Predictors of Disability and Quality of Life With an Upper-Extremity Peripheral Nerve Disorder.

OBJECTIVE: We sought to understand the wide range of problems that patients with upper-extremity peripheral nerve disorders experience and to identify predictors of disability and quality of life (QOL). METHOD: Data from standardized assessments of disability and QOL, physical examination results, and intake surveys from 627 patients were analyzed using descriptive and inferential statistics. We compared results between groups and built multivariate models measuring disability, work disability, and physical and mental QOL. RESULTS: The sample demonstrated substantial disability and even greater work disability, which both closely correlated with poorer QOL. Work status was integral in predicting disability. Common predictors across models included problems with sleep and intimate relationships, deficits in work and household performance, and higher pain. CONCLUSION: To decrease disability and improve QOL, occupational therapy practitioners should help patients with upper-extremity peripheral nerve disorders identify strategies to maintain meaningful work and household roles, intimate relationships, and sleep, while continuing to address pain.

Tissue engineered constructs for peripheral nerve surgery.

BACKGROUND: Tissue engineering has been defined as "an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ". Traumatic peripheral nerve injury resulting in significant tissue loss at the zone of injury necessitates the need for a bridge or scaffold for regenerating axons from the proximal stump to reach the distal stump. METHODS: A review of the literature was used to provide information on the components necessary for the development of a tissue engineered peripheral nerve substitute. Then, a comprehensive review of the literature is presented composed of the studies devoted to this goal. RESULTS: Extensive research has been directed toward the development of a tissue engineered peripheral nerve substitute to act as a bridge for regenerating axons from the proximal nerve stump seeking the distal nerve. Ideally this nerve substitute would consist of a scaffold component that mimics the extracellular matrix of the peripheral nerve and a cellular component that serves to stimulate and support regenerating peripheral nerve axons. CONCLUSIONS: The field of tissue engineering should consider its challenge to not only meet the autograft "gold standard" but also to understand what drives and inhibits nerve regeneration in order to surpass the results of an autograft.

Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo.

FK-506 accelerates nerve regeneration and improves functional recovery in vivo; its immunosuppressive properties, however, limit its clinical utility. Geldanamycin (GA), a non-immunosuppressive agent, shares a common binding target (heat shock protein 90) with FK-506 and may accelerate nerve regeneration through a similar mechanism. GA has been shown to augment neurite outgrowth in vitro but has not been tested in vivo. The current study investigated the effect of GA on the rate of axonal regeneration and functional recovery following peripheral nerve injury. In the first experiment, Thy1-GFP transgenic rats underwent serial transmuscular imaging to quantify the rate of axonal regeneration following saphenous nerve crush injury. In subsequent experiments, Lewis rats underwent tibial nerve crush or transection-and-repair injuries and were assessed for functional recovery by walking track analysis. All animals were randomized to receive daily administration of FK-506 (2mg/kg), GA (0.2mg/kg), or a control vehicle (dimethyl sulfoxide, 1 mL/kg) starting 3 days prior to injury. Both GA and FK-506 significantly increased the rate of axonal regeneration following crush injury in Thy1-GFP rats. In Lewis rats undergoing tibial nerve crush injury, earlier functional recovery occurred at day 5 and day 6 in animals treated with FK-506 and GA respectively, vs. day 13 for controls. Over a truncated 21-day timeframe, Lewis rats undergoing tibial nerve transection-and-repair injury and treated with FK-506 regained function at day 16, whereas those treated with GA or the control vehicle did not regain normal function. GA-treated animals, however, did exhibit significant functional improvement vs. controls. The current study demonstrated that GA accelerates axonal regeneration and enhances functional recovery in vivo. Its ability to increase the rate at which peripheral axons regenerate is comparable to that of FK-506. GA, however, did not match the performance of FK-506 in injury models where Wallerian degeneration (WD) is ongoing in the distal stump. This provides evidence that FK-506 accelerates axonal regeneration through two parallel mechanisms: the first being its well-established effect on neurons; the second is likely a newly described, as-yet poorly defined mechanism that affects WD. Finally, given the decrease in observed toxicity with GA administration, it might be a suitable non-immunosuppressive alternative to FK-506 for accelerating peripheral nerve regeneration in cases of clinical nerve injury.

