Focal periphyseal edema (FOPE) revisited: does injury severity predict presence and frequency of FOPE lesions?

Focal periphyseal edema (FOPE) revisited: does injury severity predict presence and frequency of FOPE lesions? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Focal periphyseal edema (FOPE) revisited: does injury severity predict presence and frequency of FOPE lesions? Alexandra Bishop, Pritish Bawa, Nele Haelterman, Andrew C. Sher, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6917148/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Focal periphyseal edema (FOPE) is a MRI finding identified in long bones in children nearing skeletal maturity. Existing literature is conflicting, with the majority suggesting that FOPEs are potential pain generators related to supraphysiologic sporting activities and some reports suggesting that FOPE’s represent normal physiologic physeal maturation. Objective The purpose of this study is to investigate the incidence of knee FOPE lesions in adolescent boys with ACL tears compared with a negative cohort. Materials and methods 104 knee MRI’s with ACL tears and 108 normal knee MRI records between the ages of 12 to 15 were identified from a major children’s hospital. These MRIs were then randomized and reviewed in consensus by two pediatric MSK radiologists for location and number of FOPE lesions in the proximal tibia and distal femur. Results There is no statistical difference between the presence of FOPE in the ACL tear cohort compared with our negative control (40% vs 41%) ( p = 0.913). When comparing the location of lesions in the proximal tibia vs the distal femur between ACL tear group and control group, there is no statistical difference ( p = 0.906). A transphyseal vessel was identified in 47% of all FOPE lesions, independent of ACL tear status. Conclusion The results of this study reinforce the idea that FOPE is a frequent incidental finding in adolescent knee MRIs, irrespective of predisposing supraphysiologic activity. Our findings question previous reports that suggest FOPE lesions are associated with supraphysiologic stress. FOPE lesions are frequently associated with transphyseal vessels. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction First described in 2011 by Zbojniewicz and Laor [1], focal periphyseal edema (FOPE) is an MRI finding identified in long bones near major joints like the knee or shoulder in children nearing skeletal maturity. On MRI, FOPE lesions appear as focal bone marrow edema-like signal centered around a closing physis. Current literature, mainly comprised of descriptive retrospective case-series, controversially postulates that FOPE lesions identified by MRI are related to supraphysiologic stress to a closing physis and may be a potential pain generator [2, 3]. Closure of the physis of long bones begins centrally with mineralized bridging between the metaphysis and epiphysis and involves transphyseal neovascularization and eventual endochondral ossification [4]. It is postulated that the central portion of the closing physis of long bones has increased susceptibility to trauma due to decreased elasticity compared with the periphery of the physis which remains relatively patent [1]. FOPE would then represent a transient response to the mechanical stress and redistribution of forces occurring during physeal closure, exacerbated by high-impact activity such as running or jumping in sports [5]. However, the observation that FOPE has been documented in non-weight-bearing sites, such as the greater trochanter of the hip and the humerus, suggests that weightbearing stressors may not be the sole contributing factor​ [6]. The purpose of this study is to epidemiologically determine the frequency and number of FOPE lesions present in adolescent boys with MRI evidence of ACL tears compared with normal knee MRIs. The hypothesis is that the number of FOPE lesions may occur with higher frequency in children who are predisposed to ACL tears due to increased supraphysiologic activity compared with those children who are referred for knee MRIs that are normal. Materials and Methods The present study was approved by our institutional review under exempt status and was performed in compliance with HIPAA. This was a retrospective cohort study comprised of male adolescents aged 12–15 years with confirmed ACL tear on MRI compared with a negative control cohort comprised of normal knee MRIs based on the official radiology report. Only male patients were included to reduce possible gender bias. Ages 12–15 years were selected based on previous findings from Zbojniewicz and Laor [1], citing these ages as within the range for highest incidence of FOPE lesions. Identification of patients in ACL Tear cohort A retrospective consensus review was conducted by electronic medical record keyword search in Picture Archiving and Communication System (PACS) at a tertiary-care pediatric hospital. The search was conducted using keyword “ACL tear,” yielding 11,934 MRI reports. The results of that provisional search query were filtered for reports of the knee in patients aged 12–15 years and male gender, leaving 865 remaining studies. The subsequent MRI radiology reports were sorted in reverse chronological order and manually filtered for true ACL tears. The first 110 studies fitting these criteria were added to the initial study cohort. All patients in the ACL tear cohort had surgically confirmed ACL tears that were reconstructed. 6 studies were removed from consideration during review of MRI imaging due to technical issues (n = 5) or human error (n = 1) during data collection, such as discrepancy between MRN listed in study cohort pool and MRN listed on MRI study. This resulted in 104 studies evaluated as part of the test cohort (Fig. 1 ). Identification of patients in negative control cohort When identifying the negative control cohort, an electronic medical record keyword search in Picture Archiving and Communication System (PACS) at a tertiary-care pediatric hospital was conducted. Key words “normal exam” and “negative exam” were used, yielding 25,523 MRI reports. The results of that were filtered for reports of the knee in patients aged 12–15 years and of male gender, leaving 3,804 remaining studies. The subsequent MRI radiology reports were sorted in reverse chronological order and manually filtered for exams read as completely normal or negative, with no incidental findings. The first 110 studies fitting these criteria were added to the initial control cohort. 3 studies were removed from consideration during review of MRI imaging due to human error during data collection, such as discrepancy between MRN listed in study cohort pool and MRN listed on MRI study. This resulted in 107 studies evaluated as part of the control cohort. Review of MRI Examination To reduce observer bias, MRI reports from ACL tear and control groups were combined into one list and sorted based on date. The T2 FS sagittal and PD FS coronal sequences from the knee MRI exam were then reviewed in consensus by one subspecialty trained pediatric musculoskeletal radiologist (XXX) with 19 years of experience and one subspecialty trained musculoskeletal radiologist (XXX) with 8 years of experience. The review involved identifying location and number of FOPE lesions in the proximal tibia and distal femur. FOPE lesions were defined as focal edema centered at the physis of the distal femur or proximal tibia, extending into both the adjacent juxtaphyseal metaphysis and epiphysis (Figs. 2 , 3 ) [1], excluding residual red marrow and cartilaginous tongues related to prior trauma. Additionally, focal transphyseal edema related to obvious traumatic bone contusions was excluded. Presence of FOPE lesion, number of FOPE lesion, and location (central, medial, lateral, anterior, posterior) of FOPE lesion were recorded. Identification of Transphyseal Vessels at FOPE Lesions The 86 patients determined to have FOPE lesions, both in the study and control cohorts, were sorted by reverse chronological order and given an anonymous, HIPAA compliant identifier. These MRIs were reviewed for transphyseal vessels by a medical student under direct supervision of an attending pediatric musculoskeletal radiologist (XXX). The vessel needed to be vertically oriented and extending to the physis at the level of the FOPE, suggestive of the natural growth of vessels during physis closure (Fig. 3 ) [4]. This is distinct from patients with longitudinally oriented vessels without FOPE (Fig. 4 ). From this list identified by the medical student, every 5th patient was selected to be audited by a pediatric MSK radiologist. 