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Radial nerve biopsy with Avance processed nerve allograft and Axoguard nerve protector reconstruction

    Overview

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    Nerve biopsy may be required to assist in the diagnosis of atypical neurological presentations or to direct treatment. The sural nerve is relatively expendable and is most commonly used for this purpose. Often a neurologist requests a specimen from a nerve involved in the disease process. When an upper limb nerve is required, the superficial radial nerve may be used as a biopsy site. The larger diameter nerve enables immunohistological evaluation of the fascicles and the associated blood vessels. It is helpful in the diagnosis of rare vasculitic disorders.
    The biopsy may be performed under local anaesthetic or regional anaesthesia, avoiding a general anaesthetic in a patient with neurological symptoms and diagnostic uncertainty. The superficial radial nerve lies deep to the brachioradialis muscle in the proximal third of the forearm and biopsy can be followed with immediate reconstruction to minimise the risk of a symptomatic neuroma. The typical length of nerve harvest is 10-15mm and therefore the gap length is too large for meaningful recovery to be expected through a conduit. Autologous nerve grafting would create a defect in another sensory nerve and recovery may be uncertain due to the underlying neurological condition.
    The Avance processed nerve allograft may be used to reconstruct the defect after biopsy and there is no anatomical cost to the patient. Should regeneration follow the biopsy, there is a scaffold to support regeneration and prevent local neuroma formation. The area of nerve reconstruction may further be wrapped in a collagen nerve wrap to protect the neurorraphies and to prevent scar tether at the repair site.
    The Axoguard nerve protector is a porcine extracellular matrix collagen wrap that can be used for this purpose. The operative technique described demonstrates superficial radial nerve biopsy, immediate reconstruction using Avance processed nerve allograft and the use of the Axoguard nerve protector to protect the reconstruction site.


    Indications

    INDICATIONS:
    The indication for a nerve biopsy is to help in the diagnostic pathway for patients with lower motor neurone neurological conditions affecting the peripheral nerves. The role of biopsy is when the presenting symptoms or disease course are atypical or when there is a possible intervention with a narrow indication. The use of nerve biopsy is valuable in diagnosing vasculitic pathologies. The requirement should be discussed in a multidisciplinary setting and the potential morbidity should be carefully weighed against the benefits for the patient. There are a number of locations that can be selected for nerve biopsy. Typically the sural nerve in the posterolateral lower leg or ankle is the usual first site as the nerve is often selected as an autologous graft site, the sensory deficit os predictable and of limited significance and the morbidity from stump neuromas is relatively low at approximately 1:25 cases. The lower limb nerves are useful for biopsy in the setting of neuropathies that commonly affect longer fibres due to disturbance of metabolism. When there is a predominance of upper limb symptoms, the medial or lateral cutaneous nerves of the forearm may be selected for biopsy. When there is involvement of the radial nerve, or when a larger diameter main nerve trunk is needed for biopsy, the radial nerve may be suggested. The risk of morbidity from sensory deficit to the dorsum of the hand and biopsy site neuroma must be discussed with the patient. Reconstruction of the nerve biopsy site with Avance processed nerve allograft is an intervention that aims to reduce these complications and can be done without further cost from an autologous donor nerve harvest site.
    SYMPTOMS & EXAMINATION:
    There my be no symptoms in the radial nerve prior to biopsy. The function on both the sensory and motor contributions from the nerve should be assessed and documented prior to proceeding. The surgeon should explain to the patient the potential problems related to nerve biopsy, the sensory loss to be expected and the potential for recovery. There may be benefit in performing a targeted local anaesthetic nerve block of the SRN using US prior to proceeding to simulate the sensory deficit to be expected following the biopsy. Due to the close proximity to the lateral cutaneous nerve of the forearm at the elbow, it is recommended that the block is performed 25% of the way from the lateral epicondyle to the radial styloid and that the block is delivered deep to the brachioradialis. When delivered too proximally the er may be concomitant blockade of the ECRB branch of the radial nerve and the Pin and the motor deficit may provide a false representation of the anticipated deficit too the patient.
    IMAGING:
    No imaging is needed prior to biopsy, however neurography with MRI or high resolution US may be of benefit in the diagnostic pathway for peripheral nerve disorders.
    ALTERNATIVE OPERATIVE TREATMENT:
    There are alternative sites for biopsy with different morbidity and diagnostic value. The sural nerve is easily identifiable under local anaesthetic in the posterolateral lower leg and the sensory deficit is predictable and minimal. In the upper limb the LCNF or the MCNF are suitable alternatives. The benefit of the sRN is the large and multi fascicle structure, enabling histological examination of the fascicles and the intervening interfascicular epineurium.
    NON-OPERATIVE MANAGEMENT:
    The alternative to nerve biopsy is to proceed with treatment based on clinical, neurophysiological and imaging parameters. The challenge is that any nerve biopsy produces a function deficit and may result in pain and as such it is not a procedure to be entered into lightly. Where histological diagnosis can allow early treatment or commencement of a preferred treatment modality there is merit in consideration of this option. The decision to proceed should be discussed in a multidisciplinary setting.
    CONTRAINDICATIONS:
    The contraindication to radial nerve biopsy and Avance processed nerve allograft reconstruction is patient unwillingness to have human processed nerve tissue implanted, active infection or a non-functioning radial nerve due to the underlying pathology where there is no merit in reconstruction.