[Cubital tunnel syndrome and the scratch test to determine the surgical procedure]. / Síndrome de túnel cubital y la prueba por rascado para determinar el procedimiento quirúrgico.

BACKGROUND: Neuropathy due to ulnar nerve compression at the elbow level is the second most frequent neuropathy. The scratch collapse test is useful to diagnose compression neuropathies. This test helps us rank compression sites and decide the type of treatment to use. METHODS: From May to July 2011, 34 patients, mostly females, were preoperatively analyzed with this test. Ethyl chloride was also used to show other compression sites. RESULTS: The main compression site was found to be at the level of Osborne's ligament, contrary to the idea that it was located at the medial epicondyle. Another finding was that at the hand and wrist level it is more common to find compression in the proximal fascia of the forearm than in Guyon's canal. After surgery, CRP became negative in all patients. DISCUSSION AND CONCLUSIONS: When the primary collapse point is Osborne's ligament, the patient will require ulnar nerve transposition. When the primary collapse point is located at the level of the medial epicondyle, decompression is enough. In case of several simultaneous collapse points before applying ethyl chloride, a surgical procedure will not necessarily be required for each one of them.

Costimulation blockade of CD40 and CD28 pathways in limb transplantation.

Costimulation blockade remains a promising experimental regimen for the induction of transplantation tolerance. The simultaneous blockade of both the CD40 and CD28 pathways has been synergistic in prolonging organ allograft survival but has not previously been investigated in a model of limb allotransplantation. This study determined the efficacy of this combination in the murine limb allograft model. C57B1/6 (H-2K(b)) female mice were recipients of heterotopic vascularized limb allografts from Balb/c (H-2K(d)) male donors. Experimental groups received treatment with a short course of MR1 (hamster anti-mouse anti-CD40 ligand antibody) alone or in combination with CTLA4-Ig, a fusion protein that blocks the B7/CD28 pathway. Untreated recipients rejected limb allografts at a mean of 9.6 +/- 1.1 (standard error of the mean) days postoperatively. Recipients of a prolonged course of MR1 rejected limb allografts at 75 +/- 25 days. When both MR1 and CTLA4-Ig were used, limb allograft survival of >120 days was observed despite a much shorter course of therapy. Rejection in both treatment groups was consistent with a chronic antibody-mediated process. Donor antigen rechallenge in these recipients by in vitro assay and skin allograft demonstrated a hyperacute response consistent with presensitization. Long-term limb allograft survival is produced by the synergistic effect of blocking both the CD40 and CD28 costimulatory pathways. However, permanent acceptance was not achieved, and allografts eventually succumbed to what appeared to be antibody-mediated rejection. The additional use of newer agents that block more recently described costimulatory pathways may be essential for the induction of tolerance by costimulation blockade.

Patient outcome following a thoracodorsal to musculocutaneous nerve transfer for reconstruction of elbow flexion.

This study reports patient outcome following a thoracodorsal to musculocutaneous nerve transfer. We retrospectively reviewed the charts of six patients who had undergone transfer of the thoracodorsal nerve to the musculocutaneous nerve for reconstruction of elbow flexion. The mean age was 47 years (standard deviation: 24 years; range: 17-72 years). The mean time from injury to surgery was 3 months (standard deviation: 2 months; range: 1-5 months). In all cases, the biceps muscle was successfully reinnervated; in one case the Medical Research Council (MRC) muscle grade was grade 5, in four cases it was grade 4, and in one case it was grade 2. No patients complained of functional weakness with shoulder adduction and/or internal rotation. In the majority of cases, transfer of the thoracodorsal nerve to the musculocutaneous nerve provides excellent recovery of elbow flexion.

End-to-side neurorrhaphy and lateral axonal sprouting in a long graft rat model.

