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CNS cavernous haemangioma: “popcorn” in the brain and spinal cord
Clinical Radiology 67 (2012) 380e388
Contents lists available at SciVerse ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
CNS cavernous haemangioma: “popcorn” in the brain and spinal cord A.N. Hegde a, b, S. Mohan a, c, C.C.T. Lim a, d, * a
Department of Neuroradiology, National Neuroscience Institute, Singapore Department of Diagnostic Imaging, National University Hospital, Singapore c Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, USA d Department of Neurology, Duke NUS Graduate Medical School, Singapore b
article in formation Article history: Received 31 August 2011 Received in revised form 10 October 2011 Accepted 25 October 2011
Cavernous haemangiomas (CH) are relatively uncommon non-shunting vascular malformations of the central nervous system and can present with seizures or with neurological deficits due to haemorrhage. Radiologists can often suggest the diagnosis of CH based on characteristic magnetic resonance imaging (MRI) features, thus avoiding further invasive procedures such as digital subtraction angiography or surgical biopsy. Although typical MRI appearance combined with the presence of multiple focal low signal lesions on T2*-weighted images or the presence of one or more developmental venous anomaly within the brain can improve the diagnostic confidence, serial imaging studies are often required if a solitary CH presents at a time when the imaging appearances had not yet matured to the typical “popcorn” appearance. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Cavernous haemangiomas (CHs) are uncommon, angiographically occult vascular malformations of the central nervous system (CNS), with an incidence of 0.5 and 0.7% at autopsy and magnetic resonance imaging (MRI), respectively.1,2 CHs, also called cavernous malformation, cavernous angioma, or cavernoma, are composed of abnormally enlarged, discreet, thin-walled vascular structures within the parenchyma of the CNS. There is no brain parenchyma between the vascular channels, and the presence of blood products in various stages of degradation is responsible for the typical MRI signal characteristics of these lesions.3 Although the majority of CHs develop de novo, rare associations with viruses, pregnancy, family history, and previous irradiation have been described.4e6 * Guarantor and correspondent: C.C.T. Lim, Department of Neuroradiology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: þ(65) 63577021; fax: þ(65) 63581259. E-mail address: [email protected] (C.C.T. Lim).
Symptomatic cerebral CH typically come to clinical attention in the third to fifth decades of life with headaches, seizures, or focal neurological deficits. Clinical manifestations in the paediatric age group are similar to those in adults.7 There is no sex predilection. Cerebral CH is increasingly detected at computed tomography (CT) and MRI performed in asymptomatic patients as well as those with headache, seizures, or intracranial haemorrhage.8 Although the typical imaging appearances of CH have been well described in the literature, these lesions can pose a diagnostic dilemma for radiologists, especially when atypical appearing lesions are encountered in unusual locations, or following recent intralesional haemorrhage.9 Hence, radiologists should be familiar with typical and atypical features of CH of the brain and spinal cord.
Typical imaging appearances of cerebral CH At CT, typical cerebral CHs may be identified as focal hyperdense lesions with indistinct margins, containing
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2011.10.013
A.N. Hegde et al. / Clinical Radiology 67 (2012) 380e388
areas of blood or speckles of calcific density (Fig 1).10,11 These CT appearances are, however, non-specific and differential diagnosis such as granuloma, haemorrhage from other causes, vascular malformation, and neoplasm should be considered.12 Perifocal oedema and mass effect are not typical features of uncomplicated CH, and usually signify recent haemorrhage. MRI is the technique of choice for diagnosis of cerebral CHs,9 and they exhibit characteristic features that have been described as resembling
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a “mulberry” or “popcorn” appearance.9,13 This comprises a well-circumscribed, lobulate lesion with a reticulated core of heterogeneous signal intensity on both T1 and T2-weighted sequences; histologically, the central mixed signal intensity comprises thrombosis, fibrosis, calcification, and various blood breakdown products.9,12 In addition, there is also a characteristic peripheral ring of hypointensity, which corresponds to haemosiderin and iron deposition in the surrounding brain parenchyma11,12 (Fig 1). On contrast-enhanced MRI sequences, the appearances are variable with CH appearing as non-enhancing lesions or at most, demonstrating minimal enhancement.13 Gadolinium administration is generally not indicated in patients with a suspected CH unless the appearance is significantly atypical and the imaging differential diagnoses include other conditions such as infections and malignant neoplasms. Cerebral CH may also be associated with a nearby developmental venous anomaly (DVA, Fig 2). Studies have reported an incidence of CH in up to 33% of individuals with DVA and co-existence of DVA in 23% of patients with CHs.14,15 DVA comprise normal but variant venous vasculature (in contrast to CH, they are vascular anomalies and not abnormal malformations), and their synchronous presence can increase the diagnostic confidence for the adjacent cerebral CH.
