Highlights
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In this study of optic nerve hypoplasia/septo-optic-pituitary dysplasia (ONH/SOD), mortality was estimated to be higher in patients compared to unrelated controls on long-term follow-up.
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Healthcare professionals should familiarize themselves with ONH/SOD complications, since some of these complications can be managed to reduce the mortality risk.
Introduction
Optic nerve hypoplasia (ONH) is a congenital developmental disorder of the optic nerve that causes visual impairment. In septo-optic-pituitary dysplasia (SOD), hypopituitarism or midline brain abnormalities (typically absent septum pellucidum or abnormal corpus callosum) accompany ONH. Other brain abnormalities may occur in ONH/SOD and include neuronal migration disorders. Reference Garcia-Filion and Borchert1,Reference Salman, Hossain and Rozovsky2
Developmental delay, intellectual disability, autism spectrum disorder, seizures, epilepsy, cerebral palsy (CP) and anxiety or mood disorders are associated with ONH/SOD. Reference Garcia-Filion and Borchert1,Reference Khaper, Bunge and Clark3–Reference Salman, Ruth, Yogendran and Lix7
Patients with ONH/SOD have complex medical needs. The rate of hospitalization and length of hospital stay for acute care are higher in patients with ONH/SOD than in controls. In addition, patients with SOD who have hypopituitarism have the highest rate of hospitalizations and repeat hospitalizations for acute medical care. Reference Salman, Ruth, Yogendran and Lix8
Studies about mortality in patients with ONH/SOD are sparse despite their value; they can provide insights into the health of these patients, identify risk factors that can contribute to death and assess the effectiveness of healthcare interventions, which may ultimately contribute to extending a healthier lifespan. We found no studies that estimated the mortality rate or compared mortality rates between patients with ONH/SOD and matched controls. The adoption of matched controls is important, since the matching process can help address potential unmeasured confounding biases such as environmental factors, socioeconomic status and behavioral risk factors that may affect the risk of death. Reference Khaper, Bunge and Clark3,Reference Garcia-Filion, Fink, Geffner and Borchert9–Reference Singal, Brownell, Chateau, Ruth and Katz11
In one retrospective longitudinal case series of 144 patients with SOD, the percentage of patients who died was 4.2% over a median follow-up duration of 8.0 years (range 0.4–17.5), but no controls were included in the study. Reference Cerbone, Güemes, Wade, Improda and Dattani12
Our primary objective was to test for a difference in all-cause mortality between ONH/SOD cases and unrelated controls in a population-based cohort. Our hypothesis was that mortality would be higher in patients with ONH/SOD than in matched controls.
Method
Study design
A population-based study with a case–control design was undertaken to investigate crude all-cause mortality in ONH/SOD.
Setting
Manitoba, a Canadian province with universal health care, has a population of 1.34 million residents (Statistics Canada Census, 2021). Patients with ONH/SOD are assessed and managed in the only tertiary pediatric hospital (Winnipeg Children’s Hospital) in the province.
Case ascertainment
Case ascertainment has been described in detail previously. Reference Salman, Ruth, Yogendran and Lix7,Reference Salman, Ruth, Yogendran, Rozovsky and Lix13 Briefly, since 1986, a database of patients established by the section of pediatric endocrinology at Winnipeg Children’s Hospital was searched for cases with ONH/SOD up to August 2019. Additional cases were found through searching clinic letters from the sections of pediatric ophthalmology and pediatric neurology between 1990 and August 2019, the study end date for identifying cases. This search method ensured the systematic inclusion of patients with ONH/SOD. A diagnosis of ONH/SOD at any time defined the cases for this study.
Case definition
Septo-optic-pituitary dysplasia is diagnosed when patients with ONH have any of hypopituitarism, absent/small septum pellucidum or abnormalities in the corpus callosum. ONH was diagnosed when a small optic disc was reported by a pediatric ophthalmologist.
Manitoba residents only were included. Their diagnosis was confirmed by the first author (MSS), who has expertise in this disorder, by carefully reviewing all their medical hospital charts. Patients living outside Manitoba were not included, since their clinical charts were not linkable to provincial administrative health data.
