AVMs AND DIFFUSE PROLIFERATIVE ARTERIAL DISORDERS: DIFFERENCES THAT NEURORADIOLOGISTS NEED TO KNOW Educational Exhibit Lazaro D. Causil, MD Francisco Sepulveda, MD Romy Ames, MD Monika Amunugama, MD Carlos Zamora, MD Hortensia Alvarez, MD Mauricio Castillo, MD, FACR eEdE-178

Disclosures The authors have no disclosures or conflict of interest.

Objective Our purpose is to compare the clinical, epidemiological, pathological, imaging and treatment differences between 3 cerebral arterial disorders that may look similar but represent different entities. For instance, they have different natural histories, require different treatments and have different outcomes.

Introduction Arteriovenous malformations (AVMs), cerebral proliferative angiopathy (CPA) and moyamoya are vascular disorders that may present with similar clinical manifestations, and radiological appearance, but an accurate diagnosis can be achieved based on clinical presentation and multimodality imaging findings.

Approach A retrospective search of brain vascular malformations was performed in our institution database. Representative cases of brain AVM, moyamoya and cerebral proliferative angiopathy (CPA) were retrieved from the database. A review of the recent literature was performed using Medline/Pubmed ® looking for epidemiology, clinical presentation, associated diseases, histopathology features, imaging characteristics, natural histories, treatments and outcomes. We organized a comparison of the most important features of these entities so that the neuroradiologist can become familiar with them.

ARTERIOVENOUS MALFORMATIONS CEREBRAL PROLIFERATIVE ANGIOPATHY MOYAMOYA DISEASE /MOYAMOYA SYNDROME

Definition AVM CPA MOYAMOYA Vascular abnormality consisting of feeding arteries, a nidus and draining veins. Abnormal connections between arteries that would normally supply the brain tissue (pial vessels) and veins that normally drain it, resulting in arteriovenous shunting with an intervening network of vessels (nidus) within the brain parenchyma and lack of a true capillary bed. CPA MOYAMOYA “Cerebral proliferative angiopathy” (CPA) is a term introduced in 1989 (Lasjaunias et al.) as a presumed diagnosis for a peculiar and rare type that demonstrated distinctive angiogenetic features by which they could be separated from “classical” brain AVMs. “Moyamoya Syndrome” (MMS) is used to describe those entities with Moyamoya vasculopathy characteristics and recognized associated conditions, whereas others without associated conditions are referred to as “Moyamoya Disease” (MMD). Moyamoya only refers to the angiographic features independently of the cause.

Epidemiology AVM CPA MOYAMOYA 2/3 occur before 40 years Male to female ratio 1.2 1.1:100,000 person-years and the detection rate for symptomatic AVMs is 0.94:100,000 person-years. Prevalence of detected, active (at risk) AVM disease is unknown, but it can be presumably lower than 10.3 per 100,000 population. CPA MOYAMOYA Mean age of presentation 20 years (Range 10-65) Young female (2:1) Rare condition Comprises only 2-4% of all brain AVMs in one series. 2 peaks of incidence (5 years)/(mid 40s) Female (2:1) Rare condition Japan, 3:100,000 Europe, 3:1,000,000 US: 8.6:10,000,000 Asian Americans > African Americans > Caucasians > Hispanics

Clinical History AVM CPA MOYAMOYA Most AVMs are asymptomatic and approximately 12% will present with different symptoms including: Intracranial hemorrhage (most common) Seizures (new onset) Headache Dizziness Visual disturbances Loss of consciousness Symptoms due to mass effect (hydrocephalus) CPA MOYAMOYA Seizures (most common symptom): 45% Headache (common symptom): 41% Progressive neurological deficit: 16% Hemorrhage (rare) (~12%) Hydrocephalus Transient ischemic attacks (TIAs) Related to ischemia Stroke: 50-75% TIAs: 50-75% Seizures Related to compensatory mechanism to ischemia Hemorrhage Headache

