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Resources exist to guide adversity decisions in general, for findings in ganglia of the peripheral nervous system (PNS), and for gliosis in the central nervous system (CNS). The objective of this opinion article is to describe considerations that may apply when determining the adversity (or lack thereof) of nerve fiber degeneration (NFD) in either the CNS or PNS following intrathecal (IT) administration of oligonucleotide (ON) therapeutics (such as antisense oligonucleotides and short interfering RNAs). It is important to differentiate IT delivery procedure-related NFD effects from ON-related effects or ON-related exacerbation of procedure-related findings. This article presents evidence-based approaches for deciding whether NFD associated with IT ON administration is an adverse microscopic finding in the brain, spinal cord, spinal nerve roots, ganglia, and\/or nerves. 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