Presentation of metastatic carotid body paraganglioma on F-18 FDG PET/CT: a rare disease.

Carotid body paraganglioma is a slow growing tumor of head and neck region. It can rarely be malignant in nature which is characterized by distant metastases on anatomical imaging. We share an interesting presentation of a malignant carotid body on F-18 FDG PET/CT in form of liver and skeletal metastases.

Carotid body tumor in a nine-year-old patient.

Carotid body tumors are rarely encountered pathologies in the pediatric age group but still exist in the differential diagnosis of cervical painless masses. Genetic and familial background should be studied in addition to contrast imaging studies. Complete subadventitial resection, with or without prior embolization, which is still controversial, is the mainstay of therapy. Follow-up gains importance due to its nature. Herein, we report a nine-yearold girl presented with a unilateral asymptomatic mass on the neck with a diagnosis of carotid body tumor treated surgically without embolization. We emphasize the specific aspects of the pediatric age group.

Outcomes of Head and Neck Neurogenic Tumors.

BACKGROUND: Lateral neck mass management frequently challenges surgeons. Nerve tissue neoplasms are an uncommon cause of such nodules. Neurogenic tumors form a tiny percentage of the head and neck neoplastic lesions. Considering the number of nerves in this area, it is surprising that such neoplasms are not more frequently seen. METHODS: A retrospective study was conducted on all patients who presented to the National Cancer Institute of Cairo, Egypt, with head and neck neurogenic neoplasms. RESULTS: During the last 10 years at the National Cancer Institute of Egypt (2006-2015), 40 cases of neurogenic tumors of the head and neck were treated at the head and neck unit. Patients' ages ranged from two to 78 years with a mean age of 34.7 years. Childhood neurogenic tumors accounted for nine cases (22.5%) only in this study. Male patients diagnosed with these tumors comprised 16 cases, while female patients comprised 24 cases, with a female-to-male ratio of 1.5:1. Patient presentation depends on the biological behavior of the tumor; for instance, some of them present by slowly growing painless well-circumscribed mobile swelling, and others present by rapidly growing swelling with neurological deficit. Clinical picture and imaging studies such as CT and MRI raise suspicion and may help delineate such tumors, but a definitive diagnosis is obtained by tissue biopsy. Surgery is the mainstay of treatment in most head and neck neurogenic tumors, whereas adjuvant therapy is of limited benefit in some types of neurogenic tumors. The five-year survival rate was 60% for the malignant group, while death was reported in six out of 15 cases (40%).  Conclusion: Most neurogenic head and neck tumors are benign. Accurate preoperative assessment and a high degree of suspicion are the initial steps in the management. Proper treatment involves complete surgical excision; however, debulking procedures have an important role. Malignant neurogenic tumors are aggressive and are treated with combined radical surgical resection and radiation. Chemotherapy is tried for locally advanced unresectable or metastatic disease.

Prevalence, characteristics, evaluation, and management of carotid body tumors: Systematic analysis based on available evidence.