Clinical History AVM CPA MOYAMOYA Ischemic symptoms may be present due to arterial steal. 50 percent of patients present initially with intracranial hemorrhage. Bleeding risk increases after rupture, reaching 6-8 % during the first year. CPA MOYAMOYA If hemorrhage occurs, consider Hemorragic Angiopathy. There is a low, but potential risk of critical hemorrhage. When hemorrhage has occurred the risk of recurrence is high: 67%. Ischemic symptoms are a dominant feature in children and adults. Hemorrhagic presentation is more common in adults. Changes in circulatory pattern have been associated with aneurysms (basilar tip, PCA)

Associated Conditions AVM Intracranial aneurysms Sturge-Webber syndrome Autosomal dominant polycystic kidney disease Von Hippel-Lindau syndrome Osler-Webber-Rendu syndrome Wyburn – Mason syndrome CPA MOYAMOYA Few cases have been published to date: Intracranial aneurysms Hemangioma of the face and tongue Intracranial aneurysms Sickle cell anemia Down syndrome Cranial radiotherapy Congenital cardiac anomaly NF 1 PHACE syndrome

Histopathology Features AVM Tangle of abnormal arteries and veins without an intervening capillary bed Alteration of the lamination of elastic and muscle fibers Arterial muscle fibers may be thinned forming arterial aneurysms Calcifications, atheromas and fibrosis can be present Loss of neurons and thin gliotic bands within the nidus, No neurons present CPA MOYAMOYA Intermingled normal brain tissue between the vascular spaces Collagenous thickening of veins Altered internal elastic lamina & smooth muscle cells Smooth muscle hyperplasia No inflammation Irregular elastic lamina Calcification in old infarcts

IMAGING CHARACTERISTICS

BRAIN AVM a. b. c. Figure 1. Different cases: (a) Axial non enhanced CT demonstrates a left frontal AVM with coarse calcifications. (b) Axial T2WI MRI shows the typical ”bag of black worms” appearance in the right temporal lobe. Note the absence of interspersed brain parenchyma within the nidus. (c) Lateral right ICA angiography demonstrates a glomerular (compact) type nidus in a superficial location supplied by branches of the MCA (dominant feeders) with early drainage to a cortical vein. Note the small venous pouch (arrowhead) whose presence suggest a high risk of hemorrhage. Pendiente encontrar AVM con calcificaciones o poner referencia de imagen 1 (Radiopaedia) IMAGING FINDINGS: No interimposed brain tissue. Arterialized draining vein (AV shunting) (early drainage) Large draining vein compared to nidus size. Calcifications Capillary network (the nidus) is connected to one or more afferent arteries and efferent veins. Transdural supply has been reported in large lesions (Arterial steal) No stenoses Presence of dominant feeders Case (a) courtesy of Dr. Sajoscha Sorrentino, Radiopaedia.org, rID:14785

BRAIN AVM a. b. c. IMAGING FINDINGS: Figure 2. Different cases: (a) Axial T2WI demonstrates a left frontoparietal hematoma with associated compact type superficial AVM. (b) Lateral left ICA angiogram shows a glomerular type nidus in a cortical location supplied by the sylvian branches of the left MCA, with deep venous drainage to the thalamostriate vein (arrowhead). (c) Frontal right ICA angiogram demonstrates a paramedian AVM supplied by two branches of the ACA with early venous drainage to vein of Galen (not shown). A flow related aneurysm is also noted (arrow). IMAGING FINDINGS: Supratentorial location is the most common (90%) MRI images show a nidus of compact vessel with the typical appearance of "bag of black worms” Angiography (DSA) is the gold standard, able to delineate location and number of feeding vessels and pattern of drainage No Angiogenesis Glomerular nidus (compact type) Incidence of aneurysms in AVM may be influenced by geography and ethnicity.

