Overview of Unilateral and Bilateral Pediatric Facial Paralysis: Workup, Treatment, and Frontiers.

Pediatric facial nerve paralysis can present significant challenges based on its various etiologies, unique approach to treatment options, and overall outcomes. It can impact both the child and parent when regarding function, appearance, and psychosocial implications. The etiology of facial nerve palsy can include congenital, traumatic, iatrogenic, and idiopathic causes. In some, the paralysis is transient while others have permanent loss of function. A thorough evaluation and differential diagnosis are essential to guide treatment planning. The purpose of this paper is to review facial paralysis in children with a focus on surgical management.

Corneal Neurotization: Essentials for The Facial Paralysis Surgeon.

Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.

Contralateral C7 nerve transfer for severe pediatric brachial plexus injuries: donor site morbidity.

BACKGROUND: Pediatric brachial plexus injuries (BPI) can have a devastating impact on upper extremity function. With localized lesions, nerve grafting and transfers are well-described. However, reconstruction of pan-plexus (C5-T1) injuries (PPI) requires donor nerves outside of the brachial plexus. The cross C7 (CC7) nerve transfer extended with sural nerve grafts to the contralateral recipient nerve offers the advantage of supplying robust donor axons. Though controversial in the West, CC7 transfer is routine in many Asian centers. We present a case series of pediatric patients who underwent CC7 transfer for BPI. Our objective was to catalog donor site morbidity incurred by transferring the C7 nerve root. METHODS: This retrospective study was approved by the Institutional Review Board of our university. INCLUSION CRITERIA: patients under 18 years old that underwent CC7 nerve transfer for BPI at our health system between 2021 and 2022. A chart review was completed to collect demographic and outcomes data. RESULTS: Three patients underwent a complete CC7 transfer between 2021 and 2022 for BPI reconstruction. All patients underwent concomitant additional nerve transfers. Post-operative donor site sensory deficits were minimal and transient in all but one patient, who reported mild but persistent paresthesia of the donor side hand with movement of recipient side digits; however, no patients suffered donor site motor deficits (Table 1). CONCLUSIONS: We conclude that CC7 nerve transfer is a safe surgical option to provide additional donor motor axons for PPI in pediatric patients.

Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506).

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.

The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal.

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.

Using Big Data to Assess Legitimacy of Plastic Surgery Information on Social Media.

BACKGROUND: The proliferation of social media in plastic surgery poses significant difficulties for the public in determining legitimacy of information. This work proposes a system based on social network analysis (SNA) to assess the legitimacy of information contributors within a plastic surgery community. OBJECTIVES: The aim of this study was to quantify the centrality of individual or group accounts on plastic surgery social media by means of a model based on academic plastic surgery and a single social media outlet. METHODS: To develop the model, a high-fidelity, active, and legitimate source account in academic plastic surgery (@psrc1955, Plastic Surgery Research Council) appearing only on Instagram (Facebook, Menlo Park, CA) was chosen. All follower-followed relationships were then recorded, and Gephi (https://gephi.org/) was used to compute 5 different centrality metrics for each contributor within the network. RESULTS: In total, 64,737 unique users and 116,439 unique follower-followed relationships were identified within the academic plastic surgery community. Among the metrics assessed, the in-degree centrality metric is the gold standard for SNA, hence this metric was designated as the centrality factor. Stratification of 1000 accounts by centrality factor demonstrated that all of the top 40 accounts were affiliated with a plastic surgery residency program, a board-certified academic plastic surgeon, a professional society, or a peer-reviewed journal. None of the accounts in the top decile belonged to a non-plastic surgeon or non-physician; however, this increased significantly beyond the 50th percentile. CONCLUSIONS: A data-driven approach was able to identify and successfully vet a core group of interconnected accounts within a single plastic surgery subcommunity for the purposes of determining legitimate sources of information.

Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension.

