Surgery for mononeuropathies.

Advancement in microsurgical techniques and innovative approaches including greater use of nerve and tendon transfers have resulted in better peripheral nerve injury (PNI) surgical outcomes. Clinical evaluation of the patient and their injury factors along with a shift toward earlier time frame for intervention remain key. A better understanding of the pathophysiology and biology involved in PNI and specifically mononeuropathies along with advances in ultrasound and magnetic resonance imaging allow us, nowadays, to provide our patients with a logical and sophisticated approach. While functional outcomes are constantly being refined through different surgical techniques, basic scientific concepts are being advanced and translated to clinical practice on a continuous basis. Finally, a combination of nerve transfers and technological advances in nerve/brain and machine interfaces are expanding the scope of nerve surgery to help patients with amputations, spinal cord, and brain lesions.

Distal anterior interosseous nerve to ulnar nerve motor branch reverse end-to-side transfer in a case of severe ulnar neuropathy.

Reverse end-to-side (RETS) distal transfer is gaining popularity in cases of proximal nerve damage with the nerve in continuity, allowing the nerve to potentially retain its ability to regenerate and recover. While preserving the original axon pool, RETS could provide an additional pool of motor axons and/or possibly "babysit" the muscle endplates and distal denervated nerve Schwann cells until reinnervation from the original pool occurs. The authors present a video demonstrating anterior subcutaneous transposition of the ulnar nerve at the elbow coupled with a distal anterior interosseous nerve to ulnar nerve RETS in a case of severe posttraumatic ulnar neuropathy at the elbow. The video can be found here: https://stream.cadmore.media/r10.3171/2022.9.FOCVID2282.

Successful retrograde regeneration using a sensory branch for motor nerve transfer.

OBJECTIVE: The objective of this study was to test whether regenerating motor axons from a donor nerve can travel in a retrograde fashion using sensory branches to successfully reinnervate a motor nerve end organ. METHODS: This study has two parts. In part I, rats (n = 30) were assigned to one of five groups for obturator nerve (ON)-to-femoral nerve transfer: group 1, ON-to-saphenous nerve (SN) distal stump; group 2, ON-to-SN proximal stump without femoral nerve proper (FNP) injury; group 3, ON-to-SN proximal stump with FNP crush injury; group 4, ON-to-SN proximal stump with FNP transection injury; and group 5, gold standard transfer, ON-to-motor femoral nerve (MFN) branch. At 8 weeks, retrograde labeling was done from the distal MFN, and the spinal cords were examined to assess the degree of obturator motor axon regeneration across the five groups. In part II, only group 4 was examined (n = 8). Through use of immunostaining and optical tissue clearing methods, the nerve transfer networks were cleared and imaged using light-sheet fluorescence microscopy to visualize the regeneration pathways in 2D and 3D models at 2- and 8-week time points. RESULTS: Proximal FNP transection (group 4) enabled a significantly higher number of retrogradely regenerated motor axons compared with control groups 1-3. Moreover, group 4 had modest, but nonsignificant, superiority of motor neuron counts compared with the positive control group, group 5. Optical tissue clearing demonstrated that the axons traveled in a retrograde fashion from the recipient sensory branch to the FNP mixed stump, then through complex turns, down to distal branches. Immunostaining confirmed the tissue clearing findings and suggested perineurium disruption as a means by which axons could traverse across fascicular boundaries. CONCLUSIONS: Sensory branches can transmit regenerating axons from donor nerves back to main mixed recipient nerves, then distally toward target organs. The extent of retrograde regeneration is markedly influenced by the type and severity of injury sustained by the recipient nerve. Using a sensory branch as a bridge for retrogradely regenerating axons can open new potential horizons in nerve repair surgery for severely injured mixed nerves.

Functional Gait Assessment Using Manual, Semi-Automated and Deep Learning Approaches Following Standardized Models of Peripheral Nerve Injury in Mice.

