Scientific Abstract Presentations: Migraine & Peripheral Nerve 2 Sunday, October 29 Sun, Oct 29 2:30-3:30 p.m. CDT

Purpose: Gun violence has increased 25% over five years.1 While current teaching has traditionally advocated for a "watch and wait" approach to ballistic nerve injuries, many patients treated with this paradigm fail to recover distal function and subsequently require tendon and nerve transfers.2,3 Herein, we describe our experience with early exploration in ballistic peripheral nerve injuries.

Methods: A retrospective review was performed for ballistic peripheral nerve injuries since February 2022. Data collection included demographic data, number of gunshot wounds (GSW's), concomitant vascular/orthopedic injury, and peripheral nerve outcomes. Early exploration was defined as exploration within the primary hospitalization. Primary outcome was nerve transection at initial exploration.

Results: Fourteen patients met inclusion criteria. All patients were male with an average age of 29±8.3 years with an average number of 3.6±2.6 GSW's. Of these, 42.9% (N= 6) of patients had a concomitant vascular injury, and 50% (n=7) demonstrated a concomitant fracture. Ten patients (71.4%) underwent early exploration with a mean of 16 days from injury to exploration. Among these, 70% (N=7) demonstrated nerve transection injury requiring reconstruction. Four of these ten patients had injury to a named vessel, three patients had ballistic tracking through a constrained nerve entrapment point, and two patients demonstrated retained bullet fragments on radiography. Four patients had delayed reconstruction necessitating tendon transfers. Time to exploration in these delayed patients was 258 days with lack of demonstrable neural recovery.

Conclusions:
With an understanding of the temporal window in which to reinnervate muscle, early exploration of ballistic peripheral nerve injuries allows for early detection of transected nerves and their prompt reconstruction. The "watch and wait" approach can cost these patients critical time in the reinnervation window. Certain criteria are highly suspicious for nerve transection in ballistic trauma. Patients with transection injury to a named vessel, ballistic tracking through a constrained neural entrapment point, and patients with evidence of projectile fragmentation have a high probability of neural transection injury requiring reconstruction.

1.Gramlich J. What the data says about gun deaths in the US Pew Research Center. February 3, 2022. 2. Mathieu L, Goncalves M, Murison JC, Pfister G, Oberlin C, Belkheyar Z. Ballistic peripheral nerve injuries: basic concepts, controversies, and proposal for a management strategy. European Journal of Trauma and Emergency Surgery. 2022;48(5):3529-39. 3. Hollerman JJ, Fackler M, Coldwell D, Ben-Menachem Y. Gunshot wounds: 1. Bullets, ballistics, and mechanisms of injury. AJR American journal of roentgenology. 1990;155(4):685-90.

Purpose Each year, around 150,000 nontraumatic lower-extremity amputations are performed in the USA. These surgeries are associated with high patient morbidity and decreased quality of life. Recent efforts to improve patient outcomes after amputation prompted the integration of the novel techniques Targeted Muscle Innervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI) into conventional amputation surgery. TMR and RPNI become one of the hot topics in Plastic Surgery. In this study, we analyzed the publication and authorship trends of TMR/RPNI bibliometrically. Materials and Methods A systematic search of the PubMed/Medline database was conducted, which identified 1030 articles (868 TMR and 162 RPNI). The Journal Citation Reports - Web of Science Group – Clarivate tool, gender API, and Researchgate were utilized to determine the journal Impact Factors, author genders, and the number of citations, respectively. Results One hundred seventy-four articles were included in the final analysis. As TMR was introduced to the field a decade earlier (2004 vs 2014), more than 2/3rd of the articles was on TMR. These articles were published in various journals, mainly with a medium Impact Factor (IF). The journals with the highest IFs were Lancet (202.7) for the TMR; Annals of Surgery (13.78) for the RPNI studies. The articles with the highest citations had 838 (TMR) and 98 (RPNI) citations. Gender disparity was observed in the first (TMR 68.8%; RPNI 75%) and senior authorship (86.1%; RPNI 76.9%). Conclusion TMR/RPNI is a relatively novel area of plastic surgery characterized by promising results and constant evolution. TMR/RPNI research has been published in a wide variety of both medical and surgical journals. A substantial number of articles on TMR/RPNI had >100 citations.
The first few years of the TMR/RPNI research are characterized by publications exclusively by the original group describing the technique, including those in journals with the two highest impact factors. The introduction of the RPNI overlapped with the start of the second TMR period, in which the first publications by the other USA and international institutions were noted. This study also highlights the low number of impactful publications originating from international institutions and the discrepancy between the national and international adoption rates of TMR and RPNI techniques.