Other imaging appearances of cerebral CH
Figure 1 Typical cerebral CH. (a) Unenhanced, axial CT shows left periventricular hyperdensity with a few specks of calcific density without surrounding oedema. (b) T2-weighted MRI image reveals a reticulated hyperintensity surrounded by a rim of hypointensity typical of the “popcorn” or “mulberry” appearance of (Zabramski Type II) CH.
The MRI appearances of CH may vary depending on their size and the stage of evolution of the blood products, and not all will have the characteristic “popcorn” appearance. Zabramski et al.9 have proposed a classification system ranging from types I to IV for cerebral CHs based on MRI features on conventional spin-echo (SE) and gradientrecalled echo (GRE) sequences. The classification is as follows: (a) type I lesions are subacute haematomas dominated by intracellular methaemoglobin, and therefore, appear homogeneously hyperintense on T1-weighted images (Fig 3); (b) type II lesions have the classic heterogeneous “popcorn” appearance on both T1 and T2-weighted images (Fig 1), caused by a combination of intra- and extracellular methaemoglobin centrally within the lesion with a rim of haemosiderin in the surrounding brain parenchyma; (c) type III lesions are isointense to hypointense on both T1 and T2-weighted images because of the predominance of haemosiderin (Fig 4); (d) type IV lesions are tiny, punctate, foci of hypointensity on both T1 and T2-weighted sequences. Multiple type IV CHs (especially patients with familial cavernomatosis, see below) are best detected on GRE sequences (Fig 5). On T2*-weighted GRE images, the local magnetic field inhomogeneity caused by haemosiderin-containing blood products is accentuated (compared to spin-echo images), and focal dephasing of the MR signal makes the CH appear larger and more prominent due to this “blooming effect”.16,17 More recently, susceptibility-weighted imaging (SWI) has also been found to be sensitive for detecting small CH.18 SWI is a high-spatial-resolution, three-dimensional (3D)
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Figure 2 CH with DVA. (a) Axial, T2-weighted MRI image shows a small “popcorn” lesion of mixed signal intensity with hypointense rim in the right frontal lobe. (b) On the GRE, T2*-weighted MRI image, the lesion appears larger due to the “blooming effect” caused by local magnetic field inhomogeneity caused by paramagnetic blood products (see text). Multiple hypointense radiating/branching tributaries are noted around the CH. (c, d) After contrast medium injection, the vascular structures enhance, draining centripetally into a large collecting medullary vein (arrows) typical of the “Medusa head” pattern of DVA.
gradient-echo MRI technique that makes use of the phase information to accentuate and measure the susceptibility difference between tissues.19 The technique is exquisitely sensitive in the detection of intravascular venous deoxygenated blood as well as extravascular blood products such as CH (Fig 6).20 In addition, haemosiderin and calcification can be differentiated on the filtered phase images of SWI as they affect the phase in opposite directions.21
Familial cavernomatosis and cerebral CH Most cerebral CHs are sporadic in occurrence, with a familial form of this disease comprising about 10% of cases.22 Familial cavernomatosis has an autosomaldominant pattern of inheritance with incomplete
penetrance, and genetic analysis has identified mutations on chromosome 7 (including the Krit1 gene first described in Hispanic Americans).23e25 Multiple CHs is a characteristic feature of familial cavernomatosis, with 50e85% of familial cases showing multiplicity.2,9 GRE images are very sensitive to detect multiplicity of the tiny type IV CH that characterize familial disease (16e20 lesions per patient were detected in one study), and radiologists may play a useful role in suggesting the correct diagnosis2 (Figs 5,6). The MRI appearance of multiple focal areas of susceptibility may also be similar to other causes of microhaemorrhage, and the clinical presentation of the patient should be taken into account in making a radiological diagnosis.26e28 The higher incidence of de novo lesion formation and higher annual haemorrhage rate (4.3% per patient-year) in familial cavernomatosis usually means that greater
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Figure 3 Large CH in familial cavernomatosis. (a) Unenhanced, sagittal, T1-weighted image shows a well-defined mixed hyperintense/isointense lesion in the pons. (b) T2-weighted MRI image shows that in addition to the predominantly hyperintense pontine (Zabramski type I) CH, there are smaller low signal lesions (arrow) in the right cerebellar hemisphere and left temporal lobe (arrowheads). The patient’s father also had cerebral CH demonstrated on CT.
