Vascular Malformations Of The Central Nervous System

Vascular malformations of the central nervous system Authors Robert J Singer, MD Christopher S Ogilvy, MD Guy Rordorf, MD Section Editor Jose Biller, MD, FACP, FAAN, FAHA Deputy Editor John F Dashe, MD, PhD Last literature review version 17.1: January 2009 | This topic last updated: January 24, 2009 (More) INTRODUCTION — Cerebral vascular malformations occur in 0.1 to 4.0 percent of the general population [1,2] . Four general subtypes of congenital malformations have been described: Developmental venous anomalies Capillary telangiectasias Cavernous malformations Arteriovenous malformations Developmental venous anomalies are most common in autopsy series, with an incidence of 2 percent [3,4] . This is followed by arteriovenous malformations (1 percent), capillary malformations (telangiectasias, 0.7 percent), and cavernous malformations (0.4 percent). Developmental venous anomalies and capillary telangiectasia are usually benign, while cavernous malformations and arteriovenous malformations have a greater tendency toward neurologic sequelae. This topic will review our understanding of the natural history and treatment of these three lesions, which continues to evolve with our burgeoning imaging capabilities and clinical experience. Cerebral and spinal cord arteriovenous malformations are discussed separately. (See "Brain arteriovenous malformations" and see "Disorders affecting the spinal cord", section on Vascular malformations). DEVELOPMENTAL VENOUS ANOMALIES — Developmental venous anomalies (DVAs), also known as venous angiomas, are composed of a radially arranged configuration of medullary veins separated by normal brain parenchyma (most commonly white matter). These small venous

conduits empty into a central, dilated superficial or deep vein that drains the normal brain. Microscopically, the venous structures appear largely normal with rare degenerative changes consisting of thickening and hyalinization. The lesions do not occur in the diencephalon, brainstem, or spinal cord. DVAs most often are solitary, although multiple lesions have been described in association with other clinical syndromes (eg, the blue rubber bleb nevus syndrome) [5] . DVAs also may occur concurrently with cavernous malformations [6] . A second cerebrovascular anomaly has been reported in approximately 19 percent of this patient population [7] . Clinical presentation — DVAs are considered benign lesions, although they may uncommonly present with seizures, progressive neurologic deficits, and hemorrhage [8-10] . Headache is the most common presenting complaint, followed by seizures and sensory-motor phenomena. However, a direct correlation between these symptoms and the existence of a DVA has not been firmly established [11,12] . In a ten-year prospective clinical and magnetic resonance imaging study, a symptomatic hemorrhage rate of 0.34 percent per year was observed [11] . The hemorrhages were usually benign, although fatal intracranial hemorrhages have been described [10] . The most informative study retrospectively reviewed patients with presentations that could be directly linked to vascular complications of DVAs but not to other pathologies [13] . Cases with cavernous malformations were excluded because of the known association with DVAs. Seventeen patients were identified, and a review of the literature published after the introduction of MRI identified another 51 cases fulfilling the same criteria. From these 68 cases, two major pathophysiologic categories of symptomatic DVAs were identified [13] : Mechanical compression of intracranial structures by a component of the DVA was seen in 14 patients (21 percent). The most common associated symptoms were hydrocephalus, tinnitus, brainstem deficits, hemifacial spasm, and trigeminal neuralgia Flow-related symptoms were present in 49 patients (72 percent), with two subcategories: - Increased inflow in 19 patients (28 percent), typically related to an arteriovenous malformation (AVM) draining via dilated and ectatic medullary veins through a DVA, resulting in headaches, neurologic deficits, seizures, and coma, usually secondary to parenchymal and/or intraventricular hemorrhage - Restricted outflow, either by an anatomic obstruction (eg, stenosis or thrombosis of the DVA or its draining vein) in 26 patients (38 percent) or by a physiologic obstruction (eg, increased venous pressure secondary to a distal arteriovenous shunt or AVM) in four patients (6 percent). These mechanisms were associated with variable combinations of neurologic deficits, headaches, seizures, and altered mentation. The clinical picture in several cases resembled that caused by cerebral venous thrombosis, with increased intracranial pressure, venous congestive edema, and/or intraparenchymal or subarachnoid hemorrhage No obvious alteration attributable to the DVA was found to explain symptoms in six cases (9 percent)