Study population database
We used population-based administrative data from the Manitoba Population Research Data Repository at the Manitoba Centre for Health Policy (MCHP). Reference Salman, Ruth, Yogendran, Rozovsky and Lix13,Reference Jutte, Roos and Brownell14 The repository contains de-identified and linkable databases encompassing all publicly funded healthcare services of residents of Manitoba. The validity and use of this repository have been documented. Reference Singal, Brownell, Chateau, Ruth and Katz11,Reference Jutte, Roos and Brownell14
One hundred and twenty-four independent and unrelated patients with ONH/SOD, who were born between April 1984 and March 2018, were available for matching and could be linked to MCHP Repository databases using a de-identified personal health identification number as described in prior studies. Reference Salman, Ruth, Yogendran and Lix7,Reference Salman, Ruth, Yogendran, Rozovsky and Lix13 Tables 1 and 2 show their characteristics.
Table 1. Pituitary gland functional status, frequency of hormonal replacement therapy, other morbidities and neuroimaging features in patients with optic nerve hypoplasia/septo-optic-pituitary dysplasia†
S = suppressed per policy of data provider (Manitoba Centre for Health Policy, MCHP).
†Adapted with permission from Salman MS et al. Reference Salman, Ruth, Yogendran and Lix7
‡Some patients had more than one type.
Table 2. Characteristics of the cases and their matched unrelated controls†
Q = quintile.
†Adapted with permission from Salman MS et al. Reference Salman, Ruth, Yogendran and Lix7
aAge was calculated in those alive on March 31, 2022.
bFollow-up period is birth to March 31, 2022, date of leaving the province (if any) or date of death, whichever came first.
Controls
The unrelated control group was created from the Manitoba Population Research Data Repository databases as detailed previously. Reference Salman, Ruth, Yogendran and Lix7,Reference Salman, Ruth, Yogendran, Rozovsky and Lix13 None had a diagnosis of ONH/SOD.
The control group was matched one case to five controls (N = 620) to achieve efficiency in the study design by using more controls to detect the association of group membership (i.e., case/control) with all-cause mortality. Reference Coggon, Rose and Barker15 Matching variables included sex, birth date (within one year) and Health Region Zone at birth. There are five large health regions in Manitoba with 17 smaller divisions – known as Health Region Zones. These zones were used to achieve high accuracy when matching on geographic location.
Study dates
The study start date for assessing the outcome in cases and controls was the date of birth, when all health records of Manitoba residents are entered in the population health repository. The study end date was one of the following: March 31, 2022, the date of moving out of the province prior to March 31, 2022 (if any), or the date of death.
Ethics approval was granted by the Health Research Ethics Board, University of Manitoba, and approval for data access was provided by the Provincial Health Research Privacy Committee and provincial data custodians.
Study variables
The cohort demographics included age at the end of the study period (March 31, 2022 – the date of the latest available repository data coverage), sex, follow-up duration, income quintile (IQ) and neuroimaging abnormalities. More details regarding neuroimaging features have been published previously. Reference Salman, Hossain and Rozovsky2,Reference Salman, Ruth, Yogendran, Rozovsky and Lix13 The date of death was identified for cases and controls who died prior to the study end date of March 31, 2022, from the population registry.
Supplementary Tables S1 and S2 provide detailed information on the study data sources and definitions of variables.
Data sources
The data on cases and controls were obtained from the following databases at MCHP: population registry and Statistics Canada Census (see Supplementary Table S2 for details).
Statistical analysis
Study data were descriptively analyzed using means and standard deviations (SD) (for normally distributed data), medians with interquartile ranges (for data that did not have a normal distribution), frequencies and percentages as appropriate. Follow-up duration for cases and controls was the difference between the date of birth and study end date (March 31, 2022), date of moving out of the province prior to March 31, 2022 (if any), or date of death, whichever came first. We calculated the median duration and the interquartile range.