BACKGROUND: The aim of this study was to investigate the combined effect of mesenchymal stem cells (MSC) and local delivery of tacrolimus (FK506) on nerve regeneration when applied to nerve autografts and decellularized allografts. METHODS: A three-dimensional in vitro compartmented cell culture system consisting of a neonatal dorsal root ganglion adjacent to a nerve graft was used to evaluate the regenerating neurites into the peripheral nerve scaffold. Nerve autografts and allografts were treated with (i) undifferentiated MSCs, (ii) FK506 (100 ng/mL) or (iii) both (N = 9/group). After 48 hours, neurite extension was measured to quantify nerve regeneration and stem cell viability was evaluated. RESULTS: Stem cell viability was confirmed in all MSC-treated grafts. Neurite extension was superior in autografts treated with FK506, and MSCs and FK506 combined (p < 0.001 and p = 0.0001, respectively), and autografts treated with MSCs (p = 0.12) were comparable to untreated autografts. In allografts, FK506 treatment and combined treatment were superior to controls (p < 0.001 and p = 0.0001, respectively), and treatment with MSCs (p = 0.09) was comparable to controls. All autograft groups were superior compared to their respective allograft treatment group (p < 0.05) in neurite extension. CONCLUSIONS: Alone, either MSC or FK506 treatment improved neurite outgrowth, and combined they further enhanced neurite extension in both autografts and allografts.

Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration.

The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.

Effect of moist heat reprocessing of N95 respirators on SARS-CoV-2 inactivation and respirator function.

BACKGROUND: Unprecedented demand for N95 respirators during the coronavirus disease 2019 (COVID-19) pandemic has led to a global shortage of these masks. We validated a rapidly applicable, low-cost decontamination protocol in compliance with regulatory standards to enable the safe reuse of N95 respirators. METHODS: We inoculated 4 common models of N95 respirators with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and evaluated viral inactivation after disinfection for 60 minutes at 70°C and 0% relative humidity. Similarly, we evaluated thermal disinfection at 0% to 70% relative humidity for masks inoculated with Escherichia coli. We assessed masks subjected to multiple cycles of thermal disinfection for structural integrity using scanning electron microscopy and for protective functions using standards of the United States National Institute for Occupational Safety and Health for particle filtration efficiency, breathing resistance and respirator fit. RESULTS: A single heat treatment rendered SARS-CoV-2 undetectable in all mask samples. Compared with untreated inoculated control masks, E. coli cultures at 24 hours were virtually undetectable from masks treated at 70°C and 50% relative humidity (optical density at 600 nm wavelength, 0.02 ± 0.02 v. 2.77 ± 0.09, p < 0.001), but contamination persisted for masks treated at lower relative humidity. After 10 disinfection cycles, masks maintained fibre diameters similar to untreated masks and continued to meet standards for fit, filtration efficiency and breathing resistance. INTERPRETATION: Thermal disinfection successfully decontaminated N95 respirators without impairing structural integrity or function. This process could be used in hospitals and long-term care facilities with commonly available equipment to mitigate the depletion of N95 masks.

