Approaches to Incidental Intradural Tumors of the Spine in the Pediatric Population

Primary intradural tumors of the spine account for an estimated 5–10% of central nervous system (CNS) neoplasms [1]. Intradural extramedullary tumors, located within the dura external to the cord, represent around 70–80% of lesions, while intradural intramedullary spinal cord tumors (IMSCTs) represent 20–30% of lesions [1, 2]. Intradural tumors include schwannomas, meningiomas, ependymomas, astrocytomas, hemangioblastomas (HGBMs), ganglioneuromas, and lipomas, some of which may be further classified into separate grades according to the World Health Organization categorization scheme [3]. Overall, these tumors are less prevalent than extradural spine tumors, which constitute around 60% of all spine tumors [4]. Despite their rarity, intradural lesions can produce significant morbidity, including neck or back pain, motor weakness, numbness and dysesthesias, and overt myelopathy, including gait difficulty and bowel or bladder dysfunction [4, 5]. Symptomatic lesions, particularly those producing myelopathy or motor deficits, are treated with surgical resection to prevent deterioration of neurological function [6].

Although the management of symptomatic lesions is well established, incidental intradural tumors of the spine present a more vexing management problem. Some incidental lesions may never produce focal deficits, while others would benefit from pre-emptive resection to prevent neurological deterioration. However, all intradural spine surgeries risk postoperative neurological deficits, and the risk of iatrogenic deficits can be difficult for patients with normal neurological status to consider [7, 8]. In addition to loss of neurological function, standard risks of spine surgery should be considered, including wound infection, cerebrospinal fluid leaks, spinal deformity, pneumonia, ileus, and death. Such adverse events may occur in anywhere between 10 and 20% of spine surgery cases [9]. Surgery on intradural tumors is also associated with high healthcare utilization, including extended hospitalizations and nonroutine discharges [10, 11]. Furthermore, distinguishing between a congenital, asymptomatic, stable lesion and a small, asymptomatic, slowly enlarging tumor can be challenging in the pediatric population.

Magnetic resonance imaging (MRI) provides high resolution of soft tissue structures and is typically used for diagnosis of intradural lesions [12]. MRI use in the USA has expanded rapidly over time, quadrupling between 1996 and 2010 [13]. These trends are expected to continue, and advances in MRI technology may further improve clinicians’ ability to detect small lesions. Children are frequently referred for MRIs for an array of indications, including headaches, scoliosis, lumbago, dorsalgia, and trauma workup [14, 15]. Moreover, the upper cervical spine can often be assessed on brain MRIs. Consequently, surgeons should be prepared to encounter incidental intradural tumors in children, defined as unexpected lesions with the imaging appearance characteristic of tumors. However, guidelines for dealing with incidental intradural tumors of the spine are lacking due to the rarity of these lesions. Therefore, we review the literature on incidental intradural tumors and offer recommendations for management of these lesions to aid surgeons in their decision-making and patient counseling.

Management paradigms for intracranial incidentalomas have been discussed more extensively in the literature compared to incidental intradural spine tumors. Lessons from the treatment of incidental intracranial tumors can be informative for the spine tumor population. Jumah et al. [16] performed a systematic review of 14 studies with 308 pediatric patients whose MRIs showed incidental brain tumors and found that 79% of patients were managed with follow-up surveillance, of which 73% remained stable at 30-month average follow-up and 22% progressed. Although complete remission was observed in all cases treated with prompt resection, most of the lesions that progressed did not cause symptoms and/or stabilized, obviating the need for surgery. Consequently, conservative follow-up was deemed appropriate for most cases, preventing unnecessary surgery in children whose lesions would remain stable while allowing detection of growing tumors on follow-up scans [16].

Similarly, Soleman et al. [17] conducted a systematic review of 34 studies examining incidental intracranial tumors in children. They found that most cases suggestive of low-grade tumors can be managed with follow-up, but delayed surgical resection was necessary in 9.5% of cases due to progression on imaging or new radiographic changes. The authors note that childhood brain tumors are typically slower growing than adult tumors and can occasionally regress spontaneously, favoring watchful waiting in the pediatric population.