17 total studies were selected, allowing for an audit of 20% of the evaluated patients. Within this audit of 17 patients, there were 28 FOPE lesions that needed verification by the pediatric MSK radiologist. The read of 26 (93%) lesions was agreed upon by the medical student and radiologist and the read of 2 (7%) lesions was corrected by the pediatric MSK radiologist. Statistical Analysis All analysis was conducted using IBM SPSS Statistics (version 26). Statistical analyses were performed with two-tailed p < .05 considered to denote statistical significance. All findings are categorical and presented as counts and percentages. Chi square analysis was conducted to determine significance between presence or absence of FOPE lesion in the test vs control groups, location of FOPE lesions in proximal tibia vs distal femur for test vs control, and number of FOPE lesions per patient when FOPE was identified. When considering laterality of location between distal femur central/medial/lateral vs proximal tibia central/medial/lateral, fisher’s exact test was used. Cohen's kappa was utilized to determine inter-reader agreement on the presence or absence of FOPE lesions. Results Table 1 summarizes the distribution of MRI findings when comparing the ACL tear group and the control group. 40% (n = 42) of patients in the ACL tear group were positive for FOPE lesions and 41% (n = 44) of patients in the control group were positive for FOPE lesions. There was no statistical difference between these two groups ( p = 0.913). The number of FOPE lesions per patient was compared between ACL tear group and control group. The number of lesions ranged from 1–5 per patient in which a FOPE was identified. This comparison is also not statistically significant ( p = 0.480). The total number of FOPE lesions present in the ACL tear group was 69 (49% of total FOPE lesions) and the total number of FOPE lesions present in the control group was 71 (51% of total FOPE lesions). When comparing location of FOPE lesion in the proximal tibia vs the distal femur between ACL tear group and control group, there is no statistical difference ( p = 0.906). Location was then further subdivided by laterality, looking at the medial, lateral and central proximal tibia and distal femur. No statistical difference was found based on laterality of lesion location ( p = 0.910). Table 1 MRI Findings for Patients With Anterior Cruciate Ligament–Deficient Knees and With Normal Exams Finding Patients with ACL Tears on MRI (n = 104) Patients with Normal MRI (n = 107) p Positive FOPE Lesion 42 (40%) 44 (41%) p = 0.913 Negative FOPE Lesion 62 (59%) 63 (59%) Number of FOPE Lesions when identified per patient p = 0.480 1 26 (62%) 27 (61%) 2 7 (17%) 11 (25%) 3 7 (17%) 3 (7%) 4 2 (5%) 2 (5%) 5 0 (0%) 1 (2%) Total Number of FOPE Lesions Identified 69 (49%) 71 (51%) Average number of FOPE lesions when present 1.64 1.58 p = 0.768 Location p = 0.906 Proximal Tibia 46 (33%) 48 (34%) Distal Femur 23 (16%) 23 (16%) Location – Detailed p = 0.910 Proximal Tibia Medial 7 (5%) 6 (4%) Proximal Tibia Lateral 18 (13%) 21 (15%) Proximal Tibia Central 21 (15%) 21 (15%) Distal Femur Medial 1 (0.7%) 3 (2%) Distal Femur Lateral 9 (6%) 10 (7%) Distal Femur Central 13 (9%) 10 (7%) Inter-reader variability was assessed. When evaluating combined control and test group reads, there was initial discrepancy in 49 (23%) of the total 211 evaluated MRIs in identification of FOPE lesion. Cohen's kappa demonstrated substantial inter-reader agreement on the identification of FOPE lesions, with k = .684 (95% CI, .584 to .784). Consensus was reached to produce the final report data (Table 1 ). The presence of transphyseal vessels extending directly into a FOPE lesion was identified. For the 86 knees determined to have FOPE lesions, a total of 140 FOPE lesions were identified. Of these 140 FOPEs, 66 (47%) of FOPE's were associated with a transphyseal vessel identified on a fluid sensitive sequence (Fig. 3 ). Discussion The findings of this study indicate that the presence and distribution of focal periphyseal edema (FOPE) lesions do not significantly differ between patients with anterior cruciate ligament tears and negative control subjects, occurring equally in about 40% of the entire study population. The results of this study reinforce the idea that FOPE lesions are a frequent, incidental finding in adolescent knee MRIs, irrespective of predisposing supraphysiologic activity that may or may not predispose a child to an ACL tear. Their presence, number, and anatomical distribution are independent of ACL injury status, supporting the idea that FOPE represents a benign, physiological phenomenon rather than a direct marker of knee pathology. These findings question previous studies suggesting FOPE lesions are associated with supraphysiologic activity [2, 3]. The physes are responsible for longitudinal appendicular bone growth through the process of endochondral ossification in which a cartilage model, generated by columns of dividing chondrocytes is replaced by bone through a process that involves invasion of osteoblasts and blood vessels from the metaphysis [7]. Upon dividing along longitudinal columns, chondrocytes undergo hypertrophy, during which they rapidly increase in size and secrete proteins and vesicles that alter the molecular makeup of the surrounding extracellular matrix. These hypertrophic chondrocytes also secrete peptides that recruit blood vessels, osteoblasts, and osteoclasts[4]. One such peptide is vascular endothelial growth factor (VEGF), which stimulates the ingrowth of blood vessels that carry osteoprogenitors through a process called osteoblast angiotropism (Fig. 5 ) [8]. Subsequently, towards the final rows of the hypertrophic zones, hypertrophic chondrocytes undergo rapid cell death while invaded [9] osteoclasts resorb the calcified cartilage matrix and osteoblasts deposit new bone matrix on the remnants of the cartilage [10]. Throughout childhood, physeal thickness remains relatively constant due to an intricate balance between chondrocyte proliferation and cell death [11]. In addition, it retains an overall undulated appearance due to interactions with physiologic dynamic biomechanical forces [11]. The process of normal distal femoral and proximal tibial physeal closure relies on endochondral ossification, and involves a similar series of well-coordinated biological events towards the end of puberty marking the end of longitudinal bone growth [10]. This process is tightly controlled by regulated hormones, such as estrogen, and typically occurs between the ages of 14 and 18 years, with females often experiencing physeal closure earlier than males [12]. Physeal closure starts when its chondrocytes enter senescence, which reduces their proliferative capacity and causes a gradual decrease in physeal height [9, 10]. Vascular endothelial cells are the first cell types found to invade the growth plate, prior to osteoblasts and osteoclasts. Similar to the process described above, it is thought that the vascular endothelial cells that invade the physis directly interact with osteoblasts, carrying them into the growth plate to initiate the ossification process [8]. Hence, vascular invasion is crucial for bringing in osteoprogenitor cells that replace the calcified cartilage with bone tissue, completing the ossification process [10, 13]. At this point, the ossification front grows faster than the rate at which growth plate chondrocytes replace themselves, initiating bony fusions to form across the growth plate [10]. Interestingly, the molecular and cellular process of physeal closure is conserved across species. Indeed, physeal senescence is associated with transphyseal blood vessel formation resulting in epiphyseal fusion in most mammals [14, 15]. In the distal femur and proximal tibia, the physeal ossification process progresses from the central region of the growth plate outward, ensuring uniform closure