Background: Middle meningeal artery (MMA) embolization has been increasingly applied in adult populations for the treatment of chronic subdural hematomas (cSDH). There is a paucity of literature on the indications, safety, and outcomes of MMA embolization in the pediatric population. Summary: A systematic literature review on pediatric patients undergoing MMA embolization was performed. We also report the case of successful bilateral MMA embolization for persistent subdural hematomas following resection of a juvenile pilocytic astrocytoma. Persistent bilateral subdural hematomas following resection of a large brain tumor resolved following MMA embolization in a 13-year-old male. Indications for MMA embolization in the pediatric literature included cSDH (6/13, 46.2%), treatment or preoperative embolization of arteriovenous fistula or arteriovenous malformation (3/13, 23.1%), preoperative embolization for tumor resection (1/13, 7.7%), or treatment of acute epidural hematoma (1/13, 7.7%). Embolic agents included microspheres or microparticles (2/13, 15.4%), Onyx (3/13, 23.1%), NBCA (3/13, 23.1%), or coils (4/13, 30.8%). Key Messages: Whereas MMA embolization has primarily been applied in the adult population for subdural hematoma in the setting of cardiac disease and anticoagulant use, we present a novel application of MMA embolization in the management of persistent subdural hematoma following resection of a large space-occupying lesion. A systematic review of MMA embolization in pediatric patients currently shows efficacy; a multi-institutional study is warranted to further refine indications, timing, and safety of the procedure.

Middle meningeal artery (MMA) embolization is a widely studied intervention in adults with favorable safety and efficacy for conditions like subdural hematomas, as well as in the treatment of arteriovenous fistula (AVF), arteriovenous malformation (AVM), and tumor [1‒3]. This technique was first introduced in 1994, and the majority of studies since then have focused on its benefits in adults [4]. Chronic SDH (cSDH) is one of the most common conditions requiring neurosurgical intervention within this population [5].

Fewer studies, however, have focused on the utility of MMA embolization in pediatric patients. Although subdural hematomas may form in patients with congenital cardiac disease on systemic anticoagulation and/or antiplatelet agents, within the pediatric population, cSDH is far less common than in adults. In addition, they tend to resolve over time without intervention, unless there is repeated trauma to the head or resumption of anticoagulation or antiplatelet agents [6]. The MMA is a major target for embolization due to its role in providing a vascular supply for cSDH, AVFs, AVMs, and tumors [7]. MMA embolization leads to the elimination of the blood supply to these pathologies, which in turn is associated with resolution. Here, we report a case in which a pediatric patient who presented with persistent bilateral subdural hematomas following resection of a large pilocytic astrocytoma and subsequently underwent bilateral MMA embolization with subsequent subdural hematoma resolution. In addition, we performed a systematic review of MMA embolization in pediatric patients for all indications.

Search Strategy

We performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1) [8]. The databases of PubMed, Web of Science, and Embase were queried by one author (S.V.) on January 29, 2023, using the search terms: (pediatric OR child OR children) AND (“middle meningeal” OR “MMA”) AND (embolization OR embo).

Fig. 1.

Search query, PRISMA diagram. PRISMA diagram delineating search strategy to arrive at the included articles.

Fig. 1.

Search query, PRISMA diagram. PRISMA diagram delineating search strategy to arrive at the included articles.

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Selection Process

Two authors (S.V. and D.Z.) systematically organized the query results using Microsoft Excel; duplicates were removed and abstracts, and titles were screened for inclusion and exclusion criteria. Articles were excluded if they met one of the following criteria: non-English article or letter to the editor, comment, or abstract. Articles were included if they met all of the following criteria: MMA embolization described and patients <18 years old. References were reviewed to identify any additional studies for inclusion.

Data Items and Synthesis Methods

Baseline characteristics and patient demographics were extracted from the included articles. Pathology and indication for MMA embolization, along with procedural characteristics, such as laterality and embolic agent, were also described. Any follow-up or outcome data included in the articles were explored as well. We also describe a case of successful MMA embolization for subdural hematomas after craniotomy for resection of a large tumor in a 13-year-old male at our institution.