Effectiveness of Platelet-Rich Plasma Injections for Nonsurgical Management of Carpal Tunnel Syndrome: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To systematically review and evaluate the efficacy and complication profile of platelet-rich plasma (PRP) injection into the carpal tunnel for management of carpal tunnel syndrome (CTS). DATA SOURCES: PubMed, MEDLINE, SCOPUS, EMBASE, Google Scholar, Cochrane Central Register of Controlled Trials, and Web of Sciences (from inception to January 1, 2019). STUDY SELECTION: Controlled trials addressing PRP for CTS. DATA EXTRACTION: Two reviewers independently screened the titles, abstracts, and full texts, extracting data from eligible studies. The outcomes of interest were the visual analog score (VAS) for pain and the Boston Carpal Tunnel Questionnaire (BCTQ), including the subscales of the symptom severity scale (SSS) and the Functional Status Scale (FSS). Other reported outcome measures and complications were analyzed descriptively. DATA SYNTHESIS: Four randomized controlled studies satisfied the inclusion criteria and analyzed a total of 191 cases with a final follow-up of either 3 or 6 months. Control groups included splinting in 2 studies, corticosteroid injection in 1 study, and saline injection in 1 study. There was a statistically and clinically significant improvement in the BCTQ (standardized mean difference=-2.06; 95% confidence interval [CI], -3.41 to -0.70; P=.003) between groups. Subgroup analysis showed significant improvement in SSS (standardized mean difference=-1.95; 95% CI, -3.65 to -0.25; P=.02) but not for FSS (standardized mean difference=-2.19; 95% CI, -4.77 to 0.40; P=.10). There was a similar improvement in VAS and nerve conduction studies in those receiving PRP compared to controls. Complication rate in the included studies was low with 4 of 97 participants receiving PRP injections experiencing transient pruritis, burning, or tingling. CONCLUSIONS: PRP represents a promising therapy for patients with mild to moderate CTS; however, included studies were limited as follow-up was short, the studies included patients that were heterogeneous, and the number of included studies was low. Further investigation is necessary to determine the true efficacy and effect of PRP and to better delineate the long-term results in patients with CTS.

Hanno Millesi: Pioneer of Plastic Surgery and Nerve Surgery (1927-2017).

Recently, plastic surgery lost one of its most prominent surgeons-Dr. Hanno Millesi. His contributions to the field continue to impact the practice of medicine and surgery. As such, it is appropriate to reflect upon his career and recognize his accomplishments in peripheral nerve surgery, hand surgery, and Dupuytren disease.

Systemic and Local FK506 (Tacrolimus) and its Application in Peripheral Nerve Surgery.

Peripheral nerve injuries (PNI) are common and frequently afflict otherwise healthy individuals after traumatic or iatrogenic events. Adjuvant therapies to improve functional outcomes after surgical repair of PNI have been investigated extensively in preclinical studies; however, to date, none have been clinically proven to have a notable therapeutic effect. FK506 (tacrolimus), a US Food and Drug Administration-approved systemic immunosuppressant, has demonstrated promising neuro-regenerative properties in both animal studies and clinical reports, but its adverse effects when systemically administered have precluded its broader applicability for patients with PNI. Recent advances in bioengineered drug delivery systems have made local FK506 delivery to a site of PNI an intriguing method of promoting peripheral nerve regeneration, with promising results in preclinical translational investigations. This review summarizes the preclinical and clinical evidence for FK506's beneficial effect in promoting peripheral nerve regeneration when administered systemically and locally.

Evaluation of a Pediatric Facial Paralysis Education and Family Support Day.

INTRODUCTION: Facial paralysis impairs the mimetic functions of the facial musculature. In pediatric patients, free functioning muscle transfer neurotized with an intact contralateral facial nerve is the gold standard for smile reanimation. In response to requests from families of children with facial paralysis, the Division of Plastic and Reconstructive Surgery at the Hospital for Sick Children hosted an inaugural "Facial Paralysis Family Day." The objective was to create an opportunity for families to meet, exchange stories, and build support networks. METHODS: This study was a quality improvement project to conduct a needs assessment and evaluate the feasibility and satisfaction of implementing a family support intervention for individuals living with facial paralysis. RESULTS: The needs assessment demonstrated that families were most interested in advances in medicine, therapy and coping sessions and meeting other families. The post-event evaluation questionnaire indicated that attendees enjoyed the event, would attend again and found it highly valuable connecting and networking other families. It also indicated that key needs identified were addressed, with excellent ratings for the presentation discussing advances in medicine (100% rated "good" or "very good"), the therapy sessions (92% rated "good" or "very good") and the presentations by patients and their families (100% rated "good" or "very good.") DISCUSSION:: Two areas of improvement highlighted were elaborating further on medical advances and facilitating interactions between families. Overall, this event was well regarded and will likely be repeated at our institution and serve as a valuable resource for other hospitals planning to organize a similar event.