Diagnosis — Cerebral angiography is considered the gold standard for the diagnosis of DVAs, but they are usually identified with contrast enhanced cross-sectional imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA). Computed tomography — Nonenhanced CT scans do not usually demonstrate DVAs unless there is an associated cavernous malformation. After contrast administration, the enlarged vein is all that is typically identified. CT angiography (CTA) has also been used to identify DVAs [14] . Magnetic resonance imaging and angiography — MRI typically shows medullary veins converging on the dilated transcerebral vein. A characteristic "sunburst" pattern is seen on enhanced T1weighted images. MRA usually demonstrates the dilated venous channel with variable depiction of the smaller medullary veins. Angiography — As mentioned, cerebral angiography usually is not needed for the diagnosis of DVA since axial imaging sequences on MRI often suffice to make the diagnosis. In atypical cases, angiographic findings are pathognomonic; during the late capillary or venous phase there is a paucity of normal veins in the region of the lesion and a characteristic "caput medusae" appearance of the radially arranged small medullary veins (show radiograph 1). The arterial phase is typically normal. Treatment — DVAs should be treated conservatively in the vast majority of cases, with associated symptoms such as headaches and seizures managed medically [12] . Surgery may be required in the rare patient with hemorrhage associated with a DVA or with uncontrolled seizures [10] . In patients who undergo surgery, preoperative contrast enhanced imaging is required to identify an associated cavernous malformation [6] . Venous infarction has been reported with DVA resection [15] ; thus, it is reasonable to simply evacuate the hematoma and leave the DVA in situ. Radiosurgical and endovascular techniques do not have a defined role in the management of these lesions. CAPILLARY TELANGIECTASIAS — Capillary telangiectasias are small lesions most commonly found in the pons, middle cerebellar peduncles, and dentate nuclei. Multiple lesions are common. The lesions are composed of small, dilated capillaries devoid of smooth muscle or elastic fibers. The intervening brain is often normal; it may also demonstrate areas of microhemorrhage or gliosis. A common histopathological feature of these lesions is a dilated efferent system, probably representing a venous channel. An argument has been made for these lesions representing the early stage in the spectrum of development of cavernous malformations and other "mixed" vascular malformations [16,17] . Although not proven, angiogenesis is believed to play a role in lesion evolution. Most telangiectasias represent an angiodysplastic phenomenon resulting from faulty embryogenesis of

the vascular wall and have been associated with angiomatous phacomatoses such as Osler-WeberRendu (hereditary hemorrhagic telangiectasia), Louis-Bar (ataxia-telangiectasia), and WyburnMason (unilateral retinocephalic vascular malformation) syndromes [18] . (See "Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on Cerebral AVMs and section on Unilateral disease). Clinical presentation — Capillary telangiectasias are usually clinically silent, found incidentally on neuroimaging studies or at postmortem examination. Rare symptomatic cases occur [19] ; headache, nausea, and seizures have been described in patients with these lesions, although a causal relationship is unclear. Diagnosis — MRI is the most sensitive imaging modality for the identification of capillary telangiectasias. Low signal intensity "black dots" on T1 and T2-weighted imaging are suggestive, although not diagnostic of these lesions. Telangiectasias can be identified in the late arterial/early capillary phase of angiography as a faint blush with an associated venous channel. Thus, these lesions can be distinguished from DVAs that are visualized during the venous phase of the study. Treatment — Capillary telangiectasias are nonoperable lesions. CAVERNOUS MALFORMATIONS — Cavernous malformations (CMs) are also referred to as cavernous angiomas, cavernous hemangiomas, or cavernomas. They may occur sporadically or in a familial pattern [20] . In these populations, de novo lesions have been demonstrated on serial MRIs. The de novo development of CMs after brain biopsy and after radiosurgery confirms the evolutionary nature of the lesions [21] . Three genetic loci (CCM1, CCM2, and CCM3) responsible for familial cavernous malformations have been reported. Nearly all familial cases of cerebral cavernous malformation among Hispanic Americans have been linked to a founder mutation of CCM1 localized to 7q [22-24] . Familial cases in white non-Hispanic families have been linked to CCM2 at 7p15-p13 [25] and CCM3 at 3q25.2q27 [25,26] . On gross examination, cavernous malformations have a characteristic "mulberry" appearance with engorged purplish clusters. They vary from 2 mm to several centimeters in diameter. Microscopic examination reveals that CMs are composed of dilated, thin walled capillaries with a simple endothelial lining and a thin, fibrous adventitia. Elastic fibers and smooth muscle are not present in the vessel walls. In the classic description of CMs, there is no intervening brain tissue between the channels of the lesion [27] . However, this may not be an essential criterion of CMS, as one histopathologic study of 71 CM cases noted intervening brain parenchyma in 50 (70 percent) [28] , and others have also noted intervening brain tissue in some fraction of cases [16,29] .