Case Presentation

Case History

A 13-year-old male with no significant past medical history presented with headache and vomiting. Cranial imaging showed a large pineal region mass (Fig. 2). He underwent endoscopic third ventriculostomy for obstructive hydrocephalus and endoscopic biopsy. Pathology was consistent with pilocytic astrocytoma. He then underwent craniotomy for gross total resection using a transcortical approach. He tolerated the procedure well, and his initial symptoms resolved. He was discharged to home but returned 2 weeks later with recurrence of headache and vomiting. Head CT showed bilateral subdural hygromas and a pseudomeningocele over the frontal burr hole used for ventriculostomy (Fig. 3a, b). He underwent ventriculoperitoneal shunt placement for hydrocephalus. A Codman Certas plus programmable valve with an anti-siphon guard by Integra (Princeton, NJ, USA) at a level of 4 was placed. His recurrent headache and vomiting improved. He was followed with serial imaging. Approximately 2 months after shunt placement, he developed right greater than left subdural hematomas (Fig. 3c, d). His valve resistance was raised to the highest resistance, and he underwent craniotomy for right followed by left subdural hematoma (Fig. 3e, f). Although the patient did not have recurrence of headache and vomiting at this time, the subdural hematomas persisted 3 months after surgery.

Fig. 2.

Left thalamic region juvenile pilocytic astrocytoma. Preoperative T1-contrast enhanced magnetic resonance imaging (MRI) showing left thalamic region 6-cm enhancing solid and cystic juvenile pilocytic astrocytoma in axial (a) and coronal (b) planes. Postoperative T1-contrast enhanced MRI showing gross total resection in axial (c) and coronal (d) planes.

Fig. 2.

Left thalamic region juvenile pilocytic astrocytoma. Preoperative T1-contrast enhanced magnetic resonance imaging (MRI) showing left thalamic region 6-cm enhancing solid and cystic juvenile pilocytic astrocytoma in axial (a) and coronal (b) planes. Postoperative T1-contrast enhanced MRI showing gross total resection in axial (c) and coronal (d) planes.

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Fig. 3.

Progression of subdural hematomas requiring bilateral craniotomies. Computed tomography (CT) in axial (a) and coronal (b) planes showing hydrocephalus and bilateral subdural hematomas prior to ventriculoperitoneal shunt (VPS) placement. MRI axial (c) and coronal (d) planes show the development of complex bilateral subdural hematomas following VPS placement. Axial (e) and coronal (f) CT imaging status post-bilateral craniotomies for subdural hematoma evacuations.

Fig. 3.

Progression of subdural hematomas requiring bilateral craniotomies. Computed tomography (CT) in axial (a) and coronal (b) planes showing hydrocephalus and bilateral subdural hematomas prior to ventriculoperitoneal shunt (VPS) placement. MRI axial (c) and coronal (d) planes show the development of complex bilateral subdural hematomas following VPS placement. Axial (e) and coronal (f) CT imaging status post-bilateral craniotomies for subdural hematoma evacuations.

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MMA Embolization Procedure

Options of continued clinical and radiographic monitoring versus MMA embolization to reduce the risk of enlargement or recurrence were discussed, and embolization was selected by the patient’s mother. Risks such as groin infection, groin hematoma, retroperitoneal hematoma, vessel dissection, ischemic or hemorrhage insult, neurological worsening, and failure to eliminate the subdural hematoma were discussed with the patient and family. Additional risks of trigeminocardiac dysrhythmia, facial paralysis, vision loss, and stroke were also discussed.

Informed consent was obtained, and the patient was taken to the angiography suite and intubated under general anesthesia. A cerebral angiogram was performed and found normal anatomy with filling of the retina through standard ophthalmic arteries bilaterally. The external carotid arteries were identified, and the MMAs were deemed appropriate for embolization. We then proceeded with bilateral MMA embolization. With background roadmap subtraction, an Excelsior SL-10 microcatheter (Stryker, CA, USA) was delivered over a soft microwire into the left frontal branch of the MMA. Microinjections were performed to verify the absence of dangerous collaterals, including meningeal collaterals. The artery was occluded using 150–200 μm Contour particles (Boston Scientific, MA, USA). The microcatheter was withdrawn to a slightly more proximal position, and two Avenir Coils (Wallaby Medical, CA, USA) were deployed in the frontal branch of the left MMA. The procedure was repeated on the right, with the deployment of one Avenir Coil (Wallaby Medical) in the right MMA. Final angiography showed no change in filling of the retina through the ophthalmic artery, and postoperative imaging showed no interval hemorrhage.

