CASE REPORT

Case report of a de novo brainstem arteriovenous malformationin an 18-year-old male and review of the literature

Kent J. Kilbourn & Gary Spiegel & Brendan D. Killory &

Inam Kureshi

Received: 20 July 2013 /Revised: 29 March 2014 /Accepted: 13 April 2014 /Published online: 4 July 2014# Springer-Verlag Berlin Heidelberg 2014

Abstract De novo intracerebral arteriovenous malformations(AVMs) are exceedingly rare with only seven reported casesin the literature. Although generally considered congenital bynature, the lesions do not manifest themselves clinically untilthe third or fourth decades of life. However, with the advent ofimproved imaging modalities and more frequent surveillance,an increasing number of de novo cases are being foundchallenging the concept AVMs develop in the perinatal/antenatal period. Alternatively, this phenomenon could repre-sent a distinct entity in which lesion development occurs afterbirth. A PubMed search of “de novo cerebral arteriovenousmalformation” was performed in which seven reported caseswere found. The mean age at diagnosis was 14.7 years with amean follow-up imaging study of 5.8 years. Lesion locationwas supratentorial in all previously described cases. This caseinvolves an 18-year-old male with congenital hydrocephalusand seizures diagnosed at 7 months of age. The patientunderwent a ventriculoperitoneal shunt and was followedfrequently by a neurologist. The last diagnostic imaging wasan unremarkableMRI of the brain at age 12. Seven years later,the patient presented with an intracerebral hemorrhage. A CTangiogram demonstrated a large brainstem AVM with anintraparenchymal hemorrhage and intraventricular extension.This case is unique in that it is the first infratentorial de novoAVM. The congenital nature of AVMs is challenged with theincreasingly described series of patients with previously doc-umented normal radiographic imaging. This suggests there

may be a subset of patients genetically predisposed to postna-tal development of AVMs.

Keywords Cerebral arteriovenousmalformation . De novo .

Brainstem . Angiogenesis

Introduction

Intracranial arteriovenous malformations (AVMs) are rare butoften devastating cause of stroke and disability. AVMs, whichare an abnormal collection of arterial and venous vessels withno intermediary capillary system, are usually found in thethird and fourth decades of life [7, 13]. Hemorrhage, seizures,and headaches are common presenting symptoms. De novoAVMs are exceptionally rare with only seven reported cases inthe literature [21, 17, 9, 20, 22, 4, 5]. Herein, we present thecase of an 18-year-old male with a history of congenitalhydrocephalus with a ventriculoperitoneal (VP) shunt whosuffered an intracerebral hemorrhage. Imaging at presentationrevealed a large brainstem AVM which was not present on anMRI done 7 years earlier.

Case report

This 18-year-old male with a past medical history significantfor autism was diagnosed with hydrocephalus at 7 months ofage. AVP shunt was placed at that time. At age 7, the patientwas diagnosed with absence seizures and was referred to apediatric neurologist. A non-contrast head CT scan was per-formed at that time which was normal (Fig. 1). Four yearslater, a non-contrast MRI was performed which revealedstable ventricular size and no abnormal flow voids (Fig. 2).There is no family history of AVM. The patient was in hisusual state of health until immediately prior to admission

K. J. Kilbourn (*) :G. Spiegel : B. D. Killory : I. KureshiDepartment of Neurosurgery Hartford Hospital,85 Seymour Street, Hartford, CT 06102, USAe-mail: kentkilbourn@yahoo.com

G. SpiegelDepartment of Radiology Hartford Hospital,85 Seymour Street, Hartford, CT 06102, USA

Neurosurg Rev (2014) 37:685–691DOI 10.1007/s10143-014-0557-3

when he developed a severe headache with vomiting followedby a period of unresponsiveness. The patient was intubated atan outside hospital, stabilized, and transported to our facility

by air ambulance. A non-contrast head CT revealed a 13-cchemorrhage involving the left pons extending into the fourthventricle (Fig. 3). A subsequent CTA demonstrated a

Fig. 1 Non-contrast axial CTimages (a) and (b) done 11 yearsprior to hemorrhage

Fig. 2 Unremarkable non-contrast MRI done 7 years prior to the intracerebral hemorrhage depicting a T2 coronal image (a), axial T2 image (b), andsagittal T1 image (c)

Fig. 3 Post hemorrhage non-contrast head CT scan depictingblood in the brainstem (a) andfourth ventricle (b)