    Setup

    The Avance processed nerve allograft is commercially available in lengths of 15mm, 30mm, 50mm and 70mm. It is available in diameters or 1-2mm, 2-3mm, 3-4mm and 4-5mm. The tissue is irradiated and frozen. It may be brought in on dry ice for an individual case or when used in a setting with high volume peripheral nerve surgery, it may be stored on site in a human tissue bank. The length needed for a biopsy procedure is 15mm if a 5mm biopsy is planned and 30mm if a 10-15mm biopsy is planned. This allows for the tensegrity gapping that inevitably follows nerve transection. The allograft can be cut to the required length to fill the resection plus tensegrity gap and affect a tension free reconstruction.
    The operation can be performed under local anaesthetic, WALANT or regional block. An upper arm tourniquet may be useful if bleeding is encountered.
    The instruments needed for the procedure include basic hand instruments, microsurgical instruments and background, a ruler, microsurgical suture of 8’0 or 9’0 size and an Axoguard nerve wrap – 40mm x 3.5mm is suitable.
    Neurotomes may be used to section the nerve.
    The nerve biopsy specimen should be sent fresh to a specialist neurohistopathology laboratory and the lab should be forwarded that the biopsy is planned to ensure that they can receive the specimen fresh for immediate processing.
    In the case presented, the procedure is performed under a regional anaesthetic block.
    I advise a single dose of prophylactic antibiotics for the insertion of the allograft and the collagen nerve wrap.

    Operation – 1

    The limb is placed on an arm table with a padded pneumatic tourniquet around the upper arm.
    The WHO checklist is completed prior to commencing the procedure.

    The arm is elevated to assist with exsanguination and the tourniquet is inflated.
    The skin is prepared with alcoholic chlorhexidine.

    The drapes are placed around the limb leaving the surgery site exposed.
    The limb marking is visible in the prepped and draped surgical field. A “stop” moment is completed before proceeding with the skin incision in line with local best practice guidelines.

    The mobile wad muscles (brachioradialis, ECRL and ECRB) are palpated on the proximal radial forearm. The incision is marked along the volar radial forearm at the volar limit of the mobile wad.This approach allows exposure of the superficial radial nerve through radial retraction of the brachioradialis muscle.

    The forearm is rotated into neutral rotation, resting on the ulna, prior to commencing the skin incision.This confirms that the incision site is well placed and that the BR will cover the resected and grafted nerve biopsy site.

    The skin is incised over a 5cm length, as previously marked.

    Skin hooks are used to retract the skin edges.
    Dissecting scissors are used to identify any vessels in the subcutaneous fat that are divided after bipolar cautery.
    Any branches from the LCNF should be identified, mobilised and protected.

    The Brachioradialis muscle(BR) is identified and the superficial fascia along its volar border is incised.The superficial fascia is loose and the Lateral Cutaneous of the Forearm (LCNF) lies in the fat adjacent to the BR. Deep to the LCNF is a more dense fascial plane along the volar border of the BR. This deeper fascia will also need dividing to allow retraction of the BR.
    In this plane the LCNF lies more superficially than the Superficial Radial Nerve(SRN) in the fat. I prefer to identify the LCNF and mobilise to prevent inadvertent injury. The LCNF is an alternative biopsy site, however its more superficial location may result in symptomatic nerve pain or tether at the site of biopsy and reconstruction. The more deeply place SRN is protected by the BR covering and should a biopsy site neuroma develop it may be less symptomatic. The SRN is also larger with a fascicle structure that is valuable in looking for vasculitis changes in the biopsy specimen, hence the decision to use the SRN as biopsy site in this case.

    The LCNF is identified in the fat at the volar aspect of the BR.The LCNF may be identified by its superficial location and its proximity to the cephalic vein which is usually still visible. Limb elevation for exsanguination retains some venous volume and assists in identification of the vein.

    A Mixter is passed under the LCNF to receive a sloop and the sloop is placed in the jaws of the Mixter.The Mixter has 90 degree fine tips and is useful for passing around delicate structures with minimal trauma.

    The sloop should be positioned carefully so that it has a low profile in the tips. When the Mixter is drawn out from beneath the LCNF it should be rotated 90 degrees to ensure that the sloop doesn’t snag on the posterior aspect of the nerve, producing local trauma.

    The sloop can be used to provide controlled gentle retraction on the LCNF as it is mobilised to expose the volar edge of the BR muscle.The BR and its investing fascia can be seen in the wound.
    LCNF – Lateral Cutaneous Nerve of the Forearm
    BR – brachioradialis

    A scalpel is used to incision the dense fascia along the volar aspect of the BR muscle soit can be mobilisedThe SRN is deep to the BR and so is not at risk of injury at this point.

    The facia around the BR has been released and the BR is now free to mobilise.

    The loose tissues deep to the medial border of the BR are dissected to identify the radial artery and venae commitantes.Once the vascular structures are identified, the BR may be retracted dorsally using a small Langenbeck retractor to facilitate exposure of the SRN.

    The radial artery can be seen in the deeper tissues ulnar to the BR.
    RA – Radial Artery

    The BR is retracted exposing the vascular structures.A small perforating vessel is seen passing to the BR and this will be mobilised, cauterised and divided to facilitate exposure of the SRN.

    The tissues radial to the vessels are dissected to identify the SRN.The SRN is deep to the BR and will be identified in this loose areolar tissue.

    Retraction of the BR exposes the SRN, which is carefully mobilised.Smaller crossing vessels are divided after bipolar cautery.