Postoperative Course

The patient tolerated the procedure well without complication. Follow-up imaging at 3 and 9 months showed diminishing bilateral subdural collections (Fig. 4). His presenting symptoms resolved, and he now has occasional headaches.

Fig. 4.

Progression of subdural collections before and after MMA embolization. Axial (a, c) and coronal (b, d) CT images showing subdural collections 1 month (a, b) and 3 months (c, d) following craniotomy. The vertical line depicts the time of MMA embolization. Axial (e) and coronal (f) CT showing regression of subdural collections at 3-month follow-up. Axial (g) and coronal (h) T1-contrast enhanced MRI imaging showing near-complete resolution of subdural collections at 9 months following MMA embolization.

Fig. 4.

Progression of subdural collections before and after MMA embolization. Axial (a, c) and coronal (b, d) CT images showing subdural collections 1 month (a, b) and 3 months (c, d) following craniotomy. The vertical line depicts the time of MMA embolization. Axial (e) and coronal (f) CT showing regression of subdural collections at 3-month follow-up. Axial (g) and coronal (h) T1-contrast enhanced MRI imaging showing near-complete resolution of subdural collections at 9 months following MMA embolization.

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Systematic Review

Thirteen articles describing MMA embolization in pediatric patients were included in the review after application of inclusion and exclusion criteria. All articles were case reports published between 2017 and 2022. Patient age ranged from 4 months to 16 years old, with a median of 5 years old (IQR 1.25–13.5), and embolic agents included microspheres or microparticles (2/13, 15.4%), Onyx (3/13, 23.1%), NBCA (3/13, 23.1%), or coils (4/13, 30.8%) (Table 1).

Table 1.

Characteristics of articles included in the systematic review (included articles)

