Nerve Grafting and Reconstruction: Selected Indications

Number: 0416

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses selected indications of nerve grafting and nerve reconstruction.

Experimental and Investigational

The following interventions are considered experimental and investigational because the effectiveness of these approaches has not been established:

1. Nerve grafts (e.g., sural nerve graft, cavernous nerve graft, genito-femoral nerve graft, or collagen tube nerve graft) during radical retropubic prostatectomy because there is insufficient scientific evidence demonstrating their value in the management of individuals with erectile dysfunction following radical retropubic prostatectomy;
2. The Avance Nerve Graft, Axogen 2 Nerve Wrap, AxoGen Nerve Protector and Nerve Connector, Integra Neural Wrap, the NeuraGen Nerve Guide, the NeuraWrap Nerve Protector, Neuromatrix collagen nerve cuff, and NeuroMend collagen nerve wrap for all indications because of insufficient evidence in the peer-reviewed literature. Note: Nerve wraps and conduits are considered integral to the surgical procedure and not separately reimbursed.
3. Cross-palm nerve grafting to enhance sensory recovery in ulnar neuropathy because of insufficient evidence in the peer-reviewed literature;
4. Nerve wrapping for the treatment of compression neuropathy;
5. Phrenic nerve reconstruction for the treatment of diaphragmatic paralysis (Note: this does not apply to prompt repair of acute phrenic nerve transection due to trauma or surgery);
6. The use of vascularized nerve grafts for the treatment of a nerve gap.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes not covered for indications listed in the CPB:
Sural nerve, cavernous, or genitofemoral grafts-No specific code:
64911	Nerve repair; with autogenous vein graft (includes harvest of vein graft), each nerve
64912	Nerve repair; with nerve allograft, each nerve, first strand (cable)
64913	Nerve repair; with nerve allograft, each additional strand (List separately in addition to code for primary procedure)
Other CPT codes related to the CPB:
55840	Prostatectomy, retropubic radical, with or without nerve sparing
55842	with lymph node biopsy(s) (limited pelvic lymphadenectomy)
55845	with bilateral pelvic lymphadenectomy, including external iliac, hypogastric, and obturator nodes
55866	Laparoscopy, surgical prostatectomy, retropubic radical, including nerve sparing, includes robotic assistance when performed
HCPCS codes not covered for indications listed in the CPB:
C9352	Microporous collagen implantable tube (Neuragen Nerve Guide), per centimeter length
C9353	Microporous collagen implantable slit tube (Neurawrap Nerve Protector), per centimeter length
C9355	Collagen nerve cuff (neuromatrix), per 0.5 centimeter length
C9361	Collagen matrix nerve wrap (neuromend collagen nerve wrap), per 0.5 centimeter length
ICD-10 codes not covered for indications listed in the CPB:
G51.0	Bell's Palsy
G57.0 – G58.9	Mononeuropathy [Compression neuropathy]
J98.6	Disorders of diaphragm [Diaphragmatic paralysis]
N52.01 - N52.9	Male erectile dysfunction [status post radical retropubic prostatectomy]

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Background

The incidence of erectile dysfunction (ED) in men treated for prostate cancer has been reported to be between 20 and 88 %.  Despite the use of nerve sparing techniques, ED is still a common adverse effect in patients, especially older men, after radical retropubic prostatectomy.  The successful use of autologous nerve grafts in reconstructive surgery has led to the advent of bilateral nerve graft (sural nerve) during radical retropubic prostatectomy to replace the resected cavernous nerves.

However, there is insufficient scientific evidence to demonstrate the value of sural nerve graft in the management of patients with ED following radical prostatectomy.  In particular, there are no comparative studies between this approach and standard medical therapy.  Early institution of medical therapy, specifically intracorporal injections, after 2 months post-operatively has resulted in a higher incidence of spontaneous return of erections at 1 year.  Furthermore, intracorporal injection has been reported to be the most effective approach for treating ED after radical retropubic prostatectomy.  Other methods include the use of vacuum erection devices, sildenafil (Viagra), and implantation of a penile prosthesis.  Penile prostheses are expensive and require invasive surgery, but satisfaction rates among patients and partners who have used them have been in the range of 85 %, the highest satisfaction rate among all of the treatments of ED.

Further investigation, using prospective, randomized, controlled studies, is needed to ascertain the role of sural nerve graft during radical retropubic prostatectomy in the management of patients who undergo radical prostatectomy for the treatment of localized prostate cancer.  In a study that described their preliminary experience with cavernous nerve graft reconstruction using sural nerve grafts with radical prostatectomy or radical cystectomy, Anastasiadis et al (2003) concluded that sural nerve grafts are feasible and safe after radical prostatectomy and cystectomy.  However, candidates usually present with high stage disease, high-risk for recurrence and frequent requirement for adjuvant therapy that further compromises erectile function.  Randomized studies with more patients and long follow-up periods are necessary in order to define the ideal candidate for nerve graft procedures.

In recent years, researchers have experimented with absorbable collagen matrix tubes (known as Neuragen Nerve Guide) instead of autologous nerve graft materials when performing nerve grafting to reduce the morbidity of ankle numbness as a consequence of harvesting of the sural nerve.  It is thought that by securing the proximal and distal cut ends of the neurovascular bundle into the collage matrix tube, complete capture of regrowing axons is more likely to occur than with an autologous sural nerve graft; thus improving the chances of success.  The clinical value of this approach needs to be validated by well-designed controlled studies.

Saito et al (2007) examined the effect of an interposition nerve graft on sexual function after radical prostatectomy.  This study included 64 patients, without hormonal therapy, who underwent a radical prostatectomy and intraoperative electrophysiological confirmation of cavernous nerve preservation.  Twelve patients underwent a unilateral interposition sural nerve graft (UNG) for the resected neurovascular bundle.  Twenty-one and 31 patients underwent bilateral nerve-sparing (BNS) and unilateral nerve-sparing (UNS) surgery without a nerve graft, respectively.  As the age of patients was significantly younger in the UNG group than in the other groups, age-matched analysis also was conducted.  Sexual function, evaluated by a self-administered questionnaire using the University of California Los Angeles-Prostate Cancer Index, was compared statistically among the 3 groups.  In the age-matched analysis, the post-operative sexual function (SXF) score of the UNG group showed an intermediate level of recovery between those of the BNS and UNS groups at 12 months and reached the same level as the score at 12 months of the BNS group at 18 months post-operatively.  The difference in the SXF score between the UNG and UNS groups began to appear after 6 months post-operatively and increased steadily with time.  However, the background factors, such as the baseline SXF score, the usage rate of phosphodiesterase 5 inhibitors, and the rate of co-morbidities were different between the UNG and UNS groups.  The authors concluded that the difference of the SXF score between the UNG and UNS groups increased with time after 6 months post-operatively.  However, it might be difficult at present to attribute a better recovery of the SXF score to the nerve graft because of the difference in the background factors between the groups.

Secin et al (2007) stated that cavernous nerve graft is an option for men requiring bilateral cavernous nerve resection for cancer control during radical prostatectomy.  These investigators determined the success rate and identified determinants of success of bilateral cavernous nerve grafting following resection of the 2 nerves during radical prostatectomy in patients who were potent pre-operatively.  These researchers retrospectively reviewed the records of 44 consecutive patients who underwent bilateral nerve grafting from 1999 to 2004.  Post-operative erectile function was defined as the achievement of erections satisfactory for intercourse with or without oral medication.  They calculated cumulative erectile function recovery rates using Kaplan-Meier curves.  The log rank test was used to compare variables affecting erectile function recovery with p < 0.0083 considered significant after adjusting for the number of variables evaluated using the Bonferroni correction.  The overall 5-year cumulative recovery of erectile function permitting penetration was 34 % and the rate of consistent penetration was 11 %.  None of the analyzed variables was significantly associated with recovery of post-operative erectile function, including patient age (p = 0.3), incomplete bilateral cavernous nerve resection (p = 0.045), sural nerve grafts compared to genito-femoral or ilio-inguinal nerves as donor sites (p = 0.067), post-radiation salvage radical prostatectomy (p = 0.15), neoadjuvant hormone therapy (p = 0.7) and co-morbidities (p = 0.15) or medications (p = 0.4) affecting erectile function.  The authors concluded that bilateral cavernous nerve grafts might be beneficial in select patients.  A definitive answer awaits the performance of a multi-institutional, randomized, controlled trial.