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Spetzler–Martin grade 4 AVM. A tangle of abnormal vesselswas seen along with an area of hemorrhage in the brainstem(Fig. 4). Digital subtraction angiography (DSA) demonstrateddirect communication of the vertebrobasilar vessels with theposterior communicating arteries. Venous drainage wasthrough diencephalic veins into the retroclival venous plexus(Fig. 5). After being admitted to the neuroscience ICU, thepatient received an external ventricular catheter which wasplaced adjacent to the VP shunt. The patient was sent to theinterventional neurosurgery suite for treatment. A 3-mm peri-nidal aneurysm arising from the anterior inferior cerebellarartery (AICA) was felt to have been the source of the bleedingand was subsequently embolized with 0.1 cc of N-butyl cya-noacrylate liquid. Definitive treatment of the AVM was de-ferred until the patient could recover from his initialhemorrhage.

The patient had a prolonged hospitalization ultimatelyrequiring a tracheostomy and PEG tube placement. Uponimprovement in his neurological status, he was dischargedto an acute rehabilitation facility. At the time of discharge,he was awake, alert, and moving his right leg and arm. AnMRI performed (Fig. 6) after the initial hemorrhage dem-onstrated resolving hemorrhage with persistent abnormalflow voids. The AVM appeared stable in size. The patienthas since been discharged from rehab and regained somelevel of pre-hemorrhage function with a modified RankinScale (mRS) [23] of 4. He is able to eat and answers somequestions appropriately. The patient has been scheduledfor a repeat DSA in order to assess the remaining AVM.Once this has been performed, treatment including furtherembolization and/or stereotactic radiosurgery will beconsidered.

Fig. 4 Coronal CTA recon image (a) demonstrating two large posterior communicating arteries. Axial images (b) and (c) show a collection of irregularvessels adjacent to the brainstem

Fig. 5 Digital subtraction angiography of vertebral/basilar arteries in-cluded an early (a) phase showing supplying vessels, including onedirectly from the basilar artery. An intermediate supply vessel was

selected and angiographically examined (b) demonstrating venous drain-age through the prepontine vein to the right Table 1. Previous case reportsof de novo AVMs

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Discussion

This case represents a rare occurrence of a de novo AVM anddescribes the first reported de novo infratentorial AVM. Twoprior imaging studies, including a high-resolution MRI, failedto capture any abnormality, indicating lesion developmentwithin 7 years of presentation. This case challenges the asser-tion that all AVMs develop in utero and instead may also formafter birth [19]. Improved imaging techniques and more fre-quent surveillance have resulted in the increasing number ofreported cases of de novo AVMs (Table 1). AVMs do notappear to undergo linear growth, but instead change in size ina bidirectional fashion. During a particular time interval,spontaneous thrombosis may lead to angiographic disappear-ance [2] while angiogenesis and vessel recruitment can resultin AVM growth. It is possible that there was an occult lesionnot seen on either prior imaging study as we did not have adedicated vessel study and catheter angiography may haverevealed a small arteriovenous fistula without a nidus visibleon MRI. AVM reoccurrence has been reported despite com-plete angiographic obliteration of AVMs after surgery [11, 15,10, 3] suggesting the natural history of the disease is a dy-namic process in which phenotypic expression may evolveover time.

The process of spontaneous AVM formation is not fullyunderstood. Mutations of two identified genes have beenimplicated in patients with type 1 (endoglin (ENG)) and type2 (activin-like kinase receptor 1 (ALK-1)) forms of hereditaryhemorrhagic telangiectasia (HHT) [18]. HHT is an autosomaldominant vascular disorder which manifests with pulmonaryand cerebral AVMs among other anatomical locations. A thirdgene, MADH4, which is part of the TGF-β and bone mor-phogenic protein (BMP) superfamily signaling pathway, hasbeen implicated in the third subtype of HHT [1]. The exactrole each gene defect plays in AVM development is unclear;however, ALK-1, ENG, and MADH4 are all found in thevascular endothelium and may play a role in smooth musclerecruitment.