OBJECTIVE: Although carotid body tumors (CBTs) are rare, they attract particular attention because of their propensity for malignant transformation and the high surgical risk. Because data are scarce and as it is difficult to achieve a large sample size, no study has yet comprehensively analyzed the characteristics, management, or operative complications of CBTs. Therefore, we collected and analyzed all currently available information on CBTs and used the pooled data to derive quantitative information on disease characteristics and management. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, and the Web of Science up to December 1, 2022, for studies that investigated the characteristics and management of CBTs. The primary objective was to identify the prevalence of the various characteristics and the incidence of complications. The secondary objective was to compare patients who underwent preoperative embolization (PE) and those who did not (non-PE), as well as to compare patients with different Shamblin grades and those with and without succinate dehydrogenase (SDH) mutations in terms of CBT characteristics and complications. Two reviewers selected studies for inclusion and independently extracted data. All statistical analyses were performed using the standard statistical procedures of Review Manager 5.2 and Stata 12.0. RESULTS: A total of 155 studies with 9291 patients and 9862 tumors were identified. The pooled results indicated that the median age of patients with CBT was 45.72 years, and 65% were female. The proportion of patients with bilateral lesions was 13%. In addition, 16% of patients had relevant family histories, and the proportion of those with SDH gene mutations was 36%. Sixteen percent of patients experienced multiple paragangliomas, and 12% of CBTs had catecholamine function. The incidence of cranial nerve injury (CNI) was 27%, and 14% of patients suffered from permanent CNI. The incidence rates of operative mortality and stroke were both 1%, and 4% of patients developed transient ischemic attacks. Of all CBTs, 6% were malignant or associated with metastases or recurrences. The most common metastatic locations were the lymph nodes (3%) and bone (3%), followed by the lungs (2%). Compared with non-PE, PE reduced the estimated blood loss (standardized mean difference, -0.95; 95% confidence interval [CI], -1.70 to -0.20) and the operation time (standardized mean difference, -0.56; 95% CI, -1.03 to -0.09), but it increased the incidence of stroke (odds ratio, 2.44; 95% CI, 1.04-5.73). Higher Shamblin grade tumors were associated with more operative complications. Patients who were SDH gene mutation-positive were more likely to have a relevant family history and had more symptoms. CONCLUSIONS: CBT was most common in middle-aged females, and early surgical resection was feasible; there was a low incidence of serious operative complications. Routine PE is not recommended because this may increase the incidence of stroke, although PE somewhat reduced the estimated blood loss and operation time. Higher Shamblin grade tumors increased the incidence of operative complications. Patients who were SDH gene mutation-positive had the most relevant family histories and symptoms.

Novel insights into the classification of Shamblin III carotid body tumors from a neurosurgical perspective.

BACKGROUND AND PURPOSE: The classic Shamblin system fails to provide valuable guidance in many Shamblin's III carotid body tumors (III-CBTs) due to the variable forms of carotid arteries and the complex anatomic relationships in parapharyngeal space. We proposed a modified classification to separately divide III-CBTs into different subgroups on the basis of arterial relevant features and anatomical relevant features. MATERIALS AND METHODS: From 2020 to 2023, a total of 129 III-CBTs at a single institution were retrospectively analyzed. All cases were independently classified as arterial-relevant and anatomical-relevant subgroups. The pre-, peri- and postoperative data were summarized and compared accordingly. RESULTS: Among the 129 cases, 69 cases were identified as "Classical type", 23 cases as "Medial type", 27 cases as "Lateral type" and 10 cases as "Enveloped type" according to arterial morphologies. Besides, 76 cases were identified as "Common type", 15 cases as "Pharynx- invasion type", 18 cases as "Skull base-invasion type" and 20 cases as "Mixed type" according to anatomical relationships. "Enveloped type" of tumors in arterial-relevant classification and "Mixed type" of tumors in anatomical-relevant classification are the most challenging cases for surgeons with the lowest resection rate, highest incidence of carotid arteries injury and postoperative stroke. CONCLUSION: The modified classifications provide comprehensive understanding of different III-CBTs which are applicable for individualized treatment in clinical practice.

Current management of carotid body tumors.

Carotid body tumors (CBTs) are neoplasms that occur at the bifurcation of the carotid artery and are pathologically classified as paragangliomas. In the 4th edition of the WHO classification, paragangliomas are categorized as neoplasms with malignant potential. Clinically, about 5% of CBTs present with malignant features such as metastasis. Currently, it is challenging to distinguish between tumors with benign courses and those that present malignantly. Recent advances in genetic testing have elucidated the genetic characteristics of paragangliomas, including carotid body tumors. Over 20 genes have been identified as being involved in tumor development. Particularly in head and neck paragangliomas, abnormalities in genes related to succinate dehydrogenase are frequently observed. Research is ongoing to understand the mechanisms by which these genes contribute to tumor development. The definitive treatment for CBTs is surgical resection. These tumors are prone to bleeding and often adhere firmly to the carotid artery, making intraoperative bleeding control challenging. The risk of lower cranial nerve paralysis is relatively high, and there is a risk of stroke because of manipulation of the carotid artery. Preoperative evaluation with angiography is essential, and a multi-disciplinary surgical team approach is necessary. In cases where the tumor is difficult to resect or has metastasized, radiation therapy or chemotherapy are employed. Clinical trials involving targeted molecular therapies and radiopharmaceuticals have recently been conducted, with some applied clinically. The development of various new treatments is anticipated, providing hope for therapeutic options in refractory cases.