Fujioka et al (2007) presented their experience of cavernous nerve graft reconstruction to restore potency following radical prostatectomy (RP).  A total of 8 patients with prostate cancer who required radical resection involving 1 cavernous nerve had sural nerve grafting, with 2 or 3 sutures using the autologous vein-guide technique, were included in this study.  Seven of the 8 patients had spontaneous erectile activity after grafting and 6 of these patients were able to have intercourse.  The findings of this study need to be validated by studies with larger sample size and long-term follow-up.

Joffe and Klotz (2007) evaluated the success of erectile function preservation and recovery in a select group of patients with extensive disease unilaterally on biopsy who were candidates for unilateral nerve sparing and contralateral genito-femoral interposition nerve-grafting RP.  Because of its low donor site morbidity, the genito-femoral nerve is an appealing donor source for cavernous nerve grafting during RP.  Nerve-sparing RP was performed according to the technique of Walsh on 22 patients with prostate cancer.  At follow-up, the patients completed an 11-item self-report questionnaire that included the erectile function (EF) domain of the International Index of Erectile Function.  The mean patient age was 62 years (range of 48 to 76).  The mean follow-up time was 23 months (range of 9 to 37).  Of the 22 patients, 3 reported no ED (EF score of 26 to 30), 3 reported mild ED (EF score of 22 to 25), 1 reported moderate ED (EF score of 11 to 16), and 15 reported severe ED (EF score of less than 11).  Eight men continued to experience mild chronic thigh or scrotal numbness after the genito-femoral nerve graft procedure.  The authors concluded that the benefits of unilateral nerve grafting with the genito-femoral nerve remain uncertain.  They stated that a prospective randomized trial is needed before the widespread adoption of unilateral nerve grafting.

Namiki et al (2007) performed a 3-year longitudinal study assessing the impact of unilateral sural nerve graft on recovery of potency and continence following RP.  A total of 113 patients undergoing radical retropubic prostatectomy were classified into 3 groups according to the degree of nerve sparing, that is unilateral nerve preservation with contralateral sural nerve graft interposition, bilateral nerve sparing and unilateral nerve sparing.  Urinary continence and potency were estimated by the UCLA Prostate Cancer Index questionnaire.  Patients in the nerve sparing plus sural nerve graft group were younger than those in the bilateral nerve sparing or unilateral nerve sparing groups.  At baseline the unilateral nerve sparing plus sural nerve graft group and the bilateral nerve sparing group reported better sexual function than the unilateral nerve sparing group (62.1 and 61.5 versus 49.9, p < 0.05).  The bilateral nerve sparing group showed more rapid recovery than the unilateral nerve sparing plus sural nerve graft group after radical retropubic prostatectomy (p < 0.01).  After 24 months there were no significant differences observed between the bilateral nerve sparing and the unilateral nerve sparing plus sural nerve graft group (28.7 versus 32.9).  The bilateral nerve sparing group reported a better sexual function score than the unilateral nerve sparing group throughout the postoperative period (p < 0.05).  The bilateral nerve sparing group maintained significantly better urinary function at 1 month after radical retropubic prostatectomy than the unilateral nerve sparing plus sural nerve graft group (p < 0.05).  After 3 months these groups were almost continent.  The unilateral nerve sparing group reported lower urinary function scores during the first year compared to the other groups.  The authors concluded that the nerve graft procedure may contribute to the recovery of urinary function as well as sexual function after radical retropubic prostatectomy.  They noted that this finding needs to be validated in a randomized trial.

Mikhail et al (2007) reported their experience with sural nerve grafting during robot-assisted laparoscopic radical prostatectomy (RLRP).  Patients with pre-operative potency and a minimum of 6 months follow-up were included in this prospective review.  A total of 333 patients met these criteria including 22 of the 25 patients who underwent sural nerve grafting.  Patients were divided into 5 groups to compare unilateral and bilateral sural nerve cohorts with non-nerve-sparing and unilateral and bilateral nerve-sparing groups.  Patients were followed prospectively using health-related quality-of-life questionnaires.  Twenty-two patients underwent sural nerve grafting that included 3 bilateral grafts.  Mean follow-up was 14 months.  There was no statistical difference in patients' ages, body mass index, pre-operative prostate-specific antigen level, blood loss, complications, and positive margin rate.  Operative time was statistically longer for both sural graft cohorts when compared with unilateral (without graft) and bilateral nerve sparing cohorts.  No significant differences in subjective or objective sexual function, sexual bother, or urinary function were seen with 6 and 12 months follow-up, possibly related to smaller sural cohorts.  Graft-related complications include leg pain in 1 patient.  The authors concluded that sural nerve grafting during RLRP is technically feasible and safe and offers improved dexterity and visualization deep within the pelvis.  However, they stated that a larger randomized cohort of patients will be needed to validate any improved benefits afforded by the robot system.

Zorn and colleagues (2008) assessed the functional, pathological, and oncological outcomes of men who underwent robot-assisted sural-nerve graft (SNG) interposition.  Between February 2003 and May 2007, 1,175 consecutive men underwent robot-assisted laparoscopic radical prostatectomy (RLRP).  Database analysis identified 27 men who had SNG: 4 bilateral (BL) and 23 unilateral (UL).  Sexual function (SF) was prospectively evaluated pre-operatively and at 1, 3, 6, 12, and 24 months post-operatively using validated questionnaires.  Positive surgical margins (PSMs), biochemical recurrence (BCR), and potency were evaluated.  Compared with RLRP patients without SNG, patients with SNG were younger (57.2 versus 61.8 yrs, p = 0.02), had a higher Gleason score (p = 0.02), and had a higher clinical and pathological stage (p < 0.001 for both).  Mean surgical time was significantly longer (349 versus 195 mins, p < 0.001) in patients with SNG.  With a mean follow-up of 26.1 months, 11 (47.8 %) patients with UL-SNG and zero men with BL-SNG regained potency.  No significant difference in SF was observed between UL nerve sparing and no SNG (56 %) compared with UL nerve sparing with UL-SNG (p = 0.44). Rates of return-to-baseline SF (RTB-SF) at 6, 12, and 24 months were 11 %, 36 % and 45 % for UL-SNG, respectively, which were also comparable to UL nerve sparing only (p > 0.05).  No patient (0 %) in the BL-SNG group ever achieved RTB-SF status at any time point.  Positive surgical margins were observed in 37 % (10/27) of all patients.  Biochemical recurrence occurred in 9 patients (33.3 %), 7 of whom had PSM (78 %); treatment failure occurred within 6 months of surgery, necessitating androgen deprivation therapy.  The authors concluded that despite optimism regarding SNG, long-term functional outcomes have been disappointing, particularly for BL nerve interposition.  Unilateral sural-nerve graft does not appear to improve outcomes when compared with men with UL nerve preservation.  With the greater risk of PSM and BCR in patients who are considered candidates for SNG, newer treatment modalities are needed to cure their disease while preserving SF.