and preventing angular deformities [16]). Reported in Zbojniewicz and Laor [1] along with proceeding case studies [17], FOPE lesions were most frequently observed at the center of the tibial or femoral physis. With initial ossification occurring in the central physis, it has been suggested that decreased elasticity of the ossified central physis compared to the periphery, combined with microtrauma, results in FOPE lesions. However, our data shows no significant difference in the anatomical distribution of FOPE lesions at the physis, comparing medial, lateral or central location. This suggests that microtrauma on the central portion of a partially closed physis may not entirely explain the etiology of FOPE lesions. When considering the crucial step that neovascularization plays in the process of endochondral ossification, our data suggests that FOPE lesions may be the result of transient inflammatory responses that manifest as bone marrow edema on MRI (Fig. 4 ). While this vascular hypothesis remains speculative, it may help explain why FOPE lesions are sometimes seen in asymptomatic patients, are associated with longitudinally oriented transphyseal vessels (Fig. 3 ), and why its resolution typically occurs without intervention​. Case studies and series published between 2015 and 2023 [2, 3, 6, 17–19] highlight individual cases in which FOPE zones occurred in different joints during the process of physeal closure in adolescents often experiencing joint pain, often in athletes. Our results do not support the conclusion that FOPE zones are pain generators but instead present in about 40% of our negative cohort study population, despite investigated risk factors. Notably, a case report by Giles, et al. [12] studying 4 patients found to have FOPE lesions on MRI concluded that FOPE-associated knee pain may not be clinically benign, with negative effects on the function and well-being of affected adolescents. Despite this, they suggest FOPE is likely a normal variant of physiologic physeal closure that does not warrant clinical management or surgical intervention. Our results support the conclusion that FOPE does not warrant clinical management or surgical intervention. A cross-sectional study by Fröhlich, et al. [5], investigated the prevalence of knee pain and MRI abnormalities in 108 young competitive alpine skiers between the ages of 13–15 years. The study found that a significant proportion of these athletes experienced overuse-related knee complaints, including FOPE zones in 25% of subjects. This study lacks a control to compare FOPE occurrence in alpine skiers to individuals not participating in knee overuse. The decision to include FOPE as an overuse injury presumably was based on preceding literature. Our results support their findings in that a significant portion of their population would have FOPE lesions, but our results do not support that this would be an over-use injury opposed to a normal physiologic changes to a normal physis. Our study confirms previous findings that FOPEs are typically found at the site of earliest physeal closure. We hypothesize that FOPEs originate from accidental rupture of the transphyseal blood vessels that mediate physeal closure. Several factors may contribute to blood vessel rupture at this site. For example, the corrugated structure of the closing physis likely alters the biomechanical forces on neighboring tissues. Combined with elevated shear stress in the immature blood vessels migrating into the physis [8], altered biomechanical stress in the closing growth plate would then increase the likelihood of ingrowing vessel rupture. This hypothesis is supported by the fact that FOPEs are typically observed in vicinity to the corrugated area of the physis (Figs. 3 , 5 ). However, our results suggest that supraphysiological stress, induced by exercise for example, is likely not an important contributor to FOPE development. In sum, our data suggest that FOPEs are physiological consequences of physeal closure. Neovascularization is often accompanied by neo-innervation. For example, in the case of osteoarthritis, pain-sensing nociceptive neurons are known to increasingly innervate the synovium and subchondral bone of patients and mouse models of OA, and are thought to be correlated with pain [20–22]. Similarly, the blood vessels that initiate physeal closure may be accompanied by a temporary increase in the innervation of the physeal area of the long bone, which may be responsible for the (typically transient) joint pain these patients experience. One of the significant limitations of this study is that, by nature of study design, retrospective cohort studies can only determine associations between exposures and outcomes. We cannot definitively establish causality. Both cohorts (ACL tear and normal knee MRI cohorts) were referred for symptomatic knee pain which confounds incidence of FOPE lesion incidence and could have been addressed by recruiting asymptomatic children for knee MRI assessment. Additionally, the scope of the study was limited to only include male subjects all from the same hospital system. To further improve generalizability, future studies could investigate female adolescents and expand to other geographic regions. Of note, some MR studies were difficult to call when assessing FOPE lesions due to potential confounders such as large contusions or red marrow edema. Finally, it is not possible to fully exclude cartilaginous rests from transphyseal vessels, but we believe our findings represent the latter since cartilaginous rests related to prior trauma are unlikely to be perfectly uniform and linear. Conclusion FOPEs identified on pediatric knee MRIs are a normal finding in children nearing skeletal maturity and are in part related to transphyseal vascular edema. FOPEs do not appear to be related to activities that predispose children to ACL tears. Reporting FOPEs may generate unnecessary stress to families and to referring physicians and should be discouraged by radiologists. Declarations Author Contribution AB and JHK wrote the manuscript text, with review and contribution from NH. PB assisted with reading MR studies and consensus review. ACS assisted with statistics. Acknowledgement Figure 5 contribution by Alissa Kan References A. M. Zbojniewicz and T. Laor, "Focal Periphyseal Edema (FOPE) Zone on MRI of the Adolescent Knee: A Potentially Painful Manifestation of Physiologic Physeal Fusion?," American Journal of Roentgenology, vol. 197, no. 4, pp. 998-1004, 2011, doi: 10.2214/ajr.10.6243. G. Larid, P. O. Duboe, and E. Gervais, "Shoulder Focal Periphyseal Edema: An Unusual Cause of Shoulder Pain in an Adolescent," (in eng), J Rheumatol, vol. 50, no. 9, p. 1192, Sep 2023, doi: 10.3899/jrheum.221291. J. N. Speirs, T. G. Shields, and M. J. Morrison, 3rd, "Focal Periphyseal Edema: An Uncommon Cause of Adolescent Knee Pain: A Report of Three Cases," (in eng), JBJS Case Connect, vol. 9, no. 3, p. e0391, Jul-Sep 2019, doi: 10.2106/jbjs.Cc.18.00391. E. J. Mackie, Y. A. Ahmed, L. Tatarczuch, K. S. Chen, and M. Mirams, "Endochondral ossification: how cartilage is converted into bone in the developing skeleton," (in eng), Int J Biochem Cell Biol, vol. 40, no. 1, pp. 46-62, 2008, doi: 10.1016/j.biocel.2007.06.009. S. Fröhlich, P. Loris, S. Christoph, O. F. Walter, S. Reto, and S. Jörg, "Remarkably high prevalence of overuse-related knee complaints and MRI abnormalities in youth competitive alpine skiers: a descriptive investigation in 108 athletes aged 13â15 years," BMJ Open Sport & Exercise Medicine, vol. 6, no. 1, p. e000738, 2020, doi: 10.1136/bmjsem-2020-000738. A. Sakamoto and S. Matsuda, "Focal Periphyseal Edema Zone on Magnetic Resonance Imaging in the Greater Trochanter Apophysis: A Case Report," (in eng), J Orthop Case Rep, vol. 7, no. 4, pp. 29-31, Jul-Aug 2017, doi: 10.13107/jocr.2250-0685.836. K. Foster, "Growth Plate (Physeal) Injuries," in Imaging in Pediatric Skeletal Trauma: Techniques and Applications , K. J. Johnson and E. Bache Eds. Berlin, Heidelberg: Springer Berlin Heidelberg, 2008, pp. 147-157. G. Neag, M. Finlay, and A. J. Naylor, "The Cellular Choreography of Osteoblast Angiotropism in Bone Development and Homeostasis," (in eng), Int J Mol Sci, vol. 22, no. 14, Jul 6 2021, doi: 10.3390/ijms22147253. Y. Ağırdil, "The