A case report of coexisting multinodular goiter with carotid body tumor.

INTRODUCTION: Carotid body tumor (CBT), a neuroendocrine neoplasm, and benign multinodular goiter (BMNG) are distinct pathologies affecting the neck region. Although rare, they can occur concurrently. This case contributes to the limited evidence regarding the association between these distinct pathologies and their operative management. CASE PRESENTATION: The patient was a 45-year-old female with a palpable mass on the right side of her neck. She was diagnosed with Shamblin type III non-secretory CBT alongside BMNG. The surgical intervention included resection of the CBT, carotid artery bypass, and Dunhill thyroidectomy. DISCUSSION: This case is the third reported instance of coexisting CBT and BMNG. Their causative relationship is evident in the literature without a clear explanation of the underlying mechanism. Both conditions are treated surgically. Dunhill thyroidectomy for BMNG is a safer option, offering more flexibility and advantages over other thyroidectomies. CONCLUSION: This case highlights the complexity of managing such dual pathologies and may provide further evidence of their association.

Central Nonenhancement Sign in Carotid Body Tumor on CT Angiography.

Carotid body tumors are rare benign tumors that arise in the carotid space of neck typically presenting as soft to firm, painless swelling in the neck. While specific imaging characteristics have been previously described for carotid body tumors, we report a new imaging sign in three cases of carotid body tumors on computed tomography angiography.

A Global Bibliometric Analysis of the Top 100 Most Cited Articles on Carotid Body Tumors.

The carotid body, situated at the common carotid artery bifurcation, comprises specialized glomus cells responsible for sensing blood oxygen, carbon dioxide, pH, and temperature changes, crucial for regulating breathing and maintaining oxygen homeostasis. Carotid body tumors (CBTs), arising from these cells, are rare, representing only 0.5% of head and neck tumors, often presenting as benign, slow-growing, vascularized masses. In February 2023, this bibliometric analysis was conducted, which involved screening 1733 articles from the Web of Science database. The screening process was based on citation count, and articles were selected for inclusion based on specific criteria that focused on CBTs located within the carotid bifurcation. Rigorous selection involved independent screening and data extraction by four authors. The top 100 articles, published between 1948 and 2019, totaled 6623 citations and were authored by 98 unique first authors from 22 countries and 77 institutions, spanning 42 journals. Treatment articles were the predominant category, comprising 49% of the literature. This analysis offers insights into publication trends, identifies literature gaps, and outlines areas of research focus, providing a valuable resource to guide future studies on CBTs.

Hypoxic Signaling Pathways in Carotid Body Tumors.

Carotid body tumors (CBTs) are rare tumors with a 1-2 incidence per 100,000 individuals. CBTs may initially present without apparent symptoms, and symptoms begin to arise since tumors grow bigger to compress surrounding tissue, such as recurrent laryngeal nerve and esophagus. Also, the etiology of CBTs remains unclear since it is more likely to occur in those who live in high-altitude areas or suffer from chronic hypoxic diseases such as COPD. SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we concluded the role of hypoxic signaling and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines (ICs) in tumorigenesis and treatment. Of particular interest is the role played by SDHx, which has recently been linked to oxygen sensing through mutations leading to hereditary CBTs. Among the SDH family, SDHB and SDHD exhibit remarkable characteristics associated with metastasis and multiple tumors. Besides SDH mutations in CBTs, the HIF family also plays crucial roles in CBTs via hypoxic signaling pathways. The HIF family regulates angiogenesis during mammalian development and tumor growth by gene expression in CBTs. HIF1α could induce the transcription of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit pyruvate dehydrogenase kinase (PDH) by inhibiting the TCA cycle. Then, carotid body cells begin to hyperplasia and hypertrophy. At the same time, EPAS1 mutation, an activating mutation, could decrease the degradation of HIF2α and result in Pacak-Zhuang syndrome, which could result in paraganglioma. HIFs can also activate VEGF expression, and VEGFs act on Flk-1 to control the hyperplasia of type I cells and promote neovascularization. ICs also play a pivotal signaling role within the CB, as their expression is induced under hypoxic conditions to stimulate CB hyperplasia, ultimately leading to CBTs detecting hypoxic areas in tumors, and improving the hypoxic condition could enhance photon radiotherapy efficacy. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxic signaling pathways and CBTs.