In a phase II clinical trial, Davis et al (2009) examined if UNS RP plus SNG results in a 50 % relative increase in potency at 2 yrs compared to UNS RP alone.  Participants were men with localized prostate cancer recommended for UNS RP, less than 66 yrs old, normal baseline erectile function, and willing to participate in early erectile dysfunction (ED) therapy.  Patients were followed-up to 2 yrs; they underwent UNS RP and ED therapy starting at 6 wks: oral prostaglandin type-5 (PDE5) inhibitor, vacuum erection device (VED), and intra-cavernosal injection therapy.  In the SNG group, a plastic surgeon performed the procedure at the time of RP.  Main outcome measure was the ability to have an erection suitable for intercourse with or without a PDE5 inhibitor at 2 yrs.  The hypothesis was that SNG would result in a 60 % potency rate compared to 40 % for controls (80 % power, 5 % 2-way significance).  The trial planned to enroll 200 patients, but an interim analysis at 107 patients met criteria for futility and the trial was closed.  For patients completing the protocol to 2 yrs, potency was recovered in 32 of 45 (71 %) of SNG and 14 of 21 (67 %) of controls (p = 0.777).  By intent-to-treat analysis, potency recovered in 32 of 66 (48.5 %) of SNG and 14 of 41 (34 %) of controls (p = 0.271).  No differences were seen in time to potency or quality of life scores for ED and urinary function.  Limitations included slower-than-expected accrual and poor compliance with ED therapy: less than 65 % for VED and less than 40 % for injections.  The authors concluded that the addition of SNG to a UNS RP did not improve potency at 2 yrs following surgery.

In a systematic review on "Advances of peripheral nerve repair techniques to improve hand function", Mafi and colleagues (2012) stated that concepts of neuronal damage and repair date back to ancient times.  The research in this topic has been growing ever since and numerous nerve repair techniques have evolved throughout the years.  In this review, these researchers examined advances of peripheral nerve repair techniques to improve hand function.  They noted that there are no reviews bringing together and summarizing the latest research evidence concerning the most up-to-date techniques used to improve hand function.  Thus, by identifying and evaluating all the published literature in this field, these investigators have summarized all the available information about the advances in peripheral nerve techniques used to improve hand function.  The most important ones are the use of resorbable poly[(R)-3-hydroxybutyrate] (PHB), epineural end-to-end suturing, graft repair, nerve transfer, side-to-side neurorrhaphy and end-to-side neurorrhaphy between median, radial and ulnar nerves, nerve transplant, nerve repair, external neurolysis and epineural sutures, adjacent neurotization without nerve suturing, Agee endoscopic operation, tourniquet induced anesthesia, toe transfer and meticulous intrinsic repair, free auto nerve grafting, use of distal based neurocutaneous flaps and tubulization.  At the same time the authors found that the patient's age, tension of repair, time of repair, level of injury and scar formation following surgery affect the prognosis.  They stated that despite the thorough findings of this systematic review, further research in this field is needed.

Siddiqui et al (2014) examined the long-term outcome of SNG during radical retropubic prostatectomy (RRP) performed by a single surgeon.  A total of 66 patients with clinically localized prostate cancer and pre-operative International Index of Erectile Function (IIEF) score greater than 20 who underwent RRP were included in this study.  Neuro-vascular bundles (NVB) excision was performed if the risk of side-specific extra-capsular extension (ECE) was greater than 25 % on Ohori' nomogram.  Sural nerve graft was harvested by a plastic surgeon, contemporaneously as the urologic surgeon was performing RRP; IIEF questionnaire was used pre- and post-operatively and at follow-up.  Main outcome measure was post-operative IIEF score at 3 years of men undergoing RRP with SNG.  Recovery of potency was defined as post-operative IIEF-EF domain score greater than 22.  There were 43 (65 %) unilateral SNG and 23 (35 %) bilateral SNG.  Mean surgical time was 164 minutes (71 to 221).  The mean pre-operative IIEF score was 23.4 +/- 1.6.  With a mean follow-up of 35 months, 19 (28.8 %) patients had IIEF score greater than 22.  The IIEF-EF scores for those who had unilateral SNG and bilateral SNG were 12.9 +/- 4.9 and 14.8 +/- 5.3 respectively.  History of diabetes (p = 0.001) and age (p = 0.007) negatively correlated with recovery of EF; 60 % patients used PDE5i and showed a significantly higher EF recovery (43 % versus 17 %, p = 0.009).  The authors concluded that SNG can potentially improve EF recovery for potent men with higher stage prostate cancer undergoing RP.  These findings need to be validated by well-designed studies..

Patel et al (2015) presented a propensity-matched analysis of patients undergoing placement of dehydrated human amnion/chorion membrane (dHACM) around the NVB during NS robot-assisted laparoscopic prostatectomy (RARP).  From March 2013 to July 2014, a total of 58 patients who were pre-operatively potent (Sexual Health Inventory for Men [SHIM] score greater than 19) and continent (no pads) underwent full NS RARP.  Post-operative outcomes were analyzed between propensity-matched graft and no-graft groups, including time to return to continence, potency, and biochemical recurrence.  Use of dHACM was not associated with increased operative time or blood loss or negative oncologic outcomes (p > 0.500).  Continence at 8 weeks returned in 81.0 % of the dHACM group and 74.1 % of the no-dHACM group (p = 0.373). Mean time to continence was enhanced in group 1 patients (1.21 months) versus (1.83 months; p = 0.033).  Potency at 8 weeks returned in 65.5 % of the dHACM patients and 51.7 % of the no-dHACM group (p = 0.132).  Mean time to potency was enhanced in group 1, (1.34 months), compared to group 2 (3.39 months; p = 0.007).  Graft placement enhanced mean time to continence and potency.  The authors concluded that post-operative SHIM scores were higher in the dHACM group at maximal follow-up (mean score 16.2 versus 9.1).  They stated that dHACM allograft use appears to hasten the early return of continence and potency in patients following RARP.  The major drawbacks of this study were its modest sample size and short-term follow-up; these preliminary findings need to be validated by well-designed studies.

NeuroMatrix^TM Collagen Nerve Cuff and NeuroMend^TM Collagen Nerve Wrap

Peripheral nerves possess the capacity of self-regeneration after traumatic injury.  Transected peripheral nerves can be bridged by direct surgical coaptation of the 2 nerve stumps or by interposing autografts or biological (veins) or synthetic nerve conduits.  Nerve conduits are tubular structures that guide the regenerating axons to the distal nerve stump.  Early synthetic nerve conduits were primarily made of silicone because of the relative flexibility and biocompatibility.  Nerve conduits are now made of biodegradable materials such as collagen, aliphatic polyesters, or polyurethanes (Pfister et al, 2007).  Studies are in progress to assess the long-term biocompatibility of these implants and their effectiveness in nerve reconstruction.

According to the Collagen Matrix, Inc. (Franklin Lakes, NJ) website, NeuroMatrix is a resorbable, semi-permeable collagen-based tubular matrix that provides a protective environment for peripheral nerve repair after injury and creates a conduit for axonal growth across a nerve gap.  The device slowly resorbs in vivo.  The device is engineered from highly purified type I collagen fibers and are composed of dense fibers for mechanical strength.  Collagen Nerve Cuff was cleared by the FDA via the 510(k) process in September 2001.  It is intended for use in repair of peripheral nerve discontinuities where gap closure can be achieved by flexion of the extremity; however, there is insufficient scientific evidence regarding its effectiveness for peripheral nerve repair or for any other indication.

NeuroMend Nerve Wrap is a resorbable, semi-permeable, type 1 collagen nerve wrap used in peripheral nerve repair.

NeuroMend (Collagen Matrix, Inc., Franklin Lakes, NJ) is a resorbable, collagen-based rolled membrane matrix intended for use in the management of peripheral nerve injuries in which there has been no substantial loss of nerve tissue.  It has the same technological characteristics as NeuroMatrix.  Collagen Nerve Wrap was cleared by the FDA via the 510(k) process on July 14, 2006; however, there is insufficient scientific evidence regarding its effectiveness for peripheral nerve repair or for any other indication.