OBJECTIVE/HYPOTHESIS: Controversy exists regarding collateral axonal sprouting across an end-to-side neurorrhaphy to provide functional motor reinnervation of a target organ without compromise of the donor nerve. Rat models may be limited in the study of end-to-side repair given potential contamination from the proximal nerve stump of the recipient distal nerve and the use of antagonistic muscle groups for donor and recipient. The current study attempts to address these issues by using a rat model in which an end-to-side coaptation is performed with a long graft interposed between the intact donor tibial nerve and the divided, distal contralateral tibial nerve. MATERIALS AND METHODS: The graft used in proximal end-to-side coaptation consisted of both sciatic nerves in a donor syngeneic animal. The distal repair to the contralateral tibial nerve was done immediately or in a delayed fashion to allow potential motor axons to transverse the graft before division of the recipient tibial nerve. RESULTS: After 24 weeks, axons were noted to transverse the entire distance of the graft and into the contralateral distal posterior tibial nerve. A significant increase in axonal numbers was observed in the immediate repairs compared with the delayed. No animal recovered functional motor ability on the contralateral side as assessed by walking tracks. CONCLUSIONS: These findings suggest the importance of immediate distal neurotrophic factors in encouraging nerve regeneration even in a long graft end-to-side repair. Our model is successful in demonstrating innervation through an end-to-side coaptation but questions its use given the lack of motor recovery.

Flexor digitorum superficialis nerve transfer to restore pronation: two case reports and anatomic study.

Loss of pronation affects most activities of daily living. We report 2 cases of traumatic loss of pronator teres function and successful reconstruction by transfer of a redundant motor branch to the flexor digitorum superficialis to the pronator teres branch(es). Follow-up period was 2 years and pronation strength was restored to +4/5 and 5/5 in the 2 patients. The anatomy of the median nerve in the proximal forearm was examined by dissecting 31 cadaver specimens. A branching scheme was formulated. The histomorphometric properties of the individual muscular branches were studied in 15 fresh specimens to evaluate their suitability and size match for nerve transfer.

Current approach to cubital tunnel syndrome.

The choice for surgical treatment of cubital tunnel syndrome is no clearer today than when it was reviewed 10 years ago. There continue to be no significant prospective randomized trials to adequately compare the different surgical techniques. Even if such a trial were performed, most hand surgeons would probably continue to be skeptical. In the end, each surgeon must rely on his or her own personal experience or judgment. Based on the authors' experience in the treatment of cubital tunnel syndrome, they are confident that anterior transmuscular transposition of the ulnar nerve obtains the best results when the preoperative algorithm is properly applied and early postoperative physical therapy is instituted.

Secondary carpal tunnel surgery.

A small but significant group of patients with carpal tunnel syndrome "fail" primary carpal tunnel release and require secondary surgery. The persistence or recurrence of previous symptoms or the development of new symptoms is often indicative of the nature of the patient's problem. Postoperative complications may be classified into the general areas of neurological, vascular, tendon, and wrist complaints. A thorough clinical evaluation, including a complete neurological examination of the hand and upper extremity, provides an accurate assessment of the status of the median nerve. Important surgical techniques that may be used during secondary carpal tunnel surgery include internal neurolysis, neuroma-in-continuity assessment, neuroma management, nerve grafting, and tissue interposition flaps.

Development of a mouse model for heterotopic limb and composite-tissue transplantation.

The mouse remains the most suitable model to study the complexities of the immune system and transplant rejection. The purpose of this study was to describe a new mouse model for heterotopic limb and composite tissue transplantation. Eighteen procedures were performed, including 10 heterotopic lower hind limb, four vascularized skin, and four vascularized muscle transplantations. Three transplants were allogeneic, and the rest were syngeneic. All successful syngeneic transplants were harvested at 11 days postoperatively, except for one skin and one limb transplant that were followed for over 30 days. The allogeneic transplants showed signs of rejection between 7 to 11 days postoperatively. Results of mixed lymphocyte culture (p < 0.05) and histology evaluations from the allogeneic recipients were consistent with acute rejection as the cause of allograft loss. The mortality rate was 16.7 percent, and the overall success rate was 72.2 percent. Details of the operative procedure are described, and important technical factors are discussed.

Clinical outcome following nerve allograft transplantation.

The clinical outcome of seven patients who underwent reconstruction of long upper- and lower-extremity peripheral nerve gaps with interposition peripheral nerve allografts is reported. Patients were selected for transplantation when the nerve gaps exceeded the length that could be reconstructed with available autograft tissue. Before transplantation, cadaveric allografts were harvested and preserved for 7 days in University of Wisconsin Cold Storage Solution at 5 degrees C. In the interim, patients were started on an immunosuppressive regimen consisting of either cyclosporin A or tacrolimus (FK506), azathioprine, and prednisone. Immunosuppression was discontinued 6 months after regeneration across the allograft(s) was evident. Six patients demonstrated return of motor function and sensation in the affected limb, and one patient experienced rejection of the allograft secondary to subtherapeutic immunosuppression. In addition to providing the ability to restore nerve continuity in severe extremity injuries, successful nerve allografting protocols have direct applicability to composite tissue transplantation.