Local FK506 dose-dependent study using a novel three-dimensional organotypic assay.

Local administration of FK506, an FDA approved immunosuppressant with neuroregenerative properties, is a promising technique to achieve improved peripheral nerve regeneration while preventing the side effects associated with the systemic administration of this drug. Although considerable research has been devoted to the development of clinically suitable systems for local delivery of FK506 to the site of nerve injury and repair, the optimal dose of FK506 for enhancement of axon regeneration in the peripheral nerve has not yet been established. To this end, we devised a three-dimensional (3D) organotypic assay capable of mimicking the peripheral nerve. This assay consisted of a neonatal rat dorsal root ganglion (DRG) extending its neurites into the native peripheral nerve scaffold provided by an acellular nerve allograft (ANA). A novel 3D compartmented cell culture system was adapted from the 3D organotypic assay to achieve local delivery of FK506 just to the growing neurites in vitro and establish the required local dose of FK506 for peripheral nerve regeneration. A bimodal dose response was observed by culturing the entire DRG-ANA construct with media containing different concentrations of FK506. Low drug concentration of 1 pg/ml and high drug concentration of 100 ng/ml lead to the longest neurite extension in vitro. Furthermore, regardless of the FK506 concentration, concentrating the drug to the growing neurites resulted in significant increase in both neurite extension and neurite density, an effect that was not observed with the FK506 delivery to both neurites and neural cell bodies within DRG. The findings in this study provide valuable insight into the optimal local dose of FK506 for peripheral nerve regeneration. Furthermore, for the first time, this study suggests the potential interaction of FK506 with axons at the level of the growth cone.

Effect of Reverse End-to-Side (Supercharging) Neurotization in Long Processed Acellular Nerve Allograft in a Rat Model.

PURPOSE: Processed acellular nerve allograft (PNA) has been suggested as a convenient tool for overcoming short and medium nerve defects. Although the clinical implications are unclear, animal data suggest that PNA becomes less effective at longer lengths. Although reverse or supercharging end-to-side nerve transfer may improve the neurotrophic potential in chronically denervated nerve tissue, the application of this strategy to long acellular nerve allograft has not been previously investigated. We hypothesized that supercharging acellular nerve allograft would increase its effective length. METHODS: Sprague-Dawley and Thy1-green fluorescent protein Sprague-Dawley rats underwent transection of the tibial nerve, followed by immediate repair with 20-, 40-, or 60-mm acellular nerve allografts processed identically to commercially available human acellular nerve allograft (AxoGen, Inc., Alachua, FL) or isograft. Half of the allograft group was supercharged with a reverse end-to-side transfer from the ipsilateral peroneal nerve. At 10 weeks, the reconstructed nerve in the Thy1-green fluorescent rat groups were exposed and examined under a fluorescence-enabled microscope. At 20 weeks, the remaining rats underwent motor testing and tissue harvest for morphological examination. RESULTS: In comparison with a nonenhanced allograft, supercharging had a statistically significant positive impact on the reinnervated muscle normalized force generation and distal axon counts for all graft sizes. Muscles in the supercharged group were heavier than those in the allograft group for the 40-mm-length grafts and G-ratio measurements were higher in the supercharged allograft group for 60-mm-length grafts only. CONCLUSIONS: This study supports that hypothesis that supercharging nerve transfer improves axon regeneration within PNA. CLINICAL RELEVANCE: When an appropriate donor nerve is available, supercharging nerve transfer may improve nerve regeneration in PNA across long nerve defects.

Active Range of Motion Over Time in Patients With Obstetrical Brachial Plexus Palsy: A 10-Year Analysis.

