7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Vascular malformations of the central nervous system : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 08, 2023. INTRODUCTION AND TERMINOLOGY Cerebral vascular malformations refer to a group of conditions characterized by abnormal vascular configurations occurring within the brain (and spinal cord). As a group, they occur in 0.1 to 4.0 percent of the general population [1-3]. Four general subtypes of congenital malformations include: Arteriovenous malformations (AVMs) Cavernous malformations (CMs) Developmental venous anomalies (DVAs) Capillary telangiectasias AVMs may be subcategorized into pial AVMs and dural arteriovenous fistulas. Cavernous malformations have also been called cavernous angiomas, cavernous hemangiomas, and cavernomas. Developmental venous anomalies were previously also called venous angiomas. Developmental venous anomalies are most common in autopsy series, with an incidence of 2 percent [4,5]. This is followed by arteriovenous malformations (1 percent), capillary 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 cavernous malformations, developmental venous anomalies, and capillary telangiectasias. Cerebral and spinal cord arteriovenous malformations and carotid-cavernous https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 1/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate fistulas are discussed separately. (See "Brain arteriovenous malformations" and "Disorders affecting the spinal cord", section on 'Vascular malformations' and "Carotid-cavernous fistulas".) ARTERIOVENOUS MALFORMATIONS Arteriovenous malformations are the most dangerous congenital vascular malformations. This topic is discussed separately. (See "Brain arteriovenous malformations".) CAVERNOUS MALFORMATIONS Pathogenesis Cavernous malformations (CMs) may occur sporadically or in a familial pattern [6]. Familial CMs Familial CM cases have an autosomal dominant inheritance pattern and are estimated to account for approximately 20 percent of all cases of CMs. Most familial cases have multiple CMs. Pathogenic variants in CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) are known to cause familial CMs [7-9]. The CCM proteins encoded by these three genes interact with each other and are involved with cellular signaling pathways, including formation of a CCM complex signaling platform. Loss of CCM proteins results in the dysregulation of signaling pathways in brain endothelial cells and eventual lesion formation [10,11]. Most of the pathogenic variants constitute loss-of-function mutations involving nonsense, frameshift, or splice site mutations, but larger deletions and duplications have also been reported [6,9,12]. Nearly all familial cases of cerebral CMs among Hispanic Americans have been linked to a founder variant of KRIT1 [13-15]. Familial cases in non-Hispanic White families have been linked to CCM2 [16] and PDCD10 [16,17]. CM may also be found in some patients with genetic conditions such as hereditary hemorrhagic telangiectasia. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pathophysiology'.) Sporadic CMs Approximately 80 percent of CMs are sporadic [18]. Most sporadic cerebral CMs present as solitary lesions and are often associated with a developmental venous anomaly (DVA), but sporadic CMs occasionally present as multiple lesions around the periphery of a DVA [6]. Sporadic CMs appear to be acquired lesions. De novo CMs have been demonstrated on serial magnetic resonance imaging (MRI) [19]. CMs may also develop after cranial radiation therapy [20]. Genetic susceptibilities may underly the development of CMs in some patients [21,22]. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 2/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Novel genetic variants in the CCM pathway were identified in one series of patients with sporadic CMs [23]. In a cohort of 88 patients with sporadic CM, nearly 40 percent were found to have a somatic variant in the PIK3CA oncogene, compared with 10 percent with a variant in a CCM gene [21]. Neuropathology On gross examination, CMs have a characteristic "mulberry" or "popcorn" 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 [24]. 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) [25], and others have also noted intervening brain tissue in some fraction of cases [26,27]. 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 CMs representing two ends of a spectrum in the development of CMs [26]. Inflammation, calcification, and, rarely, ossification may be identified with CMs, usually in larger lesions [28]. The cerebrum is the most common location for CMs (70 to 90 percent) [29]. 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. Spinal cord CMs are intramedullary lesions and predominantly involve the cervical and thoracic regions [30,31]. Intramedullary spinal cord CMs are more common than once recognized, with over 600 cases reported in a meta-analysis published in 2014 [30]. DVAs may be associated with CMs, particularly in sporadic cases [32-35]. 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 [32]. 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 [33]. (See 'Developmental venous anomalies' below.) Epidemiology The incidence of CMs is 0.15 to 0.56 per 100,000 in various populations [36]. CMs occur with equal frequency in males and females, with a mean age of 30 to 40, although females more commonly present with hemorrhage and neurologic deficits [37-39]. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 3/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CMs may occur sporadically or in a familial pattern. (See 'Familial CMs' above and 'Sporadic CMs' above.) Clinical presentation The presentation of CMs is specific to their location. A substantial proportion are asymptomatic and are found incidentally on brain MRI [40,41]. 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 [38,42]. Seizures and progressive neurologic deficits may be the result of mass effect and secondary compromise of the microcirculation or the result 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 [19]. Progressive neurologic decline is observed in 39 percent. Neuroimaging MRI plays a key role in the identification and diagnosis of CMs [43]. (See 'Confirming the diagnosis' below.) MRI Characteristic findings on T1- and T2-weighted images include a "popcorn" pattern of variable image intensities consistent with evolving blood products ( image 1 and image 2). A dark hemosiderin ring, best seen on T2 or gradient echo sequences at the periphery of the lesion, is suggestive of remote hemorrhage ( image 3). MRI should include gradient echo or susceptibility-weighted imaging ( image 4), which may detect smaller CMs that are not visible on conventional MRI sequences [6,44,45]. Contrast-enhanced images should be obtained once a CM is identified in order to delineate any potential associated DVAs [32]. Contrast-enhanced and susceptibility-weighted imaging sequences often demonstrate DVAs since they are associated with a classic "caput medusae" morphology and draining (or "collector") vein ( image 5 and image 6). 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 [46]. (See 'Developmental venous anomalies' below.) https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 4/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CT Computed tomography (CT) usually demonstrates a nonspecific, irregular, hyperdense mass from variable degrees of calcification ( image 6). A faint perilesional blush with contrast administration is a variable and nonspecific finding. Evaluation and diagnosis Confirming the diagnosis The diagnosis of CMs is based upon the characteristic radiologic appearance on MRI (see 'Neuroimaging' above). The diagnosis of familial CM is based upon detection of a pathogenic variant in one of the three genes (KRIT1, CCM2, or PDCD10) [6]. Catheter angiography is generally not recommended for the detection of CMs unless arteriovenous malformation is a diagnostic consideration [6]. Blood flow through CMs is minimal. Thus, they may not be seen on angiography and have been referred to as "angiographically occult." CMs demonstrate a capillary blush or early draining vein in approximately 10 percent of patients [29]. These findings may be similar to the angiographic appearance of meningiomas. Genetic testing Genetic testing for pathogenic variants in CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) is indicated for patients with multiple CMs on imaging, a history of brain radiation therapy, or a positive family history of CMs [6]. Testing should include direct sequencing and deletion/duplication analysis. For new cases of CMs, clinicians should obtain a three-generation family history at the time of diagnosis, with particular attention to family members with a history of hemorrhagic stroke, abnormal MRI scan, epilepsy, or other neurologic complications [6]. However, family history may be confounded by the incomplete penetrance and variable presentation, even within families, of familial CMs. Differential diagnosis Lesions that mimic CMs on MRI include hemorrhagic or calcified neoplastic lesions, particularly hemorrhagic metastases (eg, melanoma, renal cell carcinoma), oligodendrogliomas, pleomorphic xanthoastrocytomas, polymorphous low-grade neuroepithelial tumor of the young, and cerebral microbleeds [6,47]. Metastases Radiologic features more suggestive of metastases include associated extensive cerebral edema compared with the size of the lesion, localization at the junction of the gray and white matter, and/or heterogeneous contrast enhancement. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Imaging studies'.) Gliomas Low-grade gliomas in adults generally are expansile lesions involving both cortex and underlying white matter that appear hyperintense on MRI T2/fluid-attenuated https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 5/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate inversion recovery (FLAIR) sequences. Vasogenic edema is usually absent, and most low- grade gliomas are nonenhancing. Calcification is sometimes present. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas", section on 'Neuroimaging'.) Pleomorphic xanthoastrocytomas Pleomorphic xanthoastrocytoma is a rare type of brain tumor; the few reported lesions with MRI imaging were cortical with leptomeningeal involvement and either a solid or mixed solid-cystic appearance, with the solid component generally hypo- or isointense on T1 sequences, iso- or hyperintense on T2 sequences, and with postcontrast enhancement [48]. (See "Uncommon brain tumors", section on 'Pleomorphic xanthoastrocytoma'.) Polymorphous low-grade neuroepithelial tumors Polymorphous low-grade neuroepithelial tumor of the young is an epileptogenic tumor characterized by oligodendroglioma-like morphology, aberrant expression of CD34 and genetic alterations in the MAP kinase pathway. It is typically a well-circumscribed lesion with macroscopic calcification and cystic component located peripherally in the posteroinferior temporal lobe in children and young adults (median age of 16 years) [49]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Polymorphous low-grade neuroepithelial tumor of the young'.) Cerebral microbleeds Multiple cerebral microbleeds can be seen with multiple CMs as well as cerebral amyloid angiopathy or hypertensive vasculopathy. These conditions generally can be distinguished from multiple CMs by the clinical setting and distribution of microbleeds. Microbleeds restricted to the cerebral cortex or superficial cerebellar regions (cerebellar cortex and vermis) suggest cerebral amyloid angiopathy, while microbleeds that primarily arise from the basal ganglia, thalamus, or pons suggest hypertensive vasculopathy. (See "Cerebral amyloid angiopathy", section on 'Microbleeds'.) Management The general management of CMs involves assessing the individual risk of future bleeding or other neurologic sequela. Most CMs are treated conservatively. The routine care and additional screening for patients with CM associated with other conditions are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis" and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) Asymptomatic lesions Asymptomatic CMs are observed, irrespective of location [6]. Management of asymptomatic CMs involves annual clinical follow-up with a specialist (eg, https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 6/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate neurologist or neurosurgeon) [9]. Some experts advocate annual imaging with brain MRI [50], but such an approach would not change management for patients who are asymptomatic. Immediate brain MRI is indicated for those who develop symptoms possibly related to CMs (eg, seizure, new headache, or new or progressive neurologic deficit) to evaluate for new hemorrhage or new CM [6]. We agree that surgical resection is not recommended for asymptomatic CMs. However, some experts advise that surgical resection of a solitary asymptomatic cerebral CM located in an easily accessible noneloquent area may be considered for various reasons including prevention of future hemorrhage, reduction of burden caused by associated psychological disability and/or expensive and time-consuming follow-up visits, facilitation of lifestyle or career decisions, or risk reduction for patients who need anticoagulation [6]. Symptomatic lesions In general, acute intracerebral hemorrhage (ICH) due to a CM is evaluated and managed in the same way as ICH from other causes. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) A summary of the general approach to symptomatic CMs according to presentation is as follows [6,10]: First-time seizure Medical therapy with antiseizure medication. Medically refractory epilepsy Surgical resection. Supratentorial CM with first ICH Surgical resection if accessible lesion and symptomatic hemorrhage. Consideration for conservative management is given based on comorbidities. Brainstem or deep nucleus CM with first ICH Conservative management. Brainstem or deep nucleus CM with second or greater ICH Surgical resection (or possibly stereotactic radiosurgery, except for familial cases). Indications for surgical resection of accessible symptomatic cerebral and cerebellar lesions include progressive neurologic deficit, intractable epilepsy, and recurrent hemorrhage. Risk of new or recurrent hemorrhage Decisions about CM management should be guided by risk estimates of new or recurrent CM-related symptoms. A 2016 meta-analysis of individual data from 1620 patients with cerebral CMs reported the clinical course from CM diagnosis to the first CM treatment or last available follow-up. With a https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 7/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate median follow-up of 3.5 years, symptomatic ICH developed in 204 patients, with an estimated five-year risk of 15.8 percent (95% CI 13.7-17.9) [51]. Presentation with ICH and brainstem location appear to be risk factors for subsequent hemorrhage [51,52]. According to the meta- analysis, the estimated five-year risk of ICH in these risk categories are: Nonbrainstem CMs presenting without ICH or focal neurologic deficit 3.8 percent (95% CI 2.1-5.5) Brainstem CMs presenting without ICH or focal neurologic deficit 8 percent (95% CI 0.1- 15.9) Nonbrainstem CMs presenting with ICH or focal neurologic deficits 18.4 percent (95% CI 13.3.