Accepted Manuscript De Novo Arteriovenous Malformation in a Pediatric Patient: Case Report and Review of the Literature Roberta Santos, M.D., Pedro Aguilar-Salinas, M.D., John J. Entwistle, D.O., Philipp R. Aldana, M.D., Alexandra D. Beier, D.O., Ricardo A. Hanel, M.D., Ph.D. PII: S1878-8750(17)32261-1 DOI: 10.1016/j.wneu.2017.12.145 Reference: WNEU 7158 To appear in: World Neurosurgery Received Date: 30 August 2017 Revised Date: 20 December 2017 Accepted Date: 21 December 2017 Please cite this article as: Santos R, Aguilar-Salinas P, Entwistle JJ, Aldana PR, Beier AD, Hanel RA, De Novo Arteriovenous Malformation in a Pediatric Patient: Case Report and Review of the Literature, World Neurosurgery (2018), doi: 10.1016/j.wneu.2017.12.145. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Santos De Novo Arteriovenous Malformation in a Pediatric Patient: Case Report and Review of the Literature Pedro Aguilar-Salinas, M.D.1 Philipp R. Aldana, M.D.2 SC John J. Entwistle, D.O.1 RI PT Roberta Santos, M.D.1 M AN U Alexandra D. Beier, D.O.2 Ricardo A. Hanel, M.D., Ph.D.1 Lyerly Neurosurgery1 TE D Baptist Health, Jacksonville, Florida Division of Pediatric Neurosurgery2 EP University of Florida Health Jacksonville, Jacksonville, Florida AC C Corresponding Author: Ricardo A. Hanel, M.D., Ph.D. 800 Prudential Drive – Tower B, 11th Floor Jacksonville, FL 32207 Telephone: (904)-388-6518 Fax: (904)-384-1005 Email: rhanel@lyerlyneuro.com 1 ACCEPTED MANUSCRIPT Santos Abstract Background: An arteriovenous malformation (AVM) consists of a pathological arterio-venous RI PT shunt formed from a tangle of vessels lacking a capillary bed. AVMs were previously accepted as congenital in nature, however, an increase in the number of reported de novo cerebral AVMs challenges the assertion that all AVMs develop in utero hence, the possibility of these lesions de novo AVM formation between 1996 and 2017. SC presenting postnatally cannot be excluded. A review of literature revealed 31 published cases of M AN U Case Description: We present the case of a 7-year-old boy with a history of an intracranial aneurysm that was found to have an asymptomatic de novo AVM formation on a routine followup angiography. He was being followed since the age of 8 months when the aneurysm was incidentally found during work-up for mild hemiparesis. At that time, a MRI revealed a 4mm TE D right posterior communicating artery (PCOM) aneurysm along with a right hemispheric stroke and cortical dysplasia. No arteriovenous malformation was noted. Conclusions: The exact pathophysiology of de novo AVMs is not completely understood but a EP combination of genetic, molecular, and environmental factors may play a role. Our case report only adds to the growing body of clinical evidence supporting the notion that these lesions may AC C be acquired. It would be appropriate to consider an AVM as an abnormal vascular response to an injury rather than a static congenital lesion. 2 ACCEPTED MANUSCRIPT Santos Introduction A cerebral arteriovenous malformation (AVM) is an arterio-venous shunt formed from a tangle RI PT of blood vessels lacking a capillary bed within its arterial nidus. The nidus is supplied by a varying number of feeding arteries and draining veins. The pathogenesis of AVMs is not completely understood. In the past, the widely accepted theory was that AVMs were congenital in nature and were formed when the embryo is between 40 and 80 mm in length.1 During this SC critical stage, there is an ongoing process of vasculogenesis, vascular remodeling, and M AN U differentiation. The long-held belief that these lesions were congenital in nature was largely accepted but, lack of proof prevented certainty. Contrary to vein of Galen malformations that are easily discovered during intrauterine and neonatal ultrasonography, there has been a lack of reported cases of prenatal cerebral AVMs despite higher prevalence.1,2 The dynamic behavior of the AVMs defines the complex natural history of these lesions. AVMs have been shown to TE D spontaneously thrombose, regress, and even recur after complete surgical obliteration.2,3 Recent reports of de novo AVM formation have challenged the traditional dogma of these lesions.4-29 Hence, we report the case of a 7-year-old male with history of a treated cerebral aneurysm that EP was found to have an asymptomatic de novo AVM in the right thalamic