Endoneurial damage is associated with chronic dysfunction and neuroma formation after stretch injury in the rat median nerve

Purpose: Peripheral nerve stretch injuries are highly challenging to treat due to a poor understanding of the differences between injuries that recover naturally and those requiring surgical intervention. The rat median nerve exhibits two levels of mechanical and structural failure, epineuroclasis and endoneuroclasis, and this study investigated their long-term structural and functional outcomes. An investigation into the outcomes of distinct degrees of nerve stretch injury could help in accurately assessing the prognosis for recovery and the need for surgical treatment. Methods: Left median nerves of 17 rats were stretched to an epineuroclasis (n = 8) and endoneuroclasis injury (n = 9), right nerves served as sham-control. Nerves were stretched using a hook attached to a load-cell, generating load-deformation curves in real-time. Epineuroclasis injury was induced with a first, endoneuroclasis injury with a second rapid force reduction. Handheld electrical stimulators were used to assess function before, immediately after and 12 weeks after injury. Tissue was harvested for histology and rats were euthanized. Results: Epineuroclasis showed persistent epineurial disruption at 12 weeks, similar to an acute injury, while nerve function improved over time. Endoneuroclasis resulted in a traumatic neuroma in 8/9 nerves, in a neuroma-in-continuity in 5/6 intact nerves, and a chronic loss of function at 12 weeks. Conclusions: The prognosis for recovery and the likelihood of neuroma formation after stretch injury worsens along an outside-in sequence of connective tissue failure in the rat median nerve. Clinical relevance: The neuroclasis classification might be helpful in developing novel diagnostic tools and evaluating the prognosis for recovery and need for surgical treatment. This study further highlights a potential need for different classification systems for nerve stretch and crush injuries.