The risk of malignant transformation or tumor progression is not precisely known for pediatric intradural low-grade tumors of the spine, but similar considerations from the intracranial literature may apply. Roth et al. [18] conducted an international questionnaire concerning management of incidental brain tumors in children and found consensus favoring conservative management for lesions with stable appearance over time, with biopsy or resection reserved for growing lesions. However, applying these suggestions to intradural spine tumors must also account for differences in growth rates, malignant transformation, and surgical morbidity. Intradural extramedullary tumors usually are more amenable for safe complete resection without risking neurological deficits, whereas resection of IMSCTs can have a high risk of postoperative neurological changes.

Comparatively less literature has focused on incidental intradural tumors of the spine. Prevalence of incidentalomas of the spine and spinal cord were estimated by Hiremath et al. [19] as 8% in the cervical region, 4.7% in the thoracic region, and 9.4% in the lumbar region in the pediatric population. However, their definition was not restricted to tumors, but also included syringohydromyelia, cerebrospinal fluid flow artifacts, perineural cysts, venous enhancement of the filum terminale, and ventriculus terminalis. Smorgick et al. [20] reviewed 1,145 T2-weighted whole-spine sagittal MRIs and found that only 2 patients had intradural tumors, and both received surgical intervention. Extrapolation to the pediatric population is difficult as the average ages reported were for adults. A separate study by Carlson et al. [21] of 1,503 patients found an imaging report describing an incidental vertebral marrow signal abnormality in 65 patients, of which 31 received further workup while 10 were followed conservatively without additional testing. Only one out of the 65 patients were diagnosed with a malignancy, determined on pathology as multiple myeloma.

More commonly reported are incidental extradural tumors. Degenerative changes and spondylosis are particularly prevalent on imaging, although these incidental findings are far more common in adults [22]. In the pediatric population, common incidental findings include scoliosis, vertebral hemangiomas, congenital fusion, abnormal segmentation, os odontoideum, and spina bifida occulta [15]. Radiologists reviewing spinal MRIs are recommended to evaluate for extraspinal incidental findings, including thyroglossal duct cysts, hepatic masses, lung nodules, and renal cysts, given that they occur at a nontrivial rate and early detection can significantly improve outcomes [23].

Despite the apparent rarity of incidental intradural tumors, early detection is critical in cases that would proceed toward malignant transformation or continued expansion and cause substantial neurological decline. Therefore, careful attention should be afforded to incidental intradural findings. However, consensus guidelines are lacking on the optimal management of these findings, which must carefully consider the risks of iatrogenic deficits from aggressive early intervention, the potential for neurological impairment and death in the absence of surgery, and the anticipated natural history of a given lesion in the absence of a confirmed pathology.

Evaluation of the incidental intradural spine tumor should include a prediction of the expected natural history of the lesion. The imaging features of the lesion, such as enhancement pattern, presence of clear versus diffuse borders, and associated syrinxes, can help identify the underlying pathology even without a tissue biopsy. Based on the underlying pathology, the clinician can counsel the patient on the aggressiveness of the tumor, likelihood of malignancy, risk of neurological deficits, and feasibility of resection. For example, intramedullary astrocytomas present with poor margins and can cause significant morbidity, with resection complicated by infiltration of the cord [2, 6, 24]. However, pediatric patients have a higher frequency of low-grade astrocytomas compared to adults, with favorable outcomes after resection [25, 26]. On the other hand, intramedullary ependymomas present as well-circumscribed lesions and are often associated with syrinxes that improve identification of resection margins. The tumor can remain stable without progression over years. Indeed, Behmanesh studied 13 patients with symptomatic intramedullary ependymomas treated conservatively, finding no significant worsening of neurological function over time [27]. All the more so, conservative management of asymptomatic patients with intramedullary ependymomas constitutes a reasonable treatment option given their indolent and benign nature.

Heterogeneity exists within tumor pathologies concerning aggressiveness and growth rate, and follow-up imaging can assess the tumor’s propensity for expansion. In particular, intradural extramedullary schwannomas can adopt a wide range of growth patterns. Lee et al. [28] followed 56 spinal schwannomas and found an annual growth rate of 5.45%, although this ranged from 0.14 to 14% over an average of 43 months. They divided their cohort between growing and stable lesions, recommending careful follow-up of tumors growing more than 2.5% of their volume annually given the risk of continued expansion and aggressive behavior. Lubelski et al. [29] studied the natural history of 109 spinal schwannomas, observing that 63 were slow growing while 30 were fast growing. Although most of the tumors were slow growing, at least two follow-up images are recommended to determine the anticipated growth trajectory given the inherent variability across patients with spinal schwannomas.