Rat-strain differences in recovery following peripheral-nerve allotransplantation.

The rat model is commonly utilized in peripheral nerve research. Due to the short length of the rat limb and the animal's inherent neuroregenerative capacity, the timing of assessment of nerve regeneration is critical, and significant differences between groups can be lost if assessment is done too late. Additionally, the comparison of data from different rat-strain combinations has been questioned. This study better defines the time course of recovery after peripheral nerve grafting, and examines differences between Buffalo (BUF), Lewis (LEW), and ACI rats. Tibial-nerve isografts and allografts were performed and harvested at 6, 8, 10, or 14 weeks. Histomorphometry documented a statistically significant difference in the ACI/LEW and LEW/LEW combination at 10 weeks. No strain differences in graft rejection were noted. The optimal time to assess for histomorphometric differences in the ACI/LEW and LEW/LEW combination is at 10 weeks postoperatively.

Portal venous ultraviolet B-irradiated donor alloantigen prevents rejection in circumferential rat tracheal allografts.

BACKGROUND: Before tracheal transplantation can be considered as a method of reconstruction in patients with extensive circumferential tracheal defects, we must achieve a state of nontoxic, donor-specific tolerance so that the risks of such a transplant do not outweigh the benefits. OBJECTIVE: Our objective was to determine whether a single intraportal injection of modified donor alloantigen achieves donor-specific immunosuppression for major histocompatibility complex-mismatched rat tracheal allografts. STUDY DESIGN: Buffalo (recipient) rats were pretreated with either a single portal-vein administration of ultraviolet B (UVB)-irradiated donor splenocytes (n = 4) or an intraportal inoculation of nonirradiated donor splenocytes (n = 4). Major histocompatibility complex-mismatched Lewis (donor) tracheal allograft segments were then grafted into treatment groups 7 days after donor-cell pretreatment. Tracheal rejection was assessed by histologic analysis, mucosal cilia motility, and in vitro immunologic assessment. RESULTS: The UVB-treated group demonstrated no acute or chronic rejection as well as complete functional recovery. In vitro immunologic assessment demonstrated a donor-specific hyporesponsiveness and donor allospecificity. Untreated animals and those receiving nonirradiated donor splenocytes showed acute rejection of their tracheal allografts. CONCLUSION: Recipient pretreatment with intraportally administered UVB-irradiated donor splenocytes prevents rejection of circumferential rat tracheal allograft segments by inducing a donor-specific immune hyporesponsiveness.

FK506 rescues peripheral nerve allografts in acute rejection.

This study investigated the ability of the immunosuppressant FK506 to reverse nerve allograft rejection in progress. Eighty-four Buffalo rats received posterior tibial nerve grafts from either Lewis or Buffalo donor animals. Allografts were left untreated for either 7, 10, or 14 days before receiving daily subcutaneous FK506 injections (2 mg/kg). Time-matched control animals received either an isograft, an allograft with continuous FK506, or an allograft with no postoperative FK506 therapy. All animals underwent weekly evaluation of nerve function by walking track analysis. Experimental group animals were sacrificed either immediately prior to initiation of FK506 therapy (days 7, 10, or 14), after 2 weeks of immunosuppressive treatment, or 8 weeks postsurgery. Histomorphometric analysis, consisting of measurements of total number of nerve fibers, neural density, and percent of neural debris, demonstrated a statistically significant increase in regeneration in the isograft group relative to the untreated allograft group within 28 days of transplantation. Grafts harvested from animals receiving 2 weeks of FK506 after 7 or 10 days of rejection were histomorphometrically similar to time-matched isografts. By contrast, grafts from animals receiving 2 weeks of FK506 following 14 days without therapy resembled untreated allografts and demonstrated significant histomorphometric differences from isografts at the corresponding time point. Analysis of walking track data confirmed that relative to untreated allografts, functional recovery was hastened in animals receiving an isograft, or allograft treated with FK506. This study demonstrated that when started within 10 days of graft placement, FK506 could reverse nerve allograft rejection in rats evaluated following 2 weeks of treatment.