    The SRN is mobilised and lies visible in the wound.
    The distal self returning retractor has been repositioned more deeply in the wound to retract the BR.

    A Mixter is passed deep too the SRN.This will facilitate passage of a sloop. Sloops allow mobilisation of the nerve with controlled retraction. A circumferential neurolysis is necessary to allow the nerve to be fully mobilised prior to biopsy and then reconstruction.

    The blue sloop is delivered into the MIxter tips and then delivered deep to the SRN.

    The blue sloop is used to retract the SRN.

    A microsurgical background is placed deep to the SRN.The background material helps with nerve handling and reconstruction.

    The sloop is removed leaving the SRN lying without tension on the background material.

    Operation – 2

    The desired length of the resection specimen for biopsy is now removed.The biopsy specimen should be handled carefully to prevent damage to the architecture.

    The SRN diameter is estimated using a ruler and used to decide which diameter Avance processed nerve allograft is to be usedThe size is used to decide which diameter Avance processed nerve allograft is to be used for the reconstruction after the nerve biopsy. The length of allograft chosen can be sent for from the tissue bank.

    The SRN is sectioned with a scalpel and the nerve gaps as soon as it is transected due to tensegrity.Minimal handling of the nerve is used to prevent trauma to the specimen or residual nerve. De Bakey forceps can be used to pick up the epineurium with minimal risk of trauma. The nerve can also be cut using neurotomy if they are available.

    The nerve gaps as soon as it is transected due to tensegrity.
    Biotensegrity is a property of biological tissues, meaning that there is a pre-load with stress and strain in balance. In a nerve the different components are in balance with compression (fluid within the endometrial tubes) and tension (perineurium tissues and basement membrane collage scaffold).
    As a result of tensegrity, when a nerve is transected gapping follows at the site of section. The nerve gaps approximately 8mm at this level, depending on how much mobilisation of the nerve is performed.
    The nerve also becomes stiffer following section. When a nerve is directly repaired after injury all of the longitudinal strain forces are concentrated at the nerve-suture interface.
    Over a few hours, stress relaxation follows and the forces reduce but do not return to baseline level until the nerve collagen structure has healed and remodelled. Too much scar may cause repair site fibrosis.

    The tensegrity gap is measured at 8mm.
    As a result, when a nerve is biopsied, the reconstruction length should encompass the tensegrity gap and the resected length to allow a tension free co-aptation.

    The resected specimen is in situ with the tensegrity gap visible at both transection sites.

    The estimated reconstruction length can now be confirmed, which must include the tensegrity gap.A 10mm resection will need at least an 18mm reconstruction. The final length of allograft needed can be confirmed before removing from the tissue bank freeze. In this case a 2-3mm diameter x 30mm lengths selected as the appropriate Avance graft size.

    The specimen is sent urgently in a fresh transit bottle too the neurohistopathology laboratory.
    The processing requires a fresh specimen and so the nerve biopsy must be sent urgently and a confirmatory call placed to the laboratory to alert them of the impending arrival. The specimen may deteriorate if not processed immediately.

    The final resection gap is measured after a few minutes .
    The length of allograft used for the gap reconstruction will be approximately 20mm.

    An Axoguard nerve protector is also selected to wrap the reconstruction site and prevent scar tether.The Axoguard nerve protector is a layered porcine collagen extracellular matrix that revascularises well restoring the paraneurium gliding layers around a nerve. It is indicated after neurolysis of scarred nerves, in acute injuries where there is damage to the epineurium and it may be used to wrap co-aption sites during nerve repair or graft reconstruction. Sutures place remotely at the ends of the wrap to the adjacent epineurium can be used as a detensioning device for a suture repair.

    The selected size of Axoguard is 3.5mm diameter x 40mm length.
    The Axoguard is supplied in a number of diameters and lengths to allow versatility to different nerves in different locations. The diameter is the formed minimum diameter, however there is considerable overlap to allow for adjustment to nerves of similar size and to allow a non-constricting and accommodating wrap of the entire circumference with some redundancy.

    The box is opened and the inner pouch opened revealing the Axoguard in a plastic moulded tray.
    The scrub nerve removes the tray from the pouch and places it flat on the scrub trolley with the writing facing upwards.

    The lid is carefully hinged open and normal saline slowly introduced to the tray recess.
    The Axoguard needs approximately 5 minutes to hydrate before use. Hydration improves the handling characteristics. Care should be taken not to overfill the tray or to inject too quickly as the wrap may become dislodged easily.

    The Axoguard is allowed to soak for 5 minutes.
    The tray can be closed if required at this point.

    The Avance processed nerve allograft is then be prepared for use.The allograft is removed from the tissue bank freezer and carried to the operating theatre. The dimensions, expiry date and product codes are checked and confirmed with the scrub team.
    In some units the allograft may have been ordered in specifically for a case and will be marked with the patient’s hospital identification number. This should also be confirmed.
    The outer plastic packaging can be removed by the circulating team.
    The inner cardboard packaging is then opened to reveal a double pouch inner wrapping.

    The double pouch is confirmed as intact and then the outer is opened by the circulating theatre team member.

    The scrub nurse then removes the inner sterile pouch containing the allograft within a tray.

    The inner pouch and the tray are sterile.
    The allograft is packaged in a plastic moulded tray that can be used for defrosting of the tissue.

    The tray is removed from the inner pouch and place flat on the scrub table with the writing facing upwards.