Mutations in these same genes have been demonstrated incases of sporadic AVM; however, it is also possible that a“second hit” occurs in which the phenotypic expression of onegene causes activation of other genes setting pathologicalangiogenesis into motion. An overexpression of vascular en-dothelial growth factor (VEGF) may lead to downstreamsignaling promoting abnormal angiogenesis and the inade-quate recruitment of cells important in the formation of normalvessel structure [14]. Numerous other signaling pathwayshave been linked to AVM development including interleukin

Fig. 6 MRI with gadolinium of the brain demonstrating the partiallyembolized AVM. AT1-weighted gadolinium enhanced coronal image (a)shows numerous abnormal vessels in the pontomedullary cistern. An

axial T2 (b) image shows abnormal flow voids within the brainstem.Sagittal T1 (c) image shows magnetic susceptibility within the brainstemreveals resolving hemorrhage

Table 1 Previous reported cases of de novo AVMs

Reference Demographic AVM location Time from negative exam (y) Associated disease/condition

Gonzalez et.al [9] 7-year-old female Rt posterior temporal 4 Trauma

O’Shaughnessy et. al [20] 6-year-old-female Rt sylvian 3 Sickle cell

Alvarez et. al [4] 8-year-old-male Vein of Galen 2 CCM/angioma

Stevens et. al [22] 9-year-old-female Lt parieto-occipital 3 Seizures/band heterotopia

Schmit et. al [21] 11-year-old male Lt parietal 9 Moyamoya

Bulsara et. al [5] 32-year-old female Lt posttemporal 6 Inflammation/demyelination

Mahajan et. al [17] 30-year-old female Rt posttemporal 14 Bell’s palsy/seizure

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6 (IL-6), myeloperoxidase (MPO), and transforming growthfactor alpha (TGF-alpha) [14, 12]. Studies with inflammatorymarkers from surgical specimens of un ruptured AVMs indi-cate that high levels of neutrophils and macrophages are foundin the walls of vessels within the AVM nidus and may play arole in disease progression [6]. As described in some of theprevious case reports of de novo AVMs, trauma and inflam-mation may be predisposing factors. Inflammatory markershave long been implicated in numerous disorders of the cen-tral nervous system, and in fact, this may be the commonthread among this unique group of patients. It has been sug-gested another important factor in AVM development mayarise from a “response to injury” [14] from an insult such asinflammation, compression, infection, or other process. This,coupled with an abnormal dysplastic response, may very wellset the stage for AVM development.

Hydrocephalus is a common presenting symptom in chil-dren with AVM, especially when located in the posterior fossa[8]. In these instances, hydrocephalus may be caused by eitherdirect blockage of CSF flow from the AVM nidus, or morecommonly by venous hypertension. It is unclear whether thispatient’s VP shunt placement played any role in the formationof this AVM. It is conceivable that changes in CSF flowdynamics contributed to AVM development from an unrecog-nized congenital vascular anomaly or irregular capillary bedwhich had been previously dormant; however, this mecha-nism has never been previously established. It has been hy-pothesized that cerebral cavernous malformation (CCM) andAVM formation are secondary to changes occurring at thecapillary level leading to vessel fusion and AVM nidus for-mation [16].

De novo AVMs are rare with only seven reported cases inthe literature, with all occurrences in the supratentorial com-partment. This is the first reported infratentorial lesion. It addsto the growing number of this unique subset of vascularmalformations, further challenging the long-held belief thatall AVMs are congenital lesions.

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Comments

Martin M. Mortazavi and Louis J. Kim, Seattle, USAWith an average annual risk of bleeding of 2–4 %, arteriovenous

malformations (AVM) account for 3 % of hemorrhagic strokes and 9 %of subarachnoid hemorrhage [1]. They represent the most common causeof childhood hemorrhagic stroke [2]. Infratentorial AVMs are uncommon,comprise less than 15 % of all cerebral AVMs, and are associated withhigher annual risk of hemorrhage, reaching up to 11 % [3, 4].

Up to our knowledge, eight cases of acquired AVM have beenreported in the literature thus far [5–12]. More cases are expected dueto the advancement of neuroimaging. In all of these cases, the malforma-tion has developed in the supratentorial area. The interesting finding ofinfratentorial de novo AVM reported in the current article is thereforeunique.