Several genetic syndromes increase the likelihood of encountering intradural tumors (Table 1). Patients discovered on imaging to have multiple spinal tumors should be worked up extensively for a genetic syndrome and undergo brain MRI as well to screen for additional lesions. Although the initially discovered lesion may at first be considered “incidental,” the identification of a tumor-predisposing genetic syndrome should prompt a reconsideration of the lesion as “asymptomatic” instead as the lesion has a clear cause. Imaging in these patients often demonstrates multiple tumors in the CNS, and any given lesion may or may not be symptomatic.

Given the tumor burden associated with these conditions, resection of each lesion would likely entail prohibitive morbidity and is therefore contraindicated for asymptomatic lesions. However, the natural history of these lesions may involve continued growth and expansion over time. Moreover, a patient with spinal tumors due to a genetic syndrome may be also suffering from extraspinal tumors that require greater priority and earlier treatment. Therefore, patients with underlying genetic syndromes are afforded special consideration in workup and management.

Asymptomatic spinal tumors are frequently encountered in patients with neurofibromatosis type 2 (NF2), a rare syndrome accounting for 3% of cases of genetic neurofibromatosis [30]. Both intradural extramedullary, including schwannomas and meningiomas, and intradural intramedullary tumors, including ependymomas and astrocytomas, are encountered (shown in Fig. 1) [31]. Pediatric patients usually face increased morbidity and mortality compared to adults with NF2 [32]. Routine screening with spine MRIs is recommended beginning at ages 10–12 years and can be as frequent as every 6–12 months [31, 33]. As a result, asymptomatic spinal tumors are often discovered.

Despite the overall rarity of the syndrome, NF2 patients account for 2.5% of patients with spinal cord tumors [34, 35]. These intradural schwannomas frequently behave more aggressively compared to sporadic schwannomas and schwannomatosis, with estimates of malignancy as high as 30–50% [33, 36]. Asymptomatic schwannomas in patients with NF2 should be followed with repeat imaging, and tumor growth or development of neurological symptoms constitute indicators for resection of lesions. Patients should be cautioned about the risk for postoperative deficits from resection and counseled on quality of life deterioration in the event of an enlarging spinal tumor [37].

Neurofibromatosis type 1 (NF1) is more common than NF2 but less frequently associated with spinal tumors [38]. Spinal neurofibromas and other spinal tumors develop in around 2% of patients [39]. Routine MRI of the CNS in asymptomatic patients is not recommended, although some advocate for brain MRI to identify potentially concerning lesions [38‒40]. Nonetheless, whole-spine MRI may be warranted to evaluate for concomitant spinal deformity that often develops in NF1, allowing simultaneous monitoring of intraspinal lesions [41].

Schwannomatosis is diagnosed in patients presenting with multiple schwannomas but lacking other characteristics of NF1 or NF2, such as vestibular lesions. Spinal schwannomas are found in over 70% of cases of schwannomatosis, in addition to peripheral nerve schwannomas, with an overall low risk of malignant degeneration [42]. Symptomatic lesions should be resected surgically, as is standard for symptomatic tumors in NF1 and NF2, while asymptomatic lesions can be monitored conservatively with routine follow-up MRI [42‒44]. The literature on pediatric schwannomatosis is limited. Thomas et al. [45] described a 14-year-old male presenting with worsening episodic headaches and diagnosed with a Chiari 1 malformation who received further workup to assess for syringomyelia. MRI revealed multiple spinal schwannomas and the teenager was diagnosed with schwannomatosis after workup excluded neurofibromatosis. Surgery was deferred as the schwannomas were not believed to be contributing to symptoms, and repeat imaging was performed showing no interval growth.

HGBMs of the CNS and retina, renal cell carcinomas, and pheochromocytomas are characteristic tumors of Von-Hippel-Lindau (VHL) syndrome, an autosomal-dominant syndrome that also produces cystic lesions in solid organs [46]. Intramedullary HGBMs represent over 40% of CNS tumors found in VHL, and 10–30% of all patients with intramedullary HGBMs have VHL. Therefore, the syndrome should be considered in patients with asymptomatic spinal cord HGBMs [47]. The tumors usually present with clear dissection planes, allowing for gross total resection in nearly all cases (shown in Fig. 2) [46, 48]. They can display cycles of growth followed by arrest and can remain stable for many years [49]. Consequently, management of these lesions must consider the patient’s tumor burden, neurological status, and likelihood of future deficits.