growth plate: a physiologic overview," (in eng), EFORT Open Rev, vol. 5, no. 8, pp. 498-507, Aug 2020, doi: 10.1302/2058-5241.5.190088. E. J. Mackie, L. Tatarczuch, and M. Mirams, "The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification," (in eng), J Endocrinol, vol. 211, no. 2, pp. 109-21, Nov 2011, doi: 10.1530/joe-11-0048. J. C. Nguyen, B. K. Markhardt, A. C. Merrow, and J. R. Dwek, "Imaging of Pediatric Growth Plate Disturbances," (in eng), Radiographics, vol. 37, no. 6, pp. 1791-1812, Oct 2017, doi: 10.1148/rg.2017170029. M. K. Yamamura et al. , "Epidemiology of Physeal Fractures and Clinically Significant Growth Disturbances Affecting the Distal Tibia, Proximal Tibia, and Distal Femur: A Retrospective Cohort Study," (in eng), J Am Acad Orthop Surg, vol. 31, no. 11, pp. e507-e515, Jun 1 2023, doi: 10.5435/jaaos-d-22-00303. Y. Song, D. Lee, C. S. Shin, D. R. Carter, and N. J. Giori, "Physeal cartilage exhibits rapid consolidation and recovery in intact knees that are physiologically loaded," (in eng), J Biomech, vol. 46, no. 9, pp. 1516-23, May 31 2013, doi: 10.1016/j.jbiomech.2013.03.026. H. A. Cole, M. Yuasa, G. Hawley, J. M. Cates, J. S. Nyman, and J. G. Schoenecker, "Differential development of the distal and proximal femoral epiphysis and physis in mice," (in eng), Bone, vol. 52, no. 1, pp. 337-46, Jan 2013, doi: 10.1016/j.bone.2012.10.011. R. W. Haines, "The histology of epiphyseal union in mammals," (in eng), J Anat, vol. 120, no. Pt 1, pp. 1-25, Sep 1975. K. Ecklund and D. Jaramillo, "Patterns of premature physeal arrest: MR imaging of 111 children," (in eng), AJR Am J Roentgenol, vol. 178, no. 4, pp. 967-72, Apr 2002, doi: 10.2214/ajr.178.4.1780967. N. Beckmann and S. Spence, "Unusual Presentations of Focal Periphyseal Edema Zones: A Report of Bilateral Symmetric Presentation and Partial Physeal Closure," (in eng), Case Rep Radiol, vol. 2015, p. 465018, 2015, doi: 10.1155/2015/465018. T. Bochmann, R. Forrester, and J. Smith, "Case report: imaging the clinical course of FOPE-a cause of adolescent knee pain," (in eng), J Surg Case Rep, vol. 2016, no. 11, Nov 24 2016, doi: 10.1093/jscr/rjw178. H. Ueyama, T. Kitano, K. Nakagawa, and M. Aono, "Clinical experiences of focal periphyseal edema zones in adolescent knees: case reports," (in eng), J Pediatr Orthop B, vol. 27, no. 1, pp. 26-30, Jan 2018, doi: 10.1097/bpb.0000000000000388. J. J. McDougall, R. C. Bray, and K. A. Sharkey, "Morphological and immunohistochemical examination of nerves in normal and injured collateral ligaments of rat, rabbit, and human knee joints," (in eng), Anat Rec, vol. 248, no. 1, pp. 29-39, May 1997, doi: 10.1002/(sici)1097-0185(199705)248:13.0.Co;2-a. A. M. Obeidat, R. E. Miller, R. J. Miller, and A. M. Malfait, "The nociceptive innervation of the normal and osteoarthritic mouse knee," (in eng), Osteoarthritis Cartilage, vol. 27, no. 11, pp. 1669-1679, Nov 2019, doi: 10.1016/j.joca.2019.07.012. K. Aso et al. , "Contribution of nerves within osteochondral channels to osteoarthritis knee pain in humans and rats," (in eng), Osteoarthritis Cartilage, vol. 28, no. 9, pp. 1245-1254, Sep 2020, doi: 10.1016/j.joca.2020.05.010. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6917148","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":474853979,"identity":"5c714db6-a416-45c3-811d-5e5a30a33be1","order_by":0,"name":"Alexandra Bishop","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYDACdjDJDMQ8DAcYGxgY+CXgIjgAM7oWyRmkaGEAaTG4QUALfzPzMYmfO6zz+Rt4Dx78ucMmz/h289MNDBXWiQ04tEgcZks27D2TbjnjAF/CYd4zacVmd46Z3WA4k45TC8NhHsMHvG2HDRgO8BgcZmw7nLjtRg7bDRADlxb5w/wfDv4FapEHajn4E6hy8wyQln+4tRgc5mF8DLLFAKjlAJCRuEECpKUBtxbDw2zGxrJt6QaGh0F+aUsrlgD5JeFYujEuLXLHm59Jvm2zNpA73nv44882mzz+2c3PbnyosZbF6X04gEZEAhJJJCBJ8SgYBaNgFIwMAABd81/JipR9BQAAAABJRU5ErkJggg==","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Bishop","suffix":""},{"id":474853980,"identity":"6490ff78-cddf-41e1-a00a-5a313be9a8dc","order_by":1,"name":"Pritish Bawa","email":"","orcid":"","institution":"Texas Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pritish","middleName":"","lastName":"Bawa","suffix":""},{"id":474853982,"identity":"fd2c22fc-0d04-4e56-adbe-61b054504a65","order_by":2,"name":"Nele Haelterman","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nele","middleName":"","lastName":"Haelterman","suffix":""},{"id":474853983,"identity":"b0523821-c451-43b2-a30e-a66b55c9effe","order_by":3,"name":"Andrew C. Sher","email":"","orcid":"","institution":"Texas Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"C.","lastName":"Sher","suffix":""},{"id":474853984,"identity":"702821b0-281b-49cf-be4c-bdb991fb9ebd","order_by":4,"name":"J. Herman Kan","email":"","orcid":"","institution":"Texas Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"J.","middleName":"Herman","lastName":"Kan","suffix":""}],"badges":[],"createdAt":"2025-06-17 19:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6917148/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6917148/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85348617,"identity":"292d74f5-db14-43b2-9217-c01804b0ffdf","added_by":"auto","created_at":"2025-06-25 02:27:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":219733,"visible":true,"origin":"","legend":"\u003cp\u003eMethods Involving Inclusion and Exclusion Guidelines\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6917148/v1/4e47bbdb831e1b48233882c2.png"},{"id":85349122,"identity":"56d6ecbe-07aa-4e2c-b570-b16f58076aa2","added_by":"auto","created_at":"2025-06-25 02:35:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":433401,"visible":true,"origin":"","legend":"\u003cp\u003e14 year old boy with a central distal femur FOPE in a normal knee MRI. (A) Coronal PD FS and (B) T2 FS sagittal MRI demonstrates longitudinally oriented transphyseal edema extending from metaphysis to epiphysis (arrows) consistent with a FOPE.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6917148/v1/703258693f26b31b73f3f0cd.png"},{"id":85349858,"identity":"79ba1a0d-f930-44ef-b946-13e96ed6ce02","added_by":"auto","created_at":"2025-06-25 02:43:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":393358,"visible":true,"origin":"","legend":"\u003cp\u003e12 year old boy with distinct transphyseal vessel in contact with a FOPE lesion in a child with ACL tear. (A) Coronal PD FS and (B) T2 FS sagittal MRI demonstrates longitudinally oriented transphyseal vessel (arrowhead) with edema centered at the physis and separate from the bone contusion related to the ACL tear, extending from metaphysis to epiphysis (arrows) consistent with a vessel transecting a FOPE lesion.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6917148/v1/80f67408e631ad8661d49787.png"},{"id":85349125,"identity":"33d46a71-06fc-48a8-a8bc-6e92d503dbff","added_by":"auto","created_at":"2025-06-25 02:35:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":220983,"visible":true,"origin":"","legend":"\u003cp\u003e15 year old boy with normal knee MRI. PD FS coronal demonstrating a longitudinally oriented metaphyseal vessel (arrowhead) without FOPE. Note in the proximally located metadiaphysis, there is ill-defined longitudinally oriented cloud-like increased signal (black arrow), which may represent vessel involution.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6917148/v1/e755478a60f67d6774b1b8fe.png"},{"id":85348622,"identity":"edc4b9ae-c601-4245-9252-b4f97db687e6","added_by":"auto","created_at":"2025-06-25 02:27:09","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":340470,"visible":true,"origin":"","legend":"\u003cp\u003eIllustrative microscopic diagram of the distal femoral open (4 year old) and closing (13 year old) physis.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6917148/v1/9ffbde5bb312c1c19ef91c76.png"},{"id":87846674,"identity":"023df637-f36b-4284-8ad6-e8238d9daa61","added_by":"auto","created_at":"2025-07-29 15:09:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2194308,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6917148/v1/9eafa3c0-b4f0-4dec-ad09-06635e301604.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Focal periphyseal edema (FOPE) revisited: does injury severity predict presence and frequency of FOPE lesions?