

Sweep VEP VA (the outcome rather than the whole spatial frequency-amplitude function) has demonstrated improvement over time in children with CVI [32], and complementary functional assessments (Table 5; [33]) and neuroimaging could give further insights into the temporal processing limitations of these patients, and the effect of feedback from the dorsal and ventral streams on VEPs [34]. Functional neuroimaging would also be useful in the investigation of the neuroplastic compensatory processes [25].

The discovery of complex motion processing deficits in the absence of significant VA loss in CVI [24] highlights the limitations of the WHO definitions of VI. In the same demographic, other dorsal stream deficits were detected by the Higher Visual Function Question Inventory (HVFQI-51) [25] and there is clearly much left to learn about this condition.

Theoretically, the functional deficits of CVI should affect PL scores of VA more than VEPs given their need for eye movement. However, that did not prevent us finding good agreement between them in our study and one published experiment. These factors may, however, have contributed to poorer agreements during historical comparisons of sweep VEP and PL VA [19,20]. An eye tracking device presenting gratings agreed well with PL in pediatric CVI [35] and could become clinically useful in this cohort.

Knowledge of the normal maturation of Step VEPs should aid its interpretation in children, and for those with CVI, agreement with PL could be enhanced by employing a slower, Vernier stimulus. Consideration of the spatial-frequency-amplitude function may provide further insights to development, and a longitudinal, functional study including VEPs would reveal detail about maturation in CVI including compensatory neuroplasticity. An adult study may also be required to understand the ultimate functional limitations of this condition.

Thank you to my parents Alistair and Margaret Mackay for feeding me and believing in me. I would also like to thank the late Zandra Mackay, a nurse in the UK NHS, whose will helped with the cost of this project. Finally, I would like to cite Mr. Arvind Chandna and Mr. Sean Chen for inspiration in following through with one academic goal no matter what.

Declarations

The data were collected at the Royal Hospital for Sick Children in Glasgow, UK under the guidance of a Neuro-Ophthalmologist (GD) and a Clinical Scientist (MB).

The research followed the tenets of the declaration of Helsinki.

The author has no conflicts of interest to declare and did not receive any formal funding for this analytical project.