The immediately surrounding tissue is usually gliotic and hemosiderin-laden due to previous hemorrhages. It contains dilated capillaries that may represent telangiectasias; this finding supports the integrative concept of capillary telangiectasias and cavernous malformations representing two ends of a spectrum in the development of cavernous malformations [16] . Inflammation, calcification and, rarely, ossification may be identified with CMs, usually in larger lesions [30] . Developmental venous anomalies (DVAs) may be associated with CMs. (See "Developmental venous anomalies" above). In a series of 102 patients, DVAs associated with CMs were found in 23 percent; these occurred more often with lesions in the posterior fossa than the supratentorial compartment [6] . A later series of 57 patients with CMs found associated DVAs in 25 percent, and atypical patterns of venous drainage associated with CMs were seen in an additional 35 percent [31] . The cerebrum is the most common location for CMs (70 to 90 percent) [32] . They have been reported throughout the supratentorial compartment, but most commonly are subcortical and predisposed to the rolandic and temporal areas. Posterior fossa lesions comprise approximately 25 percent of CMs in most large series, with the majority located in the pons and cerebellar hemispheres. There have been only 36 cases of spinal cord cavernous malformations reported in the literature [33] . Clinical presentation — CMs occur with equal frequency in males and females, with a mean age of 30 to 40, although women more commonly present with hemorrhage and neurologic deficits [34,35] . CMs that are associated with DVAs or atypical venous drainage may be more likely to present with symptomatic hemorrhage than CMs that are not associated with venous anomalies [31] . The presentation of CMs is specific to their location. Supratentorial CMs commonly present with hemorrhage, seizures, and progressive neurologic deficits. Annual bleeding rates of 0.25 to 1.1 percent have been reported in several large series [35,36] . Seizures and progressive neurologic deficits may be the result of mass effect and secondary compromise of the microcirculation, or of microhemorrhages with local hemosiderin deposition irritating cortical or subcortical tissue. Infratentorial CMs commonly present with hemorrhage and progressive neurologic deficits. Lesions in the brainstem present with cranial neuropathies and long-tract signs that cause progressive neurologic decline due to the high volume of critical nuclei and fiber tracts in this area. Thus, the natural history of brainstem lesions is worse than that of lesions in other areas. The annual bleeding rate for brainstem lesions is 2 to 3 percent per year, with recurrent hemorrhage rates approaching 17 to 21 percent [21] . Progressive neurologic decline is observed in 39 percent. The natural history of asymptomatic lesions is significantly different from CMs presenting with clinical sequelae. A prospective study of 122 patients (mean age 37 years, range 4 to 82 years) found that 50 percent were initially asymptomatic [37] . At a mean follow up of 34 months, the hemorrhage rate in asymptomatic and symptomatic patients was 0.6 and 4.5 percent, respectively. This study did not find that gender or lesion location influence prognosis, although