CEREBRAL PROLIFERATIVE ANGIOPATHY Figure 3. Different cases: (a) Axial FLAIR demonstrates a diffuse angiogenetic network involving the right cerebral hemisphere consistent with holohemispheric proliferative angiopathy. (b) Axial GD enhanced T1WI shows an enhancing vascular lesion in the left parietal and occipital lobe with interimposed brain parenchyma between the aberrant vascular structures. (c) Lateral left ICA angiography demonstrates diffuse proliferation of vessels within the left cerebral hemisphere with fast capillary transit and no areas of high flow shunting. IMAGING FINDINGS: Diffuse network of enhancing vascular spaces Extensive transdural supply Late stenoses of feeding arteries (ICA, M1-2, A1-2) Absence of dominant feeders in a large nidus Interimposed brain between the vascular spaces No areas of high flow shunting (no early drainage) Small size of draining veins compared to the size of the nidus

CEREBRAL PROLIFERATIVE ANGIOPATHY Figure 4. Different cases: (a) Coronal GD enhanced T1WI shows a diffuse network of enhancing vessels in the left temporal lobe (b) Lateral left ICA angiogram shows areas of ill defined nidus (arrowhead) with fuzzy appearance (proliferative type nidus) with absence of dominant feeders or areas of high flow shunting. (c) Frontal angiogram injection of the left ECA demonstrates the presence of extensive transdural blood supply (large arrow). IMAGING FINDINGS: Multilobar involvement Basal ganglia and thalamus are frequently involved Watershed zones location Asymmetry of the frontal sinus pMRI abnormalities extend beyond the boundaries of morphological abnormalities Diffuse neoangiogenesis Fuzzy appearance of the nidus (diffuse/proliferative type nidus) No flow related aneurysm

MOYAMOYA a. b. c. IMAGING FINDINGS: Figure 5. Different cases: (a) Axial FLAIR shows bilateral prominent leptomeningeal collateral vessels resulting in hyperintense signal within the cerebral sulci due to slow flow, also known as “Ivy sign”. (b) Axial SWI shows multiple areas of susceptibility artifact due to microhemorrage. (c) Axial FLAIR shows areas of gliosis as a result of chronic infarcts in a typical watershed zone distribution. IMAGING FINDINGS: Unilateral findings is referred as MMS even in the absence of associated conditions No areas of high flow shunting (no early drainage) Leptomeningeal enhancement (flow engorgement) Bilateral findings are suggestive of MMD Transdural supply is exceptional (vault moyamoya) Early stenosis of distal ICAs, proximal ACAs and MCAs are the most common affected vessels

MOYAMOYA a. b. c. IMAGING FINDINGS: Figure 6. Different cases: (a) Axial TOF demonstrates narrowing of the right ICA (black arrowhead). (b) Coronal MRA view shows the classic “Puff of smoke” appearance due to bilateral collateral perforating vessels (arrows) and absence of flow related enhancement of bilateral MCAs. (c) Coronal MRA shows stenosis of the right MCA (white arrowhead) and occlusion of the left MCA. IMAGING FINDINGS: MRI shows reduced flow voids in ICA, ACA and MCA FLAIR and SWI demonstrate the “Ivy sign” and the “Puff of smoke sign” on DSA DSA is better to depict aneurysm and vascular malformations than MR (Gold Standard). It also reveals stenoses in ECA Secondary findings like gliosis, atrophy, hemorrhage and watershed zone infarcts No identifiable nidus or AV shunting zones. Aneurysm (main cause of hemorrhage)

MRI Comparison AVM CPA MOYAMOYA a. b. c. Cerebral proliferative angiopathy (b) typically affects multiple lobes or an entire hemisphere, and demonstrates intermingled brain parenchyma within the zone of AV shunting. CPA is usually associated with atrophy, gliosis or watershed zone infarcts, findings that have been associated with Moyamoya, but generally not with AVMs. The presence of aneurysms is expected in a minority of patients in the 3 entities, for instance it should be taken into account considering that flow-related aneurysms lead to a higher risk of developing hemorrhage and intranidal aneurysms carry a higher risk of early recurrent hemorrhage.

Angiographic Comparison b. c. AVM CPA MOYAMOYA Both cerebral proliferative angiopathy (b) and Moyamoya (c) are arterial proliferative conditions leading to stenoses in proximal vessels while AVMs (a) typically demonstrate an arterial dominant feeder without stenoses and well defined area of AV shunting. The presence of a diffuse nidus (arrow in b), transdural supply and absence of high flow shunt should raise the suspicion for CPA.