Avance Nerve Graft

Avance Nerve Graft is a processed, decedecellularized nerve allograft, used as an alternative to nerve conduits for nerve repair procedures.

In a case report and review of the literature, Gunn et al (2010) presented a rare case of facial nerve paraganglioma and novel use of a processed allograft for facial nerve reconstruction. A 34-year old female presented with progressive onset right sided facial palsy for 5 months; CT and MRI demonstrated an irregular mass in the right facial nerve canal from the intra-tympanic segment to the stylo-mastoid foramen.  Following trans-mastoid resection, the defect was repaired using processed allograft.  Pathologic analysis was consistent with a paraganglioma.  Facial nerve paraganglioma is a rare entity that has been reported only 10 times in the literature.  The authors concluded that traditional methods of facial nerve reconstruction, including autologous and cadaveric grafting, can lead to significant patient morbidity.  Autologous nerve grafts are the "gold standard" for superior regenerative capability, but are limited by the length and potential neuroma formation at the donor site.  Allogenic grafts from donors or cadavers have shown some effectiveness, but can require immunosuppression.  The Avance nerve graft (Avance Nerve Graft, AxoGen, Inc.) is a cadaveric graft, processed and decellularized to maintain an extracellular matrix with laminin and intact endoneural tubes, thus providing support for the growing axon without generating an immune response.  The authors concluded that initial studies of the Avance graft in animals and humans have examined repair of peripheral nerves, but this was the first reported case of human facial nerve reconstruction.

Brooks et al (2012) reported on the outcomes from a multi-center study on processed nerve allografts (Avance Nerve Graft). A total of 12 sites with 25 surgeons contributed data from 132 individual nerve injuries.  Data was analyzed to determine the safety and effectiveness of the nerve allograft.  Sufficient data for effectiveness analysis were reported in 76 injuries (49 sensory, 18 mixed, and 9 motor nerves).  The mean age was 41 ± 17 (18 to 86) years.  The mean graft length was 22 ± 11 (5 to 50) mm.  Subgroup analysis was performed to determine the relationship to factors known to influence outcomes of nerve repair such as nerve type, gap length, patient age, time to repair, age of injury, and mechanism of injury.  Meaningful recovery was reported in 87 % of the repairs reporting quantitative data.  Subgroup analysis demonstrated consistency, showing no significant differences with regard to recovery outcomes between the groups (p > 0.05 Fisher's Exact Test).  No graft related adverse experiences were reported and a 5 % revision rate was observed.  The authors concluded that processed nerve allografts performed well and were found to be safe and effective in sensory, mixed and motor nerve defects between 5 and 50 mm.  They stated that the outcomes for safety and meaningful recovery observed in this study compared favorably to those reported in the literature for nerve autograft and were higher than those reported for nerve conduits.  The main drawbacks of this study were its retrospective design and the lack of a comparison group.

In a case-series study, Zuniga (2015) described the results of using a processed nerve allograft, Avance Nerve Graft, as an extracellular matrix scaffold for the reconstruction of lingual nerve (LN) and inferior alveolar nerve (IAN) discontinuities. A retrospective analysis of the neurosensory outcomes for 26 subjects with 28 LN and IAN discontinuities reconstructed with a processed nerve allograft was conducted to determine the treatment safety and effectiveness.  Sensory assessments were conducted pre-operatively and 3, 6, and 12 months after surgical reconstruction.  The outcomes population, those with at least 6 months of post-operative follow-up, included 21 subjects with 23 nerve defects.  The neurosensory assessments included brush stroke directional sensation, static 2-point discrimination, contact detection, pressure pain threshold, and pressure pain tolerance.  Using the clinical neurosensory testing scale, sensory impairment scores were assigned pre-operatively and at each follow-up appointment. Improvement was defined as a score of normal, mild, or moderate.  The neurosensory outcomes from LNs and IANs that had been micro-surgically repaired with a processed nerve allograft were promising.  Of those with nerve discontinuities treated, 87 % had improved neurosensory scores with no reported adverse experiences.  Similar levels of improvement, 87 % for the LNs and 88 % for the IANs, were achieved for both nerve types.  Furthermore, 100 % sensory improvement was achieved in injuries repaired within 90 days of the injury compared with 77 % sensory improvement in injuries repaired after 90 days.  The authors concluded that these results suggested that processed nerve allografts are an acceptable treatment option for reconstructing trigeminal nerve discontinuities; additional studies will focus on reviewing the outcomes of additional cases.

Nerve Grafting after Radical Prostatectomy

Souza and colleagues (2017) examined a novel penile re-innervation technique using 4 sural nerve grafts and end-to-side neurorraphies connecting bilaterally the femoral nerve and the cavernous corpus and the femoral nerve and the dorsal penile nerves.  A total of 10 patients (mean [± SD; range] age 60.3 [± 4.8; 54 to 68] years), who had undergone RP at least 2 years previously, underwent penile re-innervation in the present study; 4 patients had undergone radiotherapy after RP.  All patients reported satisfactory sexual activity prior to RP.  The surgery involved bridging of the femoral nerve to the dorsal nerve of the penis and the inner part of the corpus cavernosum with sural nerve grafts and end-to-side neurorraphies.  Patients were evaluated using the IIEF questionnaire and pharmaco-penile Doppler ultrasonography (PPDU) pre-operatively and at 6, 12 and 18 months post-operatively, and using a Clinical Evolution of Erectile Function (CEEF) questionnaire, administered after 36 months.  The IIEF scores showed improvements with regard to ED, satisfaction with intercourse and general satisfaction.  Evaluation of PPDU velocities did not reveal any difference between the right and left sides or among the different time-points.  The introduction of nerve grafts neither caused fibrosis of the corpus cavernosum, nor reduced penile vascular flow; CEEF results showed that sexual intercourse began after a mean of 13.7 months with frequency of sexual intercourse varying from once-daily to once-monthly.  Acute complications were minimal.  The authors concluded that a total of 60 % of patients were able to achieve full penetration, on average, 13 months after re-innervation surgery.  Patients previously submitted to radiotherapy had slower return of erectile function. They stated that penile re-innervation surgery is a viable technique, with effective results, and could offer a new therapeutic option for ED after RP.  Moreover, they stated that this study was limited by the small number of cases (n = 10).

Nerve Grafting for Neonatal Brachial Plexus Palsy

Chang and colleagues (2018) stated that the use of nerve transfers versus nerve grafting for neonatal brachial plexus palsy (NBPP) remains controversial.  In adult brachial plexus injury, transfer of an ulnar fascicle to the biceps branch of the musculocutaneous nerve (Oberlin transfer) is reportedly superior to nerve grafting for restoration of elbow flexion.  In pediatric patients with NBPP, recovery of elbow flexion and forearm supination is an indicator of resolved NBPP.  Currently, limited evidence exists of outcomes for flexion and supination when comparing nerve transfer and nerve grafting for NBPP.  In a retrospective cohort study, these researchers compared 1-year post-operative outcomes for infants with NBPP who underwent Oberlin transfer versus nerve grafting.  This trial included patients with NBPP who underwent Oberlin transfer (n = 19) and nerve grafting (n = 31) at a single institution between 2005 and 2015.  A single surgeon conducted intra-operative exploration of the brachial plexus and determined the surgical nerve reconstruction strategy undertaken.  Active range of motion (ROM) was evaluated pre-operatively and post-operatively at 1 year.  No significant difference between treatment groups was observed with respect to the mean change (pre- to post-operatively) in elbow flexion in adduction and abduction and biceps strength.  The Oberlin transfer group gained significantly more supination (100 degrees versus 19 degrees; p < 0.0001).  Forearm pronation was maintained at 90 degrees in the Oberlin transfer group whereas it was slightly improved in the grafting group (0 degree versus 32 degrees; p = 0.02).  Shoulder, wrist, and hand functions were comparable between treatment groups.  The authors concluded that these preliminary data demonstrated that the Oberlin transfer conferred an advantageous early recovery of forearm supination over grafting, with equivalent elbow flexion recovery.  Moreover, they stated that further studies that monitor real-world arm usage are needed to provide more insight into the most appropriate surgical strategy for NBPP.

