A 40-Year Cohort Study of Evolving Hypothalamic Dysfunction in Infants and Young Children (<3 years) with Optic Pathway Gliomas

Abstract

Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. We aimed to assess presenting disease, tumour location, and treatment factors implicated in the evolution of neuroendocrine, metabolic, and neurobehavioural morbidity in 90 infants/children diagnosed before their third birthday and followed-up for 9.5 years (range 0.5–25.0). A total of 52 (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) of whom had hypothalamic involvement (H+) and lower endocrine event-free survival (EEFS) rates. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs. 46%, p = 0.001)), H+ (OR 6.1 95% CI 1.7–21.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7–158.6, p = 0.017) and surgery (OR 4.8 95% CI 1.3–17.2, p = 0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and was clustered with the endocrinopathies. Neurobehavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1–5.9, p = 0.043) and radiotherapy (OR 23.1 C.I. 2.9–182, p = 0.003). Very young children with OPHG carry a high risk of endo-metabolic and neurobehavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in complex, hierarchical patterns over time whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study

“…Risk stratification based on prognostic factors such as age at onset, extension along the optic pathway, hypothalamic involvement, histological subtype and tumor biology is important to improve treatment effectiveness and the quality of survival. Therefore, functional outcomes and quality-of-life measures should be considered together with mortality measures in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment [29]. In this context, targeted therapy is an attractive therapeutic approach.…”

A new era for optic pathway glioma: A developmental brain tumor with life-long health consequences

“…GHD surprisingly increased in later treatment eras when radiotherapy was used less frequently (26). 90 children in this cohort were diagnosed aged <3 years and followed for 40 years, they are reported separately (16). Endometabolic dysfunction was reported in 58.7%, the main factor contributing to this risk was a clinical presentation with diencephalic syndrome, followed by tumor involvement of hypothalamus, the use of radiotherapy and surgery.…”

“…These trials of new therapies are specifying clinical outcomes such as vision assessments as a primary outcome measure(s). Based upon the new reports of endocrine and neuro-behavioural outcomes for children with OPHG and the uncertainties of how to select patients for treatment vs. observation, we conclude that further studies are needed to dissect the impact of tumor progression vs. consequences of treatment on these additional health outcomes (16). A trial design selecting patients for randomisation between initial observation vs. initial therapy is justified by the existing uncertainty for when to treat or observe children using vision loss and endocrine outcomes as primary outcomes.…”

“…As the treatments evolve under clinical trials, visual outcomes are now specified as primary outcome measures, requiring ophthalmologists to be central to decision-making and outcome measurement. It can be anticipated that, for children who often demonstrate occult endocrine presentations or evolving consequences of both disease and therapies, lifelong endocrine follow up will be required (16). Similarly, specialist genetics clinics now often manage children with NF1, especially where there are complex features and detailed genotyping offers risk assessment for OPHG development.…”

“…A single institution cohort of children with OPHG (n = 166), studied over 30 years has reported a 20-year overall survival (OS) of 81.0%, and progression-free (PFS) and endocrine event-free survival rates (EEFS) of 47.2 and 20.8%, respectively. Growth Hormone deficiency (GHD) affected 40.3%, followed by central precocious puberty (CPP, 26.0%), gonadotropin (GnD; 20.4%), TSH (13.3%), and ACTH (13.3%) deficiencies (16,26). These develop hierarchically.…”