PWI-MRI Characteristics AVM Lower mean CBVc, MTT, and MVL have been found in patients with classical AVM who had few or no angiogenic features in comparison to higher mean values of these parameters found in patients with CPA In classic brain AVMs MTT is decreased due to rapid shunting. CPA MOYAMOYA Increased CBV Increased CBF Decreased TTP Prolonged MTT pMRI/CT can be difficult to perform in some cases due to severely narrowed or absent vessels CT perfusion data weakly correlates with DSA Perfusion studies are unreliable when bilateral stenoses Hypervasculatization within the Nidus Ischemic Nature

CEREBRAL PROLIFERATIVE ANGIOPATHY CBV MTT Same patient: (a) Axial T2WI shows a large proliferative angiopathy involving the left temporal and occipital lobe. (b) Axial CBV map shows diffuse and extensive increase in the cerebral blood volume in the temporal and occipital lobes. (c) Axial MTT map demonstrates prolonged mean transit time, which reflects capillary and venous ectasia. Special attention should be drawn when oligemia is seen in the vicinity of the affected vessels suggesting the presence of ischemia.

PWI-MRI Comparison Saliou G, Krings T, Rutgers DR, et al. PWI-MRI and contrast extravasation in brain AVM help to estimate angiogenic activity. Neuroradiology. 2011;53(10):793-800. (a and b) FLAIR CBV b. c. a. (a) AVM. Axial T2WI and CBV map demonstrates left frontal AVM with severely increased cerebral blood volume within the nidus and mild increase around it. (b) CPA. Axial FLAIR and CBV map shows a large network of vessels involving the right cerebral hemisphere associated with corresponding increased cerebral blood volume ipsilaterally. Note the increased perfusion in areas beyond the margins of the lesion visualized on FLAIR. (c) MMD. Axial FLAIR demonstrates multiple chronic infarcts in a typical watershed zone distribution and CBV map demonstrates low cerebral blood volume in deep regions of both hemispheres. No areas of AV shunting or regions of increased perfusion are visualized.

Special Imaging Considerations AVM There is high risk of hemorrhage if venous pouches are identified. Superficial lesion with deep drainage suggest (thrombosis) a more unstable lesion. Diagnosis can be difficult on non-contrast CT. The exact anatomy of feeding vessels and draining veins can be difficult to delineate, and thus, angiography remains necessary. CPA MOYAMOYA Quantitative MR imaging based mapping of cerebrovascular reactivity (CVR) has been used to measure adequate blood supply to brain tissue. Several CVR impairment in the perilesional brain tissue of patients with CPA. CT demonstrates hemorrhage (Ventr/SAH) and infarcts in watershed zones, basal ganglia, periventricular region and deep white matter. CT could be just normal, specially in TIAs. CT angiography is adequate for assessing vascular anatomy.

Subtle Imaging Differences HEMORRHAGIC ANGIOPATHY Diffuse neoangiogenesis (focal, lobar, hemispheric) Proximal aneurysms (12%) Low Incidence of bleeding Transdural supply Late stenoses of feeding arteries (ICA, M1-2, A1-2) PROLIFERATIVE ANGIOPATHY Diffuse neoangiogenesis (small pseudotumoral blush) No aneurysm High incidence of bleeding and recurrence. No transdural supply No stenoses of feeding arteries

Treatment Indication AVM CPA MOYAMOYA Based on the Spetzler – Martin Classification and the newly introduced 3-tier system (2011) AVMs have a high risk of hemorrhage directly proportional to their size Microsurgical resection is indicated for class A AVMs Multimodal approach is typically used for class B AVMs and class C AVMs, that are not appropriate for observation CPA MOYAMOYA 1. Hemorrhage if fragile angioarchitecture (intranidal aneurysmal ectasia) is identified 2. Uncontrollable seizures 3. Disabling headaches *Surgery and Radiosurgery must be reserved only for intractable headache and epilepsy. 1. Medical therapy (antiplatelets) is only indicated when surgery represents high risk. 2. Surgical treatment: when Increased blood flow to the ischemic brain is a major benefit. 3. Symptomatic hemispheres with impaired CVR

Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65:476–483. Ponce FA, Spetzler RF. Arteriovenous malformations: Classification to cure. Clin Neurosurg. 2011;58:10-12.