VHL-associated intramedullary HGBMs are frequently identified on MRI in patients. However, there is significant disagreement concerning the optimal management of asymptomatic HGBMs, which often feature minimal growth over time. Patients with VHL-associated intramedullary HGBMs often undergo multiple surgeries, and the need for additional surgeries over time should be considered when assessing the timing of intervention. Consequently, conservative follow-up of asymptomatic lesions with repeat imaging has been recommended, with surgery reserved for symptomatic lesions or tumors with concerning radiographic characteristics [50]. The Food and Drug Administration granted approval in 2021 to the HIF2α inhibitor belzutifan, the first oral targeted inhibitor for VHL, which blocks a protein that drives oncogenesis by promoting angiogenesis and growth [51]. A 30% response rate for CNS HGBMs was observed in a phase 2 open-label trial of belzutifan [52]. Treatment of patients with targeted inhibitors now represents a feasible option, and although more trials are needed, surgical management may soon be reserved for cases refractory to medical treatment.

Decision-making for incidental intradural tumors of the spine in asymptomatic patients should factor in the lesion’s radiographic features. Whereas observation and follow-up is appropriate for many incidental tumors on initial presentation, certain high-risk features may prompt consideration of early surgical intervention.

Infiltrative lesions, such as intramedullary astrocytomas, can present with diffuse borders which complicate the surgical resection, particularly for high-grade astrocytomas [53]. Patients should be counseled that continued expansion of the tumor may adversely affect the extent of resection, although achieving a gross total resection even on a small infiltrating astrocytoma may not be feasible without incurring new postoperative deficits. In pediatric patients, intramedullary astrocytomas are usually low grade and amenable to maximal resection [2]. An irregular, heterogeneous pattern of enhancement is concerning for a high-grade astrocytoma, while ependymomas can be differentiated by their homogenous, well-circumscribed appearance and often display a tumor cap, or rim of T2 hypointense hemosiderin due to hemorrhage [54].

Intradural extramedullary tumors can cause compression of the cord and produce sensory deficits and myelopathy. Although pain and myelopathy are frequently reported in patients with cord compression, a high degree of alertness should be afforded to the possibility of cord compression in asymptomatic patients, due to the potential for permanent deficits [55]. Corell et al. [56] reported that meningioma occupancy percentage of the spinal canal greater than 65% was predictive of preoperative sensory and motor symptoms. Although patients often improve after surgery, 43% remained unchanged, highlighting the high risk of permanent deficits associated with cord compression. Consequently, the authors counsel consideration of surgery in patients with intradural tumor occupancy approaching 65%, even in asymptomatic patients. Although the exact cutoff value for intervention is unclear, patients with cord compression should be counseled that despite the absence of symptoms, even small amounts of tumor growth can rapidly produce neurological deficits.

Occasionally, children and adolescents presenting with idiopathic scoliosis are found on workup to have an associated intradural tumor [57]. Although the patient may lack neurological deficits, these tumors should not be considered incidental findings as the scoliosis may arise from muscular imbalance and asymmetrical weakness due to the tumor’s effect on trunk musculature [58, 59]. Indeed, although scoliosis is only encountered in 1‒2% in adolescents, an estimated 20–33% of patients with IMSCTs present with concomitant spinal deformity [58, 60, 61]. Scoliosis is also the most frequent musculoskeletal manifestation of NF1, which accounts for approximately 2% of all pediatric scoliosis cases [62, 63]. MRI obtained for additional workup of scoliosis can identify the tumor, but clinical suspicion is warranted for occult lesions in any case of idiopathic scoliosis, given that management of the tumor is needed to improve or prevent progression of the scoliosis [60, 64]. Operative intervention and resection of the tumor is often necessary to prevent progression of scoliosis. Bouaziz et al. [64] identified 7 IMSCTs in children aged 3–10 years presenting with scoliosis as the primary complaint, including 4 astrocytomas, 2 ependymomas, and 1 epidermoid cyst. Surgical resection was performed in all cases.

Syrinx formation occurs in many patients with IMSCTs, with literature estimates ranging from 25 to 58% of patients [2]. The syrinx signals that the tumor is likely noninfiltrative and can improve detection of cleavage planes, aiding surgical resection [65]. The syrinx cavity usually resolves following surgical resection, with greater reductions correlating to the extent of resection [66]. Idiopathic asymptomatic syringomyelia is managed conservatively, but the literature on management of incidental spine tumors with syringomyelia is sparse [67].

