ABSTRACT
Septo-optic dysplasia (SOD) and optic nerve hypoplasia (ONH) cause congenital visual impairment. Their aetiology is mostly unknown. Our aim was to investigate the prevalence of selected ophthalmological features in patients with these disorders. A chart review was performed on patients with SOD/ONH. Ophthalmological data were extracted. There were 102 patients (56 males). The median age at the end of the study was 12.7 years. Best-corrected visual acuity ranged from normal to no light perception. Bilateral ONH was more common than unilateral ONH. Strabismus (85%) and to a lesser extent nystagmus (52%) were both very common in our cohort. Patients with esotropia had worse visual acuity than those who had exotropia. The presence of nystagmus was more likely in cases with bilateral ONH. Therefore, patients with SOD/ONH may have normal visual acuity. Many have strabismus, which may cause amblyopia thereby further decreasing visual acuity. Nystagmus occurs commonly and its presence typically indicates bilateral ONH.
KEYWORDS: Vision, nystagmus, strabismus, paediatrics, septo-optic dysplasia, optic nerve hypoplasia
Introduction
Septo-optic dysplasia (SOD) is a neurodevelopmental abnormality that consists of optic nerve hypoplasia (ONH) and a range of other possible central nervous system abnormalities including absent septum pellucidum, hypopituitarism, and brain malformations: hypoplasia of the corpus callosum and neuronal migration abnormalities being the most common. Less commonly, ONH may occur in isolation.1 SOD/ONH are common causes of congenital visual impairment. Their incidence in the province of Manitoba, Canada is especially high, affecting 1 in 1875 live births for unknown reasons.2
The aetiology remains mostly undetermined with a genetic aetiology being implicated in a minority of cases, usually mutations in the HESX1 homeodomain.3,4 An acquired pathological process in-utero has been implicated in some case reports.5 Primagravida and young maternal age at delivery are recognised risk factors in large observational studies.6–10 Developmental delay, intellectual disability, and hypopituitarism occur commonly in SOD/ONH (50–80% of cases). In addition, seizures, behavioural difficulties, and autism spectrum disorder may occur in up to 30% of patients.2,11–13
The best-corrected visual acuity (BCVA) in patients with SOD/ONH, ranges from normal to no light perception.1 The use of stem cell therapy to improve vision has not been successful.14
We have identified a large cohort of children with SOD/ONH in our tertiary health care facility, all of whom had years of follow-up by paediatric ophthalmologists, endocrinologists, and neurologists at the sole children’s hospital in our province where such children are followed. Our aim was to investigate the prevalence of selected ophthalmological features including impaired BCVA, nystagmus, strabismus, and relative afferent pupillary defect (RAPD) in SOD/ONH.
Methods
Case definition
The presence of a small optic disc or discs on ophthalmoscopy confirms the diagnosis of ONH. If other brain malformations are present then the diagnosis is SOD. We included only residents of Manitoba.
Clinical database
Cases were identified through two sources: clinic letters from the sections of paediatric neurology and paediatric ophthalmology from 1990 to August 2019 and searching a database of patients with SOD/ONH maintained by the section of paediatric endocrinology. The diagnosis was verified by the first (MSS) and last (IHC) authors. Both have clinical expertise in these disorders. Ethical approval was granted by the Health Research Ethics Board, University of Manitoba.
Some of the patients seen during April 1996-June 2015 have been reported previously as part of an epidemiological study.2
Our primary hypothesis was that most patients had bilateral ONH, and in those patients the majority had nystagmus; whilst in cases with unilateral ONH, strabismus was more prevalent than nystagmus. The primary aim was to investigate the prevalence of nystagmus and strabismus and correlate their presence with the laterality of ONH.