    The tray is carefully hinged open to expose the Avance processed nerve allograft and filled with warm saline.The tray can be used to defrost the nerve by irrigation with warm saline.

    The tray is filled with warm saline.
    Care should be taken to prevent washing the allograft out of the tray. The nerve takes between 5 and 15 minutes to fully thaw. The tray can be closed during this time to prevent displacing the allograft.

    The allograft should be checked to ensure that it is fully thawed and is flexible to handle.It is now ready for implantation.

    Microsurgery forceps should be used to handle the allograft.
    The allograft is human nerve tissue with an acellular endometrial tube structure and it is vulnerable to compression injury. The outer epineurium only should be handles. The nerve should be treated delicately in the same way that you would handle autograft nerve tissue.

    The nerve allograft is carefully transferred to the surgical field.

    The allograft is placed alongside the nerve gap and the appropriate length for the reconstruction is sectioned.

    Operation – 3

    The nerve allograft is trimmed to the size required.
    The nerve can be cut using serrated microsurgical nerve scissors or a neurotomy device with a guillotine blade designed for clean nerve transection.

    The nerve allograft length is place in the gap for reconstruction. Its diameter should closely match the SRN.There is no gapping as the allograft will be of sufficient length to render the reconstruction tension free.

    There is an excellent diameter match with the SRN.
    Avance nerve allograft is supplied in a series of diameter ranges (1-2mm, 2-3mm, 3-4mm and 4-5mm). The nest match was a 2-3mm which means that the allograft is in the 2-3mm range. As it is human nerve tissue there will be variation between different allograft batches.
    Larger diameters than 5mm are not processed and supplied as there may be concern regarding the ability of revascularisation. The risk of central necrosis could result in a non-recovered nerve graft.
    If a larger diameter nerve is to be reconstructed, then several nerve allografts may be grouped in a “cabled” configuration, akin to undertaking a cabled autologous nerve graft reconstruction. This approach increases the surface are available for revascularisation, however it is at a cost of loss of endometrial tube density. Smaller diameter nerve allografts have a proportionately greater connective tissue component between the fascicles.
    As an example, a single cable of sural nerve autograft has 33% of the cut cross-sectional area made up of endometrial tubes.

    The operating microscope is brought in for the nerve allograft co-aptationThere is evidence from cadaveric studies that the quality of neurorraphy with an operating microscope is superior to that from loupe magnification.

    Fine interrupted monofilament sutures are place evenly at each end off the graft. Typically 3-4 sutures placed at each co-aptation site is sufficient.Each is tied to ensure that there is no distortion of the nerve ends and that the two ends lie gently apposed without bunching.

    The nerve reconstruction has been detensioned through tensegrity gap plus physical gap reconstruction and so the longitudinal strain forces acting at each site are minimised.

    The suture co-aptions have been completed.
    The decision to protect the repair sites or to use an adjunctive wrap as a detensioning device is based on the site of the nerve reconstruction and the relative tension and mobility of the nerve reconstructed. In this case a decision was made at the outset to protect the neurorraphy to try and prevent scar tether or sensitivity to contact. The Axoguard nerve protector was selected for this purpose.

    The hydrated Axoguard wrap is removed from the tray and placed in the surgical wound.The Axoguard can be uncoiled using two pairs of forceps and then delivered under the nerve reconstruction. The microsurgical background facilitates passage of the wrap deep to the nerve.

    The Axoguard is allowed to recoil with its shape memory around the nerve reconstruction.In this case the whole length of the reconstruction has been wrapped. In long lengths of allograft the wrap can divided and used as two separate wraps at each neurorraphy site. This may be preferable to allow some revascularisation of a long allograft not only from each nparent nerve stump, but also from the wound bed. Axogen also supply nerve connector which are cylindrical wraps made of the same material that can be placed over the proximal and distal parent nerve ends and then slid over each co-aptation site after insertion of the interposition allograft to the repair site gap.
    The benefit of the nerve connectors is that the individual co-aptations may be completed in a “suture less” fashion with remote sutures between the ends of each connector and the adjacent epineurium, or the connector can be placed in such a way that a suture co-aptation can be detensioned.
    Sizing the connectors can be a challenge and the wrap nerve protector is more forgiving and can be snugged to the correct diameter.
    The wrap should not be placed too tightly to allow for swelling.

    The Axoguard nerve protector is adjusted to enclose the nerve reconstruction.The wrap can be left without sutures, however intermittent nylon fine sutures along the open edge can prevent deformation or uncoiling during normal physiological gliding motion of the nerve.

    Interrupted sutures are placed along the open edge of the Axoguard nerve wrap.The ideal suture for this is 8’0 Ethilon because the needle is of sufficient strength and length to pass through the Axoguard. The 9’0 Ethilon needle in our unit is too weak to pass through the Axoguard and tends to deform.

    The Axoguard nerve protector retaining sutures are completed.
    The sutures at the end may be sutured to the epineurium to detention the reconstruction. Two sutures can be placed at each end. The alternative is to leave the wrap loose and able to slide, particularly where there are no concerns regarding tension.
    Neuromas may occur at repair sites from poor suture technique, excessive tension at the repair site or failure the repair site. The wrapping technique and detensioning guards against this.

    The completed repair site is tested for mechanical integrity with full range of motion cycling of the wrist, forearm and elbow.There is no noted gapping or deformity during cycling and the repair is deemed of adequate quality and strength.