region diagnosed on a AC C routine follow-up angiography. Case Report A 7-year-old boy, well-known to our service, presented to our office for a routine follow-up visit of a previously treated right PCOM aneurysm. He was being followed since the age of 8 months when an aneurysm was incidentally found during work-up for mild hemiparesis. At that time, a magnetic resonance imaging (MRI) revealed a 4mm right PCOM aneurysm along with a right hemispheric stroke and cortical dysplasia. No arteriovenous malformation was noted. Due to a 3 ACCEPTED MANUSCRIPT Santos progression in size, the aneurysm was treated with endovascular coiling at the age of 2, with 2 additional retreatments (re-do coiling at 3 years and off label use of Pipeline Embolization Device at 4 years). Initial angiograms mentioned above had shown no evidence of brain AVM. RI PT During his latest follow-up visit, he was evaluated with a cerebral angiogram demonstrating complete obliteration of the aneurysm and a de novo AVM in the right thalamic region as well as a new left internal carotid supraclinoid aneurysm. The AVM was classified as a Spetzler-Martin SC grade 4 AVM with no indication for treatment at the time. A review of previous diagnostic M AN U imaging revealed no intracranial vascular anomalies (Figures 1 and 2). Discussion An increase in the number of reported de novo cerebral AVMs challenges the former assertion that all AVMs developed in utero hence, the possibility of these lesions presenting postnatally TE D cannot be excluded. The dynamic behavior of these lesions has shown its pathogenesis to be multifactorial. Recent literatures propose theories describing a combination of genetic, molecular, and environmental factors contributing to the development of de novo AVM EP formation.30-32 During development, endothelial cells will separate and acquire specific arterial or venous characteristics depending on their hemodynamic needs.32 Homeostasis is dependent AC C upon the tight regulation of various angiogenic factors. Any disturbance in the autoregulation of these factors may contribute to the formation of AVMs. AVMs have shown to promote an increase in several angiogenic factors (vascular endothelial growth factor [VEGF] and hypoxiainducible-factor 1 alpha [HIF-1]) while at the same time downregulating molecules that inhibit endothelial cell growth (TSP-1) and those responsible for vessel stabilization (angiopoietin-1).32 To our knowledge, there have been only 31 previously published cases of de novo AVM development between 1996 and 2017 (Table 1). The median age of diagnoses was 17 years 4 ACCEPTED MANUSCRIPT Santos (range 2.5-72) and the median duration between last negative diagnostic imaging to the diagnoses of de novo AVM was 5 years (range 2-25). Out of the total 32 cases, including our own, 17 patients (53%) were male. Most these patients, 75% (24/32), had history of some form RI PT of cerebrovascular insult attributed to Moyamoya disease, trauma, tumor, and ischemic or hemorrhagic strokes. The remaining group were comprised of having history of seizures, hereditary hemorrhagic telangiectasia (HHT), and Bell’s palsy. SC In our literature review, one patient was reported to have hereditary hemorrhagic telangiectasia M AN U (HHT), an autosomal dominant disorder of vascular dysplasia.26 Patients with HHT are known to have AVMs in various organs of the body including the brain but this patient presented with a de novo AVM despite a negative MRI 4.5 years prior.26 The two main subtypes of HHT (HHT1 and 2) present with a mutation in the endoglin (Eng) and activin-like kinase 1 (ALK-1) genes which are responsible for stabilizing vascular formation.26 The loss-of-function mutation in both genes TE D result in an abnormal proliferation of endothelial cells and angiogenic function.30 Studies have shown a synergistic effect between HHT and VEGF in the formation of AVMs. For instance, Eng or ALK-1 deficient mice developed AVMs at a much higher rate in VEGF-rich EP environments.26,30,31 AC C Our patient was being followed radiographically since the age of 8 months to evaluate the progression of his right PCOM aneurysm. Although a review of previous diagnostic testing revealed no vascular malformations, he was found to have right hemispheric encephalomalacia and cortical dysplasia. In our literature review, 23 patients also had some form of