Objective: To develop a standardized model of stretch−crush sciatic nerve injury in mice, and to compare outcomes of crush and novel stretch−crush injuries using standard manual gait and sensory assays, and compare them to both semi-automated as well as deep-learning gait analysis methods. Methods: Initial studies in C57/Bl6 mice were used to develop crush and stretch−crush injury models followed by histologic analysis. In total, 12 eight-week-old 129S6/SvEvTac mice were used in a six-week behavioural study. Behavioral assessments using the von Frey monofilament test and gait analysis recorded on a DigiGait platform and analyzed through both Visual Gait Lab (VGL) deep learning and standardized sciatic functional index (SFI) measurements were evaluated weekly. At the termination of the study, neurophysiological nerve conduction velocities were recorded, calf muscle weight ratios measured and histological analyses performed. Results: Histological evidence confirmed more severe histomorphological injury in the stretch−crush injured group compared to the crush-only injured group at one week post-injury. Von Frey monofilament paw withdrawal was significant for both groups at week one compared to baseline (p < 0.05), but not between groups with return to baseline at week five. SFI showed hindered gait at week one and two for both groups, compared to baseline (p < 0.0001), with return to baseline at week five. Hind stance width (HSW) showed similar trends as von Frey monofilament test as well as SFI measurements, yet hind paw angle (HPA) peaked at week two. Nerve conduction velocity (NCV), measured six weeks post-injury, at the termination of the study, did not show any significant difference between the two groups; yet, calf muscle weight measurements were significantly different between the two, with the stretch−crush group demonstrating a lower (poorer) weight ratio relative to uninjured contralateral legs (p < 0.05). Conclusion: Stretch−crush injury achieved a more reproducible and constant injury compared to crush-only injuries, with at least a Sunderland grade 3 injury (perineurial interruption) in histological samples one week post-injury in the former. However, serial behavioral outcomes were comparable between the two crush groups, with similar kinetics of recovery by von Frey testing, SFI and certain VGL parameters, the latter reported for the first time in rodent peripheral nerve injury. Semi-automated and deep learning-based approaches for gait analysis are promising, but require further validation for evaluation in murine hind-limb nerve injuries.

Utilization of focused ultrasound for opening of the blood-nerve barrier.

Objective. Focused ultrasound (FUS) use with and without microbubbles (MB) for investigation of the blood-nerve barrier (BNB) within the peripheral nervous system (PNS) has been performed in this study. We evaluate the feasibility of BNB opening in a rodent sciatic nerve model by direct vision FUS treatment and provide preliminary results of magnetic resonance guided FUS (MRgFUS).Approach. Twenty rodent bilateral sciatic nerves were investigated. Rodents were treated using a benchtop FUS system to directly visualize nerve FUS studies. Definity MB, Evans blue dye (EB) and latex micro beads were injected during studies. Selected animals underwent further compound muscle action potential (CMAP) studies. Sonication peak pressure (MPa), width, duty-cycle and duration as well as MB concentration were varied to investigate effective pressure threshold. Further preliminary MRgFUS studies were performed on selected animals. Immunohistochemistry and histological analysis under florescent microscopy were performed at termination of experiments to verify treatment outcomes.Main results. Three ultrasound pressures and three microbubble concentrations at a single sonication frequency (476.5 kHz) were performed under direct open targeting. Histological analysis demonstrated nerve internal architecture disruption at 1.2 MPa with 166.7µl kg-1while 0.3 MPa, with 40µl kg-1MB concentration was the lower threshold for consistently observed disruption of the BNB without anatomical microarchitecture disruption. EB leakage was confirmed at the target region in histological evaluation of nerve following MB injection and FUS sonication. Supra-harmonic emissions were detected during FUS exposures following MB injection but not at baseline reference, indicating effective MB response and stable cavitation. CMAP amplitudes showed delayed onset latency and lower amplitudes in sonicated nerves compared to control nerves without evidence of complete conduction block, suggesting a transient BNB disruption, while at lower limit pressure subtle conduction changes were observed. In MRgFUS, targeted nerves demonstrated further contrast agent leak as well as supra-harmonic frequency detection.Significance. Opening of the BNB in the PNS was achieved using FUS and MB in a rodent model. Ongoing work aims to refine FUS parameters for drug delivery into the nerve after experimental transient BNB disruption.

Comparison of human skin- and nerve-derived Schwann cells reveals many similarities and subtle genomic and functional differences.

Skin is an easily accessible tissue and a rich source of Schwann cells (SCs). Toward potential clinical application of autologous SC therapies, we aim to improve the reliability and specificity of our protocol to obtain SCs from small skin samples. As well, to explore potential functional distinctions between skin-derived SCs (Sk-SCs) and nerve-derived SCs (N-SCs), we used single-cell RNA-sequencing and a series of in vitro and in vivo assays. Our results showed that Sk-SCs expressed typical SC markers. Single-cell sequencing of Sk- and N-SCs revealed an overwhelming overlap in gene expression with the exception of HLA genes which were preferentially up-regulated in Sk-SCs. In vitro, both cell types exhibited similar levels of proliferation, migration, uptake of myelin debris and readily associated with neurites when co-cultured with human iPSC-induced motor neurons. Both exhibited ensheathment of multiple neurites and early phase of myelination, especially in N-SCs. Interestingly, dorsal root ganglion (DRG) neurite outgrowth assay showed substantially more complexed neurite outgrowth in DRGs exposed to Sk-SC conditioned media compared to those from N-SCs. Multiplex ELISA array revealed shared growth factor profiles, but Sk-SCs expressed a higher level of VEGF. Transplantation of Sk- and N-SCs into injured peripheral nerve in nude rats and NOD-SCID mice showed close association of both SCs to regenerating axons. Myelination of rodent axons was observed infrequently by N-SCs, but absent in Sk-SC xenografts. Overall, our results showed that Sk-SCs share near-identical properties to N-SCs but with subtle differences that could potentially enhance their therapeutic utility.