Hardcastle and colleagues (2020) stated that brachial plexus palsy is a surgically manageable condition.  Re-animating the shoulder is a high priority for restoring upper extremity function.  Methods for re-innervating injured nerves include the transfer of a healthy nerve or fascicle distal to the site of injury, or grafting a healthy sensory nerve to restore motor function.  Studies aiming to compare these 2 techniques for restoring shoulder abduction have yielded conflicting results.  These researchers conducted a systematic review and meta-analysis following the PRISMA guidelines.  They reviewed the PubMed database for studies comparing nerve transfer and nerve grafting for shoulder abduction published by December 2018.  Outcomes using the MRC for muscle strength were assessed using a random effects model meta-analysis.  A total of 5 studies comprising 212 patients (n = 158, nerve transfer; n = 54, nerve grafts) were used for the analysis.  The rate of functional recovery of shoulder function was slightly better for nerve transfer (n = 114/158, 72 %) than for nerve graft patients (n = 36/54, 67 %).  However, this was not statistically significant (OR 1.34, 95 % CI: 0.27-6.72, I2 = 62.9 %).  The authors concluded that nerve transfer and grafting were similarly effective in terms of shoulder abduction.  These researchers stated that future prospective studies are needed to validate these findings and identify the optimal shoulder re-animation strategy in patients with brachial plexus injuries.

In a systematic review, Ayhan and associates (2020) compared elbow flexion restoration with nerve transfers or nerve grafting after traumatic brachial plexus palsy injury; a total of 52 studies were included.  Patients were allocated as C5-C6 (n = 285), C5-C6-C7 (n = 150), and total brachial plexus injury (n = 245) groups.  In each group, 2 treatment modalities were compared, and effects of age and pre-operative interval were analyzed.  In C5-C6 injuries, 93.1 % of nerve transfer patients achieved elbow flexion force greater than or equal to M3, which was significantly better when compared to 69.2 % of nerve graft patients (p < 0.001).  For improved outcomes of nerve transfer patients, shorter pre-operative interval was a significant factor in all injury patterns (p < 0.001 for C5-C6 injuries and total brachial plexus injuries, p = 0.018 for C5-C6-C7 injuries), and young age was a significant factor in total brachial plexus injury pattern (p = 0.022).  The authors concluded that this analyses showed that nerve transfers appeared superior to nerve grafting especially in patients with a C5-C6 injury.  These researchers stated that unnecessary delays in surgery must be prevented, and younger patients may have more chance for better recovery.  Level of Evidence = II.

NeuraGen

van Neerven and colleagues (2017) noted that progress in material development has enabled the production of nerve guides that increasingly resemble the characteristics of an autologous nerve graft.  In the present study, 20 mm adult rat sciatic nerve defects were bridged with the collagen-based, 2-component nerve guide "Neuromaix", the commercially available NeuraGen nerve tube or an autologous nerve graft.  Neuromaix was able to support structural as well as functional regeneration across this gap.  The majority of the axons grew across the scaffold into the distal nerve segment and retrograde tracing confirmed that these axons were of somatosensory and motor origin.  Histomorphology revealed that axons regenerating through Neuromaix exhibited reduced myelin sheath thickness, whereas axon diameter and axon density were comparable to those of the autograft.  Neuromaix implantation resulted in re-innervation of the gastrocnemius muscle to a level that was not significantly different from that supported by the autograft, as shown by electrophysiology.  The authors concluded that these findings showed that the use of the Neuromaix scaffold not only allowed axonal regeneration across large nerve gaps, but that the regenerating axons were also able to functionally re-innervate the muscles.  They noted that these data provided a promising perspective for the first in human application of the materials.

AxoGen Nerve Protector and Nerve Connector / Nerve Grafting for Cubital Tunnel Syndrome

Papatheodorou and colleagues (2015) evaluated the clinical results of revision neurolysis and wrapping with porcine extra-cellular matrix (AxoGuard Nerve Protector, AxoGen Inc., Alachua, FL) for cubital tunnel syndrome (CTS) after 1 previous surgical decompression.  A total of 12 patients with recurrent CTS were treated with decompression, porcine extra-cellular matrix nerve wrap, and minimal medial epicondylectomy (if not previously performed).  The average follow-up period was 41 months (range of 24 to 61 months).  All patients had recurrent symptoms after having previously undergone 1 surgical decompression.  The mean patient age was 45 years (range of 30 to 58 years).  All patients were evaluated subjectively and objectively (pain, satisfaction, static 2-point discrimination, grip strength, and pinch strength).  A significant improvement was demonstrated in post-operative pain levels (from 8.5 to 1.7), grip strength (from 41 % to 86 % of the unaffected side), and pinch strength (from 64 % to 83 % of the unaffected side).  Static 2-point discrimination improved from an average 10.4 mm pre-operatively to 7.6 mm post-operatively; 11 of 12 patients demonstrated 2 mm or more improvement in 2-point discrimination post-operatively.  There were no complications related to the use of the porcine extra-cellular matrix for nerve wrapping.  The authors concluded that the findings of this study showed that secondary decompression combined with porcine extra-cellular matrix nerve wrapping was a safe and effective treatment for patients with recurrent CTS.  Level of evidence = IV.  This was a small study (n = 12) and its findings were confounded by the combined use of decompression and nerve wrapping.  These preliminary findings need to be validated by well-designed studies.

Dy and associates (2018) stated the physiological limitations of neural regeneration make peripheral nerve surgery challenging to both the surgeon and the patient.  Presence of nerve gaps and local wound factors may all influence outcome, suggesting that barriers to reduce peri-neural scarring, minimize fibrosis, and avoid ischemia would be beneficial.  These researchers examined the evidence supporting their use; they reviewed the autologous and commercially-available options for barriers against scarring around a nerve.  Numerous clinical case series demonstrated the safety and effectiveness of local/rotational flaps and autologous vein wrapping when used in the presence of recurrent compressive neuropathy. Translational research in animal models supports the biocompatibility of commercially available nerve wraps following nerve repair.  The authors concluded that there are no reports of clinical use of commercially available nerve wraps in acute nerve repair, but a growing number of case series demonstrated their safety and effectiveness in chronic compressive neuropathy.  Moreover, these investigators noted that limited clinical evidence exists to support the efficacy of vein or flap coverage in acute nerve repairs.

Babovic and co-workers (2018) noted that outcomes following digital nerve repair are sub-optimal despite much research and various methods of repair.  Increased tensile strength of the repair and decreased suture material at the repair site may be 2 methods of improving biologic and biomechanical outcomes, and conduit-assisted repair could aid in achieving both of these goals.  A total of 99 fresh-frozen digital nerves were equally divided into 11 different groups.  Each group used a different combination of number of sutures at the coaptation site and number of sutures at each end of the nerve-conduit junction, as well as 2 calibers of nylon suture.  Nerves were transected, repaired with these various suture configurations using an AxoGuard conduit, and loaded to failure.  The 2-way analysis of variance (ANOVA) showed that repairs performed with 8-0 suture had significantly higher maximum failure load compared with 9-0 suture repairs (p < 0.01).  Increasing the number of sutures in the repair significantly increased the maximum failure load in all groups regardless of suture caliber used (p < 0.01).  Repairs with 9-0 suture at the coaptation site did not jeopardize repair strength when compared with 8-0 suture.  Conduit-assisted primary digital nerve repairs with 8-0 suture increased the maximum load to failure compared with repairs with 9-0 suture, as did increasing the overall number of sutures.  Using 9-0 suture at the coaptation site with 8-0 suture at the nerve-conduit junction did not jeopardize tensile strength when compared with similar repairs using all 8-0 suture and may decrease inflammation at the repair site while still achieving sufficient tensile strength.