cerebrovascular insult years before being diagnosed with an AVM. (Table 1) The discovery of a de novo AVM years after an initial insult suggests a connection between a pathological insult and AVM formation. Kim and colleagues30 have proposed a “response-to-injury” theory to 5 ACCEPTED MANUSCRIPT Santos explain a possible de novo AVM etiology. It is a stark contrast to the previous belief that these lesions were solely congenital in nature. The hypothesis suggests that insults such as stroke, trauma, infection, and inflammation could all potentially promote the development of AVMs. RI PT Angiogenesis is a normal response to these insults, however, when superimposed with an underlying genetic predisposition, or a structural defect microscopically the response results in a pathological “response-to-injury”.30 Hypoxia triggers vascular proliferation by increasing the SC expression of HIF-1. The increased levels of HIF-1 in turn stimulates an overexpression of VEGF leading to vasculogenesis and possible AVM formation.33 Patients with AVMs have been M AN U shown to have increased levels of VEGF, VEGF receptors, and HIF-1 34 as well as other inflammatory markers including myeloperoxidase (MPO) and interleukin-6 (IL-6).30 It is our belief that our patient’s initial insult (right hemispheric stroke) could potentially have created a Conclusions TE D hyperangiogenic environment and triggered a de novo AVM formation. The exact mechanism of AVM formation is not completely understood. Available data are EP consistent with the hypothesis that a combination of genetic, environmental, and biologic factors contribute to its development. Our case report only adds to the growing body of clinical evidence AC C supporting the notion that these lesions may be acquired. It would be appropriate to consider an AVM as an abnormal vascular response to an injury rather than a static congenital lesion. Cerebrovascular practitioners should be aware of the possibility of de novo AVM formation after a brain injury. 6 ACCEPTED MANUSCRIPT Santos References 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. RI PT SC 5. M AN U 4. TE D 3. EP 2. Mullan S, Mojtahedi S, Johnson DL, Macdonald RL. Embryological basis of some aspects of cerebral vascular fistulas and malformations. J Neurosurg. 1996;85(1):1-8. DeCesare B, Omojola MF, Fogarty EF, Brown JC, Taylon C. Spontaneous thrombosis of congenital cerebral arteriovenous malformation complicated by subdural collection: in utero detection with disappearance in infancy. Br J Radiol. 2006;79(946):e140-144. Stapf C, Mohr JP. New concepts in adult brain arteriovenous malformations. Curr Opin Neurol. 2000;13(1):63-67. Schmit BP, Burrows PE, Kuban K, Goumnerova L, Scott RM. Acquired cerebral arteriovenous malformation in a child with moyamoya disease. Case report. J Neurosurg. 1996;84(4):677-680. Friedman JA, Pollock BE, Nichols DA. Development of a cerebral arteriovenous malformation documented in an adult by serial angiography. Case report. J Neurosurg. 2000;93(6):1058-1061. Bulsara KR, Alexander MJ, Villavicencio AT, Graffagnino C. De novo cerebral arteriovenous malformation: case report. Neurosurgery. 2002;50(5):1137-1140; discussion 1140-1131. Akimoto H, Komatsu K, Kubota Y. Symptomatic de novo arteriovenous malformation appearing 17 years after the resection of two other arteriovenous malformations in childhood: case report. Neurosurgery. 2003;52(1):228-231; discussion 231-222. Miyasaka Y, Nakahara K, Takagi H, Hagiwara H. Development of multiple cerebral arteriovenous malformations documented in an adult by serial angiography. Case report. J Neurosurg. 2003;98(1):190-193. O'Shaughnessy BA, DiPatri AJ, Jr., Parkinson RJ, Batjer HH. Development of a de novo cerebral arteriovenous malformation in a child with sickle cell disease and moyamoya arteriopathy. Case report. J Neurosurg. 2005;102(2 Suppl):238-243. Gonzalez LF, Bristol RE, Porter RW, Spetzler RF. De novo presentation of an arteriovenous malformation. Case report and review of the literature. J Neurosurg. 2005;102(4):726-729. Song JK, Niimi Y, Kupersmith MJ, Berenstein A. Postnatal growth and development of a cerebral arteriovenous malformation on serial magnetic resonance imaging in a child with hemangiomatosis. Case report. J Neurosurg. 2007;106(5 Suppl):384-387. Stevens J, Leach JL, Abruzzo T, Jones BV. De novo cerebral arteriovenous malformation: case report and literature review. AJNR Am J Neuroradiol. 