Basic demographic and ophthalmological data gathered included sex, age at the end of the study (30th June 2020), reliable monocular quantitative BCVA in each eye at last clinic visit, side of the worse BCVA (right, left, bilaterally equal), laterality (unilateral versus bilateral), nystagmus and its type and direction, strabismus and its type, pupillary reaction to light, presence and side of the RAPD, and funduscopy findings i.e., optic disc size and colour for each eye. Patients whose BCVA could not be quantified by way of a monocular logarithm of the minimum angle of resolution (logMAR) acuity at their last clinic visit were excluded, i.e., patients whose vision was documented as ‘central, steady, and maintained’, ‘fix and follow’ or if they only had a documented binocular BCVA were excluded. We used standardised VA tests based on the children’s developmental age and level of cooperation. Visual impairment was defined as BCVA less than 20/40.
Some of the acuity tests employed as part of routine clinical practice were routinely recorded as the negative logMAR. BCVA data were converted to logMAR when this was not the case, to facilitate analysis (e.g., when Teller cards were used, since acuities are recorded in cycles per degree with this test). Since the laterality of the affected eye(s) (i.e., right, left, bilateral) varied from patient to patient, the BCVA data were split into two categories: the eye with the worse BCVA and the eye with the better or equally affected BCVA for each patient.
Off-chart BCVA data were assigned logMAR values as described previously,15–18: counting fingers: 2; hand motion: 2.3; light perception: 4; and no light perception: 4.5.
All extracted data were checked twice. In addition, the extracted data on 30 patients were audited by another investigator (IHC) to ensure accuracy of the data extraction. The conversion of BCVA to logMAR was also double-checked in all patients.
Statistical analysis
All analyses were performed using SAS/STAT® software, version 9.4 (SAS Institute Inc., Cary, NC). The Pearson chi-squared test was used to identify the association of patients’ age, sex, side of the worse BCVA (right, left, bilaterally equal), laterality (unilateral, bilateral), BCVA on last clinic visit for the worse, and better or equally affected eye with each of nystagmus, strabismus, side and laterality of RAPD, and side and laterality of the optic disc hypoplasia. Chi-squared and Fisher exact tests were used to investigate the association between two categorical variables. Continuous variables were tested for normality of their distribution and presented as mean and standard deviation (SD) if they had a normal distribution, otherwise median, quartiles, minimum, and maximum values were reported.
Results
There were 102 patients (56 male). Their median age at the end of the study was 12.7 years. Twelve patients were only seen once. Further demographic details are available in Table 1. The laterality of the worse eye (i.e., the eye with the most reduced BCVA) at last clinic visit was right in 32 (36.3%), left 38 (43.2%), and was equal bilaterally in 18 (20.5%). Table 2 shows the BCVA distribution at the last clinic visit. The optic disc colour was described as pale in 39 cases on the right and 41 cases on the left. Bilateral tortuous retinal blood vessels were reported in three cases. Bilateral optic nerve head drusen were noted in one case.
Table 1.
Age at the last clinic visit and at the end of the study, and follow up duration (in years) of all patients
| No. | Mean | Median | SD | Lower quartile | Upper quartile | Min. | Max. | |
|---|---|---|---|---|---|---|---|---|
| Age at last clinic visit (years): | ‡90 | 9.09 | 8.71 | 4.22 | 5.83 | 11.51 | 1.52 | 21.13 |
| Age at end of the study (years): | 102 | 14.02 | 12.68 | 7.04 | 8.62 | 17.89 | 1.92 | 36.94 |
| ¥Follow up duration(years): | ‡90 | 5.36 | 4.46 | 3.45 | 3.01 | 7.23 | 0.19 | 13.82 |
‡Twelve patients were only seen once and were excluded from this analysis.
¥This refers to the time period between the first and last clinic visits when reliable monocular visual acuity data were available.
Max. = maximum; Min. = minimum; No. = number of patients; SD = standard deviation.
Table 2.