Purpose: Targeted Muscle Reinnervation (TMR) is an effective modality in the surgical management of neuropathic pain for amputees. TMR can be performed within 14 days of the amputation (primary TMR) for prevention of neuropathic pain, or secondarily (> 14 days post-op) for treatment of neuropathic pain (1-3). Patients may experience significant pain relief, and cases of remission or complete absence of pain have been reported. However, it is not known when pain relief is achieved and which patients benefit the most from this technique.

Methods: We examined the charts of 218 patients who underwent TMR at the Massachusetts General Hospital between 2017 and 2023. Demographic, epidemiological, and surgery-related data was collected and analyzed. Longitudinal data of pain scores collected with a 0-10 numerical pain scale were used to assess the postoperative pain course and factors associated with effective pain remission and prevention. Locally weighted scatterplot smoothing (LOWESS) curves were utilized to visualize postoperative pain courses.

Results: A total of 100 patients were included in the final analysis. Compared to Secondary TMR patients, primary TMR Patients (n = 47) reported lower pain scores, pain intensity, and pain interference up to 12 months post-op, with a statistically significant difference in pain levels at 3 and 6 months (p<0.05). Sustainable pain remission/prevention (pain level of 3/10 or lower for >3 months up until the last follow-up) was achieved for 52.3% of primary and 18.9% of secondary TMR patients. For primary TMR patients, 19.1% reported complete pain disappearance (NRS = 0 for more than 3 months until the last follow-up). This occurred in 1.9% of secondary TMR patients. Primary TMR patients have significantly higher odds (OR=4.89; 95% CI 1.84-13.37. p=0. 0003) of achieving sustained mild pain, than secondary TMR patients. Effective pain prevention in primary TMR patients was correlated with an absent history of psychiatric comorbidities and depression. In secondary TMR patients, higher BMI, distal amputation levels, lower preoperative pain interference scores, and absence of psychiatric diseases were significantly associated with sustainable pain remission.

Conclusions: Patients undergoing primary TMR report lower pain scores overall and demonstrate a higher percentage of patients achieving optimal outcomes. Psychiatric comorbidities appear to be a risk factor for worse outcomes in both groups and we associate further epidemiological characteristics to an increased likelihood of successful outcomes in secondary TMR patients.

References 1. Kuiken TA, Barlow AK, Hargrove LJ, Dumanian GA. Targeted muscle reinnervation for the upper and lower extremity. Tech Orthop. 2017;32(2):109-116. 2. Dumanian GA, Potter BK, Mioton LM, et al. Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial. Ann Surg. 2019;270(2):238-246. 3. O'Brien AL, Jordan SW, West JM, Mioton LM, Dumanian GA, Valerio IL. Targeted Muscle Reinnervation at the Time of Upper-Extremity Amputation for the Treatment of Pain Severity and Symptoms. J Hand Surg Am. 2021;46(1):72.e1-72.e10.

Hypothesis: The relationship between nerve regeneration and osseous growth has been described previously(1-3). During treatment of surgical neuroma in below-knee amputees, we have noticed that heterotopic ossification (HO) depicted on preoperative X-ray appears to correlate with the location of symptomatic neuromas in both the peroneal (fibula) and tibial (tibia) nerve distributions.