2009;30(1):111-112. Jeffree RL, Stoodley MA. Postnatal development of arteriovenous malformations. Pediatr Neurosurg. 2009;45(4):296-304. Mahajan A, Manchandia TC, Gould G, Bulsara KR. De novo arteriovenous malformations: case report and review of the literature. Neurosurg Rev. 2010;33(1):115-119. Alvarez H, Perry V, Solle M, Castillo M. De novo cerebral arteriovenous malformation in a child with previous cavernous malformation and developmental venous anomaly. J Neurosurg Pediatr. 2012;9(3):327-330. Ozsarac M, Aksay E, Kiyan S, Unek O, Gulec FF. De novo cerebral arteriovenous malformation: Pink Floyd's song "Brick in the Wall" as a warning sign. J Emerg Med. 2012;43(1):e17-20. Mathon B, Blauwblomme T, Bolle S, et al. De novo arteriovenous malformation after brain radiotherapy for medulloblastoma in a child. Neurology. 2013;81(4):398-399. Kilbourn KJ, Spiegel G, Killory BD, Kureshi I. Case report of a de novo brainstem arteriovenous malformation in an 18-year-old male and review of the literature. Neurosurg Rev. 2014;37(4):685-691. AC C 1. 7 ACCEPTED MANUSCRIPT Santos 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. RI PT 24. SC 23. M AN U 22. TE D 21. EP 20. Fujimura M, Kimura N, Ezura M, Niizuma K, Uenohara H, Tominaga T. Development of a de novo arteriovenous malformation after bilateral revascularization surgery in a child with moyamoya disease. J Neurosurg Pediatr. 2014;13(6):647-649. Morales-Valero SF, Bortolotti C, Sturiale C, Lanzino G. Are parenchymal AVMs congenital lesions? Neurosurg Focus. 2014;37(3):E2. Miller BA, Bass DI, Chern JJ. Development of a de novo arteriovenous malformation after severe traumatic brain injury. J Neurosurg Pediatr. 2014;14(4):418-420. Neil JA, Li D, Stiefel MF, Hu YC. Symptomatic de novo arteriovenous malformation in an adult: Case report and review of the literature. Surg Neurol Int. 2014;5:148. Yeo JJ, Low SY, Seow WT, Low DC. Pediatric de novo cerebral AVM: report of two cases and review of literature. Childs Nerv Syst. 2015;31(4):609-614. Nakamura M, Samii A, Lang JM, Gotz F, Samii M, Krauss JK. De Novo Arteriovenous Malformation Growth Secondary to Implantation of Genetically Modified Allogeneic Mesenchymal Stem Cells in the Brain. Neurosurgery. 2016;78(4):E596-600. Markham L, Hollingworth M. De Novo Arteriovenous Malformation in a 4 Year-Old Boy with Headache, with No Previous Cerebrovascular Disease. Journal of Neurology and Neuroscience. 2016;6(3). Shimoda Y, Osanai T, Nakayama N, et al. De novo arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia. J Neurosurg Pediatr. 2016;17(3):330-335. Pabaney AH, Rammo RA, Tahir RA, Seyfried D. Development of De Novo Arteriovenous Malformation Following Ischemic Stroke: Case Report and Review of Current Literature. World Neurosurg. 2016;96:608 e605-608 e612. Koch MJ, Agarwalla PK, Stapleton CJ, Ogilvy CS, Loeffler JS. De novo development of a cerebral arteriovenous malformation following radiation therapy: Case report and an update to classical arteriovenous malformation nomenclature. J Clin Neurosci. 2016;28:162-167. Shi S, Gupta R, Moore JM, et al. De novo AVM formation following venous sinus thrombosis and prior AVM resection in adults: report of 2 cases. J Neurosurg. 2017:1-5. Kim H, Su H, Weinsheimer S, Pawlikowska L, Young WL. Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl. 2011;111:83-92. Chen W, Choi EJ, McDougall CM, Su H. Brain arteriovenous malformation modeling, pathogenesis, and novel therapeutic targets. Transl Stroke Res. 2014;5(3):316-329. Storkebaum E, Quaegebeur A, Vikkula M, Carmeliet P. Cerebrovascular disorders: molecular insights and therapeutic opportunities. Nat Neurosci. 2011;14(11):1390-1397. Leblanc GG, Golanov E, Awad IA, Young WL, Biology of Vascular Malformations of the Brain NWC. Biology of vascular malformations of the brain. Stroke. 2009;40(12):e694-702. Sandalcioglu IE, Wende D, Eggert A, et al. Vascular endothelial growth factor plasma levels are significantly elevated in patients with cerebral arteriovenous malformations. Cerebrovasc Dis. 2006;21(3):154-158. AC C 19. 