The Surgical Treatment of Carotid Body Tumor as Well as the Prevention and Management of Complications.

The carotid body tumor (CBT) is a rare paraganglioma neoplasm that often occurs in the head and neck anatomical region. Carotid angiography continues to be widely regarded as the preferred diagnostic method for this particular malignancy. Surgical intervention has been widely acknowledged as the primary approach for managing CBTs. However, the resection of CBTs poses significant technical challenges due to its specific anatomical position. To mitigate the incidence of intraoperative and postoperative challenges, we have conducted a comprehensive review of both domestic and international literature to consolidate the surgical approach and strategies for preventing and managing complications associated with this particular tumor.

Tumor de cuerpo carotídeo en adolescente. Reporte de un caso / Carotid body tumor in an adolescent. A case report

Introducción. Los paragangliomas del cuerpo carotídeo son neoplasias infrecuentes y representan el 0,6 % de los tumores de cabeza y cuello. La edad de presentación promedio es la quinta década de vida. El objetivo de este artículo fue describir un caso de paraganglioma del cuerpo carotídeo en una adolescente. Caso clínico. Se presenta el caso de una paciente adolescente con paraganglioma de cuerpo carotídeo derecho, de 5x3x3 cm, Shamblin III. Se analizaron la historia clínica, los exámenes diagnósticos, la técnica quirúrgica utilizada y su evolución correspondiente. La información fue obtenida a partir de la ficha clínica, previa autorización por consentimiento de los padres de la paciente. Resultados. Se hizo resección quirúrgica completa y reparo vascular con injerto de vena safena invertida, con evolución favorable y permeabilidad completa del puente vascular, sin secuelas. Conclusión. Este caso podía corresponder a un tumor de etiología familiar, dada su edad temprana de presentación. Se hizo necesario complementar su estudio con imágenes y objetivar el compromiso vascular asociado para la planificación quirúrgica. En estos pacientes, la complejidad de su localización y el compromiso vascular del tumor requiere de un equipo multidisciplinario, con cirujanos de cabeza y cuello y cirujanos vasculares para un resultado exitoso.

Introduction. Carotid body paragangliomas are rare, representing 0.6% of head and neck tumors, with average age of presentation in the fifth decade of life. The objective of this article is to describe a clinical case of carotid body paraganglioma in an adolescent. Clinical case. Review and analysis of the clinical case, reviewing its clinical history, study tests, surgical technique used and its corresponding evolution. Information obtained from the clinical record prior authorization by consent of the patient's parents. Results. Adolescent patient with paraganglioma of the right carotid body, 5x3x3 cm, Shamblin III. With complete surgical resection and inverted saphenous vein graft, favorable evolution, with complete permeability of the vascular bridge, without sequelae. Conclusion. This case could correspond to a tumor of familiar etiology, given its early age of presentation. It is necessary to complement the study with images and to objectively determine the associated vascular involvement for surgical planning. In these patients, the complexity of their location and vascular involvement of the tumor requires a multidisciplinary team with head and neck and vascular surgeons for a successful outcome.

Malignant carotid body tumors: What we know, what we do, and what we need to achieve. A systematic review of the literature.

Malignant carotid body tumors (MCBT) are rare and diagnosed after detection of nodal or distant metastases. This systematic review (SR) focuses on MCBT initially approached by surgery. Preferred Reporting Items for SR and Meta-Analysis (MA) guided the articles search from 2000 to 2023 on PubMed, Scopus, and Web of Science. Among 3548 papers, 132 (337 patients) were considered for SR; of these, 20 (158 patients) for MA. Malignancy rate was 7.3%, succinate dehydrogenase (SDH) mutation 17%, age at diagnosis between 4th and 6th decades, with a higher prevalence of females. MCBTs were mostly Shamblin III, with nodal and distant metastasis in 79.7% and 44.7%, respectively. Malignancy should be suspected if CBT >4 cm, Shamblin III, painful or otherwise symptomatic, at the extremes of age, bilateral, with multifocal disease, and SDHx mutations. Levels II-III clearance should be performed to exclude nodal metastases and adjuvant treatments considered on a case-by-case basis.