Methods: A retrospective review of amputees enrolled in a prospective repository between 2018 and 2023, treated with neuroma excision and Targeted Muscle Reinnervation (TMR) for neuropathic pain, was performed. Patients were included if a pre-operative X-ray of the stump was obtained and a pre-operative pain score within three months was reported. X-rays were assessed for the presence of heterotopic ossification (HO), location, and severity. HO was classified as the presence or absence of HO on the distal fibula and tibia. The presence of tibial and/or peroneal neuroma was collected by chart review. Pre-operative pain scores on a 0-10 Numeric Rating Scale (NRS) were included.

Results: Sixty-two limbs of 59 amputees were included in this study, with 24 (38.8%) female patients and 38 (61.2%) having HO on X-ray. The median X-ray-to-surgery interval was 3.0 (IQR 2.0-5.0) months, and the median pain score-to-surgery interval was 0 (IQR 0-0.7) months. The overall presence of HO, distal fibular HO, and distal tibial HO correlated with higher pain, compared to the absence of HO on X-ray (all P< 0.01) (Figure 1A). Identifying peroneal neuroma with distal fibular HO showed significantly higher pain than those without HO (6.7±2.0 vs. 5.0±2.6, P= 0.03); this was also the case for presence of tibial neuroma with distal tibial HO (6.6±1.8 vs. 3.8±3.1, P< 0.01) (Figure 1B). The presence of distal fibular HO correlated with presence of a peroneal neuroma (X2= 9.1, df= 1, N=62, P< 0.01), and shows significantly higher odds of having a symptomatic peroneal neuroma (OR, 9.1; 95% CI [1.9-44.7], P< 0.01). However, the presence of distal tibial HO did not correlate with the presence of a tibial neuroma (X2= 3.9, df= 1, N=62, P= 0.09) (Figure 2).

Conclusion: In below-knee amputees undergoing neuroma excision and TMR, identifying HO on X-ray correlates with higher preoperative pain. Identifying distal fibular HO on pre-operative X-rays indicates presence of a symptomatic peroneal neuroma, while no correlation between symptomatic tibial neuroma and the presence of tibial HO was shown. These findings may assist in intraoperative decision-making on which nerves to address in neuroma surgery and inform the biology of neuroma formation and development.

References: 1. Lee S, Hwang C, Marini S, et al. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun. 2021;12(1). 2. Minarelli J, Davis EL, Dickerson A, et al. Characterization of neuromas in peripheral nerves and their effects on heterotopic bone formation. Mol Pain. 2019;15. 3. Qin Q, Gomez-Salazar M, Cherief M, et al. Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma. Bone Res. 2022;10(1).

Purpose: Chronic compression neuropathies are characterized by demyelination, impaired nerve conduction speed (NCS), and muscle loss. Previous studies have established a murine model of CNC, however they did not investigate changes to the muscle.1 We aim to validate a mouse model of muscle loss in CNC, and to determine the mechanism and timing of muscle and nerve related changes.

Methods: CNC was induced by placing a silastic tube around the sciatic nerve with the contralateral limb as control. At 6, 8, 12, and 16 weeks, NCS was assessed, and the sciatic nerve, tibialis anterior (TA), and extensor digitorum longus (EDL) were harvested bilaterally. Muscle weight and fiber size, and nerve myelin thickness and axon diameter were measured. RT-PCR of TA and EDL muscle tissue was also performed. Genes assayed included atrogenes Foxo-3, atrogin-1, and MuRF1, markers of myogenesis, myoD and myogenin (MyoG), fatty-acid synthase (FAS), type-I collagen (Col1a1), and inflammatory markers TNF-alpha and IL-1beta.

Results: We observed a progressive decline in NCS that peaked at 16 weeks with a 23% decline compared to control. At 16 weeks, we also observed a 31.7% increase in g-ratio indicating demyelination and 37.7% decline in axon density suggesting axon loss.

At 6 weeks, we observed a maximum 18.5% decline in TA+EDL muscle weight. Muscle fiber cross-sectional area was reduced 15.3% in the non-oxidative TA composed of large type IIB fibers, and elevated 9.0% in the EDL composed of smaller type IIA, IIB, and IIX fibers at 16 weeks. In addition, at 16 weeks, atrogene expression was increased 1.4–1.7x implying ongoing atrophy. MyoD and MyoG expression was reduced 0.5x, FAS expression was increased 1.5x, Col1a1 expression was increased 1.5x, and inflammatory marker expression was increased >2x. All findings were significant at p<0.05.