8 ACCEPTED MANUSCRIPT Santos Figure Legends: Figure 1: (A) Sagittal and (B) coronal views of brain MRI obtained at initial presentation of the RI PT patient. No signs of vascular malformation present. (C) Sagittal and (D) coronal views of brain MRI obtained 2 years after initial one shows no sign of any vascular malformation in the right thalamic region. At 5-year follow up, brain MRI (E) sagittal and (F) coronal views demonstrates M AN U malformation in the right thalamic region. SC increased vascularity at the region of right basal ganglia, possible evidence of a vascular Figure 2: Anteroposterior cerebral angiogram of the initial treatment, approximately 2 years after initial presentation, demonstrating immediate results post endovascular coiling of the right PCOM aneurysm in the early (A), mid (B), and late (C) arterial phases without any evidence of a TE D vascular malformation in the right thalamic region. Anteroposterior cerebral angiogram at 7-year follow-up in the early (D), mid (E), and late (Fs) arterial phases showing complete obliteration of right PCOM aneurysm and a de novo AVM in the right thalamic region with signs of early AC C EP venous shunting into the right transverse sigmoid sinus. 9 ACCEPTED MANUSCRIPT Schmit, 19964 11, M Friedman, 20005 Bulsara, 20026 61, M 32, F Akimoto, 20037 27, F Miyasaka, 20038 O’Shaughnessy, 20059 Gonzalez, 200510 50, F 6, F Left posterior parietal Right cerebellum Right posterior temporal Cingulate gyrus, Corpus Callosum Multiple AVMs Right sylvian Song, 200711 Stevens, 200912 2.5, F 9, F Jeffree, 200913 5, M 7, F 15, M Alvarez, 201215 8, M Ozsarac, 201216 50, M Mathon, 201317 9, M Kilbourn, 201418 18, M 14, F 35, F Miller, 2014 21 Neil, 201422 Yeo, 201523 Nakamura, 201624 Markham, 201625 5 Prior ICH 10 Prior ICH 14 Bell’s palsy, seizure 2 Cavernous malformation, DVA 25 Epilepsy 4 Medulloblastoma 7 Congenital hydrocephalus, absence seizures Moyamoya disease None 56, M 12, F Right occipital Left parietaloccipital Left temporal Left parietal 14 6 24, M 7, M Left parietal Left cerebellar 9 6 TIA Left traumatic subdural hematoma Seizures (None) Seizures (None) 16, F Left anterior temporal Left frontal 9 Seizures (None) 3 Left frontal ICH 4 None (history of seizures) AC C Fujimura, 201419 Morales-Valero, 201420 EP 30, F TE D 18, M Mahajan, 201014 Right posterior temporal Left CPA Left temporaloccipital Right insula, Basal ganglia Right temporalparietal Left parietaloccipital Left frontalparietal Posterior 3rd ventricle (Vein of Galen) Left temporoparietal Right Sylvian fissure Pons Time from Predisposing negative exam factor/associated condition (years) 9 Moyamoya disease – parietal infarct 2 Tentorial dural AV fistula 6 Inflammatory/demyelinating disease 17 Previously resected AVM (splenium, occipital lobe) 8 Right parietal ICH 3 Sickle Cell and Moyamoya disease 4 Trauma – Left frontal ICH Intractable seizures 2.5 Hemangiomatosis 3 Seizures/ band heterotopia (increased seizures) 5 Prior ICH RI PT AVM Location SC Age (years), sex M AN U Reference, year 53, M 4, M Left posterior superior temporal 4 4 ACCEPTED MANUSCRIPT Shimoda, 2016 Pabaney, 201627 Koch, 201628 5, M 52, F 24, F Shi, 201729 33, F gyrus Right parietal Left basal frontal Left medial temporal (Left choroidal) Left temporaloccipital Right temporaloccipital Left thalamic 72, M 7, M HHT Ischemic stroke Radiation therapy 2 Left transverse sinus thrombosis Previous Left frontal AVM 11 3 Right hemispheric stroke, cerebral aneurysm SC Present case 4.5 8 5 RI PT 26 AC C EP TE D M AN U Table 1. Reported cases of de novo AVM formation. AVM: arteriovenous malformation; AV: arteriovenous; CPA: cerebellopontine angle; DVA: developmental venous anomaly; F: female; HHT: hereditary hemorrhagic telangiectasia ICH: intracerebral hemorrhage; M: male; TIA: transient ischemic attack. AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Highlights RI PT SC M AN U TE D • EP • A combination of genetic, molecular, and environmental factors may play a role in the formation of AVMs. The discovery of a de novo AVM years after an initial brain insult suggests a connection between a pathological injury and AVM formation. AVMs are dynamic, rather than static congenital lesions. AC C • ACCEPTED MANUSCRIPT Abbreviations List ALK-1 - Activin-like Kinase 1 AVM – Arteriovenous malformation RI PT Eng – Endoglin HHT - Hereditary Hemorrhagic Telangiectasia HIF-1 – Hypoxia-inducible Factor 1 IL-6 – Interleukin-6 SC MPO – Myeloperoxidase MRI – Magnetic Resonance Imaging TSP-1 – Thrombospondin 1 AC C EP TE D VEGF – Vascular Endothelial Growth Factor; M AN U PCOM – Posterior Communicating Artery