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFirst described in 2011 by Zbojniewicz and Laor [1], focal periphyseal edema (FOPE) is an MRI finding identified in long bones near major joints like the knee or shoulder in children nearing skeletal maturity. On MRI, FOPE lesions appear as focal bone marrow edema-like signal centered around a closing physis. Current literature, mainly comprised of descriptive retrospective case-series, controversially postulates that FOPE lesions identified by MRI are related to supraphysiologic stress to a closing physis and may be a potential pain generator [2, 3].\u003c/p\u003e \u003cp\u003eClosure of the physis of long bones begins centrally with mineralized bridging between the metaphysis and epiphysis and involves transphyseal neovascularization and eventual endochondral ossification [4]. It is postulated that the central portion of the closing physis of long bones has increased susceptibility to trauma due to decreased elasticity compared with the periphery of the physis which remains relatively patent [1]. FOPE would then represent a transient response to the mechanical stress and redistribution of forces occurring during physeal closure, exacerbated by high-impact activity such as running or jumping in sports [5]. However, the observation that FOPE has been documented in non-weight-bearing sites, such as the greater trochanter of the hip and the humerus, suggests that weightbearing stressors may not be the sole contributing factor​ [6].\u003c/p\u003e \u003cp\u003eThe purpose of this study is to epidemiologically determine the frequency and number of FOPE lesions present in adolescent boys with MRI evidence of ACL tears compared with normal knee MRIs. The hypothesis is that the number of FOPE lesions may occur with higher frequency in children who are predisposed to ACL tears due to increased supraphysiologic activity compared with those children who are referred for knee MRIs that are normal.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e The present study was approved by our institutional review under exempt status and was performed in compliance with HIPAA. This was a retrospective cohort study comprised of male adolescents aged 12\u0026ndash;15 years with confirmed ACL tear on MRI compared with a negative control cohort comprised of normal knee MRIs based on the official radiology report. Only male patients were included to reduce possible gender bias. Ages 12\u0026ndash;15 years were selected based on previous findings from Zbojniewicz and Laor [1], citing these ages as within the range for highest incidence of FOPE lesions.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eIdentification of patients in ACL Tear cohort\u003c/h2\u003e \u003cp\u003eA retrospective consensus review was conducted by electronic medical record keyword search in Picture Archiving and Communication System (PACS) at a tertiary-care pediatric hospital. The search was conducted using keyword \u0026ldquo;ACL tear,\u0026rdquo; yielding 11,934 MRI reports. The results of that provisional search query were filtered for reports of the knee in patients aged 12\u0026ndash;15 years and male gender, leaving 865 remaining studies. The subsequent MRI radiology reports were sorted in reverse chronological order and manually filtered for true ACL tears. The first 110 studies fitting these criteria were added to the initial study cohort. All patients in the ACL tear cohort had surgically confirmed ACL tears that were reconstructed. 6 studies were removed from consideration during review of MRI imaging due to technical issues (n\u0026thinsp;=\u0026thinsp;5) or human error (n\u0026thinsp;=\u0026thinsp;1) during data collection, such as discrepancy between MRN listed in study cohort pool and MRN listed on MRI study. This resulted in 104 studies evaluated as part of the test cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIdentification of patients in negative control cohort\u003c/h3\u003e\n\u003cp\u003eWhen identifying the negative control cohort, an electronic medical record keyword search in Picture Archiving and Communication System (PACS) at a tertiary-care pediatric hospital was conducted. Key words \u0026ldquo;normal exam\u0026rdquo; and \u0026ldquo;negative exam\u0026rdquo; were used, yielding 25,523 MRI reports. The results of that were filtered for reports of the knee in patients aged 12\u0026ndash;15 years and of male gender, leaving 3,804 remaining studies. The subsequent MRI radiology reports were sorted in reverse chronological order and manually filtered for exams read as completely normal or negative, with no incidental findings. The first 110 studies fitting these criteria were added to the initial control cohort. 3 studies were removed from consideration during review of MRI imaging due to human error during data collection, such as discrepancy between MRN listed in study cohort pool and MRN listed on MRI study. This resulted in 107 studies evaluated as part of the control cohort.\u003c/p\u003e\n\u003ch3\u003eReview of MRI Examination\u003c/h3\u003e\n\u003cp\u003eTo reduce observer bias, MRI reports from ACL tear and control groups were combined into one list and sorted based on date. The T2 FS sagittal and PD FS coronal sequences from the knee MRI exam were then reviewed in consensus by one subspecialty trained pediatric musculoskeletal radiologist (XXX) with 19 years of experience and one subspecialty trained musculoskeletal radiologist (XXX) with 8 years of experience. The review involved identifying location and number of FOPE lesions in the proximal tibia and distal femur. FOPE lesions were defined as focal edema centered at the physis of the distal femur or proximal tibia, extending into both the adjacent juxtaphyseal metaphysis and epiphysis (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) [1], excluding residual red marrow and cartilaginous tongues related to prior trauma. Additionally, focal transphyseal edema related to obvious traumatic bone contusions was excluded. Presence of FOPE lesion, number of FOPE lesion, and location (central, medial, lateral, anterior, posterior) of FOPE lesion were recorded.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eIdentification of Transphyseal Vessels at FOPE Lesions\u003c/h3\u003e\n\u003cp\u003eThe 86 patients determined to have FOPE lesions, both in the study and control cohorts, were sorted by reverse chronological order and given an anonymous, HIPAA compliant identifier. These MRIs were reviewed for transphyseal vessels by a medical student under direct supervision of an attending pediatric musculoskeletal radiologist (XXX). The vessel needed to be vertically oriented and extending to the physis at the level of the FOPE, suggestive of the natural growth of vessels during physis closure (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) [4]. This is distinct from patients with longitudinally oriented vessels without FOPE (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). From this list identified by the medical student, every 5th patient was selected to be audited by a pediatric MSK radiologist. 17 total studies were selected, allowing for an audit of 20% of the evaluated patients. Within this audit of 17 patients, there were 28 FOPE lesions that needed verification by the pediatric MSK radiologist. The read of 26 (93%) lesions was agreed upon by the medical student and radiologist and the read of 2 (7%) lesions was corrected by the pediatric MSK radiologist.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll analysis was conducted using IBM SPSS Statistics (version 26). Statistical analyses were performed with two-tailed p\u0026thinsp;\u0026lt;\u0026thinsp;.05 considered to denote statistical significance. All findings are categorical and presented as counts and percentages. Chi square analysis was conducted to determine significance between presence or absence of FOPE lesion in the test vs control groups, location of FOPE lesions in proximal tibia vs distal femur for test vs control, and number of FOPE lesions per patient when FOPE was identified. When considering laterality of location between distal femur central/medial/lateral vs proximal tibia central/medial/lateral, fisher\u0026rsquo;s exact test was used. Cohen's kappa was utilized to determine inter-reader agreement on the presence or absence of FOPE lesions.