Conclusions: The murine model of CNC demonstrates progressive muscle loss that correlates with slower NCS, demyelination, and reduced axon density. Gene expression of markers of atrophy, fatty acid synthesis, inflammation, and fibrosis were elevated, while markers of myogenesis were reduced. Ongoing studies will further define muscle changes with time including fatty replacement, atrophy, and fibrosis. Together, these findings validate a murine model of muscle loss in CNC.

Citations: 1. Gupta R, Nassiri N, Hazel A, Bathen M, Mozaffar T. Chronic nerve compression alters schwann cell myelin architecture in a murine model. Muscle Nerve. 2012;45(2):231-241. doi:10.1002/mus.22276

Purpose:

Neuropathic pain is characterized by intricate interactions between peripheral and central nervous system mechanisms, including peripheral sensitization, central sensitization, and neuroinflammation. Calcitonin gene-related peptide (CGRP) plays a crucial role in these processes and has been found to be upregulated in neuropathic pain in both animal models and patients. With the established safety profile and regulatory approval of CGRP therapeutics for indications such as migraine, cluster headaches, and trigeminal neuralgia, we have a favorable opportunity to leverage these agents for a novel indication–neuropathic pain. However, despite the potential, there is currently no consensus on the effectiveness of CGRP therapeutics for neuropathic pain in animal studies. This systematic review and meta-analysis aim to comprehensively evaluate the existing data and consolidate evidence on the effectiveness of CGRP antagonists and monoclonal antibodies as a potential treatment for neuropathic pain.

Methods:

The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted in four electronic bibliographic databases (MEDLINE, EMBASE, Web of Science, and Scopus) to identify English-language animal studies published from 1980-2022 that evaluated the effectiveness of CGRP antagonists or monoclonal antibodies in treating neuropathic pain. Out of 3705 articles initially identified, 2001 duplicates were removed, and 1704 articles were screened based on their titles and abstracts. After full-text assessment of 172 articles, 23 studies were included in the final meta-analysis. Statistical analysis was performed using R software version 4.2.2. The MBESS package in R was employed to transform withdrawal thresholds measured in grams for mechanical allodynia and in seconds for thermal hypersensitivity into standardized mean differences (SMD). The meta package (version 4.9-6) with the metagen function was used to combine the studies into a pooled estimate of SMD. We performed separate meta-analyses for mechanical allodynia and thermal hypersensitivity outcomes, using random-effects inverse variance meta-analysis methods and assessed between-study heterogeneity using the I2 index.

Results:

The overall SMD for mechanical allodynia in the 11 studies was -5.30 (95% CI [-6.65, -3.96]), indicating a significant reduction in mechanical allodynia with CGRP therapeutics compared to controls. For thermal hypersensitivity, the overall SMD was -2.28 (95% CI [-6.65, -3.96]), indicating a significant reduction in thermal hypersensitivity after CGRP therapeutic administration. Both outcomes exhibited high heterogeneity, with I2 values of 84.5% and 89.1%, respectively that may be attributed to differences in study design, type of animal, and model of neuropathic pain used.

Conclusion:

These results indicate a statistically significant effect in favor of CGRP therapeutics as a potential treatment for neuropathic pain. However, the significant heterogeneity among the studies should be taken into consideration when interpreting the overall effect and further evaluation is needed to explore sources of heterogeneity. Nonetheless, given the established safety profile and regulatory approval of CGRP therapeutics for other indications, the results of this study provide an impetus for the development of clinical trials to evaluate the effectiveness of CGRP antagonists and monoclonal antibodies for neuropathic pain.

Background: Reconstruction of nerve injuries using nerve allograft still results in inferior regeneration and motor outcomes to the nerve autograft. Nerve regeneration can be enhanced by modulating the local microenvironment of the nerve reconstruction site. The aim of this study was to investigate the combined effect of local delivery of Purified Exosome Product (PEP), mesenchymal stem cells (MSCs) and Tacrolimus (FK506) alone and combined on nerve regeneration.