Detection of a syrinx on a spine MRI should prompt investigation of a cause, and whole-spine MRI may be needed to examine for intradural lesions proximal or distal to the syrinx otherwise hidden from view on the initial imaging. Symptoms are usually expected from either the tumor or syrinx. Wu et al. [68] describe a 20-year-old male with right upper extremity numbness reflecting a syrinx, with MRI workup finding an unexpected T10-11 HGBM that was subsequently resected. Ng et al. [69] presented an asymptomatic adult initially diagnosed with idiopathic syringomyelia on the basis of a cervical cystic MRI, with no other abnormalities detected. Eight years later, she developed progressive dysesthesias in the bilateral hands, and cervical MRI showed a new solid and enhancing component. Resection was performed given the patient’s new symptoms, and pathology showed a grade 2 ependymoma, highlighting that careful attention ought to be paid to presumed idiopathic syrinxes.

Hydrocephalus is associated with spinal cord tumors in approximately 1% of patients on initial presentation, and patients can present with signs and symptoms of hydrocephalus rather than myelopathy in the setting of an IMSCT [70]. Hydrocephalus can also develop over time as the IMSCT expands [71]. CSF analysis often reveals increased protein content concerning for neoplasm, prompting further workup. The diagnosis of an IMSCT is frequently delayed when papilledema or signs of increased intracranial pressure constitute the initial presentation. The search for an intracranial pathology generally takes precedence over spinal etiologies. Consideration should be afforded to the possibility of a spinal cord tumor in patients with no clear explanation for their increased intracranial pressure. CSF analysis of shunted fluid or fluid from a lumbar puncture should be performed promptly but may be within normal range early in the disease course [72]. For example, Caviness et al. [72] noted the case of a 4-month-old child with developmental delay and macrocephaly, treated with a VP shunt for communicating hydrocephalus. At 24 months, a neurological examination showed hypotonia and increased reflexes, and a spine MRI confirmed an IMSCT that was resected and diagnosed as a low-grade astrocytoma.

Several theories for the development of hydrocephalus in patients with IMSCTs have been proposed, including release of protein products into CSF by the tumor that increase CSF viscosity, blockage of CSF flow, and meningeal spread of the tumor causing obstruction and reduced meningeal compliance [72, 73]. Consequently, consideration of IMSCTs was recommended by Hussain and Haines in patients with papilledema and elevated proteins in CSF, noting the case of a 15-year-old girl with a grade 1 myxopapillary ependymoma initially presenting with headaches and found to have high-grade papilledema on fundoscopic examination [73].

Caution should be applied in the workup of patients with neurological deficits concerning for intradural tumors, as non-neoplastic pathologies can also present in similar fashions. The rarity of these conditions and similarities on imaging with intradural tumors can complicate diagnosis and management. These pathologies include inflammatory lesions, such as multiple sclerosis and transverse myelitis; vascular lesions, such as cavernous malformations and dural arteriovenous fistulas; arachnoid adhesions, sarcoidosis, spinal cord injury, and cystic structures [74, 75]. For example, Fanous et al. [76] described a 66-year-old man who underwent surgical intervention in the setting of gait instability and neck pain with radiographic features concerning for an intramedullary tumor. However, no discrete plane was identified intraoperatively, and initial pathology suggested inflammatory cells, prompting a termination to the resection. The final pathology confirmed transverse myelitis, and oral dexamethasone therapy resolved the lesion and symptoms. Ishiwata et al. [77] reported a case of a 32-year-old man with hand weakness and gait instability whose MRI showed a dural tail sign suggestive of a meningioma, prompting gross total resection. However, the pathology was consistent with spinal sarcoidosis.

Intradural spine tumors are rare, and management of pediatric patients presenting with incidental findings is an understudied topic. Nonetheless, several principles can be established based on our experience and review of the literature (shown in Fig. 3). Consideration of the incidental lesion should first assess whether other tumors are also present, either within the spine, intracranial space, or other body cavities, suggesting an underlying genetic syndrome. These tumors are more properly considered asymptomatic rather than incidental as the underlying cause is known. Patients presenting with multiple tumors are usually followed closely over time, given that some tumors may remain stable for years and the large tumor burden increases the morbidity of extensive surgery. Exceptions exist, particularly in the case of VHL-associated intramedullary HGBMs, where aggressive early treatment prior to the onset of neurological deficits may improve quality of life in patients.