-23.5) Brainstem CMs presenting with ICH or focal neurologic deficits 30.8 percent (95% CI 26.3- 35.2) There was no independent prognostic significance for risk related to age, sex, or CM multiplicity [51]. It is uncertain if the presence of a DVA is a risk factor for future hemorrhage. Retrospective studies have suggested that an associated DVA is a risk factor for hemorrhage at presentation [33,53]. However, in one registry of 731 patients with sporadic cerebral CM, associated DVAs were negatively correlated with initial ICH (odds ratio [OR] 0.635, 95% CI 0.459-0.878) and were also not predictive of subsequent hemorrhage [52]. Efficacy of surgery There are no randomized controlled trials of interventions for CMs, but observational data from uncontrolled case series suggest that surgical resection is beneficial for select patients with CMs. A 2022 systematic review and meta-analysis identified 100 cohorts with nearly 9000 patients who had treatment of cerebral CMs [54]. With a mean follow-up of 4 years, the mean hemorrhage rate was lower for patients who underwent surgery (2.6 percent) compared with those treated with radiosurgery or conservative treatment (14 and 22 percent, respectively). Prior hemorrhage and brainstem location were associated with higher bleeding risk in both nonsurgical patients and those treated with surgery or radiosurgery. In an earlier systematic review involving over 3400 patients with CM, the incidence of the composite outcome (death, nonfatal intracranial hemorrhage, or new/worse persistent focal neurological deficit) after neurosurgical resection was 6.6 per 100 person-years (95% CI 5.7-7.5) [55]. The incidence increased with each percentage point increase in patients with brainstem CMs (rate ratio [RR] 1.03, 95% CI 1.01-1.05) and decreased with each percentage point increase in patients who presented with hemorrhage (RR 0.98, 95% CI 0.96-1.00) and with each more https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 8/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate recent study midyear, defined as the middle of the time frame of the year in which treatment took place (RR 0.91, 95% CI 0.85-0.98). Thus, although direct comparisons are lacking and data are observational, indirect comparisons suggest that the overall risks at approximately three years of surgical excision (approximately 7 percent risk of death, nonfatal stroke, or neurologic deficit) compares favorably to the overall estimated five-year ICH recurrence risk, which in one cohort was as high as 29.5 percent [56]. The inherent risks of surgery are higher with CMs removed from eloquent ares of the brain (ie, brain regions that directly control neurologic functions such as language, vision, movement, or sensation) or deep brain regions, particularly with brainstem lesions. In a 2019 systematic review of surgical resection of brainstem CMs involving 2493 adult and pediatric patients, the rate of early postoperative morbidity was 35 percent; at last follow-up, neurologic function was improved in 58 percent, stable in 26 percent, and worse in 12 percent, with a mortality rate of approximately 2 percent [57]. Therefore, surgery is typically reserved for patients with a second symptomatic hemorrhage involving brainstem or deep CMs, whereas surgery is usually recommended after a first symptomatic hemorrhage for CMs in noneloquent, superficial locations [6]. However, due to their aggressive natural history, some experts advise treating brainstem CMs even in the absence of recurrent hemorrhage when there is neurologic deterioration if the lesion is surgically accessible (ie, near the pial surface or via a noneloquent tissue corridor to the lesion) [58]. Microsurgical techniques are also being used with success in some centers for patients with several hemorrhages or progression of symptoms [59]. Role of stereotactic radiosurgery We suggest not using stereotactic radiosurgery as the primary treatment for CMs. 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 [60]. Nevertheless, high complication rates in available published series coupled with clinical experience has dissuaded many from using stereotactic radiosurgery for the treatment of CMs. In addition, there is concern that radiation exposure may promote the development of new CMs in familial cases [6]. (See "Stereotactic cranial radiosurgery".) 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 [61]. 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. In a 2019 systematic review https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 9/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate and meta-analysis of 14 observational studies with 576 patients who had stereotactic radiosurgery for brainstem CMs, symptomatic adverse radiation effects developed in 7.3 percent, and permanent adverse radiation effects were noted in 2.2 percent [60]. However, data regarding the long-term safety and adverse effects of stereotactic radiosurgery remain sparse [55]. Management of epilepsy Patients with a first seizure related to cerebral CM should be managed with medical therapy using antiseizure medication. In one prospective report of patients with a first CM-related seizure, the risk of developing epilepsy was 94 percent [62], warranting the diagnosis of probable epilepsy after a single seizure and supporting the use of antiseizure medication treatment [63]. In contrast, prophylactic antiseizure medication treatment is not indicated for patients with asymptomatic or symptomatic CMs who do not have seizures [63]. Medically refractory epilepsy is an indication for surgical resection [6,63]. 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 [64]. 