Crude all-cause mortality rates were calculated for cases and controls per 1000 person-years. Cox proportional hazards semi-parametric regression models were used to test for a difference in the time to all-cause death for cases and controls; censoring was at the date of death, end of the study period (i.e., March 31, 2022) or date of moving out of province prior to March 31, 2022. The assumption of proportional hazards was assessed via visual assessment of the plots of the survival function for the groups. The hazard ratio (HR) and 95% confidence interval (CI) were estimated. A nominal α = 0.05 was used to assess statistical significance. All statistical tests were two sided.
Results
Of the 124 cases with ONH/SOD identified, 70 were males. The mean (SD) age of the cases was 13 years (7.2) on March 31, 2022, the latest date of available data. The median (25th–75th percentiles) duration of follow-up was 12.0 (7.0–17.1) years for the cases and 11.4 (6.8–16.9) years for the controls. Characteristics of the cohort are displayed in Tables 1 and 2. Further clinical details on this cohort of patients have been published. Reference Salman, Hossain and Rozovsky2,Reference Salman, Ruth, Yogendran and Lix7,Reference Salman, Ruth, Yogendran, Rozovsky and Lix13
Six of 124 (4.8%) cases with ONH/SOD died during the study’s follow-up period in comparison to 8 of 620 (1.3%) controls. The median age of death of the 6 patients with ONH/SOD was 4.6 years (25th percentile: 2.7; 75th percentile: 9.1; minimum: 0.5; and maximum: 12.9 years). Since the number of patients with ONH/SOD who died is small, individual-level clinical data including sex and their cause of death were suppressed per MCHP protocol. However, they collectively had at least one of the following diagnoses in addition to visual acuity impairment: hypopituitarism, neuronal migration abnormalities, developmental delay, CP or epilepsy.
The crude all-cause mortality rate was 3.7 per 1000 person-years in patients with ONH/SOD in comparison to 1.0 per 1000 person-years in unrelated matched controls (Table 3). The risk of death was estimated to be significantly higher in the former (HR = 3.7, 95% CI = 1.3–10.5).
Table 3. Crude all-cause mortality rate in patients with optic nerve hypoplasia (ONH)/septo-optic-pituitary dysplasia (SOD) matched with unrelated controls. P-values and hazard ratios (HR) for crude all-cause mortality with 95% confidence intervals (CI) are displayed
Discussion
We report a significantly higher mortality rate and risk of crude all-cause mortality in ONH/SOD cases in comparison to controls in our local population. Our figures are likely to be reasonably accurate, since our methodology was population-based with a matched case–control design. Reference Garcia-Filion, Fink, Geffner and Borchert9,Reference Jutte, Roos and Brownell14 Since our cases were matched to controls based on geographic location and the IQs were similar between our cases and controls, the difference in socioeconomic status is unlikely to be driving the difference in mortality rate and risk between the cases and controls.
The higher risk of mortality in ONH/SOD cases compared to controls is likely to be multifactorial and may include complications caused by hypopituitarism, which occurs relatively commonly in SOD patients. Reference Dahl, Kristoffersen Wiberg, Teär Fahnehjelm, Sävendahl and Wickström16 For example, hyponatremia and hyperkalemia are caused by cortisol deficiency, or hypernatremia is caused by antidiuretic hormone deficiency. These electrolyte disturbances can precipitate life-threatening adrenal crises with cardiovascular collapse, cardiac arrhythmias and coma. Reference Ryabets-Lienhard, Stewart, Borchert and Geffner17–Reference Rushworth, Chrisp, Dean, Falhammar and Torpy19 In addition, unrecognized hypoglycemia from cortisol or growth hormone deficiency, which usually manifests during an intercurrent illness, can cause seizures and even lead to coma and death. Reference Ryabets-Lienhard, Stewart, Borchert and Geffner17,Reference Rushworth, Torpy, Stratakis and Falhammar18
Furthermore, seizures caused by hypoglycemia, electrolyte disturbances and neuronal migration abnormalities, which are reported in some patients with SOD, Reference Salman, Hossain and Rozovsky2,Reference Margalith, Jan, McCormick, Tze and Lapointe5,Reference Salman, Ruth, Yogendran and Lix7 may precipitate the demise of patients with ONH/SOD, either as a sudden unexpected death Reference Brodsky, Conte, Taylor, Hoyt and Mrak20–Reference Martínez-Sánchez, Arce, Caritg-Bosch, Campistol, Pavía and Gean-Molins22 or through hypoxic-ischemic encephalopathy from prolonged seizures or hypernatremic dehydration. Reference Gilbert, Scott and Byard21 One paper postulated that the combination of factors including thermoregulatory disturbance from hypothalamic involvement in SOD, together with low cortisol and antidiuretic hormones, in the presence of a febrile illness, all contributes to sudden unexpected death. Reference Gilbert, Scott and Byard21