1. Chokron S, Kovarski K, Dutton GN. Cortical Visual Impairments and Learning Disabilities. Front Hum Neurosci. 2021 Oct 13;15:713316. doi: 10.3389/fnhum.2021.713316. PMID: 34720906; PMCID: PMC8548846.
2. Fazzi E, Signorini SG, Bova SM, La Piana R, Ondei P, Bertone C, Misefari W, Bianchi PE. Spectrum of visual disorders in children with cerebral visual impairment. J Child Neurol. 2007 Mar;22(3):294-301. doi: 10.1177/08830738070220030801. PMID: 17621499.
3. Colenbrander A. What’s in a Name? Appropriate Terminology for CVI. Journal of Visual Impairment and Blindness 104 (10): 583-585.
4. Pehere N, Chougule P, Dutton GN. Cerebral visual impairment in children: Causes and associated ophthalmological problems. Indian J Ophthalmol. 2018 Jun;66(6):812-815. doi: 10.4103/ijo.IJO_1274_17. PMID: 29785989; PMCID: PMC5989503.
5. Rahi JS, Cable N; British Childhood Visual Impairment Study Group. Severe visual impairment and blindness in children in the UK. Lancet. 2003 Oct 25;362(9393):1359-65. doi: 10.1016/S0140-6736(03)14631-4. PMID: 14585637.
6. Fazzi E, Signorini SG, LA Piana R, Bertone C, Misefari W, Galli J, Balottin U, Bianchi PE. Neuro-ophthalmological disorders in cerebral palsy: ophthalmological, oculomotor, and visual aspects. Dev Med Child Neurol. 2012 Aug;54(8):730-6. doi: 10.1111/j.1469-8749.2012.04324.x. Epub 2012 Jun 19. PMID: 22712803.
7. Dufresne D, Dagenais L, Shevell MI; REPACQ Consortium. Spectrum of visual disorders in a population-based cerebral palsy cohort. Pediatr Neurol. 2014 Apr;50(4):324-8. doi: 10.1016/j.pediatrneurol.2013.11.022. Epub 2013 Dec 5. PMID: 24468636.
8. Galli J, Loi E, Molinaro A, Calza S, Franzoni A, Micheletti S, Rossi A, Semeraro F, Fazzi E; CP Collaborative Group. Age-Related Effects on the Spectrum of Cerebral Visual Impairment in Children With Cerebral Palsy. Front Hum Neurosci. 2022 Mar 2;16:750464. doi: 10.3389/fnhum.2022.750464. PMID: 35308614; PMCID: PMC8924515.
9. Orel-Bixler D, Haegerstrom-Portnoy G, Hall A. Visual assessment of the multiply handicapped patient. Optom Vis Sci. 1989 Aug;66(8):530-6. doi: 10.1097/00006324-198908000-00007. PMID: 2528103.
10. Mackie RT, McCulloch DL. Assessment of visual acuity in multiply handicapped children. Br J Ophthalmol. 1995 Mar;79(3):290-6. doi: 10.1136/bjo.79.3.290. PMID: 7703212; PMCID: PMC505081.
11. Mackay AM. Step VEP visual acuity in a pediatric Neuro-Ophthalmological cohort. Int. J Clin Exp Ophthalmol. 2022; 6: 026-030.
12. Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Mizota A, Tormene AP; International Society for Clinical Electrophysiology of Vision. ISCEV standard for clinical visual evoked potentials: (2016 update). Doc Ophthalmol. 2016 Aug;133(1):1-9. doi: 10.1007/s10633-016-9553-y. Epub 2016 Jul 21. PMID: 27443562.
13. Hamilton R, Bach M, Heinrich SP, Hoffmann MB, Odom JV, McCulloch DL, Thompson DA. ISCEV extended protocol for VEP methods of estimation of visual acuity. Doc Ophthalmol. 2021 Feb;142(1):17-24. doi: 10.1007/s10633-020-09780-1. Epub 2020 Jul 16. PMID: 32676804; PMCID: PMC7906925.
14. Sokol S. Measurement of infant visual acuity from pattern reversal evoked potentials. Vision Res. 1978;18(1):33-9. doi: 10.1016/0042-6989(78)90074-3. PMID: 664274.
15. Mackay AM. Estimating Children’s Visual Acuity with Steady State VEPS. PhD Thesis. University of Glasgow. 2002.
16. Mackay AM, Bradnam MS, Hamilton R, Elliot AT, Dutton GN. Real-time rapid acuity assessment using VEPs: development and validation of the step VEP technique. Invest Ophthalmol Vis Sci. 2008 Jan;49(1):438-41. doi: 10.1167/iovs.06-0944. PMID: 18172123.
17. Hamilton R, Bach M, Heinrich SP, Hoffmann MB, Odom JV, McCulloch DL, Thompson DA. VEP estimation of visual acuity: a systematic review. Doc Ophthalmol. 2021 Feb;142(1):25-74. doi: 10.1007/s10633-020-09770-3. Epub 2020 Jun 2. PMID: 32488810; PMCID: PMC7907051.