Best-corrected visual acuity in logMAR at the last clinic assessment
| *No. | Mean | Median | Mode | SD | Min. | Max. | Lower quartile | Upper quartile | |
|---|---|---|---|---|---|---|---|---|---|
| BCVA of the worse eye: | |||||||||
| ‡88 | 2.02 | 1.3 | 4 | 1.53 | 0 | 4.5 | 0.7 | 4 | |
| BCVA of the better or equally affected eye: | |||||||||
| ‡90 | 0.68 | 0.4 | 0 | 1.13 | 0 | 4.5 | 0.1 | 0.7 | |
‡Patients who were only seen once or did not have BCVA available from the last clinic visit were excluded from this analysis.
BCVA = best-corrected visual acuity; Max. = maximum; Min. = minimum;No. = number of patients; SD = standard deviation.
Nystagmus
Nystagmus or wandering eyes were noted in 53 cases. Table 3 shows further details. There was no significant association between the presence of nystagmus and age at last clinic visit (p = .6), or age at the end of the study (p = .07).
Table 3.
Ophthalmological clinical features
| Number of patients (%) | |
|---|---|
| Nystagmus or wandering eyes | 53/102 (52) |
| Wandering eyes only | 4 |
| Latent nystagmus | 7 |
| Pendular nystagmus | 8 |
| Nystagmus direction: | |
| Horizontal | 27/53 (51) |
| Vertical | 1 |
| Both horizontal and vertical | 3 |
| Rotational | 2 |
| Strabismus | 87 (85.3) |
| Strabismus surgery | 21/87 (24.1) |
| Strabismus type: | |
| 1) Horizontal | 85 |
| Horizontal strabismus with hypotropia | 3/85 |
| Exotropia | 45/87 (51.7) |
| Esotropia | 40/87 (46) |
| 2) Dissociated vertical divergence | 1 |
| 3) Strabismus type missing | 1 |
| Laterality of BCVA at last clinic visit: | |
| Decreased bilaterally | 54 (52.9) |
| Decreased unilaterally | 42 (41.2) |
| Normal BCVA in both eyes | 6 (5.9) |
| Side(s) of BCVA decrease at last clinic visit – more details: | |
| R or R > L | 37 (36.3) |
| L or L > R | 42 (41.2) |
| Equally decreased BCVA in both eyes | 17 (16.6) |
| Normal BCVA in both eyes | 6 (5.9) |
| RAPD | 46 (45.1) |
| Right | 21 |
| Left | 25 |
| Poorly reactive pupils OU | 5 (4.9) |
| Missing data | 1 |
| Laterality of optic disc hypoplasia: | |
| Bilateral | 59 (57.8) |
| Unilateral | 38 (37.3) |
| Right only | 17 |
| Left only | 21 |
| Borderline | 3 |
| Missing data on laterality | 2 |
BCVA = best-corrected visual acuity; L = left; OU = both eyes; R = right; RAPD = relative afferent pupillary defect.
The presence of nystagmus was not associated with sex (p = .4) or side of the worse BCVA at last clinic visit (p = .29). Neither was there any significant association between the presence of nystagmus and BCVA in the worse eye at the last clinic visit (p = .89). There was an association between nystagmus presence and laterality of the last clinic visit’s BCVA, where nystagmus was significantly more prevalent if the impairment in BCVA was bilateral rather than unilateral (p < .0001). Nystagmus was also significantly more prevalent when the hypoplastic optic disc was present bilaterally rather than unilaterally (p < .0001).
Strabismus
Strabismus was noted in 87 cases. Table 3 provides further information. There was no significant statistical association between the presence of strabismus and age at last clinic visit (p = .24), or age at the end of the study (p = .77). Strabismus was not associated with sex (p = .79).
The presence of strabismus was not significantly associated with the side of the worse eye on last clinic visit (p = .36) even after combining the asymmetrical or unilateral cases together (p = .19). There was no significant statistical association between the presence of strabismus and BCVA in the worse eye at last clinic visit (N = 86; p = .13).