Author, yearAgePathologyEtiologyIndicationPrior interventionSide of MMA embo (Embolic agent)Presenting symptomsComplicationsClinical outcomeRadiographic outcome
Scouter et al. [9] (2022) 15 months cSDH AC, awaiting heart transplant Recurrent and expanding SDH, AC requirement for cardiac condition Monitored via serial cranial ultrasounds Bilateral (microspheres) Intact  Neurologic status remained intact 1 month: stable L SDH, recurrent R SDH 
Yazawa et al. [10] (2022) 15 months cSDH AC, awaiting heart transplant AC requirement with ventricular assist device (VAD) Craniotomy Left (NBCA) Vomiting Migration of embolic material into intracranial circulation, mortality Intact at 2 months, died of VAD-associated infection 8-month post-procedure Diminishing SDH at 2 months, NBCA migration into intracranial vessels (no neurological deficits) 
Shigematsu et al. [11] (2021) 7 months SDH AC, awaiting heart transplant Bilateral SDH expanding on repeat imaging  Bilateral (NBCA) Intact  Intact Improvement of cSDH at 10 months 
Saenz et al. [18] (2021) 4 months DAVF  Prepare for DAVF resection  NBCA Vomiting  DAVF resection DAVF partially thrombosed 
Martinez et al. [19] (2017) Adolescent AVF Trauma, temporal bone fracture Symptom relief and treatment  Left (coils) Bruit and tinnitus in L ear  Resolution of tinnitus Obliteration of fistulous connection 
Faber et al. [12] (2021) 18 months cSDH Non-accidental trauma Residual SDH after craniotomy Bilateral bur hole, right craniotomy Right (Onyx) Enlarging head circumference, dysconjugate gaze  Resolution of dysconjugate gaze Diminishing SDH at 6 months 
Ravi et al. [13] (2022) 2 years SDH Non-accidental trauma cSDH after decompressive hemicraniectomy (DHC) R DHC and acute SDH evacuation Right (Onyx) Stable CN III palsy  Stable CN III palsy, overall improved neurologic function, Diminishing SDH at 6 months Diminishing SDH at 6 months 
Khatibi et al. [20] (2016) 16 years AVM  AVM embolization NBCA embolization, SRS Left (Onyx) Balance difficulty, worsening fine motor skills Trigeminocardiac reflex, asystole Repeat embolization  
Tawfik et al. [21] (2018) 13 years JNA  Preoperative embolization  Left (coils) Nasal congestion, self-limited epistaxis, snoring, labored breathing Transient CN VII palsy Self-resolved CN VII palsy Tumor resection 
Madison et al. [17] (2021) 14 years Epidural hematoma (EDH) Trauma Prevent EDH expansion  Right (coils) Vomiting, lethargy  Intact Resolved epidural hematoma 
Paro et al. [14] (2023) 8 years Acute on cSDH Idiopathic Clinical stability, minimal mass effect, plan for endovascular access for diagnostic  Right (particles, coils) Headaches  Resolution of headaches Complete SDH resolution at 6 months 
Kang et al. [15] (2015) 13 years cSDH, arachnoid cyst  Recurrent cSDH 2 Burr-hole evacuation Right (coils) Headache, nausea, vomiting  Intact Complete SDH resolution 
Marnat et al. [16] (2021) 16 years cSDH, arachnoid cyst  Recurrent cSDH Burr-hole evacuation Left (microparticles) Asymptomatic  Intact Complete SDH resolution at 6 months 
Current study 13 years Bilateral SDH Craniotomy for tumor followed by subdural hygroma formation Headache, persistent subdural hematomas Bilateral craniotomy for SDH Bilateral (particles, coils) Headache  Occasional headache SDH resolution without recurrence at 9 months 
Author, yearAgePathologyEtiologyIndicationPrior interventionSide of MMA embo (Embolic agent)Presenting symptomsComplicationsClinical outcomeRadiographic outcome
Scouter et al. [9] (2022) 15 months cSDH AC, awaiting heart transplant Recurrent and expanding SDH, AC requirement for cardiac condition Monitored via serial cranial ultrasounds Bilateral (microspheres) Intact  Neurologic status remained intact 1 month: stable L SDH, recurrent R SDH 
Yazawa et al. [10] (2022) 15 months cSDH AC, awaiting heart transplant AC requirement with ventricular assist device (VAD) Craniotomy Left (NBCA) Vomiting Migration of embolic material into intracranial circulation, mortality Intact at 2 months, died of VAD-associated infection 8-month post-procedure Diminishing SDH at 2 months, NBCA migration into intracranial vessels (no neurological deficits) 
Shigematsu et al. [11] (2021) 7 months SDH AC, awaiting heart transplant Bilateral SDH expanding on repeat imaging  Bilateral (NBCA) Intact  Intact Improvement of cSDH at 10 months 
Saenz et al. [18] (2021) 4 months DAVF  Prepare for DAVF resection  NBCA Vomiting  DAVF resection DAVF partially thrombosed 
Martinez et al. [19] (2017) Adolescent AVF Trauma, temporal bone fracture Symptom relief and treatment  Left (coils) Bruit and tinnitus in L ear  Resolution of tinnitus Obliteration of fistulous connection 
Faber et al. [12] (2021) 18 months cSDH Non-accidental trauma Residual SDH after craniotomy Bilateral bur hole, right craniotomy Right (Onyx) Enlarging head circumference, dysconjugate gaze  Resolution of dysconjugate gaze Diminishing SDH at 6 months 
Ravi et al. [13] (2022) 2 years SDH Non-accidental trauma cSDH after decompressive hemicraniectomy (DHC) R DHC and acute SDH evacuation Right (Onyx) Stable CN III palsy  Stable CN III palsy, overall improved neurologic function, Diminishing SDH at 6 months Diminishing SDH at 6 months 
Khatibi et al. [20] (2016) 16 years AVM  AVM embolization NBCA embolization, SRS Left (Onyx) Balance difficulty, worsening fine motor skills Trigeminocardiac reflex, asystole Repeat embolization  
Tawfik et al. [21] (2018) 13 years JNA  Preoperative embolization  Left (coils) Nasal congestion, self-limited epistaxis, snoring, labored breathing Transient CN VII palsy Self-resolved CN VII palsy Tumor resection 
Madison et al. [17] (2021) 14 years Epidural hematoma (EDH) Trauma Prevent EDH expansion  Right (coils) Vomiting, lethargy  Intact Resolved epidural hematoma 
Paro et al. [14] (2023) 8 years Acute on cSDH Idiopathic Clinical stability, minimal mass effect, plan for endovascular access for diagnostic  Right (particles, coils) Headaches  Resolution of headaches Complete SDH resolution at 6 months 
Kang et al. [15] (2015) 13 years cSDH, arachnoid cyst  Recurrent cSDH 2 Burr-hole evacuation Right (coils) Headache, nausea, vomiting  Intact Complete SDH resolution 
Marnat et al. [16] (2021) 16 years cSDH, arachnoid cyst  Recurrent cSDH Burr-hole evacuation Left (microparticles) Asymptomatic  Intact Complete SDH resolution at 6 months 
Current study 13 years Bilateral SDH Craniotomy for tumor followed by subdural hygroma formation Headache, persistent subdural hematomas Bilateral craniotomy for SDH Bilateral (particles, coils) Headache  Occasional headache SDH resolution without recurrence at 9 months 