More commonly, patients who have a severe neurological disease with at least one of: developmental delay, CP and seizures, as some patients with SOD may have, are at higher risk of death from respiratory compromise, for example, aspiration and pneumonia. Reference Reddihough, Baikie and Walstab23,Reference O’Leary, Cooper and Hughes-McCormack24
Study limitations
Administrative data are subject to some limitations; for example, some databases do not cover the entire study period (Table S2). The accuracy of data is dependent on the submission by the organizations that deliver services. Reference Singal, Brownell, Chateau, Ruth and Katz11,Reference Jutte, Roos and Brownell14 Some information in the repository is not available annually. Hence, data extraction was from the closest available years.
In addition, since the number of deaths is small and the causes of death are variable, we were unable to access clinical details, including the cause of death at an individual level as MCHP protocol dictates, because such data are suppressed.
Conclusions
Our study revealed that patients with ONH/SOD have a higher risk of mortality in comparison to unrelated controls. Healthcare professionals looking after these patients should be familiar with the morbidities and comorbidities associated with ONH/SOD and the complications that may lead to their demise, since some of these complications can be managed to reduce the mortality risk.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/cjn.2025.10452.
Data availability statement
The data used for this study are owned by the data providers: Manitoba Health, Seniors and Active Living and Winnipeg Regional Health Authority. Access to data is given upon approval from the University of Manitoba Health Research Ethics Board and the Provincial Health Research Privacy Committee and permission from all data providers. More information on access to these databases can be found at http://umanitoba.ca/faculties/health_sciences/medicine/units/community_health_sciences/departmental_units/mchp/resources/access.html.
Acknowledgments
We thank the staff at the section of endocrinology for sharing their clinical database of patients with ONH/SOD. The authors acknowledge the MCHP for the use of data contained in the Manitoba Population Research Data Repository under project number: 2019-060 and the Provincial Health Research Privacy Committee under project number: 2019/2020 – 28. The results and conclusions are those of the authors, and no official endorsement by the MCHP, Manitoba Health or other data providers is intended or should be inferred. Data used in this study are from the Manitoba Population Research Data Repository housed at the MCHP, University of Manitoba, and were derived from data provided by Manitoba Health and Winnipeg Regional Health Authority.
Author contributions
MSS conceptualized, designed and initiated the study. He aided in data collection, analysis and interpretation. He wrote the first draft and edited subsequent drafts of the paper. CAR contributed to the research design, definitions of variables, analysis interpretation and editing the manuscript. She reviewed and edited a few draft manuscripts for intellectual content. MSY contributed to definitions of variables, data extraction, statistical analysis, interpretation of results and editing the manuscript. LML contributed to study design, statistical analysis, interpretation of results and preparation of manuscript drafts. All authors approved the final version of the manuscript.
Funding statement
Manitoba Center for Health Policy support fund, Children’s Hospital Research Institute of Manitoba and Fighting Blindness Canada. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. LML is supported by a Canada Research Chair in Methods for Electronic Health Data Quality (CRC-2023-00349).
Competing interests
None declared.
Ethical standards
Ethical and other approvals have been obtained from the University of Manitoba’s Health Research Ethics Board and the Provincial Health Research Privacy Committee, as well as all agencies whose data were accessed.
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