There was no significant statistical association between the presence of strabismus and the laterality of the impaired BCVA at the last clinic visit (p = .38) or the laterality of the hypoplastic optic disc (p = .17).
Strabismus type and strabismus surgery
Forty-five patients had exotropia and 40 had esotropia. Twenty-one patients had strabismus surgery (Table 3). BCVA of the worse eye at the last clinic was significantly associated with strabismus type (N = 77; p = .005). The group with esotropia had significantly worse BCVA (median = 2, interquartile range = 1–4, N = 35), than the group with exotropia (median = 1.1, interquartile range = 0.67–2, N = 42). The BCVA of the better or equally affected eyes at the last clinic was not significantly associated with strabismus type (N = 79; p = .34).
There was no significant statistical difference in mean BCVA of the worse eye at the last clinic visit between the two groups of patients who had or did not have strabismus surgery (N = 81; p = .97). There was no significant statistical difference in mean BCVA of the better or equally affected eye at the last clinic visit between the two groups of patients who had or did not have strabismus surgery (N = 83; p = .09).
There was no significant statistical association between the laterality of the decreased BCVA at the last clinic visit and strabismus type (N = 85; p = .57) or strabismus surgery (N = 92; p = .18).
There was no significant statistical association between the laterality of hypoplastic optic discs and strabismus type (N = 83; p = .79) or strabismus surgery (N = 90; p = .73).
RAPD
An RAPD was present in 46 cases (Table 3). The presence of an RAPD was associated with more impaired (i.e., reduced) BCVA in the worse eye at the last clinic visit (p = .004; odds ratio [OR]: 1.58; 95% confidence intervals [CI]: 1.16–2.14). There were 30 cases with asymmetrical or unilateral reductions in BCVA yet with no documented RAPD. In three of the 30, the BCVA in each eye was in the non-impaired acuity range i.e., 20/40 or better. Four of the remaining 27 with impaired BCVA were unilateral cases and 23 were asymmetrical. Of these 27 cases, the median difference in BCVA between the two eyes was 0.38 logMAR (interquartile range: 0.24–0.70). Fourteen of the 27 cases had a difference in BCVA > 0.32 logMAR between the two eyes. Nine of the 14 cases had nystagmus and 13 of the 14 had strabismus.
Side and laterality analysis of BCVA, optic disc size, and RAPD
Impairment of the BCVA at last clinic visit was bilateral in 54 cases and unilateral in 42 (Table 3). The BCVA of the worse eye was not associated with the laterality of the worse eye (right, left, bilaterally equal) at the last clinic visit (N = 88; p = .99).
Hypoplastic optic discs were bilateral in 59 cases and unilateral in 38 (Table 3). The laterality of the impaired BCVA on last clinic visit was statistically significantly associated with the laterality of the hypoplastic optic disc (N = 100, p < .0001). Specifically, the side (right, left, equal) with the worse BCVA at last clinic visit (N = 86) was significantly associated and concordant with the side (right, left, both) of the hypoplastic optic disc (p < .0001).
RAPD presence was significantly associated with both the laterality of the decreased BCVA (present in unilateral in comparison with bilateral cases) at the last clinic visit (N = 101; p < .0001) and laterality (present in unilateral in comparison with bilateral cases) of the hypoplastic optic disc (N = 100; p < .0001). More specifically, the side of the RAPD was significantly associated with the worse side (right, left, equally affected) of the impaired BCVA at last clinic visit (N = 45, p < .0001).
More detailed analysis of the side of the decreased BCVA that takes into account the asymmetry in BCVA impairment in patients with bilateral involvement, in addition to patients with unilateral involvement (patients were divided into the following decreased BCVA groups: right only; right > left; left only; left > right; bilaterally equal) at the last clinic visit also showed significant statistical association with the side of the RAPD (N = 51; p < .0001). In addition, the side of the hypoplastic optic disc (right, left, bilateral) was significantly associated with the side of the RAPD (N = 51; p < .0001).