Weller (2019) stated that in the field of upper extremity surgery there are myriad new and developing technologies.  The author high-lighted a few of the most compelling new technologies and reviewed their background, indications for use, and most recently reported outcomes in clinical practice.  This researcher stated that current data suggested that processed nerve allografts are indicated for digital nerve gaps of greater than 10 mm or more with high rates of sensory recovery.  Moreover, the author stated that larger studies with longer follow-up are needed to clarify indications, outcomes ,and safety of these technologies.

Furthermore, an UpToDate review on "Overview of upper extremity peripheral nerve syndromes" (Rutkove, 2019) does not mention nerve grafting as a therapeutic option for CTS.

Cross-Palm Nerve Grafts for Ulnar Neuropathy

Felder and colleagues (2020) stated that intrinsic atrophy and debilitating sensory loss are prominent features of severe ulnar neuropathy with limited surgical options to reliably improve recovery.  Restoration of sensation is important to provide protection for the vulnerable ulnar border of the hand.  These investigators reported their experience with side-to-side sensory nerve grafting from the median to ulnar nerve in the palm to enhance ulnar sensory recovery.  A retrospective chart review identified patients with severe ulnar neuropathy who underwent cross-palm nerve grafting.  Included patients had objective loss of protective sensation in the ulnar distribution with 2-point discrimination of greater than 8 mm, Semmes-Weinstein monofilament testing (SWMT) of greater than 4.56, or no sensory response on nerve conduction testing.  Cross-palm side-to-side tension-free grafting from median to ulnar sensory components was performed using short-segment allograft or autografts.  Analysis included patient etiology, procedures, nerve conduction studies, objective sensory testing, and Disabilities of the Arm, Shoulder, and Hand (DASH) score.  A total of 48 patients with severe ulnar neuropathy underwent cross-palm nerve grafting between 2014 and 2017; 24 patients had adequate follow-up for inclusion.  Of the 24 patients, 21 (87 %) had return of protective sensation, 16 (66.7 %) had return of diminished light touch sensation, and 6 (25 %) had return to normal range sensation within 1 year as assessed by SWMT and/or 2-point discrimination.  Patients treated with autograft demonstrated referred sensation to the median nerve distribution.  The authors concluded that cross-palm nerve grafting may be a useful adjunct to enhance sensory recovery in severe ulnar neuropathy.  These researchers stated that further study to quantify differences in sensory recovery between traditional operative techniques and cross-palm nerve grafting is needed.

Nerve Wrapping for Compression Neuropathy

Thakker and colleagues (2021) noted that the recurrence of symptoms following primary nerve compression surgery could occur in up to 25 % of cases . Nerve wrapping can be employed for revision surgery.  An ideal barrier should minimize the chance of fibrosis, scarring and allow for adequate nerve gliding.  In a systematic review, these investigators examined the use of autologous or commercially available allograft and xenograft options as barriers against nerve scarring following revision surgery.  PubMed, Ovid Embase and Cochrane databases were searched using the “All Fields Index”.  A total of 900 titles underwent title screening with 11 studies being included in the final analysis.  The risk of bias was evaluated using the Methodological Index for Non-Randomized Studies (MINORS) tool.  PRISMA guidelines were followed at all stages and the review was registered with PROSPERO (CRD 42020182818).  The 11 studies comprised of all case series; and a total of 114 patients were included, with ages ranging from 28 to 90 years.  Previously, the number of revision surgeries ranged from 0 to 5.  Autologous veins were used in 6 studies, collagen in 3 studies and human amniotic membrane in 2 studies . Improvements in subjective and objective outcomes were observed with all wrap types.  Pain was the most common residual symptom (46 % of patients).  The most common complication was pain at the donor site following vein harvest (19 % of patients).  The authors concluded that this was the 1st systematic review to summarize the outcomes of nerve wraps for revision compression neuropathy.  These researchers stated that while improvements in outcomes were reported, further comparative studies are needed to determine the best nerve wrap.

Furthermore, an UpToDate review on “Overview of lower extremity peripheral nerve syndromes” (Rutkove, 2021) does not mention nerve wrapping as a management / therapeutic option.

Vascularized Nerve Grafts for the Treatment of a Nerve Gap

Donzelli and associates (2016) defined an experimental model to promote the functional recovery of the nerves using grafts with vascular support (vascular nerve grafts [VNG]).  The objective of this study was to define, on an experimental model in normal recipient bed, whether the functional recovery with VNG is superior to that obtained non-vascularized nerve graft (NNG).  A total of 20 male rabbits, which underwent dissection of sciatic nerve, were later treated by re-innervation via an autograft . In 10 animals the reconstruction of sciatic nerve was realized with VNG; in 10 control animals the reconstruction of sciatic nerve was realized with NNG.  The VNG group showed a better axonal organization and a significantly higher number of regenerated axons in the early phases (after 30 days) than the NNG group, whereas the difference in the axonal number at day 90 was less significant.  In addition, the axon diameter and the myelin thickness were not significantly improved by VNG group.  The authors concluded that these findings suggested that the use of VNG led to a faster regeneration process and a better functional recovery, although the final results were comparable to those of the NNG.  VNG improve the quality of the axonal regeneration (axonal diameter and Schwann cells), although the increase in the axonal number was not significant and did not improve the long-term functional outcome.

Saffari and co-workers (2020) noted that vascularization is an important factor in nerve graft survival and function.  The specific molecular regulations and patterns of angiogenesis following peripheral nerve injury are in a broad complex of pathways.  These investigators examined the available evidence on the role of vascularization in nerve regeneration, including the key regulation molecules, and mechanisms and patterns of re-vascularization following nerve injury.  Angiogenesis, the maturation of pre-existing vessels into new areas, is stimulated via angiogenic factors such as vascular endothelial growth factor (VEGF) and precedes the repair of damaged nerves.  Administration of VEGF to nerves has been reported to increase re-vascularization after injury in basic science research.  In the clinical setting, VNGs could be used in the reconstruction of large segmental peripheral nerve injuries.  VNGs are postulated to accelerate re-vascularization and enhance nerve regeneration by providing an optimal nutritional environment, especially in scarred beds, and decrease fibroblast infiltration.  This could improve functional recovery following nerve grafting; however, conclusive evidence of the superiority VNGs is lacking in human studies.  A well-designed randomized controlled trial (RCT) comparing VNGs to NNGs involving patients with similar injuries, nerve graft repair and follow-up times is needed to demonstrate the effectiveness of VNGs.  Due to technical challenges, composite transfer of a nerve graft along with its adipose tissue has been proposed to provide a healthy tissue bed.  Basic science research has shown that a vascularized fascial flap containing adipose tissue and a vascular bundle improves re-vascularization via excreted angiogenic factors, provided by the stem cells in the adipose tissue as well as by the blood supply and environmental support.  While it was previously believed that re-vascularization occurred from both nerve ends, recent studies proposed that re-vascularization occurred primarily from the proximal nerve coaptation.  The authors concluded that fascial flaps or VNGs have limited applicability and future directions could lead towards off-the-shelf alternatives to autografting, such as biodegradable nerve scaffolds that include capillary-like networks to enable vascularization and avoid graft necrosis and ischemia.

