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Show Anterograde Axonal Degeneration in Children with Vision Loss Secondary to NF1 Associated Optic Pathway Glioma Robert A. Avery, DO, MSCE Division of Ophthalmology Children's Hospital of Philadelphia and Assistant Professor of Ophthalmology and Neurology Perelman School of Medicine University of Pennsylvania Philadelphia, PA Disclosures Conflict of interest: none Financial support: NIH grants EY022673, EY029687 and CA180886-S1 Dept of Defense W81XWH1910376 Roche/Toronto Sick Kids Children's Tumor Foundation Gilbert Family Foundation W81XWH191 Collaborators CHOP/Penn Neuro-Ophthalmology: Grant T. Liu, MD CHOP Neuro-Oncology: Michael J. Fisher, MD CHOP Neurology: Ritobrato Datta, PhD University of Pennsylvania: Aditya Rao Background • ~20% of children with Neurofibromatosis type 1 will develop optic pathway gliomas (OPGs). Background • ~20% of children with Neurofibromatosis type 1 will develop optic pathway gliomas (OPGs). • ~30-50% of children with NF1-OPGs may experience vision loss and undergo treatment. • Treatment success of NF1-OPGs varies:1 -1/3 have improvement in vision -1/3 have stable vision -1/3 have continued decline in vision 1Fisher MJ et al, Neuro-Oncology 2012 Background • A number of factors may impact the success of treatment outcomes: Demographic -Age1 -Sex2 Clinical -Baseline vision -Presence/absence of optic atrophy2 -Tumor location (i.e., optic tract)1 -Chemotherapy 1Fisher 2Fisher MJ et al, Neuro-Oncology 2012 MJ et al, Annals of Neurology 2014 Background • What other anatomic/physiologic factors may influence treatment outcomes? Background • What other anatomic/physiologic factors may influence treatment outcomes? de Blank et al, JNO 2017 Background • Anterograde axonal degeneration secondary to glaucoma has been reported to cause decreased lateral geniculate nucleus (LGN)1,2 and visual cortex volume2. Glaucoma Control 1Gupta 2Lee et et al., BJO 2006 al., IOVS 2014 Objective • To investigate the association between measures of striate cortex volume and vision loss in children with NF1-OPGs. Methods • Cross sectional, sex-matched design Inclusion Criteria • Children with NF1-OPGs • With or without vision loss • SD-OCT of cpRNFL within ± 6 weeks of MRI • MRI isotropic T1-weighted sequences on a 3T Siemen's scanner (0.9 mm slice thickness). Exclusion Criteria • VA loss secondary to amblyopia • VA loss/optic atrophy secondary to papilledema Methods • VA Loss: > 0.2 logMAR in at least one eye • The logMAR from each eye was averaged into a single value. • The global cpRNFL thickness from both eyes was averaged. • Both VA and cpRNFL compared to individual retinotopic and whole striate cortex volumes using linear regression. MRI Methods Pia l Skull-stripping and N4-correction & GM-WM junction Visual Cortex Volume Inflated surface with cortical volume overlay Cortica l volume Results Age § Sex Vision Loss (N = 10) 8.1 (3.8 - 10.7) Normal Vision (N = 17) 6.7 (4.5 - 11.0) F=8 M=2 F = 15 M=2 § Mean (range) Results Chemotherapy Tumor Location§ Nerve Chiasm Tracts Vision Loss (N = 10) 80% Normal Vision (N = 17) 0% 40% 20% 40% 47% 24% 29% § Most posterior location Results VA (logMAR) § cpRNFL (µ) § GCIPL (µ) § * 3 mm 6 mm Vision Loss (N = 10) 0.50 (0.1 - 1.2) Normal Vision (N = 17) 0.0 (-0.1 - 0.15) 61 (28 - 80) 95 (74 - 105) 70 55 95 69 § Mean (range) Results • No significant difference in total brain volumes between subject groups (p = 0.75). • VA (logMAR) was NOT significantly associated with V1 or V3 volumes (p > 0.05). • VA (logMAR) demonstrated a negative association with V2 volume (p < 0.05) even when controlling for whole brain volume (p < 0.05). .5 0 logMAR 1 Results 10000 12000 14000 16000 V2 Volume (mm3) 18000 Results • cpRNFL thickness demonstrated a positive association with whole striate cortex (p < 0.01) even when controlling for whole brain volume (p < 0.05). • cpRNFL thickness demonstrated a positive association with individual (dorsal/ventral) and averaged retinotopic regions (p < 0.05). 80 60 40 20 Average cpRNFL 100 Results 5000 10000 15000 V1 Volume (mm3) 20000 80 60 40 20 Average cpRNFL 100 Results 5000 10000 15000 V2 Volume (mm3) 20000 80 60 40 20 Average cpRNFL 100 Results 10000 15000 V3 Volume (mm3) 20000 100 80 60 40 3 mm GCIPL 120 Results 300000 400000 500000 600000 Striate Cortex Volume (mm3) Medial Visual Cortex Volumes Normal Vision Loss Normal Vision Loss Limitations • Modest sized convenience sample. • Unknown impact of chemotherapy on cortex volume. • Timing from insult to cortical volume change is unknown. Summary • Injury to first order axons results in decreased visual cortex volume-evidence of anterograde axonal degeneration. • Anterograde axonal degeneration is an important concept to consider in: 1) Clinical trial outcomes 2) Neuroprotection trials 3) Visual restoration strategies |