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 [65]. Epilepsy surgery is reviewed in greater detail separately. (See "Surgical treatment of epilepsy in adults", section on 'Vascular malformations'.) Management during pregnancy Observational data from several large series suggest that the risk of developing clinical symptoms due to cerebral CMs during pregnancy is similar to the baseline risk before pregnancy [6,66-68], but this view is not universally held [69]. For patients with cerebral CMs who develop new focal neurologic deficit, acute severe headache, or worsening seizures during pregnancy, a brain MRI is indicated to determine if the symptoms are related to CMs or another intracranial etiology [6]. The approach to managing a new CM- related brain hemorrhage during pregnancy should account for the additional risk that surgical intervention may have on the pregnancy and the unborn child, but otherwise is similar to that in the nonpregnant state [70]. Females with epilepsy related to cerebral CMs should be evaluated and counseled, ideally before conception, about the risks associated with epilepsy during pregnancy. These include the potential for perinatal complications, seizure worsening, and adverse effects of antiseizure medications on the fetus and later development. These risks may be minimized by interventions https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 10/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate before and during pregnancy, as reviewed elsewhere. (See "Risks associated with epilepsy during pregnancy and postpartum period" and "Management of epilepsy during preconception, pregnancy, and the postpartum period".) The mode of delivery should be dictated by obstetrical indications; most patients can have a normal vaginal delivery unless there is a recent intracranial hemorrhage or a precluding neurologic deficit [6,68]. Safety of antithrombotic therapy In contrast to conventional wisdom, the available data suggest that the bleeding risk associated with CMs is not increased with the use of antithrombotic or oral anticoagulant therapy [71,72]. In a population-based cohort study of 300 prospectively identified people (age 16 years and older) in Scotland who were diagnosed with a cerebral CM, there were 61 who used antithrombotic therapy (including 10 who used anticoagulant therapy) [73]. Compared with no antithrombotics, the use of antithrombotics was associated with a lower risk of subsequent intracranial hemorrhage or focal neurologic deficit (2 versus 12 percent; adjusted hazard ratio [HR] 0.12, 95% CI 0.02-0.88). Similarly, in a meta- analysis performed by the same investigators of six studies, mainly retrospective, with over 1300 patients, antithrombotic therapy use was associated with a lower risk of intracranial hemorrhage (3 versus 14 percent; incidence rate ratio 0.25, 95% CI 0.13-0.51). It is likely that the indication for antithrombotic therapy in the patients so treated was the prevention of arterial or venous occlusive disease, but individual patient data were not available; these results do not provide a rationale for treating CMs with antithrombotic therapy. Use of contraceptive and menopausal hormonal medications Limited data suggest use of hormonal contraception or menopausal therapy is associated with an elevated risk of hemorrhage [74,75]. In a multicenter cohort study of 722 female patients with CM, the incidence rate of symptomatic hemorrhage was elevated among patients using hormonal therapy (7.4 versus 5.1 per 100 person-years) [75]. Mean follow-up was 3.3 years. Hormonal therapy included estrogen and/or progesterone and most patients were taking an oral agent. This elevated risk of hemorrhage was present among both patients <45 years old taking oral contraception (aHR 2.0, 95% CI 1.3-3.2) and those 45 years old taking menopausal therapy (aHR 2.4, 95% CI 1.1-5.1). These data are limited by nonrandomized study design, relatively short-term follow-up, and heterogeneity of both hormonal therapy and CM features. The use of hormonal contraceptive or menopausal therapy in patients with CM should be individualized, after informed discussion of risks and benefits. Nonhormonal options may be preferred for patients with CM to reduce the risk of hemorrhage. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 11/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate DEVELOPMENTAL VENOUS ANOMALIES Developmental venous anomalies (DVAs) are composed of a radially arranged configuration of medullary veins ("caput medusae") separated by normal brain parenchyma (most commonly white matter) [76]. These small venous conduits empty into a dilated superficial or deep vein that drains normal brain. A stenosis is common on the collecting vein at the point of penetration into the draining dural sinus. Microscopically, the venous structures appear largely normal with rare degenerative changes consisting of thickening and hyalinization. The lesions are common in supratentorial regions of the brain, with a frontal lobe predominance, but may also be found in the cerebellum and basis pontis. DVAs most often are solitary, although multiple lesions have been described in association with other clinical syndromes (eg, the blue rubber bleb nevus syndrome) [77]. DVAs also may occur concurrently with cavernous malformations (CMs) in 13 to 40 percent, as well as with other intracranial vascular malformations and with superficial venous malformations of the head and neck [32,78,79]. Clinical presentation DVAs are considered benign lesions, although they may uncommonly present with seizures, progressive neurologic deficits, and hemorrhage [52,76,80-83]. Headache is the most common presenting complaint, followed by seizures and sensory-motor phenomena. However, a direct correlation between these symptoms and the DVA is uncertain [84,85]. In a 10-year prospective clinical and MRI