The value of color doppler ultrasonography combined with computed tomography angiography and magnetic resonance angiography in the preoperative quantification and classification of carotid body tumors: a retrospective analysis.

BACKGROUND: Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) provide accurate vascular imaging information, but their use may be contraindicated. Color Doppler ultrasonography (CDU) provides simple, safe, noninvasive, and reproducible imaging. We therefore investigated the role of preoperative CDU combined with CTA and MRA in the quantification, typing, and diagnosis of carotid body tumors (CBTs). METHODS: We retrospectively analyzed patients with CBTs categorized into group A (type I [n = 1] and type II [n = 10]) or group B (type III [n = 56]) per the intraoperative Shamblin classification. CDU, CTA, and MRA characteristics of CBTs were observed, surgical results were correlated, and the diagnostic threshold of the CBT classification was calculated. RESULTS: CBTs were usually located at the common carotid artery bifurcation, encircling the carotid artery. An increased angle was found between the internal and external carotid arteries. On CDU, CBTs primarily presented as homogeneous hypoechoic masses with clear boundaries, rich flow signals, and a high-speed, low-resistance artery-like flow spectrum. CTA showed uniform or heterogeneous marked enhancement. MRA showed mixed T1 and slightly longer T2 signals and uniform or uneven obvious enhancement. With increases in the lesion size, amount of blood transfused, and operation time, the intraoperative classification level and possibility of skull-base invasion increased. When the maximum diameter of the lesion, the volume of the tumor, the distance between the upper margin of the tumor to the mastoid and the mandibular angle were 3.10 cm, 10.15 cm3, - 3.26 cm, and 0.57 cm, respectively, the largest Youden index was the best diagnostic boundary value for Shamblin type III tumors. CONCLUSIONS: CDU combined with CTA and MRA can accurately evaluate the size and classification of CBTs.

Single-cell transcriptome analysis reveals tumoral microenvironment heterogenicity and hypervascularization in human carotid body tumor.

Carotid body tumor (CBT) is a rare neck tumor located at the adventitia of the common carotid artery bifurcation. The prominent pathological features of CBT are high vascularization and abnormal proliferation. However, single-cell transcriptome analysis of the microenvironment composition and molecular complexity in CBT has yet to be performed. In this study, we performed single-cell RNA sequencing (scRNA-seq) analysis on human CBT to define the cells that contribute to hypervascularization and chronic hyperplasia. Unbiased clustering analysis of transcriptional profiles identified 16 distinct cell populations including endothelial cells (ECs), smooth muscle cells (SMCs), neuron cells, macrophage cells, neutrophil cells, and T cells. Within the ECs population, we defined subsets with angiogenic capacity plus clear signs of later endothelial progenitor cells (EPCs) to normal ECs. Two populations of macrophages were detectable in CBT, macrophage1 showed enrichment in hypoxia-inducible factor-1 (HIF-1) and as well as an early EPCs cell-like population expressing CD14 and vascular endothelial growth factor. In addition to HIF-1-related transcriptional protein expression, macrophages1 also display a neovasculogenesis-promoting phenotype. SMCs included three populations showing platelet-derived growth factor receptor beta and vimentin expression, indicative of a cancer-associated fibroblast phenotype. Finally, we identified three types of neuronal cells, including chief cells and sustentacular cells, and elucidated their distinct roles in the pathogenesis of CBT and abnormal proliferation of tumors. Overall, our study provided the first comprehensive characterization of the transcriptional landscape of CBT at scRNA-seq profiles, providing novel insights into the mechanisms underlying its formation.

Succinate dehydrogenase mutations in head and neck paragangliomas: A systematic review and meta-analysis of individual patients' data.