Methods: A three-dimensional in vitro compartmented cell culture system was used to evaluate regenerating neurites from a rat neonatal dorsal root ganglion into the adjacent nerve. Decellularized allografts were augmented with local application of (i) MSCs, (ii) PEP (5%), (iii) FK506 (100 ng/mL), (iv) combined PEP and FK506, and (v) combined MSC and FK506 (N=9/group). Outcomes were compared to untreated autografts and allografts. After 48 hours, constructs were stained against Neurofilament-160 to measure neurite extension as a measure of nerve regeneration, and CD90-DAPI to confirm stem cell characterization.

Results: Stem cell viability was confirmed in all MSC-treated grafts using CD90-DAPI staining. Treatment with PEP, PEP and FK506, and MSCs and FK506 significantly improved outcomes of untreated allografts (p<0.0001, p<0.0001, p<0.001) and were found comparable to the untreated autograft (p>0.99, p>0.99, 0.99). Combined treatments of PEP and FK506 and MSCs and FK506 were found comparable (p>0.99). Combined MSCs and FK506 treatment was found superior to MSCs alone (p<0.02).

Conclusion: PEP treatment alone, PEP combined with FK506 and MSCs combined with FK506 resulted in a significant neurite extension, and was found comparable to the current gold standard, the autograft. These results suggest that the neuroregenerative effect of PEP is similar to MSCs. PEP could overcome the limitations of harvesting, culturing and seeding of stem cells, making this more translatable to clinical care. In vivo animal models are needed to further investigate the effect of PEP alone and combined with FK506 in nerve regeneration.

Purpose: Acute flaccid myelitis (AFM) is a polio-like illness largely affecting children that leads to weakness or paralysis of one or more limbs. To date, AFM has affected an estimated 701 patients in the United States. AFM is rare, but the effects are life-altering. Nerve surgeons can offer interventions in the form of nerve transfers or decompressions largely dependent on the time and symptoms at which a patient presents. To overcome gaps in referral patterns, the AFM community has created a social media network to exchange resources and experiences among patients and families. The overarching goal of this study was to understand the gaps in care as perceived by caregiver experience and to collate our substantial clinical experience to establish a management framework for healthcare providers and families affected by AFM.

Materials and Methods A retrospective chart review was conducted of patients who presented to the senior author's peripheral nerve clinic with the diagnosis of AFM made between 2014 to 2020. Demographic data and outcomes were reviewed. To understand the influence of social media on patient and family experience, an anonymous survey was distributed via Qualtrics to the "AFM Facebook group" from April through June 2022. The survey consisted of 17 questions.

Results Thirty-one patients diagnosed with AFM were identified (average age of 5.6 years ± SD ). Among this cohort, 9.7% presented to nerve clinic within 6 months, 48.4% presented between 6-12 months, and 41.9% presented after 12 months from diagnosis. Twenty-three patients underwent surgical intervention to improve function and/or pain. Intervention included nerve transfers and/or nerve decompressions at an average time from onset to nerve surgery of 11.7 ± 4.5 months (average ± SD). Based on our clinical experience, a treatment algorithm was developed to provide guidelines for multidisciplinary care (Figure 1).

Our distributed survey yielded 91 responses. Sixty percent of respondents found the social media platform via an internet search and 74% did so within the six months from AFM diagnosis. Social media was found to aid in the parents' medical decision making (73%), lead to a self-referral (59%) and to an intervention for 51 patients (56%). Family members quit working to become the primary caregiver in 45% of cases. More than half of patients traveled out of state for the medical care, including rehabilitation (40%).

Conclusions

AFM is a rare illness with a natural history that can have life-altering long-term effects on patients and caregivers alike. Social media provides a platform for those affected to find support, gather information, and advocate to improve their child's medical care. As healthcare providers, it is imperative that we combine our clinical experience caring for AFM patients with the information provided by AFM families to improve care for new patients. Our proposed treatment algorithm seeks to provide the necessary guidelines to treat AFM patients in a timely fashion in order to improve outcomes.