PURPOSE: In our experience, and from the personal report of others, children with obstetrical brachial plexus palsy appear to lose some of their initially recovered active range of motion over the time in both operated and nonsurgical patients. This study investigates whether such a diminution of active movement occurs over time. METHODS: We performed a retrospective analysis of data from our obstetrical brachial plexus clinic. Between 1991 and 2000, 139 patients with a minimum follow-up of 10 years were included in the study. Patients were divided into a nonsurgical group (n = 42) and a group who underwent either primary or secondary brachial plexus reconstruction or both (n = 97). Fifteen joint movements were assessed at 2, 4 to 6, and 9 to 11 years of age and at later final follow-up using the Active Movement Scale. Repeated measures analysis using age at each visit as the repeated measures covariate was undertaken. RESULTS: Active movement scores were not diminished when patients were evaluated at the 10-year follow-up visit. CONCLUSIONS: The suggested loss of active range of motion over time is not demonstrated at 10-year follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III.

ErbB2 blockade with Herceptin (trastuzumab) enhances peripheral nerve regeneration after repair of acute or chronic peripheral nerve injury.

OBJECTIVE: Attenuation of the growth supportive environment within the distal nerve stump after delayed peripheral nerve repair profoundly limits nerve regeneration. Levels of the potent Schwann cell mitogen neuregulin and its receptor ErbB2 decline during this period, but the regenerative impact of this change is not completely understood. Herein, the ErbB2 receptor pathway is inhibited with the selective monoclonal antibody Herceptin (trastuzumab) to determine its significance in regulating acute and chronic regeneration in a rat hindlimb. METHODS: The common peroneal nerve of Sprague-Dawley rats was transected and repaired immediately or after 4 months of chronic denervation, followed by administration of Herceptin or saline solution. Regenerated motor and sensory neurons were counted using a retrograde tracer 1, 2, or 4, weeks after repair. Distal myelinated axon outgrowth after 4 weeks was quantified using histomorphometry. Immunofluorescent imaging was used to evaluate Schwann cell proliferation and epidermal growth factor receptor (EGFR) activation in the regenerating nerves. RESULTS: Herceptin administration increased the rate of motor and sensory neuron regeneration and the number of proliferating Schwann cells in the distal stump after the first week. Herceptin also increased the number of myelinated axons that regenerated 4 weeks after immediate and delayed repair. Reduced EGFR activation was observed using immunofluorescent imaging. INTERPRETATION: Inhibition of the ErbB2 receptor with Herceptin unexpectedly enhances nerve regeneration after acute and delayed nerve repair. This finding raises the possibility of using targeted molecular therapies to improve outcomes of peripheral nerve injuries. The mechanism may involve a novel inhibitory association between ErbB2 and EGFR. Ann Neurol 2016;80:112-126.

MRI of thoracic outlet syndrome in children.

Thoracic outlet syndrome is caused by compression of the neurovascular bundle as it passes from the upper thorax to the axilla. The neurovascular bundle can be compressed by bony structures such as the first rib, cervical ribs or bone tubercles, or from soft-tissue abnormalities like a fibrous band, muscle hypertrophy or space-occupying lesion. Thoracic outlet syndrome commonly affects young adults but can be seen in the pediatric age group, especially in older children. Diagnosis is based on a holistic approach encompassing clinical features, physical examination findings including those triggered by various maneuvers, electromyography, nerve conduction studies and imaging. Imaging is performed to confirm the diagnosis, exclude mimics and classify thoracic outlet syndrome into neurogenic, arterial, venous or mixed causes. MRI and MR angiography are useful in this process. A complete MRI examination for suspected thoracic outlet syndrome should include the assessment of anatomy and any abnormalities using routine sequences, vessel assessment with the arms in adduction by MR angiography and assessment of dynamic compression of vessels with abduction of the arms. The purpose of this paper is to describe the anatomy of the thoracic outlet, causes of thoracic outlet syndrome, the MR imaging techniques used in its diagnosis and the principles of image interpretation.