BACKGROUND: Head and neck paragangliomas (HNPs) have been associated with gene mutations in the succinate dehydrogenase (SDH) complex, but the clinical significance remains unclear. We sought to explore the demographics, clinical characteristics, treatment methods, and outcomes of SDH-mutated HNPs. METHODS: Databases were systematically searched. Pooled event ratio and relative 95% confidence intervals were calculated for dichotomous outcomes. Meta-regression was performed. Cochran's Q test and I2 test assessed heterogeneity. Funnel plot and Egger's regression test assessed publication bias. RESULTS: Forty-two studies with 8849 patients were included. Meta-regression revealed a significant correlation between multifocality and SDHD mutations (0.03 ± 0.006, p < 0.0001) and between distant metastases and SDHB mutations (0.06 ± 0.023, p = 0.008). There was no correlation between sex, age, tumor size, or familial occurrences and SDH-related mutations. CONCLUSION: Multifocality of HNPs correlates with the SDHD mutational subtype, and metastases correlate with the SDHB subtype. Knowledge of HNP phenotypes associated with SDH-related mutations has the potential to influence the management approach to such HNPs.

Synchronous Carotid Body and Glomus Jugulare Tumors : A Case Report and Review of Literature.

Paragangliomas are rare neuroendocrine tumors that are usually benign in nature. They may be either familial or sporadic in their occurrence. Numerous neuroendocrine tumors are collectively included under the umbrella of paragangliomas. Among them, carotid body tumors and glomus jugulare tumors are extremely rare. Thus, we present a rare case of 29-year-old male who was admitted with hearing difficulties and tinnitus in the left ear, with swelling on the left side of the neck. Based on clinical and radiological findings, a diagnosis of left-sided glomus jugulare with carotid body tumor was made. The patient underwent a twostage surgery with an interval of approximately 2 months. Histopathology revealed a paraganglioma. Herein, we present the clinical features, imaging findings, management, and a brief review of literature on the classification, evaluation, and management of carotid body and glomus jugulare tumors. Paraganglioma is a slow-growing tumor. The synchronous occurrence of carotid body and glomus jugulare tumors is infrequent. Microsurgical resection remains the primary treatment modality. Therefore, our patient underwent two-stage surgery. The rarity of occurrence and the proximity and adherence to vital neurovascular structures have resulted in the treatment of paragangliomas remaining a challenge.

Carotid Body Tumor in a 26-Year-Old Male Patient Managed With Preoperative Embolization.

Carotid body tumors are rare, highly vascularized neuroendocrine tumors that arise near the bifurcation of the common carotid artery (CCA). Controversy exists in the management of those tumors about whether preoperative embolization facilitates surgical excision and decreases perioperative complication risk. We present the case of a 26-year-old patient with a carotid body tumor manifesting as a painless pulsatile mass in the anterior triangle over the left side of the neck and provide details of the preoperative diagnostic steps. Treatment included preoperative embolization of the tumor followed by surgical excision after 48 hours to safely address this rare pathology, resulting in a favorable outcome for the patient.

Role of Preoperative Embolization in Surgical Management of Carotid Body Tumors: A Systematic Review and Meta-Analysis.

The objective of this study is to evaluate the effect of preoperative embolization on carotid body tumor resection. A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed, Scopus, and Web of Science were screened for studies published between 2010 and 2022. Primary outcomes investigated were intraoperative blood loss, operative time, length of hospital stay, and perioperative complications such as transient ischemic attack (TIA)/stroke, vascular injury, and cranial nerve injury (CNI). A random effects model was used in cases where study heterogeneity was high. Overall, 25 studies were included in the systematic review, involving 1649 patients: 23 studies were eligible for meta-analysis. The incidence of vascular injury was significantly less in the preoperative embolization group (odds ratio (OR) = 0.60; 95% CI: 0.42-0.84; P = .003). There was no statistically significant difference between the two groups regarding intraoperative blood loss, operative time, length of hospital stay, incidence of TIA/stroke, and CNI. Subgroup analyses did not demonstrate significant difference between Shamblin I, II, and III subgroups regarding operative time. This meta-analysis found preoperative embolization to be significantly beneficial in reducing incidence of vascular injury.