    The microsurgery background material can now be removed from the wound and recorded at part of the scrub count.
    The completed reconstruction is seen alongside the radial artery and venue commit antes.

    The BR muscle is allowed to fall back into its normal positioning the reconstruction will be well covered.

    The final position of BR after removal of the retractors demonstrates complete coverage of the reconstruction.

    The wound closure is in layers with monaural sutures.

    A subcuticular closure completes the skin repair.

    The monaural knots should be buried and the sutures ends cut flush with the skin surface.

    The closed wound will be supported by steristrips.

    Steristrips are used to detention the skin ages and support the subcuticular repair.

    The completed operation site is ready for dressings.
    Local anaesthetic is not required for the wound as the operation was performed under a regional anaesthetic blockade. In complex nerve reconstruction cases for neuromas, after trauma, after neurolysis or when the anaesthetic method is general, a supplementary indwelling nerve catheter proximal to the surgery site can be used to help manage peri-operative neuropathic pain.

    An occlusive waterproof dressing is applied to the surgery site.

    A bulky wool and crepe bandage wrap is applied to support the surgery site.

    Post Operative

    The bulky dressings should be left in place for 72 hours and then can be reduced. The detensioning reconstruction allows full range of motion without restriction. The wound should be kept clean and dry for 10 days and then can be soaked and moisturising cream massage may be commences to assist with rapid scar maturation and remodelling. Allowing early functional range of motion ensures adequate neural gliding and reduces the risk of nerve tether pain (neurostenalgia).
    The patient can be seen back in the neurology clinic to discuss the histological findings which should also be discussed in an MDT setting.
    The patient can be seen in the nerve clinic at 3 months to confirm regeneration across the repair site and absence of a neuroma. A further appointment should be made to assess sensory outcome and pain at 12 months following the biopsy and reconstruction.