Pretreatment with portal venous ultraviolet B-irradiated donor alloantigen promotes donor-specific tolerance to rat nerve allografts.

OBJECTIVE: To determine if a single intraportal inoculation of ultraviolet B-irradiated (UVB) donor splenocytes can prevent nerve allograft rejection and confer donor-specific immunotolerance to rat nerve allograft segments. METHODS: Age-matched, class I and class II major histocompatibility complex (MHC) mismatched Buffalo (RT1b) rats were transplanted with a syngeneic nerve isograft, a Lewis (RT1l) nerve allograft, or a Brown-Norway (RT1n) rat nerve allograft segment. Control Buffalo rats in group I received a 3.0-cm Lewis (RT11) sciatic-posterior tibial interposition nerve allograft without pretreatment; group II Buffalo rats received a syngeneic Buffalo nerve isograft without pretreatment. Group III Buffalo recipients were inoculated with 2.5 x 107 UVB-irradiated Lewis donor splenocyte cells by portal venous administration 7 days before transplantation with a 3.0-cm sciatic-posterior tibial nerve allograft from a Lewis (RT11) or a third party Brown-Norway rat (RT1n) donor (group IV). Nerve graft regeneration was assessed with walking track analysis, nerve conduction studies, retrograde neural tracing, nerve graft histology, and morphometry. Recipient immune tolerance was assessed through in vitro immunological assessment. RESULTS: Pretreatment with UVB-irradiated donor splenocytes 7 days before transplantation prevented nerve allograft rejection. Pretreated animals receiving a nerve allograft recovered limb function, and demonstrated morphological, histological, and electrophysiologic parameters of nerve regeneration similar to that measured in rats receiving a nerve isograft. In vitro immunological assessment by mixed lymphocyte culture (MLC), cytotoxic T lymphocyte (CTL) assay, limiting dilution analysis (LDA) of helper (pTH) and cytotoxic (pCTL) precursor frequencies, and IL-2 production demonstrated a marked donor-specific suppression in allografted animals pretreated with intraportal UVB-irradiated donor splenocytes. These assessments correlated with indefinite acceptance of donor nerve allografts. CONCLUSIONS: A single pretreatment with a single intraportal dose of UVB-modified donor antigen specifically induces tolerance to peripheral nerve allografts in rats.

Development of the blood-nerve barrier in neonatal rats.

The blood-nerve barrier (BNB) is constituted by the perineurium and the endothelium of endoneurial microvessels. We investigated the age at which the vascular component of BNB function is established in the rat and the ultrastructural modifications accompanying changes in permeability. BNB permeability was assessed with injections of Evans blue albumin (EBA) and horseradish peroxidase (HRP) in rats of different ages. Sciatic nerve sections were studied using fluorescence and electron microscopy. Nerves from animals injected with EBA indicated that the BNB is not functional before 13 days of life but that its function is established by 16 days. These results were confirmed by electron microscope examination of nerve sections from animals injected with HRP, which showed clefts between the endothelial cells of endoneurial vessels in young rats. In rats over 18 days, these clefts were occluded by tight junctions, which prevented HRP from leaving the vessel lumen and conferred BNB function. Systematic morphometric analysis of nerves from different age groups allowed the establishment of baseline normal histologic neural development with age.

A subcutaneous heterotopic limb transplantation model in the mouse for prolonged allograft survival.

A heterotopic position of a limb allograft is advantageous in the fragile mouse model to reduce mortality but is prone to autotomy. The purpose of this study was to describe a new heterotopic limb transplantation model in the mouse for prolonged allograft survival. Eleven lower hindlimbs were transplanted in a heterotopic subcutaneous position in the groin of the recipient animal with the donor skin inset as a skin paddle for monitoring. Seven transplants were syngeneic (Balb/c) and four were allogeneic (C57Bl/6 donor). The overall success rate (acute survival < 7 days) was 73% (8/11) and the mortality rate was 18% (2/11). Five of seven syngeneic transplants survived for 60 days and were harvested for histology. Recipients of successful allogeneic transplants (n = 3) received no immunosuppression and rejected their allografts between 8 and 11 days postoperatively. Mixed lymphocyte culture and flow cytometry demonstrated secondary immune responses by pre-sensitized animals, and histology showed lymphocytic infiltration and necrosis consistent with acute rejection.