18. Brigell M, Bach M, Barber C, Moskowitz A, Robson J; Calibration Standard Committee of the International Society for Clinical Electrophysiology of Vision. Guidelines for calibration of stimulus and recording parameters used in clinical electrophysiology of vision. Doc Ophthalmol. 2003 Sep;107(2):185-93. doi: 10.1023/a:1026244901657. PMID: 14661909.
19. Good WV. Development of a quantitative method to measure vision in children with chronic cortical visual impairment. Trans Am Ophthalmol Soc. 2001;99:253-69. PMID: 11797314; PMCID: PMC1359017.
20. Lim M, Soul JS, Hansen RM, Mayer DL, Moskowitz A, Fulton AB. Development of visual acuity in children with cerebral visual impairment. Arch Ophthalmol. 2005 Sep;123(9):1215-20. doi: 10.1001/archopht.123.9.1215. PMID: 16157801.
21. Watson T, Orel-Bixler D, Haegerstrom-Portnoy G. VEP vernier, VEP grating, and behavioral grating acuity in patients with cortical visual impairment. Optom Vis Sci. 2009 Jun;86(6):774-80. doi: 10.1097/OPX.0b013e3181a59d2a. PMID: 19390471; PMCID: PMC3862531.
22. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986 Feb 8;1(8476):307-10. PMID: 2868172.
23. Osborne JW, Waters E. Four assumptions of multiple regression that Researchers Should Always Test. Practical Assessment, Research and Evaluation. 2002; 8(2).
24. Chandna A, Nichiporuk N, Nicholas S, Kumar R, Norcia AM. Motion Processing Deficits in Children With Cerebral Visual Impairment and Good Visual Acuity. Invest Ophthalmol Vis Sci. 2021 Nov 1;62(14):12. doi: 10.1167/iovs.62.14.12. PMID: 34779820; PMCID: PMC8606874.
25. Chandna A, Ghahghaei S, Foster S, Kumar R. Higher Visual Function Deficits in Children With Cerebral Visual Impairment and Good Visual Acuity. Front Hum Neurosci. 2021 Nov 16;15:711873. doi: 10.3389/fnhum.2021.711873. PMID: 34867236; PMCID: PMC8636735.
26. Skoczenski AM, Norcia AM. Development of VEP Vernier acuity and grating acuity in human infants. Invest Ophthalmol Vis Sci. 1999 Sep;40(10):2411-7. PMID: 10476810.
27. Carkeet A, Levi DM, Manny RE. Development of Vernier acuity in childhood. Optom Vis Sci. 1997 Sep;74(9):741-50. doi: 10.1097/00006324-199709000-00022. PMID: 9380372.
28. Brecelj J, Strucl M, Zidar I, Tekavcic-Pompe M. Pattern ERG and VEP maturation in schoolchildren. Clin Neurophysiol. 2002 Nov;113(11):1764-70. doi: 10.1016/s1388-2457(02)00254-7. PMID: 12417229.
29. Spekreijse H. Maturation of contrast EPs and development of visual resolution. Arch Ital Biol. 1978 Sep;116(3-4):358-69. PMID: 749715.
30. Good WV, Hou C, Norcia AM. Spatial contrast sensitivity vision loss in children with cortical visual impairment. Invest Ophthalmol Vis Sci. 2012 Nov 19;53(12):7730-4. doi: 10.1167/iovs.12-9775. PMID: 23060143; PMCID: PMC3501833.
31. Good WV, Hou C. Sweep visual evoked potential grating acuity thresholds paradoxically improve in low-luminance conditions in children with cortical visual impairment. Invest Ophthalmol Vis Sci. 2006 Jul;47(7):3220-4. doi: 10.1167/iovs.05-1252. PMID: 16799070.
32. Watson T, Orel-Bixler D, Haegerstrom-Portnoy G. Longitudinal quantitative assessment of vision function in children with cortical visual impairment. Optom Vis Sci. 2007 Jun;84(6):471-80. doi: 10.1097/OPX.0b013e31806dba5f. PMID: 17568316.
33. McConnell EL, Saunders KJ, Little JA. What assessments are currently used to investigate and diagnose cerebral visual impairment (CVI) in children? A systematic review. Ophthalmic Physiol Opt. 2021 Mar;41(2):224-244. doi: 10.1111/opo.12776. Epub 2020 Dec 27. PMID: 33368471; PMCID: PMC8048590.
34. Bennett CR, Bauer CM, Bailin ES, Merabet LB. Neuroplasticity in cerebral visual impairment (CVI): Assessing functional vision and the neurophysiological correlates of dorsal stream dysfunction. Neurosci Biobehav Rev. 2020 Jan;108:171-181. doi: 10.1016/j.neubiorev.2019.10.011. Epub 2019 Oct 23. PMID: 31655075; PMCID: PMC6949360.
35. Chang MY, Borchert MS. Validity and reliability of eye tracking for visual acuity assessment in children with cortical visual impairment. J AAPOS. 2021 Dec;25(6):334.e1-334.e5. doi: 10.1016/j.jaapos.2021.07.008. Epub 2021 Oct 20. PMID: 34687876.