    Recommended Reading

    The results of sensory nerve reconstruction using Avance processed nerve allograft are excellent and similar to those of autograft reconstruction in digital nerve gaps after trauma up to 25mm. In larger sensory nerve trunks the numbers published are fewer, however the evidence from the RANGER study demonstrate near equivalence in gaps of this length.
    The RANGER study is an industry funded study looking at registry multicentre outcome data on the use of processed nerve allograft in nerve injury reconstruction. The study reports on safety, utility and efficacy.
    The National Institute for Health and Care excellence on the UK reviewed all the existing data and published Interventional Procedure Guidance (IPG 597) on the use of Avance processed nerve allograft in nerve repair: NICE Interventional Procedure Guidance: 597 (www.nice.org.uk/guidance/ipg597).Enhanced governance arrangements and audit of outcomes is recommended for use outside sensory digital nerve in the hand. A summary of the guidance and the published literature is provided below.
    NICE: Processed nerve allografts to repair peripheral nerve discontinuities IPG 597
    1 Recommendations:
    1.1 Current evidence on the safety and efficacy of processed nerve allografts to repair peripheral nerve discontinuities is adequate to support the use of this procedure for digital nerves provided that standard arrangements are in place for clinical governance, consent and audit.
    1.2 The evidence on the safety of processed nerve allografts to repair peripheral nerve discontinuities in other sites raises no major safety concerns. However, current evidence on its efficacy in these sites is limited in quantity. Therefore, for indications other than digital nerve repair, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
    1.3 Clinicians wishing to do processed nerve allografts to repair peripheral nerve discontinuities in sites other than the digital nerves should:
    Inform the clinical governance leads in their NHS trusts.
    Ensure that patients understand the uncertainty about the procedure’s efficacy on mixed nerve repair and provide them with clear written information. In addition, the use of NICE’s information for the public is recommended.
    Audit and review clinical outcomes of all patients having processed nerve allografts to repair peripheral nerve discontinuities
    1.4 This procedure should only be done by surgeons with training and experience in peripheral nerve repair.
    1.5 Patient selection should take into consideration the site, type of nerve (motor, sensory, mixed) and the size of the defect.
    1.6 NICE encourages further research into processed nerve allografts to repair peripheral nerve discontinuities. This should include information on the type of nerve repaired, the anatomical site, the size of the defect, patient reported outcome measures, functional outcomes, time to recovery and long-term outcomes (12 months to 18 months).
    2 Indications and current treatments
    2.1 Peripheral nerve damage can be caused by trauma or surgery, and can lead to reduced sensation and mobility of the affected limb or region. If direct repair is not possible because the section of nerve discontinuity is too long, grafts or artificial nerve conduits can be used.
    2.2 Autologous nerve grafting (using another nerve from the same patient) is used most frequently (usually using the sural nerve from the leg). However, this can be associated with donor site morbidity. Untreated allografts (using a nerve from a donor) have also been used. However, postoperative immunosuppressive treatment is needed with untreated allografts.
    3 The procedure
    3.1 Acellular processed nerve allografts are nerves from deceased human donors that have had their immunogenic components removed using tissue processing techniques. They are stored frozen until implantation and are available in different sizes. Immunosuppressive treatment is not needed.
    3.2 The procedure is done under general anaesthesia. The injured nerve is exposed, and the nerve ends are cleared of necrotic tissues and resected to allow for tension-free alignment with the graft. The graft is sutured to the exposed nerve ends. After grafting, limb splinting may be needed for several weeks to allow optimal nerve regeneration. The typical length of an allograft implant is 1 cm to 3 cm.
    3.3 The aim of the procedure is to bridge the peripheral nerve discontinuity to allow axonal regeneration and growth through the allograft towards the distal nerve.
    4 Efficacy
    This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
    4.1 In a randomised controlled trial (RCT) of 23 patients needing digital nerve repair comparing processed nerve allograft (PNA) with treated bovine graft at 12-month follow-up, static 2-point discrimination assessment (s2PD, which tests the ability to discern the difference between 1 and 2 static pressure points) was statistically significantly better in the PNA group (n=5) than the bovine graft group (n=7; 5±1 mm versus 8±5 mm, p<0.05). In the same study, moving 2-point discrimination assessment (m2PD) was not statistically significantly different between the PNA group and the bovine graft group (5±1 mm versus 7±5 mm, p>0.05) at 12-month follow-up.
    In a non-randomised comparative study of 153 patients needing digital nerve repair comparing PNA repair (n=72) with tension-free suture nerve repair (n=81), s2PD scores (excellent plus good, defined as the ability to distinguish between 2 static pressure points at a maximum distance of 15 mm) were not statistically significantly different between the PNA group (67% [48/72]) and the tension- free suture group (64% [52/81]) at 6-month follow-up (p=0.749). In a case series of 17 patients with digital nerve injuries treated by PNA grafting, s2PD was excellent or good in 78% (14/18) of digits repaired, at a mean follow-up of 15 months. In the RCT of 23 patients, Semmes–Weinstein monofilament test (testing of pressure threshold using a monofilament; range: 2.833=normal sensation to 6.650=residual sensation) was statistically significantly better in the PNA group than the treated bovine graft group (3.6±0.7 versus 4.4±1.4, p<0.05) at 12-month follow-up. In the same study, thermal sensation was totally improved from baseline at 12-month follow-up and not statistically significantly different between the treatment (PNA group: from 7% [1/14] to 100% [6/6] and bovine graft group: from 33% [3/9] to 100% [7/7]).
    In a case series of 64 patients needing nerve repair in the upper extremity and treated by grafting using PNA, there was meaningful recovery in 75% (48/64) of all patients. Univariate analysis showed that distal sites of injuries have a statistically significantly higher likelihood of recovery than proximal upper limb sites (odds ratio [OR] 5.606, 95% confidence interval [CI] 1.663 to 18.903; p<0.05). In the same study, discontinuities smaller than 30 mm had a statistically significantly greater likelihood of meaningful repair than those greater than 50 mm (OR 14.333, 95% CI 2.143 to 95.848; p<0.05).
    In a case series of 26 patients with lingual nerve and inferior alveolar nerve discontinuities treated by PNA grafting, meaningful sensory recovery was assessed using a neurosensory test improvement tool (ranging from normal=best, through mild, moderate and severe to complete=worse). At 12-month follow-up, neurosensory test improvement scores were normal in 52% (12/23), mild in 9% (2/23), moderate in 26% (6/23) and severe in 13% (3/23) of patients. In the same study, neurosensory improvement was reported in 86% (12/14) of patients with discontinuities 8–20 mm in length and 89% (8/9) of patients with discontinuities 30–70 mm in length.