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the distribution of MRI findings when comparing the ACL tear group and the control group. 40% (n\u0026thinsp;=\u0026thinsp;42) of patients in the ACL tear group were positive for FOPE lesions and 41% (n\u0026thinsp;=\u0026thinsp;44) of patients in the control group were positive for FOPE lesions. There was no statistical difference between these two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.913). The number of FOPE lesions per patient was compared between ACL tear group and control group. The number of lesions ranged from 1\u0026ndash;5 per patient in which a FOPE was identified. This comparison is also not statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.480). The total number of FOPE lesions present in the ACL tear group was 69 (49% of total FOPE lesions) and the total number of FOPE lesions present in the control group was 71 (51% of total FOPE lesions). When comparing location of FOPE lesion in the proximal tibia vs the distal femur between ACL tear group and control group, there is no statistical difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.906). Location was then further subdivided by laterality, looking at the medial, lateral and central proximal tibia and distal femur. No statistical difference was found based on laterality of lesion location (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.910).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMRI Findings for Patients With Anterior Cruciate Ligament\u0026ndash;Deficient Knees and With Normal Exams\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinding\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients with ACL Tears on MRI (n\u0026thinsp;=\u0026thinsp;104)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with Normal MRI (n\u0026thinsp;=\u0026thinsp;107)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive FOPE Lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.913\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative FOPE Lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of FOPE Lesions when identified per patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.480\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Number of FOPE Lesions Identified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage number of FOPE lesions when present\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.768\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.906\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProximal Tibia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal Femur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation \u0026ndash; Detailed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.910\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProximal Tibia Medial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProximal Tibia Lateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProximal Tibia Central\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal Femur Medial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal Femur Lateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal Femur Central\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eInter-reader variability was assessed. When evaluating combined control and test group reads, there was initial discrepancy in 49 (23%) of the total 211 evaluated MRIs in identification of FOPE lesion. Cohen's kappa demonstrated substantial inter-reader agreement on the identification of FOPE lesions, with k\u0026thinsp;=\u0026thinsp;.684 (95% CI, .584 to .784). Consensus was reached to produce the final report data (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe presence of transphyseal vessels extending directly into a FOPE lesion was identified. For the 86 knees determined to have FOPE lesions, a total of 140 FOPE lesions were identified. Of these 140 FOPEs, 66 (47%) of FOPE's were associated with a transphyseal vessel identified on a fluid sensitive sequence (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this study indicate that the presence and distribution of focal periphyseal edema (FOPE) lesions do not significantly differ between patients with anterior cruciate ligament tears and negative control subjects, occurring equally in about 40% of the entire study population. The results of this study reinforce the idea that FOPE lesions are a frequent, incidental finding in adolescent knee MRIs, irrespective of predisposing supraphysiologic activity that may or may not predispose a child to an ACL tear. Their presence, number, and anatomical distribution are independent of ACL injury status, supporting the idea that FOPE represents a benign, physiological phenomenon rather than a direct marker of knee pathology. These findings question previous studies suggesting FOPE lesions are associated with supraphysiologic activity [2, 3].\u003c/p\u003e \u003cp\u003eThe physes are responsible for longitudinal appendicular bone growth through the process of endochondral ossification in which a cartilage model, generated by columns of dividing chondrocytes is replaced by bone through a process that involves invasion of osteoblasts and blood vessels from the metaphysis [7]. Upon dividing along longitudinal columns, chondrocytes undergo hypertrophy, during which they rapidly increase in size and secrete proteins and vesicles that alter the molecular makeup of the surrounding extracellular matrix. These hypertrophic chondrocytes also secrete peptides that recruit blood vessels, osteoblasts, and osteoclasts[4]. One such peptide is vascular endothelial growth factor (VEGF), which stimulates the ingrowth of blood vessels that carry osteoprogenitors through a process called osteoblast angiotropism (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) [8]. Subsequently, towards the final rows of the hypertrophic zones, hypertrophic chondrocytes undergo rapid cell death while invaded [9] osteoclasts resorb the calcified cartilage matrix and osteoblasts deposit new bone matrix on the remnants of the cartilage [10]. Throughout childhood, physeal thickness remains relatively constant due to an intricate balance between chondrocyte proliferation and cell death [11]. In addition, it retains an overall undulated appearance due to interactions with physiologic dynamic biomechanical forces [11].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe process of normal distal femoral and proximal tibial physeal closure relies on endochondral ossification, and involves a similar series of well-coordinated biological events towards the end of puberty marking the end of longitudinal bone growth [10]. This process is tightly controlled by regulated hormones, such as estrogen, and typically occurs between the ages of 14 and 18 years, with females often experiencing physeal closure earlier than males [12]. Physeal closure starts when its chondrocytes enter senescence, which reduces their proliferative capacity and causes a gradual decrease in physeal height [9, 10]. Vascular endothelial cells are the first cell types found to invade the growth plate, prior to osteoblasts and osteoclasts. Similar to the process described above, it is thought that the vascular endothelial cells that invade the physis directly interact with osteoblasts, carrying them into the growth plate to initiate the ossification process [8]. Hence, vascular invasion is crucial for bringing in osteoprogenitor cells that replace the calcified cartilage with bone tissue, completing the ossification process [10, 13]. At this point, the ossification front grows faster than the rate at which growth plate chondrocytes replace themselves, initiating bony fusions to form across the growth plate [10]. Interestingly, the molecular and cellular process of physeal closure is conserved across species. Indeed, physeal senescence is associated with transphyseal blood vessel formation resulting in epiphyseal fusion in most mammals [14, 15]. In the distal femur and proximal tibia, the physeal ossification process progresses from the central region of the growth plate outward, ensuring uniform closure and preventing angular deformities [16]).