Pediatric AVMs

Introduction

As with many rare disease entities, the incidence of pediatric intracranial arteriovenous malformations (iAVMs) has risen in accordance with the improving sensitivity of evolving imaging modalities and the earlier detection of asymptomatic and small iAVMs in childhood. The guiding principles for emergent management have always been patient stabilization in an intensive care unit, treatment of raised intracranial pressure, and possible hematoma evacuation and AVM resection if indicated. The acute period further requires the diagnostic identification of any potential high-risk features of the ruptured AVM angioarchitecture. As endovascular and radiosurgical techniques for dealing with pediatric AVMs have improved in the last few decades, subsequent management necessitates interdisciplinary discussion and a holistic assessment of the risks and benefits of treatment.

In this chapter, we will review the biology, natural history, and common presentations of pediatric iAVMs. Indications and considerations for intervention are considered, including a focus on multidisciplinary management. Guidelines for pre- and postoperative imaging are offered. Literature on AVM management during pregnancy and childbirth is not addressed here, and our focus remains on pial AVMs only as opposed to choroidal AVMs or vein of Galen malformations.

Incidence

There are no population-level screening studies on iAVMs in the pediatric literature, therefore inferences about frequency are made from clinical samples. Autopsy studies suggest that the prevalence of iAVMs in the general population is 0.06%–0.11%, with pediatric iAVMs comprising 10%–20%. However, ruptured AVMs account for a much higher proportion of spontaneous intracranial hemorrhages in pediatric patients than in adults: 30%–50% compared to 1.4%–2%, respectively. Once diagnosed, the annual risk of rupture of pediatric iAVMs, though dependent on factors described later, tends to vary between 4% and 5.5%. Once ruptured, the rerupture rate remains roughly the same (2%–4%), though with a mortality rate of 25% per event. AVMs remain the most common cause of spontaneous intracranial hemorrhage in children.

Historically, iAVMs in children were discovered after the development of symptoms: hemorrhage, seizure, mass effect, or hydrocephalus represent the most common presentations. However, as with many neurosurgical pathologies, as both the sensitivity of imaging modalities and access to healthcare improves, more iAVMs are being discovered before symptom onset. Prior to 2000, the discovery of asymptomatic pediatric iAVMs was rare. Recent data from the last decade suggest that improved imaging and its frequent use are responsible for up to 33% of newly diagnosed iAVMs in children being found incidentally. This percentage would only be expected to rise as access to and resolution of imaging technology improves.

Ultimately, though the incidence of pediatric iAVMs may not be high, the severity of the clinical setting in which they present combined with the morbidity associated with observation of ruptured or otherwise symptomatic lesions make this an important disease entity to recognize and treat when indicated.

Developmental Biology

While it is believed that there is a subset of adult iAVMs that are acquired later in life, pediatric iAVMs are understood to be largely congenital or at least immediately postnatal acquisitions. Normal vasculogenesis and angiogenesis are driven by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-B1 (TGF-B1), and these growth factors undoubtedly play a role in the pathophysiology of AVMs. VEGF receptors are highly expressed during embryonic vascular development, resulting in ensuing proliferation and, in pathological entities, overdevelopment of vascular structures—these receptors subsequently become downregulated throughout adult life to a more quiescent state. Abnormally low levels of endothelial cell–specific receptor tyrosine kinases have been found on the surfaces of iAVM specimens, suggesting aberrant vascular phenotype. Low expression may contribute to poor peri-endothelial cell support structures in iAVMs, leading to a theoretically higher risk of hemorrhage. Pediatric iAVMs are, relative to cortical volume, larger on average than adult iAVMs; suggested reasons for the larger size of pediatric iAVMs include the high postnatal expression of VEGF on endothelial cells, as well as upregulation of various growth factors following insult or subclinical ischemia during the postnatal period. In fact, VEGF expression has shown some correlation with recurrence of iAVMs in the pediatric population. Mutations in the KRAS signaling pathway have also been discovered to play a role in both intra- and extracranial AVMs; molecular inhibitors of this pathway have shown promise in the treatment of AVMs as well.

With respect to the timing of development, AVMs have classically been conceptualized as congenital lesions. However, detection rates in Japan suggest that, relative to vein of Galen malformations and dural arteriovenous fistulas, iAVMs are less common in early childhood (<1 year of age) than later (>5 years of age), suggesting that postnatal development may account for a proportionally larger number of pediatric iAVMs.

Natural History and Common Presentations

ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations), which purported superior neurologic outcomes of conservative management over active intervention in adult patients with unruptured iAVMs, led to much debate regarding the best management practices for these patients. However, with a longer life expectancy and evidence of superior neurologic outcomes in the pediatric population compared with adults, there is reason to advocate for curative therapies for pediatric iAVMs to prevent future hemorrhages. Only 18% of iAVMs become symptomatic prior to presentation; historical data suggest the following breakdown of clinical presentations in these cases: hemorrhage in 50%, seizure and/or hydrocephalus in 36%, and congestive cardiac failure secondary to shunting in 18% (more common in newborns). Once symptomatic, pediatric iAVMs carry significant prospective morbidity and have a more malignant course. Subsequent hemorrhages correspond with a 50% morbidity rate and a 10% mortality rate. A child with a new intracranial hemorrhage in the absence of trauma is presumed to have an underlying vascular anomaly until proven otherwise, at least in early management—any attempts to resect clot must be performed in anticipation of discovering an underlying AVM. Children are often therefore treated as aggressively as—if not more aggressively than—their adult counterparts when asymptomatic or symptomatic iAVMs are discovered.