    In the RCT of 23 patients, disability of the arm, shoulder and hand score (DASH: 0=no disability, 100=most severe disability) was not statistically significantly different between the PNA group (5±6.5) and the bovine graft group (8±6.3) at 12-month follow-up (p=0.318).
    In a case series of 108 patients needing nerve repair, there was no sensory recovery because of graft failure in 5% (4/76) of patients at last follow-up and surgical revision was needed.
    In the RCT of 23 patients, at 12-month follow-up, pain measured using a visual analogue scale (VAS, 0=no pain, 10=extreme pain) had improved from baseline in both groups (PNA group: from 4.7±3.4 to 0.5±0.6; treated bovine graft: from 4.4±2.1 to 0.9±1.0) but there was no statistically significant difference between the groups (p=0.432). In another case series of 26 patients needing PNA after resection of neuromas of the foot and ankle, mean ordinal pain score (0=no pain to 10=worse pain) statistically significantly reduced from 7.5 points at baseline to 4.9 points at a mean 66-week follow-up (difference 2.6, range +2.0 to −8.0; p=0.016). In the same study, patient reported outcome measurement information system scores were used to assess the impact of pain on patients’ behaviour and daily function (reported as T-scores with a population mean of 50 and a standard deviation of 10). Pain behaviour T-score decreased by 7.3 (range+2.0 to −22.0) from 63.0 at baseline (percentile decrease of 24%, p<0.003). Pain interference T-score decreased by 11.3 (range +2.0 to −27.0) from 68.0 at baseline (mean percentile change of 31%, p<0.003).
    In a case series of 17 patients with digital nerve injury treated by grafting with PNA, pain (measured using a VAS: 0=no pain, 10=extreme pain) worsened in 1 patient (VAS score increased from 5 at baseline to 8 at 15-month follow)
    In the non-randomised comparative study of 153 patients, difference in satisfaction rate was not statistically significantly different between the PNA group and the tension-free suture group (2.02%, 95% CI −6.07 to 10.87) at 6-month follow-up.
    The specialist advisers listed key efficacy outcomes as re-innervation of target organs, nerve regeneration rate, clinical sensory and motor outcome scales, and patient reported outcomes.
    5 Safety
    This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
    5.1 Tenolysis was needed in 3% (2/78) of patients at 6-month follow-up in a non- randomised comparative study of 153 patients needing digital nerve repair comparing processed nerve allograft (PNA) repair (n=72) with tension-free suture nerve repair (n=81).
    5.2 Neuroma was reported after 1 nerve repair of 132 nerves in a case series of 108 patients needing nerve repair.
    5.3 Local infection that improved after treatment (not specified) was reported in 1 patient in a case series of 15 patients treated by PNA grafting.
    5.4 In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: immunological reaction or rejection, and inflammatory reaction to preservatives. They considered that the following were theoretical adverse events: immunological reaction or rejection, inflammatory reaction to preservatives and sub-optimal results because of preference in using the allograft when patients could be treated by more established interventions.
    6 Committee comments
    6.1 The grafts used in this procedure are regulated by the Human Tissue Authority.
    6.2 The grafts can be used in a variety of anatomical sites but most published evidence reviewed by the committee came from the repair of digital nerves.
    6.3 The type of nerve being repaired (motor, sensory, mixed) and the size of the defect potentially affect the outcome.
    6.4 The use of this type of graft avoids the need to harvest a donor nerve from the same patient, and avoids the use of non-human-derived tissue and immunosuppression.
    1.1 Current evidence on the safety and efficacy of processed nerve allografts to repair peripheral nerve discontinuities is adequate to support the use of this procedure for digital nerves provided that standard arrangements are in place for clinical governance, consent and audit.
    1.2 The evidence on the safety of processed nerve allografts to repair peripheral nerve discontinuities in other sites raises no major safety concerns. However, current evidence on its efficacy in these sites is limited in quantity. Therefore, for indications other than digital nerve repair, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
    1.3 Clinicians wishing to do processed nerve allografts to repair peripheral nerve discontinuities in sites other than the digital nerves should:
    Inform the clinical governance leads in their NHS trusts.
    Ensure that patients understand the uncertainty about the procedure’s efficacy on mixed nerve repair and provide them with clear written information. In addition, the use of NICE’s information for the public is recommended.
    Audit and review clinical outcomes of all patients having processed nerve allografts to repair peripheral nerve discontinuities
    1.4 This procedure should only be done by surgeons with training and experience in peripheral nerve repair.
    1.5 Patient selection should take into consideration the site, type of nerve (motor, sensory, mixed) and the size of the defect.
    1.6 NICE encourages further research into processed nerve allografts to repair peripheral nerve discontinuities. This should include information on the type of nerve repaired, the anatomical site, the size of the defect, patient reported outcome measures, functional outcomes, time to recovery and long-term outcomes (12 months to 18 months).
    2 Indications and current treatments
    2.1 Peripheral nerve damage can be caused by trauma or surgery, and can lead to reduced sensation and mobility of the affected limb or region. If direct repair is not possible because the section of nerve discontinuity is too long, grafts or artificial nerve conduits can be used.
    2.2 Autologous nerve grafting (using another nerve from the same patient) is used most frequently (usually using the sural nerve from the leg). However, this can be associated with donor site morbidity. Untreated allografts (using a nerve from a donor) have also been used. However, postoperative immunosuppressive treatment is needed with untreated allografts.
    3 The procedure
    3.1 Acellular processed nerve allografts are nerves from deceased human donors that have had their immunogenic components removed using tissue processing techniques. They are stored frozen until implantation and are available in different sizes. Immunosuppressive treatment is not needed.
    3.2 The procedure is done under general anaesthesia. The injured nerve is exposed, and the nerve ends are cleared of necrotic tissues and resected to allow for tension-free alignment with the graft. The graft is sutured to the exposed nerve ends. After grafting, limb splinting may be needed for several weeks to allow optimal nerve regeneration. The typical length of an allograft implant is 1 cm to 3 cm.
    3.3 The aim of the procedure is to bridge the peripheral nerve discontinuity to allow axonal regeneration and growth through the allograft towards the distal nerve.
    4 Efficacy
    This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