others suggest that female gender and infratentorial location are risk factors for subsequent neurologic disability [36,38] . Lesion size and multiplicity do not appear to influence prognosis. Diagnosis — Blood flow through CMs is minimal. Thus, they may not be seen on angiography and often are referred to as "angiographically occult." Other imaging modalities, particularly MRI, play a more important role in the diagnosis [20] . Magnetic resonance imaging — MRI usually establishes the diagnosis of cavernous malformation. Characteristic findings on T-1 and T-2 weighted images include a "popcorn" pattern of variable image intensities consistent with evolving blood products (show radiograph 2). A dark hemosiderin ring, best seen on T2 or gradient echo sequences at the periphery of the lesion, is suggestive of remote hemorrhage (show radiograph 3). Lesions that mimic CMs on MRI include low grade gliomas, hemorrhagic metastases (particularly melanoma), and choriocarcinoma [33] . Contrast enhanced images should be obtained once a CM is identified in order to delineate any potential associated DVAs [6] . Contrast enhanced images often demonstrate DVAs since they are associated with normal flow. On the other hand, CMs may have only scattered enhancement that is variable and inconsequential. This is critical in surgical planning since the resection of DVAs may compromise normal cortical venous drainage patterns and lead to venous infarction [15] . Computed tomography — CT usually demonstrates a nonspecific, irregular, hyperdense mass with variable degrees of calcification. A faint perilesional blush with contrast administration is a variable and nonspecific finding. Angiography — CMs demonstrate a capillary blush or early draining vein in approximately 10 percent of patients [32] . These findings may be similar to the angiographic appearance of meningiomas. Digital subtraction angiography appears to be much more sensitive than MRI for detecting the presence of CM-associated atypical venous drainage [31] . Treatment — Asymptomatic CMs are observed, irrespective of location. Indications for surgical resection of accessible symptomatic cerebral and cerebellar lesions include progressive neurologic deficit, intractable epilepsy, and recurrent hemorrhage. One group reported excellent or good surgical outcomes in 97 percent of 65 patients with cerebral and cerebellar CMs at a mean followup of one year [32] . A poor outcome was reported in 1.5 percent with an overall mortality of 1.5 percent. In a case series of 168 patients with symptomatic epilepsy attributed to CM, more than two-thirds of patients were seizure free at three years after surgery [39] . Predictors for good outcome included mesiotemporal location, size <1.5 cm, and the absence of secondarily generalized seizures. Another series identified a long preoperative seizure history and poorer preoperative seizure control as unfavorable prognostic indicators [40] . Surgically inaccessible lesions — Patients with symptomatic CMs entirely surrounded by eloquent tissue (eg, rolandic cortex, brainstem, thalamus/basal ganglia) are usually observed despite the poor natural history associated with untreated brainstem and thalamic lesions.

Stereotactic radiosurgery is a potential alternative to conservative therapy in patients with such surgically inaccessible lesions, and the available evidence suggests that it does lead to a reduction in hemorrhage, especially two years or more after radiosurgery [41-44] . Nevertheless, high complication rates in available published series coupled with clinical experience has dissuaded many from using stereotactic radiosurgery for the treatment of CMs. (See "Stereotactic cranial radiosurgery and radiotherapy" and see "Complications of cranial stereotactic radiosurgery", section on Late reactions). As an example, one retrospective analysis of 95 patients with 98 lesions found that stereotactic radiosurgery was associated with a significant drop in the annualized hemorrhage rate from 17 to 5 percent after a two-year post-treatment latency period [42] . However, at an average follow-up of 5.4 years, the incidence of permanent neurologic deficit and mortality was 16 and 3 percent, respectively, and these complications were attributed to radiation-induced injury. In addition, the combined effects of radiation-related injury and clinical progression of the lesion led to a significant decline in neurologic function during