\u003c/p\u003e \u003cp\u003eReported in Zbojniewicz and Laor [1] along with proceeding case studies [17], FOPE lesions were most frequently observed at the center of the tibial or femoral physis. With initial ossification occurring in the central physis, it has been suggested that decreased elasticity of the ossified central physis compared to the periphery, combined with microtrauma, results in FOPE lesions. However, our data shows no significant difference in the anatomical distribution of FOPE lesions at the physis, comparing medial, lateral or central location. This suggests that microtrauma on the central portion of a partially closed physis may not entirely explain the etiology of FOPE lesions. When considering the crucial step that neovascularization plays in the process of endochondral ossification, our data suggests that FOPE lesions may be the result of transient inflammatory responses that manifest as bone marrow edema on MRI (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). While this vascular hypothesis remains speculative, it may help explain why FOPE lesions are sometimes seen in asymptomatic patients, are associated with longitudinally oriented transphyseal vessels (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), and why its resolution typically occurs without intervention​.\u003c/p\u003e \u003cp\u003eCase studies and series published between 2015 and 2023 [2, 3, 6, 17\u0026ndash;19] highlight individual cases in which FOPE zones occurred in different joints during the process of physeal closure in adolescents often experiencing joint pain, often in athletes. Our results do not support the conclusion that FOPE zones are pain generators but instead present in about 40% of our negative cohort study population, despite investigated risk factors. Notably, a case report by Giles, et al. [12] studying 4 patients found to have FOPE lesions on MRI concluded that FOPE-associated knee pain may not be clinically benign, with negative effects on the function and well-being of affected adolescents. Despite this, they suggest FOPE is likely a normal variant of physiologic physeal closure that does not warrant clinical management or surgical intervention. Our results support the conclusion that FOPE does not warrant clinical management or surgical intervention.\u003c/p\u003e \u003cp\u003eA cross-sectional study by Fr\u0026ouml;hlich, et al. [5], investigated the prevalence of knee pain and MRI abnormalities in 108 young competitive alpine skiers between the ages of 13\u0026ndash;15 years. The study found that a significant proportion of these athletes experienced overuse-related knee complaints, including FOPE zones in 25% of subjects. This study lacks a control to compare FOPE occurrence in alpine skiers to individuals not participating in knee overuse. The decision to include FOPE as an overuse injury presumably was based on preceding literature. Our results support their findings in that a significant portion of their population would have FOPE lesions, but our results do not support that this would be an over-use injury opposed to a normal physiologic changes to a normal physis.\u003c/p\u003e \u003cp\u003eOur study confirms previous findings that FOPEs are typically found at the site of earliest physeal closure. We hypothesize that FOPEs originate from accidental rupture of the transphyseal blood vessels that mediate physeal closure. Several factors may contribute to blood vessel rupture at this site. For example, the corrugated structure of the closing physis likely alters the biomechanical forces on neighboring tissues. Combined with elevated shear stress in the immature blood vessels migrating into the physis [8], altered biomechanical stress in the closing growth plate would then increase the likelihood of ingrowing vessel rupture. This hypothesis is supported by the fact that FOPEs are typically observed in vicinity to the corrugated area of the physis (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). However, our results suggest that supraphysiological stress, induced by exercise for example, is likely not an important contributor to FOPE development. In sum, our data suggest that FOPEs are physiological consequences of physeal closure.\u003c/p\u003e \u003cp\u003eNeovascularization is often accompanied by neo-innervation. For example, in the case of osteoarthritis, pain-sensing nociceptive neurons are known to increasingly innervate the synovium and subchondral bone of patients and mouse models of OA, and are thought to be correlated with pain [20\u0026ndash;22]. Similarly, the blood vessels that initiate physeal closure may be accompanied by a temporary increase in the innervation of the physeal area of the long bone, which may be responsible for the (typically transient) joint pain these patients experience.\u003c/p\u003e \u003cp\u003eOne of the significant limitations of this study is that, by nature of study design, retrospective cohort studies can only determine associations between exposures and outcomes. We cannot definitively establish causality. Both cohorts (ACL tear and normal knee MRI cohorts) were referred for symptomatic knee pain which confounds incidence of FOPE lesion incidence and could have been addressed by recruiting asymptomatic children for knee MRI assessment. Additionally, the scope of the study was limited to only include male subjects all from the same hospital system. To further improve generalizability, future studies could investigate female adolescents and expand to other geographic regions. Of note, some MR studies were difficult to call when assessing FOPE lesions due to potential confounders such as large contusions or red marrow edema. Finally, it is not possible to fully exclude cartilaginous rests from transphyseal vessels, but we believe our findings represent the latter since cartilaginous rests related to prior trauma are unlikely to be perfectly uniform and linear.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFOPEs identified on pediatric knee MRIs are a normal finding in children nearing skeletal maturity and are in part related to transphyseal vascular edema. FOPEs do not appear to be related to activities that predispose children to ACL tears. Reporting FOPEs may generate unnecessary stress to families and to referring physicians and should be discouraged by radiologists.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAB and JHK wrote the manuscript text, with review and contribution from NH. PB assisted with reading MR studies and consensus review. ACS assisted with statistics.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eFigure 5 contribution by Alissa Kan\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eA. M. Zbojniewicz and T. Laor, \u0026quot;Focal Periphyseal Edema (FOPE) Zone on MRI of the Adolescent Knee: A Potentially Painful Manifestation of Physiologic Physeal Fusion?,\u0026quot; \u003cem\u003eAmerican Journal of Roentgenology,\u0026nbsp;\u003c/em\u003evol. 197, no. 4, pp. 998-1004, 2011, doi: 10.2214/ajr.10.6243.\u003c/li\u003e\n \u003cli\u003eG. Larid, P. O. Duboe, and E. Gervais, \u0026quot;Shoulder Focal Periphyseal Edema: An Unusual Cause of Shoulder Pain in an Adolescent,\u0026quot; (in eng), \u003cem\u003eJ Rheumatol,\u0026nbsp;\u003c/em\u003evol. 50, no. 9, p. 1192, Sep 2023, doi: 10.3899/jrheum.221291.\u003c/li\u003e\n \u003cli\u003eJ. N. Speirs, T. G. Shields, and M. J. Morrison, 3rd, \u0026quot;Focal Periphyseal Edema: An Uncommon Cause of Adolescent Knee Pain: A Report of Three Cases,\u0026quot; (in eng), \u003cem\u003eJBJS Case Connect,\u0026nbsp;\u003c/em\u003evol. 9, no. 3, p. e0391, Jul-Sep 2019, doi: 10.2106/jbjs.Cc.18.00391.\u003c/li\u003e\n \u003cli\u003eE. J. Mackie, Y. A. Ahmed, L. Tatarczuch, K. S. Chen, and M. Mirams, \u0026quot;Endochondral ossification: how cartilage is converted into bone in the developing skeleton,\u0026quot; (in eng), \u003cem\u003eInt J Biochem Cell Biol,\u0026nbsp;\u003c/em\u003evol. 40, no. 1, pp. 46-62, 2008, doi: 10.1016/j.biocel.2007.06.009.\u003c/li\u003e\n \u003cli\u003eS. Fr\u0026ouml;hlich, P. Loris, S. Christoph, O. F. Walter, S. Reto, and S. J\u0026ouml;rg, \u0026quot;Remarkably high prevalence of overuse-related knee complaints and MRI abnormalities in youth competitive alpine skiers: a descriptive investigation in 108 athletes aged 13\u0026acirc;15 years,\u0026quot; \u003cem\u003eBMJ Open Sport \u0026amp; Exercise Medicine,\u0026nbsp;\u003c/em\u003evol. 6, no. 1, p. e000738, 2020, doi: 10.1136/bmjsem-2020-000738.