    4.1 In a randomised controlled trial (RCT) of 23 patients needing digital nerve repair comparing processed nerve allograft (PNA) with treated bovine graft at 12-month follow-up, static 2-point discrimination assessment (s2PD, which tests the ability to discern the difference between 1 and 2 static pressure points) was statistically significantly better in the PNA group (n=5) than the bovine graft group (n=7; 5±1 mm versus 8±5 mm, p<0.05). In the same study, moving 2-point discrimination assessment (m2PD) was not statistically significantly different between the PNA group and the bovine graft group (5±1 mm versus 7±5 mm, p>0.05) at 12-month follow-up.
    In a non-randomised comparative study of 153 patients needing digital nerve repair comparing PNA repair (n=72) with tension-free suture nerve repair (n=81), s2PD scores (excellent plus good, defined as the ability to distinguish between 2 static pressure points at a maximum distance of 15 mm) were not statistically significantly different between the PNA group (67% [48/72]) and the tension- free suture group (64% [52/81]) at 6-month follow-up (p=0.749). In a case series of 17 patients with digital nerve injuries treated by PNA grafting, s2PD was excellent or good in 78% (14/18) of digits repaired, at a mean follow-up of 15 months. In the RCT of 23 patients, Semmes–Weinstein monofilament test (testing of pressure threshold using a monofilament; range: 2.833=normal sensation to 6.650=residual sensation) was statistically significantly better in the PNA group than the treated bovine graft group (3.6±0.7 versus 4.4±1.4, p<0.05) at 12-month follow-up. In the same study, thermal sensation was totally improved from baseline at 12-month follow-up and not statistically significantly different between the treatment (PNA group: from 7% [1/14] to 100% [6/6] and bovine graft group: from 33% [3/9] to 100% [7/7]).
    In a case series of 64 patients needing nerve repair in the upper extremity and treated by grafting using PNA, there was meaningful recovery in 75% (48/64) of all patients. Univariate analysis showed that distal sites of injuries have a statistically significantly higher likelihood of recovery than proximal upper limb sites (odds ratio [OR] 5.606, 95% confidence interval [CI] 1.663 to 18.903; p<0.05). In the same study, discontinuities smaller than 30 mm had a statistically significantly greater likelihood of meaningful repair than those greater than 50 mm (OR 14.333, 95% CI 2.143 to 95.848; p<0.05).
    In a case series of 26 patients with lingual nerve and inferior alveolar nerve discontinuities treated by PNA grafting, meaningful sensory recovery was assessed using a neurosensory test improvement tool (ranging from normal=best, through mild, moderate and severe to complete=worse). At 12-month follow-up, neurosensory test improvement scores were normal in 52% (12/23), mild in 9% (2/23), moderate in 26% (6/23) and severe in 13% (3/23) of patients. In the same study, neurosensory improvement was reported in 86% (12/14) of patients with discontinuities 8–20 mm in length and 89% (8/9) of patients with discontinuities 30–70 mm in length.
    In the RCT of 23 patients, disability of the arm, shoulder and hand score (DASH: 0=no disability, 100=most severe disability) was not statistically significantly different between the PNA group (5±6.5) and the bovine graft group (8±6.3) at 12-month follow-up (p=0.318).
    In a case series of 108 patients needing nerve repair, there was no sensory recovery because of graft failure in 5% (4/76) of patients at last follow-up and surgical revision was needed.
    In the RCT of 23 patients, at 12-month follow-up, pain measured using a visual analogue scale (VAS, 0=no pain, 10=extreme pain) had improved from baseline in both groups (PNA group: from 4.7±3.4 to 0.5±0.6; treated bovine graft: from 4.4±2.1 to 0.9±1.0) but there was no statistically significant difference between the groups (p=0.432). In another case series of 26 patients needing PNA after resection of neuromas of the foot and ankle, mean ordinal pain score (0=no pain to 10=worse pain) statistically significantly reduced from 7.5 points at baseline to 4.9 points at a mean 66-week follow-up (difference 2.6, range +2.0 to −8.0; p=0.016). In the same study, patient reported outcome measurement information system scores were used to assess the impact of pain on patients’ behaviour and daily function (reported as T-scores with a population mean of 50 and a standard deviation of 10). Pain behaviour T-score decreased by 7.3 (range+2.0 to −22.0) from 63.0 at baseline (percentile decrease of 24%, p<0.003). Pain interference T-score decreased by 11.3 (range +2.0 to −27.0) from 68.0 at baseline (mean percentile change of 31%, p<0.003).
    In a case series of 17 patients with digital nerve injury treated by grafting with PNA, pain (measured using a VAS: 0=no pain, 10=extreme pain) worsened in 1 patient (VAS score increased from 5 at baseline to 8 at 15-month follow)
    In the non-randomised comparative study of 153 patients, difference in satisfaction rate was not statistically significantly different between the PNA group and the tension-free suture group (2.02%, 95% CI −6.07 to 10.87) at 6-month follow-up.
    The specialist advisers listed key efficacy outcomes as re-innervation of target organs, nerve regeneration rate, clinical sensory and motor outcome scales, and patient reported outcomes.
    5 Safety
    This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
    5.1 Tenolysis was needed in 3% (2/78) of patients at 6-month follow-up in a non- randomised comparative study of 153 patients needing digital nerve repair comparing processed nerve allograft (PNA) repair (n=72) with tension-free suture nerve repair (n=81).
    5.2 Neuroma was reported after 1 nerve repair of 132 nerves in a case series of 108 patients needing nerve repair.
    5.3 Local infection that improved after treatment (not specified) was reported in 1 patient in a case series of 15 patients treated by PNA grafting.
    5.4 In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: immunological reaction or rejection, and inflammatory reaction to preservatives. They considered that the following were theoretical adverse events: immunological reaction or rejection, inflammatory reaction to preservatives and sub-optimal results because of preference in using the allograft when patients could be treated by more established interventions.
    6 Committee comments
    6.1 The grafts used in this procedure are regulated by the Human Tissue Authority.
    6.2 The grafts can be used in a variety of anatomical sites but most published evidence reviewed by the committee came from the repair of digital nerves.
    6.3 The type of nerve being repaired (motor, sensory, mixed) and the size of the defect potentially affect the outcome.
    6.4 The use of this type of graft avoids the need to harvest a donor nerve from the same patient, and avoids the use of non-human-derived tissue and immunosuppression.

    References:
    Rinker et al. Use of Processed Nerve Allografts to Repair Nerve Injuries Greater Than 25 mm in the Hand.Ann Plast Surg. 2017 Jun;78(6S Suppl 5):S292-S295
    The RANGER database is an industry registry of outcomes for Avance processed nerve allograft use in nerve gap reconstruction. A subset analysis for digital nerve injury with gaps of 25mm or greater demonstrated recovery to S3 level in 86% of repairs which compares favourably to historical data using autologous nerve graft (60-88%).The study to date demonstrated excellent safety data and an advantage of nerve allograft is the absence of potential donor site problems.



    Reference

    • orthoracle.com

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