follow-up. Given the available data, we suggest not using stereotactic radiosurgery for the treatment of CMs. Brainstem location — Brainstem CMs often are treated due to their aggressive natural history when there is progressive neurologic deterioration, with or without recurrent hemorrhage, if the lesion lies near the pial surface or if a non-eloquent tissue corridor exists to the lesion [45] . In one series of 23 patients with surgically treated brainstem CMs, 46 percent had transient neurologic deficits, 17 percent had new or worsened deficits, and 83 percent were significantly improved at a mean follow-up of 3.9 years [33] . In a second retrospective analysis, no or only slight neurologic deficit was reported in 67 percent of 30 patients treated conservatively compared with 84 percent of 93 patients treated surgically [21] . Microsurgical techniques are also being used with success in some centers [46] . ARTERIOVENOUS MALFORMATIONS — Arteriovenous malformations (AVMs) are the most dangerous congenital vascular malformations. This topic is discussed separately. (See "Brain arteriovenous malformations"). BIBLIOGRAFIA El-Gohary, JM, Tomita, T, Guitierrez, FA, et al. Angiographically occult vascular malformations in childhood. Neurosurgery 1987; 20:759. McCormick, WF. The pathology of vascular ("arteriovenous") malformations. J Neurosurg 1966; 24:807. McCormick, WF. Pathology of vascular malformations of the brain. In: Intracranial Arteriovenous Malformations, Wilson, CB, Stein, BM (Eds), William & Wilkins, Baltimore, MD 1984. p.44. Russell, DS, Rubinstein, LJ. Pathology of Tumors of the Nervous System. 5th ed. Williams & Wilkins, Baltimore, MD 1989. p.727. Osborn, AG. Intracranial vascular malformations. In: Diagnostic Neuroradiology, Osborn, AG (Ed), Mosby Year-Book, St. Louis 1994. p.316. Abe, T, Singer, RJ, Marks, MP, et al. Coexistence of occult vascular malformations and developmental venous anomalies in the central nervous system: MR evaluation. AJNR Am J Neuroradiol 1998; 19:51. Boukobza, M, Enjolras, O, Guichard, JP, et al.

Cerebral developmental venous anomalies associated with head and neck venous malformations. AJNR Am J Neuroradiol 1996; 17:987. Numaguchi, Y. Intracranial venous angiomas. Surg Neurol 1982; 18:193. Rothfus, W. Cerebellar venous angioma: "Benign" entity? AJNR Am J Neuroradiol 1984; 5:61. Malik, GM, Morgan, JK, Boulos, RS, et al. Venous angiomas: An underestimated cause of intracranial hemorrhage. Surg Neurol 1988; 30:350. McLaughlin, MR, Kondziolka, D, Flickinger, JC, et al. The prospective natural history of cerebral venous malformations. Neurosurgery 1998; 43:195. Garner, TB, Del Curling, O Jr, Kelly, DI Jr, Laster, DW. The natural history of intracranial venous angiomas. J Neurosurg 1991; 75:715. Pereira, VM, Geibprasert, S, Krings, T, et al. Pathomechanisms of symptomatic developmental venous anomalies. Stroke 2008; 39:3201. Peebles, TR, Vieco, PT. Intracranial developmental venous anomalies: Diagnosis using CT angiography. J Comput Assist Tomogr 1997; 21:582. Senegor, M, Dohrmann, GJ, Wollman, RL. Venous angiomas of the posterior fossa should be considered as anomalous venous drainage. Surg Neurol 1983; 19:26. Rigamonti, D, Johnson, PC, Spetzler, RF. Cavernous malformations and capillary telangiectasia: A spectrum within a single pathological entity. Neurosurgery 1991; 28:60. Maeder, P, Gudinchet, F, Meuli, R, de Tribolet, N. Development of a cavernous malformation of the brain. AJNR Am J Neuroradiol 1998; 19:1141. Garcia, J, Anderson, M. Circulatory disorders and their effects on the brain. In: Textbook of neuropathology, Davis, R, Robertson, D (Eds), Williams & Wilkins, Baltimore 1991. p.625. Farrell, DF, Forno, LS. Symptomatic capillary telangiectasis of the brainstem without hemorrhage. Report of an unusual case. Neurology 1970; 20:341. Rigamonti, D, Hadley, MN, Drayer, BP, et al. Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 1988; 319:343. Fritschi, JA, Reulen, HJ, Spetzler, RF, Zabramski, JM. Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir (Wien) 1994; 130:35. Dubovsky, J, Zabramski, JM, Kurth, J. A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995; 4:453. Laberge-le Couteulx, S, Jung, HH, Labauge, P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999; 23:189. Verlaan, DJ, Davenport, WJ, Stefan, H, et al. Cerebral cavernous malformations: Mutations in Krit1. Neurology 2002; 58:853. Craig, HD, Gunel, M, Cepeda, O, et al. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 1998; 7:1851. Bergametti, F, Denier, C, Labauge, P, et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005; 76:42. Raychaudhuri, R, Batjer, HH, Awad, IA. Intracranial cavernous angioma: a practical review of clinical and biological aspects. Surg Neurol 2005; 63:319. Frischer, JM, Pipp, I, Stavrou, I, et al. Cerebral cavernous malformations: congruency of histopathological features with the current clinical definition. J Neurol Neurosurg Psychiatry 2008; 79:783. Tomlinson, FH, Houser, OW, Scheithauer, BW, et al. Angiographically occult vascular malformations: a correlative study of features on magnetic resonance imaging and histological examination. Neurosurgery 1994; 34:792. Runnels, JB, Gifford, DB, Forsberg, PL, Hanbery, JW. Dense calcification in a large cavernous angioma. Case report. J Neurosurg 1969; 30:293. Kamezawa, T, Hamada, J, Niiro, M, et al. Clinical implications of associated venous drainage in patients with cavernous malformation. J Neurosurg 2005; 102:24. McCormick, PC, Michelson, WJ. Management of intracranial cavernous and venous malformations. In: Intracranial Vascular Malformations, Barrow, DL (Ed), American Association of Neurological Surgeons. Park

Ridge, IL 1990. p.197. Tew, JM, Sathi, S. Cavernous Malformations. In: Primer on Cerebrovascular Diseases, Welch, KM, Caplan, LR, Reis, DJ, et al. (Eds), Academic Press. San Diego, CA 1997. p.550. Del Curling, O, Kelly, DL, Elster, AD, et al. An analysis of the natural history of cavernous malformations. J Neurosurg 1991; 75:702. Robinson, JR, Awad, IA, Little, JR. Natural history of the cavernous angioma. J Neurosurg 1991; 75:709. Aiba, T, Tanaka, R, Koike, T. Natural history of intracranial cavernous malformations. J Neurosurg 1995; 83:56. Kondziolka, D, Lunsford, LD, Kestle, JR. The natural history of cerebral cavernous malformations. J Neurosurg 1995; 83:820. Robinson, JR, Awad, IA, Magdinec, M, Paranandi, L. Factors predisposing to clinical disability in patients with cavernous malformations of the brain. Neurosurgery 1993; 32:730. Baumann, CR, Acciarri, N, Bertalanffy, H, et al. Seizure outcome after resection of supratentorial cavernous malformations: a study of 168 patients. Epilepsia 2007; 48:559. Cohen, DS, Zubay, GP, Goodman, RR. Seizure outcome after lesionectomy for cavernous malformations. J Neurosurg 1995; 83:237. Kondziolka, D, Lunsford, LD, Flickinger, JC, Kestle, JR. Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 1995; 83:825. Amin-Hanjani, S, Ogilvy, CS, Candia, GJ. Stereotactic radiosurgery for cavernous malformations: Kjellberg's experience with proton beam therapy in 98 cases at the Harvard cyclotron. Neurosurgery 1998; 42:1229. Hasegawa, T, McInerney, J, Kondziolka, D, et al. Long-term results after stereotactic radiosurgery for patients with cavernous malformations. Neurosurgery 2002; 50:1190. Liu, KD, Chung, WY, Wu, HM, et al. Gamma knife surgery for cavernous hemangiomas: an analysis of 125 patients. J Neurosurg 2005; 102 Suppl:81. Zimmerman, RS, Spetzler, RF, Lee, KS, et al. Cavernous malformations of the brainstem. J Neurosurg 1991; 75:32. Sandalcioglu, IE, Wiedemayer, H, Secer, S, et al. Surgical removal of brain stem cavernous malformations: surgical indications, technical considerations, and results. J Neurol Neurosurg Psychiatry 2002; 72:351.