Subsequently, clinicians should consider the location of the tumor, including whether it is intradural extramedullary or intradural intramedullary. Resection of IMSCTs entails direct manipulation and excision of spinal cord tissue, which increases the morbidity and risks of surgery compared to extramedullary operations. The cranial-caudal location of the tumor within the spine can also influence decision-making. Expansion of cervical tumors is likely to produce more substantial neurological deficits compared to lower thoracic or upper lumbar tumors, potentially favoring a more aggressive approach or closer follow-up in cervical tumors.

The radiographic features of the tumor should be inspected to suggest the likely diagnosis. Patterns of intensity on T1- and T2-weighted imaging and enhancement are instructive, in addition to the appearance of the tumor margins and the presence of an associated syrinx or hemorrhage. Based on the diagnosis, clinicians should consider the anticipated natural history and counsel patients appropriately, although it should be emphasized that significant heterogeneity in growth rates exists across lesions. Close monitoring of incidental lesions is often reasonable, with an initial MRI performed after 3 months, then 6 months, and then annually to assess growth or radiographic changes. Features concerning for malignancy or cord compression should raise consideration of early intervention to prevent catastrophic deficits. Additionally, patients presenting with concomitant scoliosis or hydrocephalus likely warrant early surgical intervention to correct the anomaly and prevent worsening of the scoliosis or hydrocephalus.

The management paradigm for incidental spine tumors may eventually change with the development of liquid biopsies, which uses a blood sample to analyze cell-free tumor DNA without the need for invasive surgery [78, 79]. Liquid biopsies could be used for more frequent follow-up compared to MRI scans. Additionally, the molecular profile of tumor cells and tumor stem-like cells driving proliferative activity can be analyzed to generate personalized therapies [80]. Several clinical trials are underway examining use of liquid biopsies in intracranial tumors [81]. Limitations have been reported with detection of cell-free DNA for spinal tumors related to anatomic sequestration, low grade of lesions, and small size limiting the quantity of DNA released [82]. Continued investigation is necessary to determine its potential impact on management of patients with spinal tumors.

New treatment strategies may also shift the approach to management of incidental lesions. Surgical resection is presently the mainstay of treatment for symptomatic tumors, but new technologies are being investigated to improve localized drug delivery and sensitize tumors to radiation therapy. For example, clinical trials are underway examining the effectiveness of focused ultrasound for reversible disruption of the blood-brain barrier, the tight microvascular network that restricts diffusion of most chemotherapeutics [83‒85]. Extension of focused ultrasound to the spine may offer a noninvasive treatment option and favor earlier management of incidental lesions.

Intradural tumors of the spine often present symptomatically with neurological deficits, and surgery is considered the mainstay of treatment. However, treatment of incidental lesions in the pediatric population can be more challenging. Clinical decision-making must consider the benefit of early resection to prevent neurological deterioration with the possibility that the child will remain asymptomatic without tumor growth for years, such that surgery only poses undue risks. Workup of the incidental tumor should carefully examine the likelihood of a genetic syndrome predisposing to tumor formation in the child, in which case multiple asymptomatic tumors are likely to present. Incidental tumors can often be managed conservatively with close follow-up and surgical intervention in the setting of progressive tumors or new symptoms. Earlier aggressive treatment should be considered in tumors associated with significant cord compression, scoliosis, or hydrocephalus.

Nicholas Theodore: consultant for, owns stock in, and on the scientific advisory board of Globus Medical; royalties from Globus Medical and DePuy Synthes; consultant for Bioventus; fellowship support from AO North America and NREF; research support from Department of Defense; and grant support from DARPA. Daniel M. Sciubba: consultant for Baxter, DePuy Synthes, Medtronic, Stryker, and Augmedics. The remaining authors have no conflicts of interest to disclose.

The authors did not receive any funding for the manuscript.

A.M.H.: investigation, data curation, and writing – original draft; D.L.: writing – review and editing and visualization; N.T. and D.S.: writing – review and editing and supervision; G.I.J.: conceptualization, writing – review and editing, supervision, and project administration; N.S.: conceptualization, writing – review and editing, visualization, supervision, and project administration.

IRB approval was not required for this work.