Treatment Options AVM CPA MOYAMOYA Microsurgery Radiosurgery Embolization Observation CPA MOYAMOYA Targeted embolization (glue) in non-eloquent areas Calvarial burr holes, improve circulation to cortical areas * Even partial treatment has led to sufficient control of symptoms. Extracranial-intracranial bypass to improve cortical blood supply. There is no known treatment to reverse the primary disease. Current treatment are designed to prevent stroke, reduce collaterals and frequency of symptoms. Surgical Treatment: Synangiogenesis: Direct: Sup. temporal artery and cortical artery. Indirect: Dura or temporalis muscle and the piamater.

Treatment Considerations AVM Treatment is aimed at preventing hemorrhage in the future. Rarely they are treated to improve symptomatology The risk of hemorrhage is essentially the same in a patient with an AVM that has never bled compared to a patient with an AVM that has bled in the past (longer than 6 months) CPA MOYAMOYA Surgery, radiosurgery an large and non targeted embolization carry the risk of permanent neurological deficit (intermingled functional brain tissue). Direct, indirect and combined techniques have shown excellent results. Indirect techniques take some weeks to demonstrate improvement in blood flow Its use is preferred in the absence of suitable recipient vessels

CASE REPORTS

Case 1 We present imaging findings in a 25 year old male who presented with a 2 year history of headaches and seizures. Coronal T2WI (a) and axial FLAIR (b) demonstrate a diffuse network of vessels involving the posterior frontal and parietal lobe of the left cerebral hemisphere with fast capillary transit and intermingled brain parenchyma (white star on b). No glomerular nidus was identified and a preliminary diagnosis of CPA was done. a. b. c.

Same patient: After analyzing the DSA images we also confirmed the presence of a proximal flow related aneurysm (arrow) and high flow AV shunt (arrowhead) which would be unusual for a proliferative cerebral angiopathy. d. e.

Case 2 10 year old boy who presented with history of left hemispheric symptoms and mild extremity weakness that has evolved to right hemiplegia and expressive aphasia. (a) Axial GD enhanced T1WI shows a diffuse network of engorged vessels involving predominantly the left cerebral hemisphere with some collateral vessels overlaying the right hemisphere (arrows). (b) Axial T2WI shows associated left hemisphere volume loss, gliosis and encephalomalacia with resultant ipsilateral ventricular dilatation. (c) Frontal left ICA angiogram also confirms occlusion of the M1 segment of the middle cerebral artery (arrowhead). The perforating vessels have a moyamoya-like appearance. A preliminary diagnosis of CPA was done. a. b. c.

f. d. CBV MTT e. Same patient: (d) Lateral angiogram also demonstrates the presence of a proliferative type nidus (arrow) and multiple areas of high flow AV shunting (arrowheads). (e) Axial CBV map shows increase of the cerebral blood volume in the left cerebral hemisphere, matching the areas where the vascular abnormality was seen. (f) Axial MTT map also demonstrates severely decreased mean transit time along the left cerebral hemisphere, findings in relation with a chronic left middle cerebral artery occlusion. These findings go against the usual appearance of AVM or CPA.

Cases summary The classic findings of AVMs and 2 arterial proliferative conditions have been summarized. To the best of our knowledge, CPA has never been reported to occur with high flow shunt. These findings are part of a very unusual “hybrid angiopathy” with imaging features of AVM and CPA, which is unlike anything that we have ever seen before. Further studies are needed to identify characteristics that may be present in such entities and which may have implications for treatment decisions.

Discussion The presence of extensive neoangiogenesis, transdural supply, stenosis of the feeding arteries and absence of high flow shunting are findings most commonly seen in CPAs and Moyamoya, but not in classic AVMs. In addition, incidental findings in all include perfusion disturbances. Special care should be taken when deciding treatment because while AVMs can be treated with microsurgery, non targeted embolization and radiosurgery, this treatment may not be adequate for CPA and moyamoya and may result in permanent neurological deficits.

Conclusions CPA differs from moyamoya and AVMs in its angiomorphology, histology, epidemiology, natural history, clinical presentation and treatment and despite similar imaging appearances it may be classified as a separate vascular malformation. MRI with dedicated vascular techniques aids in differentiating these disorders and neuroradiologists should be aware of their imaging characteristics, differences and outcomes.

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