Discussion
Patients with SOD/ONH make up one of the largest groups of patients with congenital visual impairment. Table 4 shows the prevalence of selected ophthalmological features in patients with SOD/ONH from several studies in comparison with our patients.2,11,12,19–27 Bilateral visual acuity impairment and bilateral hypoplastic optic discs were more prevalent in our cohort, similar to reports in other studies.28,29 Laterality, and more specifically, the laterality of the BCVA impairment and optic disc hypoplasia are typically correlated,19 as our investigation also shows. There was no predisposition for the right or left eye to be more commonly involved. We did not find other studies on SOD/ONH that reported a specific ocular side predisposition.
Table 4.
Selected ophthalmological features in septo-optic dysplasia and optic nerve hypoplasia based on reports from the medical literature
| Study | Number of patients | Proportion with nystagmus (%) | Proportion with strabismus (%) | Strabismus type: Proportion in those with strabismus (%) | Proportion with RAPD (%) | Proportion with poorly reactive pupils (%) |
|---|---|---|---|---|---|---|
| Current study | 102 | 52 | 85.3 | 51.7 XT, 46 ET, 2.3 other | 45.1 | 4.9 |
| Khaper et al.2 | 93 | 38.7 | NA | NA | NA | NA |
| Mohney et al.11 | 19 | 26.3 | 42.1 | 50 XT, 50 ET | NA | NA |
| Cemeroglu et al.12 | 80 | 36 | 13.8 | NA | NA | NA |
| McCulloch et al.19 | 85 | 85.4 (N = 82) | 92.5 (N = 80) | 36.5 XT, 63.5 ET | NA | NA |
| Birkebaek et al.20 | 46 | 79.1 (N = 43) | 51.2 (N = 43) | NA | NA | NA |
| Pilat et al.21 | 16 | 75 | NA | NA | NA | NA |
| Siatkowski et al.22 | 35 | 85.7 | 51.4 | 27.8 XT, 66.7 ET, 5.5 other | NA | NA |
| Garcia et al.23 | 100 | 34 | 58 | 39.7 XT, 55.2 ET, 5.1 other | 18 | NA |
| Signorini et al.24 | 17 | 94.1 | 72.7 (N = 11) | 12.5 XT, 75 ET, 12.5 ET to XT | NA | 100 |
| Hellström et al.25 | 117 | 18.8 | 23.1 | NA | NA | NA |
| Borchert et al.26 | 19 | 42.1 | NA | NA | NA | 29.4 (N = 17) |
| Weiss et al.27 | 28 | 85.7 | 50 | 42.9 XT, 57.1 ET | 14.3 | 46.4 |
ET = esotropia; N = number of patients where information (whether present/absent) was available; NA = not available; RAPD = relative afferent pupillary defect; XT = exotropia.
A few case series reported a slightly higher incidence in males or females.2,8 There were slightly more males in our study. There were no associations between sex and nystagmus, or sex and strabismus.
Nystagmus was reported in about half of our patients. The prevalence of nystagmus among different studies is variable (18.8–94.1%, Table 4) reflecting the different study populations, their sizes, and the laterality, if any, of the hypoplastic optic discs. In our study, nystagmus was present more commonly when BCVA was decreased in both eyes and when both optic nerve discs were hypoplastic. Such findings are consistent with other studies.28,29 The presence of nystagmus reflects failure of a gaze-holding mechanism that has never been calibrated by visual input in bilateral ONH. Ocular drifts cannot be corrected since fixation mechanisms depends on an intact visual system. Thus, ocular oscillations occur.30 ONH should always be considered as a possible explanation for nystagmus in infancy.