Indications for MMA embolization included cSDH (8/13, 61.5%), treatment or preparation for AVF/AVM resection (3/13, 23.1%), preparation for tumor resection (1/13, 7.7%), or treatment of acute epidural hematoma (1/13, 7.7%). Three of the patients with SDH were awaiting heart transplants; their anticoagulation requirements rendered open surgery high-risk, and MMA embolization was chosen [9‒11]. For all 3 cases, the SDH was either stable or diminishing at follow-up [9‒11]. Two cases of cSDH were the result of non-accidental trauma [12, 13]. Both of these cases were treated with Onyx embolization and had diminishing SDH at 6 months [12, 13]. One case proceeded with MMA embolization given lack of midline shift and plan for endovascular access for diagnostic purposes [14]. Two cases proceeded with MMA embolization after recurrence of SDH that had formed following rupture of arachnoid cysts [15, 16]. In another case report, MMA embolization was chosen over open surgery to successfully treat acute epidural hematoma [17]. Three cases described MMA embolization in preparation for AVF or AVM resection [18‒20]. One case described embolization of the MMA contribution of a large cerebellar recurrent AVM [20]. This patient required repeat embolization of the left anterior inferior cerebellar artery and posterior inferior cerebellar artery on future admissions [20]. Saenz et al. and Martinez et al. [18, 19] describe cases of MMA embolization in preparation for open AVF resection. Finally, 1 case report describes MMA embolization in a 13-year-old boy with a large juvenile nasopharyngeal angiofibroma (JNA) [21].

One reported complication was the occurrence of the trigeminocardiac reflex in which a 16-year-old patient became bradycardic and then proceeded to asystole following MMA embolization in the setting of a large cerebellar AVM with arterial feeders from the external carotid artery [20]. After resuscitation, there was a return of spontaneous circulation, but the patient quickly became tachycardic. Nitroprusside and labetalol were administered, leading to rebound hypotension and asystole. Following further resuscitation, there was return of normal cardiac rhythm. On evaluation, the patient had sustained ventricular hypokinesis with an ejection fraction of 28%; however, by the next day, repeat evaluation showed normalization of his left ventricular function. In another report, embolisate migrated into the intracranial vessels, although no neurological deficits were noted [10]. Another patient developed a transient facial palsy during preoperative embolization of a JNA that resolved over time [21]. One mortality was reported in a patient 8 months after MMA embolization from infection associated with a ventricular assist device.

While pediatric MMA embolization itself is uncommon, our report is the first, to our knowledge, to report MMA embolization applied for persistent subdural hematoma following craniotomy for large tumor resection. The development of a subdural fluid collection or hygroma after craniotomy for a large space-occupying lesion is common in pediatric neurosurgery [22]. Hygroma formation after transcortical approaches for intraventricular or paraventricular tumors has been reported in up to 40% of cases [22, 23]. The mechanism may relate to the presence of preoperative hydrocephalus and escape of cerebrospinal fluid through an ependymal and cortical defect into the subdural space [24]. Although less than 20% of cases typically warrant surgical intervention [22], subdural hygromas may become symptomatic subdural hematomas over time, as occurred in the presently reported patient. In this clinical scenario, compared to repeat craniotomy, MMA embolization offered a less invasive option to reduce the risk of subdural progression and encourage absorption of the blood and brain re-expansion over time. Following craniotomy for hematoma evacuation, the remnant subdural hematoma persisted for over 3 months, despite raising the valve resistance, before MMA embolization was pursued. Following embolization, the subdural hematoma significantly decreased within 3 months, suggesting that the intervention, rather than additional time, contributed to hematoma resolution.