Combined treatment approach to cerebral arteriovenous malformation in pediatric patients: stereotactic radiosurgery to partially Onyx-embolized AVM.

PURPOSE: Treatment of cerebral arteriovenous malformations (AVM)-the most common cause of stroke in the pediatric population-can be challenging due to the complexity of size, morphology, and location. There is a significant risk in comparison to AVM treatment among adults. Thus, AVM treatment in the pediatric population imposes unique challenges. Recent improvements include optimized catheter techniques and better embolization materials, such as Onyx, a non-adhesive liquid embolic agent used in the adult population. These improvements have increased the success rate of total and near-total obliteration of cerebral AVM. However, the use of Onyx causes significant distortion of the MR and CT images, which must be accounted for in any radiation treatment planning predicated on CT and MRI. These image distortions impact on the actual delivered dose to the nidus and behoove heterogeneity correction. Our group has previously shared a solution for heterogeneity correction in the adult population. The purpose of this study is to show our experience in this unique group of pediatric patients. METHODS: This is a retrospective review of pediatric patients, who were undergoing combined endovascular embolization followed by SRS. The cohort consists of 14 patients undergoing SRS treatment in our institute between November 2006 and December 2012 with a mean follow-up of 49.9 months. Within this cohort, we retrospectively reviewed 12 consecutive pediatric patients who underwent a combined endovascular and SRS approach with a mean follow-up of 52.1 months and two patients receiving SRS-only treatment were excluded. RESULTS: In our cohort of 14 patients, 7 (50%) were male, with a mean age of 17.3 years (12.0-22.9) at the time of radiosurgery treatment. Mean age of beginning the combined modality treatment was 15.3 years (8.4-20). The median time from diagnosis to SRS was 24.3 months (11.1-64.4 months) in the complete cohort and 25.6 months (11.1-64.4) in the multimodality group. The overall median follow-up period was 49.9 months (range 12.8-118.8 months) in the complete cohort and 52.1 months (range 12.8-118.8 months) in the multimodality group. Eleven (78.6%) patients had at least one episode of hemorrhage prior to treatment. Spezler-Martin grades at baseline ranged from 2 to 5 (mean 3.2). Fifty percent had grade IV and V. Patients underwent a median of 2 (range 1-5) embolization procedures. The radiosurgical treatment dose to the margin of the angiography-based nidus: median prescription dose of 21.49 Gy (14.39-27.51) with a median max dose of 27.77 Gy (18.93-32.52). The median treatment volume was 0.6 cm3 (0.1-7.3 cm3). The Onyx embolization reduced the nidus target volume by a median of 66.7% (12.0-92.7%). We confirmed 10/14 (71%) complete closures. In 2/14 (14.2%) additional patients, a significant flow reduction was noted. In 1/14 (7.1%) patients, no significant change was noted during the observation period and two (14.2%) patients were without follow-up information. In two patients, post-treatment edema was noted; however, none was clinically significant and resolved without additional intervention or treatment. CONCLUSIONS: This cohort comprises the largest combined Onyx-SRS pediatric experience in the literature. In conjunction with our adult group study, we show that the use of Onyx reduces the SRS treatment target volume significantly. Importantly, we implemented the heterogeneity correction to avoid increased radiation exposure to normal surrounding brain tissue. The combined approach appears to be safe provided that the above-mentioned corrections are implemented.

Impact of Onyx Embolization on Radiosurgical Management of Cerebral Arteriovenous Malformations: Treatment and Outcome.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-established treatment modality for cerebral arteriovenous malformations (AVMs). The main limiting factor in the radiosurgical treatment of AVMs is the volume of the nidus, with high-grade lesions often requiring combined treatment to reduce the SRS target volume. To overcome this limitation, we have been using a combined treatment approach consisting of endovascular embolization with Onyx followed by SRS. OBJECTIVE: To evaluate our clinical experience for safety and feasibility of this multimodality treatment approach. METHODS: This is a retrospective review of all adult patients with cerebral AVMs who received SRS treatment to their AVM after endovascular embolization with Onyx between June 2007 and June 2014. RESULTS: Thirty-five consecutive patients were identified. The mean follow-up period was 52.4 ± 22.6 months (range 18-97 months). We confirmed 18 (51.4%) complete nidus closures at a median time of 49.5 months (range 6.5-81 months) from SRS. High-resolution Magnetic resonance imaging/magnetic resonance angiography was performed routinely in all patients until closure of the nidus. Digital subtraction angiography was performed to confirm complete obliteration in 5 of the patients (28%); 13 patients are either planned for digital subtraction angiography or have refused it. In 6 patients (17%) a significant flow reduction was noted after a mean of 32 ± 16 months. No significant improvement was observed in 9 patients (26%) during the follow-up period. Two patients were lost to follow-up. CONCLUSIONS: The multimodality treatment of cerebral AVMs using embolization with Onyx followed by SRS is feasible and safe. The use of Onyx significantly reduced the SRS treatment target volume.