Effect on Laryngeal Adductor Function of Vincristine Block of Posterior Cricoarytenoid Muscle 3 to 5 Months After Recurrent Laryngeal Nerve Injury

Abstract

Objectives It has been shown, in a canine model, that a single injection of vincristine into the PCA muscle at the time of recurrent laryngeal nerve (RLN) injury effectively blocks its reinnervation and results in improved adductor strength. But clinically, such injuries are usually diagnosed weeks or months after onset. Vincristine injection does not affect a muscle that is already innervated; thus, there is a limited time frame following RLN injury during which a vincristine injection could effectively improve ultimate laryngeal adductor functional recovery. A series of delayed injections were performed in a canine model and results assessed. Study Design Animal (canine) experiment. Methods The RLN was transected and repaired, and vincristine (0.4 mg) was injected into the PCA muscle at the time of injury (n=12), or at 3, 4, and 5 months later (n=8 each study group). Six months after RLN injury, laryngeal adductor function was measured. Results of vincristine injection without RLN injury (n=6), and longer-term (12 months) follow-up for time zero injections (n=4), are also reported. Results The animals injected at time zero had better adductor function than non-injected controls, as reported previously, and this result was further increased at 12 months. The 3-month delay gave results similar to the time zero group. The 5-month delay group showed no vincristine benefit, and the 4-month delay group gave an intermediate result. Vincristine to the PCA had no effect on adductor function when the RLN was left intact. Plasma levels showed 19% of injected vincristine reached systemic circulation, which was cleared within 69 hours. Conclusions Vincristine injection of the PCA muscle after RLN injury, which blocks this functional recovery. The window of opportunity to apply this treatment closes by four months after RLN injury in the canine model. Human RLN recovery follows a similar time course and can reasonably be expected to have a similar therapeutic window.

Paclitaxel inhibits post‐traumatic recurrent laryngeal nerve regeneration into the posterior cricoarytenoid muscle in a canine model

“…Further studies are needed to define the correlation between the LAP results and the functional voice/swallowing outcomes. Previous work has demonstrated that there is diminished effectiveness of neural inhibition beyond the first 3 months following injury and repair . After 3 months, some reinnervation has already occurred, and intramuscular injection of these microtubule inhibitors does not damage intact innervation .…”

“…Previous work has demonstrated that there is diminished effectiveness of neural inhibition beyond the first 3 months following injury and repair . After 3 months, some reinnervation has already occurred, and intramuscular injection of these microtubule inhibitors does not damage intact innervation . In the setting of new‐onset vocal fold paralysis, there appears to be therapeutic value of intramuscular injection of paclitaxel into the PCA muscle within the first few months after onset.…”

“…Although low‐dose administration of vincristine following vocal fold paralysis may avoid toxicity and achieve the desired effects, paclitaxel provides an alternative with a possibly wider therapeutic index . Additionally, prior studies have demonstrated that paclitaxel and vincristine have no effect after reinnervation has occurred . Therefore, outside of this 3‐month therapeutic‐window of opportunity, administration of these neurotoxins would likely not be beneficial.…”

“…A total of 0.5 mL of paclitaxel solubilized in Cremophor EL (6 mg/mL; APP Pharmaceuticals, Schaumburg, IL) or 0.4 mL of vincristine sulfate solubilized with mannitol in water (2 mg/2 mL; Hospira, Lake Forest, IL) was injected into each PCA muscle. The amount of neurotoxin to be injected was determined by upscaling the dosages used in prior rat studies to accommodate the increased muscle mass of the canine PCA muscle …”

“…Paniello et al demonstrated that when a single intramuscular injection of vincristine was administered to the PCA within 3 months of RLN transection injury and repair, enhanced adductor muscle squeeze pressures were observed . Both vincristine and paclitaxel are well‐established chemotherapeutic agents that are known to be potent microtubule inhibitors that interfere with cellular division, and thus with nerve regeneration .…”