Strabismus is common in patients with SOD/ONH and its prevalence varies from 13.8% to 92.5% (Table 4). It was very commonly seen in our cohort, likely reflecting the high prevalence of patients with asymmetrical bilateral and unilateral ONH, as documented previously.28 Untreated childhood manifest strabismus is a common cause of amblyopia and should therefore be identified and treated. Superimposed amblyopia may also occur secondary to anisometropia, or other refractive errors, so these should also be addressed.1,31 Both esotropia and exotropia were common, but BCVA of the worse eye on last clinic visit was more impaired in patients with esotropia. Esotropia has been reported to occur more commonly in patients with early onset visual loss;32 this would be associated with a worse visual outcome and higher risk of additional visual loss through suppression and amblyopia.
Strabismus surgery, performed in 24% of the patients who had strabismus, showed no association with last clinic BCVA outcomes in the worse eye or the fellow eye. Our study was not designed to analyse the alignment outcomes for ONH patients after such surgery.
An RAPD is more likely to be present: 1) in cases in which there is more severe BCVA impairment in the worse eye; 2) on the side of the hypoplastic optic disc; and 3) in cases with asymmetrical or unilateral BCVA impairment, specifically on the side with the greater visual impairment. Such findings have been described in patients with acquired unilateral or asymmetrical optic neuropathy from many causes but only in few studies on patients with SOD/ONH.26,27 The absence of an RAPD in cases with asymmetrical or unilaterally impaired BCVA may have been due to technical difficulties in eliciting the sign for example, due to poor cooperation of the child, the presence of nystagmus, or the presence of strabismus. Alternatively, the absence of RAPD in cases with asymmetrical or unilateral BCVA may point to the presence of amblyopia, which is not typically associated with RAPD. Therefore, such patients should be assessed carefully for amblyopia.
Study limitations
Our investigation is subject to the limitations of chart review. It is reliant upon the accuracy of the extracted data. Missing information in some patients decreased the sample size. Our patients have all been verified by two of the authors to have SOD/ONH; we thus avoided misclassification of cases. However, only patients with monocular BCVA that could be quantified were included; patients who were designated as ‘fix and follow’ or ‘central, steady, and maintained’ were excluded. Hence, some patients are not represented in this investigation.
Assessing VA in young infants, toddlers, and children with or without developmental delay is not easy at times, with variable degrees of abilities based on developmental age and cooperation that may be different from one clinic visit to the next. Such factors will add some degree of difficulty in obtaining consistently accurate measures of BCVA. However, this is unavoidable and represents the realities of everyday clinical ophthalmology practice.
Future research directions
We are working towards including neurological, endocrine, and neuroimaging data to describe our cohort in more detail. Future studies to investigate VA outcomes in a larger cohort of adults with SOD/ONH will be important. In addition, more research is needed to quantify the economic cost of this life-long and disabling disorder.
Acknowledgement
We thank the staff at the section of endocrinology for sharing their clinical database of patients with SOD/ONH.
Funding Statement
The authors reported there is no funding associated with the work featured in this article.
Authors’contributions
MSS designed and initiated the study. He contributed to finding the patients, data collection, analysis, and interpretation. He wrote the first draft of the paper and edited subsequent drafts. SH performed most of the statistical analysis, checked and interpreted the results, and edited a few versions of the manuscript. EC extracted, organised, and re-checked the data from the ophthalmology charts. She converted the visual acuity data into logMAR and double checked the converted data. She helped interpret the results and edited the paper. CAR helped in the results’ interpretation. She reviewed and edited the draft manuscript for readability, flow, and intellectual content. IHC helped with the literature search, clinical data collection, auditing the dataset for accuracy, helping with data interpretation, and edited a few drafts. All authors approved the last version of the paper.
Data availability statement
Inquiry about the data should be directed to the corresponding author.
Disclosure statement
No potential conflict of interest was reported by the authors.
Ethical approval and consent to participate
Ethical approval for the study has been granted by the Research Ethics Board of the University of Manitoba.
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Data Availability Statement
Inquiry about the data should be directed to the corresponding author.