Broeren and colleagues (2021) stated that treatment of nerve injuries proves to be a worldwide clinical challenge; VNG are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous NNG.  However, there is no adequate clinical evidence for the beneficial effect of VNGs; and they are still disputed in clinical practice.  In a systematical review, these investigators examined if VNGs would provide a superior nerve recovery compared to NNG autografts regarding histological and electrophysiological outcomes in animal models.  PubMed and Embase were systematically searched.  The inclusion criteria were as follows: the study was an original full paper that presented unique data; a clear comparison between a VNG and a NNG autologous nerve transfer was made; the population study were animals of all genders and ages.  A standardized mean difference (SMD) and 95 % confidence intervals (CIs) for each comparison was calculated to estimate the overall effect.  Subgroup analyses were conducted on graft length, species and time frames.  A total of 14 articles were included in this review and all were included in the meta-analyses.  A VNG resulted in a significantly larger diameter, higher nerve conduction velocity and axonal count compared to an autologous NNG.  However, during sensitivity analysis the effect on axonal count disappeared.  No significant difference was observed in muscle weight.  The authors concluded that treating a nerve gap with a VNG resulted in superior nerve recovery compared to NNG autografts in terms of axon count, diameter and nerve conduction velocity.  No difference in muscle weight was observed.  However, this conclusion needs to be taken with some caution due to the inherent limitations of this meta-analysis.  These researchers recommended future studies to be carried out under conditions more closely resembling human circumstances and to use long nerve defects.  Furthermore, these investigators emphasized that future studies should employ the Gold Standard Publication Checklist or ARRIVE guidelines to improve the reporting and methodological quality of animal studies.  This is essential to improve the quality of the evidence presented in animal studies and the successful translation to humans in a clinical setting.

The authors stated that this study had several drawbacks.  First, the risk of bias analysis showed that most studies reported poorly on important methodological details; thus, most of the risk of bias items assessed had to be scored as unclear risk of bias.  Even though this is quite commonly observed in animal studies, it is something to be taken into account.  The absence of reporting such methodological details could, to a certain extent, indicated the negligence of using these methods to minimize bias and confounding.  This could hamper the possibility to draw reliable conclusions from the included animal studies.  Second, the number of studies included in this meta-analysis was relatively low, especially on nerve conduction velocity and muscle weight.  This resulted in subgroups being relatively small, even to the extent that some subgroup analysis could not be interpreted.  Furthermore, heterogeneity was moderate-to-high.  However, because of their explorative nature, a moderate-to-high heterogeneity between animal studies was expected.  To account for anticipated heterogeneity, these researchers used a random effects model, conducted sensitivity analyses and examined the suggested causes for between study heterogeneity by means of subgroup analyses.  Exploring this heterogeneity was one of the added values of meta-analyses of animal studies and might help to inform the design of future animal studies and subsequent clinical trials.  Third, the graft length used to repair a nerve defect in rat and rabbit models is presumably smaller than those needed in humans; thus, the results shown in these animal experiments might not be correlated with the expected clinical outcomes.  Fourth, a possible reason for heterogeneity could be the use of animals as their own control in some studies; thus, a sensitivity analysis was performed.  This led to 3 studies being excluded because animals were used as their own control group.  Fifth, histomorphometry is difficult to compare between different laboratories, because other methods to measure the outcome were used.  To compensate for these differences, these investigators used a SMD for the meta-analysis.  Over the years methods have evolved from manually calculating axonal count from a light microscopic photograph to a computer calculated estimate.  The methods used by the studies in this review varied as well.  Searching the publication databases, these researchers found little evidence on which one is the best or on a clear sensitivity or specificity for these methods.  Lastly, the presence of publication bias was identified.  The funnel plot suggested some asymmetry and Duval and Tweedie’s Trim and Fill analysis predicted some over-estimation of the identified summary effect size of axonal count.

Phrenic Nerve Reconstruction for the Treatment of Diaphragmatic Paralysis

Kaufman et al (2014) noted that unilateral diaphragmatic paralysis causes respiratory deficits and could occur following iatrogenic or traumatic phrenic nerve injury in the neck or chest.  Patients are examined using spirometry and imaging studies; however, phrenic nerve conduction studies and electromyography (EMG) are not widely available or considered; therefore, the degree of dysfunction is often unknown.  Treatment has been limited to diaphragmatic plication.  Phrenic nerve operations to restore diaphragmatic function may broaden therapeutic options.  In a non-randomized study, these researchers reported the findings of an interventional study of 92 patients with symptomatic diaphragmatic paralysis: 68 subjects (based on their clinical condition) were assigned to phrenic nerve surgical intervention (PS), 24 to non-surgical (NS) care; and these investigators evaluated a third group of 68 patients (derived from literature review) treated with diaphragmatic plication (DP).  Variables for assessment included spirometry, the Short-Form 36-Item (SF-36) survey, electro-diagnostics, and complications.  In the PS group, there was an average 13 % improvement in forced expiratory volume in 1 second (FEV1; p < 0.0001) and 14 % improvement in forced vital capacity (FVC; p < 0.0001), and there was corresponding 17 % (p < 0.0001) and 16 % (p < 0.0001) improvement in the DP cohort.  In the PS and DP groups, the average post-operative values were 71 % for FEV1 and 73 % for FVC.  The PS group showed an average 28 % (p < 0.01) improvement in SF-36-Item survey reporting.  Electro-diagnostic testing in the PS group revealed a mean 69 % (p < 0.05) improvement in conduction latency and a 37 % (p < 0.0001) increase in motor amplitude.  In the NS group, there was no significant change in SF-36-Item survey or spirometry values.  The authors concluded that phrenic nerve operations for functional restoration of the paralyzed diaphragm should be part of the standard treatment algorithm in the management of symptomatic patients with this condition.  Assessment of neuromuscular dysfunction could aid in determining the most effective therapy.  These researchers stated that the drawbacks of this study included its non-randomized design, the follow-up of the PS group was only 12 months, and the DP group was a historical cohort.

Kawashima et al (2015) stated that primary or metastatic lung cancer or mediastinal tumors may at times involve the phrenic nerve and pericardium.  To remove the pathology en bloc, the phrenic nerve must be resected; resulting in phrenic nerve paralysis, which in turn reduces pulmonary function and quality of life (QOL).  As a curative measure of this paralysis, and thus a preventive measure against decreased pulmonary function and QOL, these investigators had carried out immediate phrenic nerve reconstruction under complete video-assisted thoracic surgery, and with minimal additional stress to the patient.  This study sought to ascertain the use of this procedure from an evaluation of the cases experienced to-date.  These researchers carried out 6 cases of complete video-assisted thoracic surgery phrenic nerve reconstruction from October 2009 to December 2013 in patients who had undergone phrenic nerve resection or separation to remove tumors en bloc.  In all cases, it was difficult to separate the phrenic nerve from the tumor.  Reconstruction entailed direct anastomosis in 3 cases and intercostal nerve (ICN) inter-position anastomosis in the remaining 3 cases.  In the 6 patients (3 men, 3 women; mean age of 50.8 years), these investigators carried out 2 right-sided and 4 left-sided procedures.  The mean anastomosis time was 5.3 mins for direct anastomosis and 35.3 mins for ICN inter-position anastomosis.  Post-operative phrenic nerve function was measured on chest X-ray during inspiration and expiration.  Direct anastomosis was effective in 2 of the 3 patients, and ICN inter-position anastomosis was effective in all 3 patients.  Diaphragm function was confirmed on X-ray to be improved in these 5 patients.  The authors concluded that complete video-assisted thoracic surgery phrenic nerve reconstruction was effective for direct anastomosis as well as for ICN inter-position anastomosis in a small sample of selected patients.  These researchers stated that this approach demonstrated promise for phrenic nerve reconstruction and further data should be accumulated over time.

