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surgery is usually postponed for at least 6 months to

allow for possible spontaneous recovery or compensation

from the contralateral vocal fold. However, the studies

on regeneration of other peripheral nerves showed that

the degree of functional reinnervation lessens as the

period of denervation increases; and there appears to be

a time range beyond which effective reinnervation

declines dramatically.

But a significant body of evi-

dence indicates that this does not necessarily apply to

the larynx.

8,14,15

Clinical and experimental evidences

have demonstrated that spontaneous regeneration com-

monly takes place after RLN injuries.

16–18

Although this

type of reinnervation is usually nonfunctional and sel-

dom occurs with laryngeal mobility (termed subclinical

reinnervation), it can help to halt or even reverse muscle

atrophy and/or fibrosis caused by denervation.

There-

fore, the researchers think that denervation duration

does not affect the surgical outcome of laryngeal reinner-

vation in a linear fashion. However, so far we have not

seen any report regarding the stratification analysis of

denervation duration on the laryngeal reinnervation

effect. Thus, it is of great clinical importance to explore

whether the same situation in the regeneration of other

peripheral nerves also happens to the recurrent laryn-

geal nerve—that regeneration capacity declines progres-

sively as the denervation duration increases.

Delayed reinnervation procedures have proven

effective after peripheral nerve injury in animal experi-

ments. For example, selective reinnervation of the poste-

rior cricoarytenoid muscle with a phrenic nerve transfer

has been feasible after a 9-month delay in cat models;

however, functional recovery was less successful than

with immediate reinnervation.

We previously reported

that laryngeal reinnervation is still possible to some

degree, even after an 18-month denervation period in

dogs; however, the degree of RLN regeneration is less

than those with an 8-month denervation period.

In the

clinical studies, Maronian et al. reported on nine

patients, eight of whom had an interval between RLN

injury and surgery that exceeded 12 months. These

patients had a normal or improved voice after laryngeal

reinnervation. The longest denervation interval in that

series was 9 years, and the postoperative voice in that

case was improved.

Olson et al. reported excellent

acoustic and perceptual results in patients with the

maximal interval of 6 years between injury and sur-

gery.

Our study of a large sample of UVFP patients, in

which the longest denervation course was more than 3

years, confirmed that delayed reinnervation can be effec-

tive.

Nevertheless, the relationship between denerva-

tion duration and degree of functional recovery of the

laryngeal muscle in UVFP patients remains to be

elucidated.

Results of the present study showed that there was

no significant difference with regard to glottal closure

among the three groups. This was probably due to a lack

of standardization of inspiratory effort while the patients

were undergoing videostroboscopy examination. In addi-

tion, a difference in the vertical plane of the vocal folds

can result in a significant glottic gap, even when the

apparent closure as viewed from above seems

adequate.

However, all of the parameters of vocal func-

tion assessment, including perceptual evaluation, objec-

tive acoustic analysis, and aerodynamics parameter

MPT, showed that denervation duration was an influen-

tial factor to the surgical outcome of laryngeal reinner-

vation. Data of postoperative motor-unit recruitment

also support the vocal function results. The perceptual

and acoustic parameters showed no significant difference

postoperatively among patients with denervation inter-

vals of less than 24 months, and the parameter values

in these patients were better than those in patients with

longer denervation intervals. These results indicate that

delayed reinnervation is still effective. There are several

reasons that may support delayed laryngeal reinnerva-

tion. There may be an inherent cellular mechanism for

preserving the structure of denervated laryngeal

muscles.

Johns et al. found that 6 months after RLN

resection there was no significant difference in maximal

isometric force of the TA muscle between the experimen-

tal and control cats,

possibly due to spontaneous

regeneration of the RLN. Our previous study indicated a

strong tendency for regeneration in the RLN following

injury, which may at least partially reinnervate the

laryngeal muscle, helping to maintain its structural

integrity and function and to alleviate excessive muscle

atrophy and fibrosis.

In addition, laryngeal muscle

stem cells provide persistent regenerative potential for

delayed laryngeal reinnervation for up to 2 years after

denervation, as revealed by our previous study.

The

population of activated muscle stem cells in the laryn-

geal muscles may be more resistant to apoptosis than

those in limb muscles, which may contribute to regener-

ative myogenesis in denervated laryngeal muscles

through compensatory mechanisms.

Nevertheless, after 2 years of denervation, the sur-

gical outcomes were less favorable in the present study,

although most postoperative parameters in these

patients showed improvement compared with the corre-

sponding preoperative values. As fixation of the cricoary-

tenoid joint was precluded preoperatively in these cases,

the compromise of the recovery of voice quality might

have been due to insufficient laryngeal reinnervation,

which was confirmed by postoperative EMG.

One cause of poor functional recovery after exces-

sive long-term muscle denervation is the failure of many

regenerating axons to elongate and/or make synaptic

connections with denervated muscle fibers. The ability of

nerve sheaths to support axon regeneration to long-term

denervated muscle fibers may progressively deteriorate

because of: a decrease in the number of Schwann cells to

a level that cannot provide adequate support for regen-

erating axons

; degeneration and collagenization of

endoneurial tubes, which may obstruct axonal regenera-

tion

; and an inability of the basal lamina to be

renewed without Schwann cell–axon contact.

These

factors contribute to a profound reduction in the number

of axons that eventually reach denervated muscles.

Another possible explanation is occupation of the dener-

vated muscle end plates by axons coming from adjacent

nerves or by fibers of autonomous origin, precluding

delayed reinnervation.

In addition, muscle fiber

Laryngoscope 124: August 2014

Li et al.: Denervated Duration on Reinnervation for UVFP