study involving 80 patients, a symptomatic hemorrhage rate of 0.34 percent per year was observed [84]. In another study of 93 patients with 492 person- years of follow-up, no symptomatic hemorrhages occurred [83]. The hemorrhages were usually minor, although fatal intracranial hemorrhages have been described [82]. A retrospective case series reviewed the clinical presentations of 68 patients with imaging findings suggestive of DVAs whose symptoms could not be attributed to other pathologies [86]. Cases with associated CMs were excluded. Two major pathophysiologic mechanisms were reported: Mechanical compression of intracranial structures by a component of the vein was seen in 21 percent. The most common associated symptoms were hydrocephalus, tinnitus, brainstem deficits, hemifacial spasm, and trigeminal neuralgia. Flow-related symptoms were present in 72 percent. Increased inflow was present in 28 percent, typically related to an arteriovenous malformation (AVM) draining via dilated and ectatic medullary veins, resulting parenchymal and/or intraventricular hemorrhage, or https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 12/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate venous infarction. Symptoms included headaches, neurologic deficits, seizures, and coma. Restricted outflow, either by an anatomic obstruction (eg, stenosis or thrombosis of the vein) in 38 percent or by a physiologic obstruction (eg, increased venous pressure secondary to a distal arteriovenous shunt or AVM) was observed in 6 percent. Patients presented with variable combinations of neurologic deficits, headaches, seizures, and altered mentation, a clinical picture that resembled that of cerebral venous thrombosis, with increased intracranial pressure, venous congestive edema, and/or intraparenchymal or subarachnoid hemorrhage. No obvious alteration was found to explain symptoms in 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 CT, MRI, and magnetic resonance angiography (MRA) [78]. 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 ( image 6) [87]. Magnetic resonance imaging and angiography MRI with gadolinium typically shows medullary veins in "caput medusae" pattern that converge on a dilated transcerebral draining vein. A characteristic "sunburst" pattern is seen on enhanced T1-weighted images ( image 7) [88]. Gradient echo sequences should be included to increase sensitivity for detecting associated CMs [78]. White matter abnormalities and/or calcifications may be observed in the parenchyma adjacent to the DVA. MRA usually demonstrates the dilated venous channel with variable depiction of the smaller medullary veins. Catheter angiography Cerebral angiography usually is not needed for the diagnosis of DVA since MRI is often sufficient 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 ( image 8). The arterial phase is typically normal; however, so-called arterialized DVAs have been described with early-phase opacification on angiography and/or enlarged arterial feeders [78]. These lesions may have a bleeding risk that is more similar to an arteriovenous malformation. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 13/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Management DVAs should be treated conservatively in the vast majority of cases, with associated symptoms such as headaches and seizures managed medically [85]. Obliteration may be considered in the rare patient with hemorrhage or uncontrolled seizures associated with a DVA [82]. However, surgical or endovascular obliteration is associated with a risk of venous infarction [76]. In patients who undergo surgery, preoperative MRI with gadolinium is required to identify an associated cavernous malformation [32]. Venous infarction has been reported with DVA resection [46]; 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. In rare patients who present with symptomatic thrombosis of a DVA, there is anecdotal support for considering the use of systematic anticoagulation [78]. (See "Cerebral venous thrombosis: Treatment and prognosis".) CAPILLARY TELANGIECTASIAS Capillary telangiectasias are small lesions most commonly found in the pons, middle cerebellar peduncles, and cerebellar 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 [26,89]. 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- Weber-Rendu (hereditary hemorrhagic telangiectasia), Louis-Bar (ataxia-telangiectasia), and Wyburn-Mason (unilateral retinocephalic vascular malformation) syndromes [90]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Ataxia-telangiectasia", section on 'Neuroimaging features'.) Clinical presentation Capillary telangiectasias are usually clinically silent, found incidentally on neuroimaging studies or at postmortem examination. In a systematic review of 10 series and https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 14/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate 203 patients with capillary telangiectasias, symptomatic cases accounted for 6 percent [91]; headache, nausea, and seizures have been described in patients with these lesions, although a causal relationship is unclear. Diagnosis MRI with gadolinium contrast is the most sensitive imaging modality for the identification of brain capillary telangiectasias, but the lesions may be inconspicuous on precontrast MRI. Small lesions that are hypo- to isointense on T1-weighted sequences and iso- to