Indications for MMA embolization in pediatric patients continue to be under investigation. In pediatrics, case reports describe MMA embolization as an alternative for cSDH treatment when surgery is deemed high-risk due to anticoagulation requirements or as preparation for AVM/AVF or tumor resection [9, 20]. In adults, the overwhelming majority of papers discuss MMA embolization in the context of cSDHs [1, 25, 26]. One systematic review identified four more specific indications for MMA embolization, which include preventing surgery in patients with minimally symptomatic cSDHs, prophylaxis against recurrence after a first surgery, prevention of second recurrence after a preceding recurrence, and as an adjunctive treatment in the case of a second surgery [27]. Because patients with subdural hygromas are at increased risk of developing chronic subdural hematoma [28, 29], the current study raises the question of whether to offer MMA embolization at the subdural hygroma stage, such as in the weeks following craniotomy for large tumor resection, with the goal of decreasing the rate of future symptomatic subdural hematoma formation. At this time, due to the difficulty in predicting which patients with subdural hygromas will become symptomatic, the authors recommend clinical and radiographic surveillance. Should enlargement of the subdural collection or early evidence of subdural hematoma formation be noted without significant mass effect, MMA embolization may be considered as a treatment option, especially in patients with an ongoing need for anticoagulation or antiplatelet agents or for those who are poor surgical candidates due to comorbidities.

Our study is unique in that it includes data from MMA embolization in pediatric patients for multiple pathologies and not only chronic subdural hematoma, which has most commonly been reported in the literature. By including multiple indications, additional data were collected regarding techniques, complications, and outcomes. A variety of embolic agents, such as NBCA and Onyx, were used to perform MMA embolization in the studies analyzed in our systematic review. Coils were used in several cases to reduce the risk of recurrence in treated SDH and as the primary method of embolization for AVF and JNA. Among identified patients, ranging from 4 months to 16 years old, no vascular or access-related complications were reported. Among the reported complications, none had long-term consequences. For example, unintended migration of embolic material into the intracranial circulation was not associated with neurological deficit [10], a transient facial nerve palsy after embolization for a JNA resolved [21], and cardiac function in a patient with a significant trigeminocardiac reflex normalized 1 day after the procedure [20].

In terms of outcomes, when performed for SDH, the majority of studies reported stability or resolution; however, one study reported initial stabilization followed by recurrent hemorrhages after antiplatelet and anticoagulants were restarted [9]. In the only study to report a mortality, the patient expired from infectious causes unrelated to MMA embolization several months after the embolization procedure [10]. Taken together, these findings favor safety of MMA embolization in pediatric patients. However, potential serious complications, such as vision loss and stroke, may occur and must be discussed with the patient and family during the consent process. Prospective clinical studies are needed to assess risk factors and ways to minimize such complications. Pre-procedural angiography, careful choice of embolic material, and verification of the lack of dangerous collaterals may help minimize the risk of serious complications.

Limitations

Our systematic review has several limitations. Although efforts were made to incorporate all studies up to the time of literature search, the growing popularity of MMA is such that papers published following the date of our systematic review are not included in the results. Additionally, our data may be limited by publication bias, as reports of lasting or serious complications are less likely to have been published than successful outcomes. Also, procedural details describing access sites and embolization materials were not explored in further detail due to the wide range of techniques described in the included articles. Finally, due to the relative paucity of literature on MMA embolization in pediatric patients, most of the papers included in our systematic review were case reports, which are associated with inherent biases.

MMA embolization can be considered for subdural hematoma formation following craniotomy for resection of a large space-occupying lesion, such as tumor, in pediatric patients. In pediatric patients, a systematic review was performed, showing that the technique has been safely applied with high efficacy in cases of SDH as well as preoperative embolization of tumors and vascular lesions. A clinical registry or multi-institutional study is warranted to further refine indications, timing, and safety of MMA embolization in the pediatric population.

Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

No funding was obtained for this study.

Sima Vazquez: conceptualization, methodology, investigation, and writing – review and editing; David Zuckerman: methodology, investigation, and writing – review and editing; Chirag Gandhi, Fawaz Al-Mufti, Carrie Muh, and Justin Santarelli: reviewing and editing; and Jared Pisapia: conceptualization, methodology, supervision, writing – review and editing, and project administration.

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