Kaufman et al (2017) noted that phrenic nerve reconstruction has been studied as a method of restoring functional activity and may be an effective alternative to DP.  Longer follow-up and a larger cohort for analysis are needed to confirm the effectiveness of this procedure for diaphragmatic paralysis.  A total of 180 patients treated with phrenic nerve reconstruction for chronic diaphragmatic paralysis were followed for a median 2.7 years.  Assessment parameters included: SF-36 physical functioning survey, spirometry, chest fluoroscopy, electro-diagnostic evaluation, a 5-item questionnaire to evaluate specific functional issues, and overall patient-reported outcome (PROs).  A total of 134 males and 46 females with an average age of 56 years (range of 10 to 79 years) were treated.  Mean baseline percent predicted values for FEV1, FVC, vital capacity (VC), and total lung capacity, were 61 %, 63 %, 67 %, and 75 %, respectively.  The corresponding percent improvements in percent predicted values were: 11 %, 6 %, 9 %, and 13 % (p ≤ 0.01; ≤ 0.01; ≤ 0.05; ≤ 0.01).  Mean pre-operative SF-36 physical functioning survey scores were 39 %, and an improvement to 65 % was reported following surgery (p ≤ 0.0001).  Nerve conduction latency, improved by an average 23 % (p ≤ 0.005), and there was a corresponding 125 % increase in diaphragm motor amplitude (p ≤ 0.0001).  A total of 89 % of patients reported an overall improvement in breathing function.  The authors concluded that long-term assessment of phrenic nerve reconstruction for diaphragmatic paralysis indicated functional correction and symptomatic relief.

Nandra et al (2017) noted that diaphragmatic pacing has been employed in the management of patients experiencing ventilator-dependent respiratory failure due to spinal cord injury (SCI) as a means to reduce or eliminate the need for mechanical ventilation.  However, this technique relies on intact phrenic nerve function.  Recently, phrenic nerve reconstruction with ICN grafting has expanded the indications for diaphragmatic pacing.  These researchers examined early outcomes and effectiveness of ICN transfer in diaphragmatic pacing.  A total of 4 ventilator-dependent patients with high cervical spinal cord injuries were include in this study.  Each patient showed absence of phrenic nerve function via external neck stimulation and laparoscopic diaphragm mapping.  Each patient underwent intercostal to phrenic nerve grafting with implantation of a phrenic nerve pacer.  The patients were followed, and ventilator dependence was re-assessed at 1 year post-operatively.  The primary outcome was measured by the amount of time these subjects tolerated off the ventilator per day.  These investigators found that all 4 patients had tolerated paced breathing independent of mechanical ventilation, with 1 patient achieving 24 hours of tracheostomy collar.  The authors concluded that intercostal to phrenic nerve transfers are a new and relatively safe technique with potential to re-innervate paralyzed diaphragms in patients with C3 to C5 SCI; thus, it appeared to be a promising approach in reducing or eliminating ventilator support in patients with high SCI.

The authors stated that drawbacks of this study included the small sample size (n = 4) and the inability to provide a comparison with a control group.  Because of the highly selective requirements for diaphragmatic pacing with phrenic nerve reconstruction, it was difficult to develop a large study population.

Frasca et al (2020) stated that primary synovial sarcoma is a soft tissue tumor that originates from synovial-like undeveloped mesenchymal structures.  These investigators reported the case of a giant mediastinal sarcoma in a 41-year-old woman.  Following diagnosis, she underwent neoadjuvant chemotherapy.  Due to its low effectiveness, these researchers recommended cytoreductive debulking surgery.  The mass invaded the phrenic nerve bilaterally and its excision resulted in a severe lesion of the left phrenic nerve, and a partial impairment of the right phrenic nerve.  As a consequence, plastic surgeons decided to reconstruct the right phrenic nerve employing the contralateral remaining fibers.  The invasiveness of this tumor, the difficulty of its removal, histological profile, and the peculiar technique to preserve diaphragmatic function classified this case as very rare.  The therapeutic strategy was based on inter-disciplinary teamwork that comprised several specialists' opinions.  This strategy allowed these investigators to pursue the challenging objective to give a young woman with a severe diagnosis the best possible chance of achieving good QOL.  The authors stated that to the best of their knowledge, this phrenic nerve reconstructive technique was very rare; and there have been no reports in the literature that have focused on the technique performed here, even though some researchers have proposed other approaches such as neurotization of the phrenic nerve with the trapezius branch of the ipsilateral spinal accessory nerve, or reconstruction of the phrenic nerve utilizing fibers of sural nerve.

Kaufman et al (2021) noted that diaphragmatic paralysis due to phrenic nerve injury may cause orthopnea, exertional dyspnea, and sleep-disordered breathing (SDB).  Phrenic nerve reconstruction may relieve symptoms and improve respiratory function.  In a retrospective study, these researchers carried out a review of 400 cases of consecutive patients undergoing phrenic nerve reconstruction for diaphragmatic paralysis at 2 tertiary treatment centers between 2007 and 2019.  Symptomatic patients were identified, and the diagnosis was confirmed on radiographic evaluations.  Assessment parameters included pulmonary spirometry (FEV1 and FVC), maximal inspiratory pressure, compound muscle action potentials (cMAP), diaphragm thickness, chest fluoroscopy, and SF-36 survey.  There were 81 females and 319 males with an average age of 54 years (range of 19 to 79 years).  The mean duration from diagnosis to surgery was 29 months (range of 1 to 320 months).  The most common etiologies were acute or chronic injury (29 %), interscalene nerve block (17 %), and cardiothoracic surgery (15 %).  The mean improvements in FEV1 and FVC at 1 year were 10 % (p < 0.01) and 8 % (p < 0.05), respectively.  At 2-year follow-up, the corresponding values were 22 % (p < 0.05) and 18 % (p < 0.05), respectively.  Improvement on chest fluoroscopy was reported in 63 % and 71 % of patients at 1- and 2-year follow-up, respectively.  There was a 20 % (p < 0.01) improvement in maximal inspiratory pressure, and cMAP increased by 82 % (p < 0.001).  Diaphragm thickness demonstrated a 27 % (p < 0.01) increase, and SF-36 revealed a 59 % (p < 0.001) improvement in physical functioning.  Symptomatic diaphragmatic paralysis should be considered for surgical treatment.  The authors concluded that phrenic nerve reconstruction could achieve symptomatic relief and improve respiratory function.  Increasing spirometry and improvements on Sniff from 1 to 2 years support incremental recovery with longer follow-up.

StatPearls’ webpage on “Phrenic nerve injury” (Mandoorah and Mead, 2023) states that “Most patients with asymptomatic unilateral diaphragmatic paralysis do not require treatment.  When identified, the underlying cause should be treated.  Surgical options are considered if the underlying cause is treated and the patient still has symptoms, or if the patient has bilateral diaphragmatic paralysis.  There are various treatment options including plication and phrenic nerve stimulation.  Plication of the affected site is a very useful treatment method that allows weaning from mechanical ventilation.  Plication is preferably performed in unilateral diaphragmatic paralysis in non-morbidly obese patients.  Phrenic nerve stimulation is performed in intact phrenic nerve without evidence of myopathy.  This procedure can be performed in patients with bilateral diaphragmatic paralysis with cervical spine injuries”.

An UpToDate review on “Surgical treatment of phrenic nerve injury” (Kaufman and Brown, 2023) states that “Persistently symptomatic patients with phrenic nerve injury and intact voluntary motor units (VMUs) are candidates for phrenic nerve reconstruction.  Phrenic nerve reconstruction may involve neurolysis, neurotization, or nerve interposition depending on the extent of the injury.  If phrenic nerve reconstruction is available directly or through referral, then diaphragm plication is reserved for those without intact VMUs, or as a salvage procedure after the failure of other treatments”.

Furthermore, an UpToDate review on “Treatment of bilateral diaphragmatic paralysis in adults” (Celli, 2023) states that “Combined surgical nerve reconstruction with or without diaphragm pacing is an investigational therapy that is performed at very few centers.  It can be considered in select patients with phrenic nerve trauma (surgical or other) but requires immediate transfer to a specialized center, which is not universally available.  Rarely, some patients can be considered for surgical repair at a later point in time.  It is typically more suitable for patients with unilateral disease rather than bilateral paralysis”.

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References