The etiology of AVM is still unknown. The early theory of a staticcongenital malformation of solely genetic origin has been questionedwith the reported cases of de novo AVM and AVM recurrence aftersuccessful treatment. Therefore, later studies have suggested that acquiredsomatic conditions including trauma, inflammation, and radiation arepotentially involved, and they may represent a second hit for de novoAVMdevelopment [2, 13]. This may also explain the occurrence of AVMin certain vascular territory and absence in another, in a geneticallypredisposed patient. However, this theory was only tested on mice, andno genetic studies were performed on patients with de novo AVM to date.Certain genes have been associated with AVM and well documented inthis current manuscript. The incidence of a “second hit” is interesting asthere is a potential parallel in hereditary hemorrhagic telangiectasia(HHT). Park et al. [13] reported de novo subdermal AVM formationfollowing wounding of an activin receptor-like kinase-1 (ALK-1)-defi-cient mouse. ALK-1 is a transforming growth factor-β (TGF-β) receptorprotein that inhibits the TGF-β-induced vascular endothelial growthfactor (VEGF) expression in endothelial cells, and its deficiency is oneof the main underlying causes of a “second hit,” in this case, the wounditself that could induce the release of multiple angiogenic factors, includ-ing VEGF, which potentially could lead to local AVM formation [13].

It must again be noted that none of reported cases of de novo AVMwere for patients with HHT, and unique molecular mechanism is, there-fore, sought after.

At our institution, the treatment approach to brainstem AVMs isdictated by the accessibility and size of the lesion. In general, Spetzler–Martin grade 3 lesions are suitable for resection. For grade 4 and 5 AVMs,treatment is conservative or radiosurgery. In our experience, the specificlocation within the brainstem and degree of surgical accessibility greatlyinfluences the likelihood of surgical success without permanent neuro-logical morbidity.

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arteriovenous malformation using gamma knife therapy: a review withillustrative case. Brain Behav 3(4): 329–334

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Oliver Müller and Ulrich Sure, Essen, GermanyKilbourn et al. report on the first de novo AVM of the posterior fossa,

so far. De novo AVMs are indeed exceptional occurrences with respect tothis latest review. Scarce information is available on the incidence of brainAVMs. Large prospective studies estimated an incidence of brain AVMsof 1.3 per 100,000 person-years with a cumulative bleeding risk of 0.51[1]. On the other hand, a large study on incidental MRI findings did notdetect any brain AVMs among 2,000 scans [2]. With this in mind, thepresent report should inspire us to dig even deeper into the potentialbiology of brain AVMs.

Are AVMs hereditary, connatal, or acquired lesions? Several studieshave uncovered proliferative and neoangiogenetic abilities within theAVM vasculature [3–6] that might even be induced by previous partialtreatment. Are AVMs benign vascular tumors rather than truemalformations?

ARUBA has told us that medical treatment is superior to medicaltreatment and intervention over a (too short for a benign tumor ormalformation) 33-month period in unruptured AVMs [7]. However, thisconclusion must be discussed highly controversially since 87 % of themalformations (assessed for eligibility) were excluded from statisticalanalysis in this prospective study. In the treatment arm group, the vastmajority of patients was not treated surgically (more than 80 %), suggest-ing that these AVMswere only occluded partially with all potential risk ofa remaining nidus. If future research reveals a more aggressive growthbehavior as shown in de novo AVMs, this finding will furthermoredownsize the significance of the results of the ARUBA study whichwas designed under the assumption that AVMs are rather stable non-neoplastic non-growing lesions.

Therefore, the present well-documented case is an important contri-bution to the literature.

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study progress, and initial results. Stroke 34(5): e29–33

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2. Vernooij MW et al (2007) Incidental findings on brain MRI in thegeneral population. N Engl J Med 357(18): 1821–8

3. Rothbart D et al (1996) Expression of angiogenic factors andstructural proteins in central nervous system vascular malformations.Neurosurgery 38(5): 915–24; discussion 924–5

4. Kilic Tet al (2000) Expression of structural proteins and angiogenicfactors in cerebrovascular anomalies. Neurosurgery 46(5): 1179–91; dis-cussion 1191–2

5. Sure U et al (2001) Treatment-induced neoangiogenesis in cerebralarteriovenous malformations. Clin Neurol Neurosurg 103(1): 29–32

6. Sandalcioglu IE et al (2010) Proliferation activity is significantlyelevated in partially embolized cerebral arteriovenous malformations.Cerebrovasc Dis 30(4): 396–401

7. Mohr JP et al (2014) Medical management with or without interven-tional therapy for unruptured brain arteriovenous malformations (ARUBA):a multicentre, non-blinded, randomised trial. Lancet 383(9917): 614–21

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