\u003c/li\u003e\n \u003cli\u003eA. Sakamoto and S. Matsuda, \u0026quot;Focal Periphyseal Edema Zone on Magnetic Resonance Imaging in the Greater Trochanter Apophysis: A Case Report,\u0026quot; (in eng), \u003cem\u003eJ Orthop Case Rep,\u0026nbsp;\u003c/em\u003evol. 7, no. 4, pp. 29-31, Jul-Aug 2017, doi: 10.13107/jocr.2250-0685.836.\u003c/li\u003e\n \u003cli\u003eK. Foster, \u0026quot;Growth Plate (Physeal) Injuries,\u0026quot; in \u003cem\u003eImaging in Pediatric Skeletal Trauma: Techniques and Applications\u003c/em\u003e, K. J. Johnson and E. Bache Eds. Berlin, Heidelberg: Springer Berlin Heidelberg, 2008, pp. 147-157.\u003c/li\u003e\n \u003cli\u003eG. Neag, M. Finlay, and A. J. Naylor, \u0026quot;The Cellular Choreography of Osteoblast Angiotropism in Bone Development and Homeostasis,\u0026quot; (in eng), \u003cem\u003eInt J Mol Sci,\u0026nbsp;\u003c/em\u003evol. 22, no. 14, Jul 6 2021, doi: 10.3390/ijms22147253.\u003c/li\u003e\n \u003cli\u003eY. Ağırdil, \u0026quot;The growth plate: a physiologic overview,\u0026quot; (in eng), \u003cem\u003eEFORT Open Rev,\u0026nbsp;\u003c/em\u003evol. 5, no. 8, pp. 498-507, Aug 2020, doi: 10.1302/2058-5241.5.190088.\u003c/li\u003e\n \u003cli\u003eE. J. Mackie, L. Tatarczuch, and M. Mirams, \u0026quot;The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification,\u0026quot; (in eng), \u003cem\u003eJ Endocrinol,\u0026nbsp;\u003c/em\u003evol. 211, no. 2, pp. 109-21, Nov 2011, doi: 10.1530/joe-11-0048.\u003c/li\u003e\n \u003cli\u003eJ. C. Nguyen, B. K. Markhardt, A. C. Merrow, and J. R. Dwek, \u0026quot;Imaging of Pediatric Growth Plate Disturbances,\u0026quot; (in eng), \u003cem\u003eRadiographics,\u0026nbsp;\u003c/em\u003evol. 37, no. 6, pp. 1791-1812, Oct 2017, doi: 10.1148/rg.2017170029.\u003c/li\u003e\n \u003cli\u003eM. K. Yamamura\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e, \u0026quot;Epidemiology of Physeal Fractures and Clinically Significant Growth Disturbances Affecting the Distal Tibia, Proximal Tibia, and Distal Femur: A Retrospective Cohort Study,\u0026quot; (in eng), \u003cem\u003eJ Am Acad Orthop Surg,\u0026nbsp;\u003c/em\u003evol. 31, no. 11, pp. e507-e515, Jun 1 2023, doi: 10.5435/jaaos-d-22-00303.\u003c/li\u003e\n \u003cli\u003eY. Song, D. Lee, C. S. Shin, D. R. Carter, and N. J. Giori, \u0026quot;Physeal cartilage exhibits rapid consolidation and recovery in intact knees that are physiologically loaded,\u0026quot; (in eng), \u003cem\u003eJ Biomech,\u0026nbsp;\u003c/em\u003evol. 46, no. 9, pp. 1516-23, May 31 2013, doi: 10.1016/j.jbiomech.2013.03.026.\u003c/li\u003e\n \u003cli\u003eH. A. Cole, M. Yuasa, G. Hawley, J. M. Cates, J. S. Nyman, and J. G. Schoenecker, \u0026quot;Differential development of the distal and proximal femoral epiphysis and physis in mice,\u0026quot; (in eng), \u003cem\u003eBone,\u0026nbsp;\u003c/em\u003evol. 52, no. 1, pp. 337-46, Jan 2013, doi: 10.1016/j.bone.2012.10.011.\u003c/li\u003e\n \u003cli\u003eR. W. Haines, \u0026quot;The histology of epiphyseal union in mammals,\u0026quot; (in eng), \u003cem\u003eJ Anat,\u0026nbsp;\u003c/em\u003evol. 120, no. Pt 1, pp. 1-25, Sep 1975.\u003c/li\u003e\n \u003cli\u003eK. Ecklund and D. Jaramillo, \u0026quot;Patterns of premature physeal arrest: MR imaging of 111 children,\u0026quot; (in eng), \u003cem\u003eAJR Am J Roentgenol,\u0026nbsp;\u003c/em\u003evol. 178, no. 4, pp. 967-72, Apr 2002, doi: 10.2214/ajr.178.4.1780967.\u003c/li\u003e\n \u003cli\u003eN. Beckmann and S. Spence, \u0026quot;Unusual Presentations of Focal Periphyseal Edema Zones: A Report of Bilateral Symmetric Presentation and Partial Physeal Closure,\u0026quot; (in eng), \u003cem\u003eCase Rep Radiol,\u0026nbsp;\u003c/em\u003evol. 2015, p. 465018, 2015, doi: 10.1155/2015/465018.\u003c/li\u003e\n \u003cli\u003eT. Bochmann, R. Forrester, and J. Smith, \u0026quot;Case report: imaging the clinical course of FOPE-a cause of adolescent knee pain,\u0026quot; (in eng), \u003cem\u003eJ Surg Case Rep,\u0026nbsp;\u003c/em\u003evol. 2016, no. 11, Nov 24 2016, doi: 10.1093/jscr/rjw178.\u003c/li\u003e\n \u003cli\u003eH. Ueyama, T. Kitano, K. Nakagawa, and M. Aono, \u0026quot;Clinical experiences of focal periphyseal edema zones in adolescent knees: case reports,\u0026quot; (in eng), \u003cem\u003eJ Pediatr Orthop B,\u0026nbsp;\u003c/em\u003evol. 27, no. 1, pp. 26-30, Jan 2018, doi: 10.1097/bpb.0000000000000388.\u003c/li\u003e\n \u003cli\u003eJ. J. McDougall, R. C. Bray, and K. A. Sharkey, \u0026quot;Morphological and immunohistochemical examination of nerves in normal and injured collateral ligaments of rat, rabbit, and human knee joints,\u0026quot; (in eng), \u003cem\u003eAnat Rec,\u0026nbsp;\u003c/em\u003evol. 248, no. 1, pp. 29-39, May 1997, doi: 10.1002/(sici)1097-0185(199705)248:1\u0026lt;29::Aid-ar4\u0026gt;3.0.Co;2-a.\u003c/li\u003e\n \u003cli\u003eA. M. Obeidat, R. E. Miller, R. J. Miller, and A. M. Malfait, \u0026quot;The nociceptive innervation of the normal and osteoarthritic mouse knee,\u0026quot; (in eng), \u003cem\u003eOsteoarthritis Cartilage,\u0026nbsp;\u003c/em\u003evol. 27, no. 11, pp. 1669-1679, Nov 2019, doi: 10.1016/j.joca.2019.07.012.\u003c/li\u003e\n \u003cli\u003eK. Aso\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e, \u0026quot;Contribution of nerves within osteochondral channels to osteoarthritis knee pain in humans and rats,\u0026quot; (in eng), \u003cem\u003eOsteoarthritis Cartilage,\u0026nbsp;\u003c/em\u003evol. 28, no. 9, pp. 1245-1254, Sep 2020, doi: 10.1016/j.joca.2020.05.010.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6917148/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6917148/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFocal periphyseal edema (FOPE) is a MRI finding identified in long bones in children nearing skeletal maturity. Existing literature is conflicting, with the majority suggesting that FOPEs are potential pain generators related to supraphysiologic sporting activities and some reports suggesting that FOPE\u0026rsquo;s represent normal physiologic physeal maturation.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe purpose of this study is to investigate the incidence of knee FOPE lesions in adolescent boys with ACL tears compared with a negative cohort.\u003c/p\u003e\u003ch2\u003eMaterials and methods\u003c/h2\u003e \u003cp\u003e104 knee MRI\u0026rsquo;s with ACL tears and 108 normal knee MRI records between the ages of 12 to 15 were identified from a major children\u0026rsquo;s hospital. These MRIs were then randomized and reviewed in consensus by two pediatric MSK radiologists for location and number of FOPE lesions in the proximal tibia and distal femur.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThere is no statistical difference between the presence of FOPE in the ACL tear cohort compared with our negative control (40% vs 41%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.913). When comparing the location of lesions in the proximal tibia vs the distal femur between ACL tear group and control group, there is no statistical difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.906). A transphyseal vessel was identified in 47% of all FOPE lesions, independent of ACL tear status.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe results of this study reinforce the idea that FOPE is a frequent incidental finding in adolescent knee MRIs, irrespective of predisposing supraphysiologic activity. Our findings question previous reports that suggest FOPE lesions are associated with supraphysiologic stress. FOPE lesions are frequently associated with transphyseal vessels.\u003c/p\u003e","manuscriptTitle":"Focal periphyseal edema (FOPE) revisited: does injury severity predict presence and frequency of FOPE lesions?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 02:27:04","doi":"10.21203/rs.3.rs-6917148/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b03f687e-12a0-45e6-bb2f-fe3b931c5877","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-29T15:08:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 02:27:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6917148","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6917148","identity":"rs-6917148","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}