disability may result. Hence there is a need for genetic counselling in the management of this form of the disease.22
Haemorrhagic complications and diagnosis of cerebral CH Cerebral CH may be complicated by intralesional haemorrhage. On CT or MRI it may be recognized as acute or
Figure 4 CH with surrounding blood products. (a) Unenhanced, axial, T1-weighted MRI image showing left temporal lobe hypointensity (arrow) without surrounding oedema. (b) However, T2-weighted and (c) fluid-attenuated inversion recovery MRI images show that the hypointense lesion (Zabramski type III) is surrounded by a larger area of low signal consistent with haemosiderin from previous bleeding.
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Figure 5 Multiple tiny CH in familial cavernomatosis. (a) Axial, T2-weighted MRI image shows only a few small foci of low signal intensity (arrows). (b) GRE, T2*-weighted MRI images reveal the full extent of multiple tiny hypointense lesions (Zabramski type IV) typical of familial cavernomatosis.
subacute blood products located outside the haemosiderin ring or an increase in lesion size by at least 20% in diameter on serial imaging. There is typically associated mass effect and perilesional oedema.29 The mass effect and oedema typically decrease over time and the lesion may return to its typical appearance on follow-up MRI (Fig 7). Rarely, haemorrhage from CH may result in superficial siderosis.29 Intraventricular CHs are rare, rapidly growing, haemorrhagic lesions that
Figure 6 CH on SWI. (a) Axial, GRE, T2*-weighted MRI image shows multiple hypointense lesions of varying sizes. (b) SWI reveals and accentuates even more lesions with local magnetic field inhomogeneity, including deoxygenated blood in the normal veins (arrowheads).
often mimic neoplasm. The characteristic hypointense rim on T2-weighted images may be absent in these lesions.30 On imaging, the diagnosis of CH is one of exclusion; other causes of a single haemorrhagic lesion, such as arteriovenous malformation, bland intraparenchymal haemorrhage, haemorrhagic infection, and neoplasm must be excluded.
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Figure 7 Symptomatic haemorrhage and oedema in CH. (a) Unenhanced, axial CT showing right frontal lobe hyperdensity with peripheral cerebral oedema (arrow) in a patient with seizures. (b) Corresponding T2-weighted MRI image confirms mixed signal intensity consistent with haemorrhage with cerebral oedema (arrow). Note the presence of multiple smaller CHs (arrowheads), which suggests the diagnosis of familial cavernomatosis and may help prevent unnecessary investigation and biopsy. (c) Eight years later, the cerebral oedema has resolved in the asymptomatic patient. The largest lesion shows alteration of the internal signal intensity and appearance of hypointense haemosiderin rim (arrow), and waxing and waning of the multiple smaller CHs (arrowheads).
Figure 8 CH: diagnosis of exclusion. (a) T1-weighted MRI image showing left temporal lobe hyperintensity in a patient with headache. (b) Corresponding T2-weighted MRI image shows mixed signal intensity consistent with blood products. (c) MR angiography shows no evidence of dilated feeding arteries or draining veins. (d) However, 3 years later, new bloodefluid level (arrow) was found when the patient complained of headache again. Digital subtraction angiography ruled out the possibility of small arteriovenous malformations. On MRI performed 7 years after the initial diagnosis (not shown), the bloodefluid level had resolved, and the CH had not increased in size in the asymptomatic patient.
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CH may sometimes be confused with capillary telangiectasias, which are also rare angiographically occult vascular malformations typically found in the pons.31 Capillary telangiectasias are nearly always asymptomatic and on contrast-enhanced MRI, they typically display a faint “brush-like” or “stippled” pattern of enhancement.32e34 The differential diagnosis of multiple small CH includes amyloid angiopathy, cerebral microhaemorrhages associated with chronic hypertension, neurovasculitis, and diffuse axonal injury. Cerebral amyloid angiopathy is typically found in patients over 60 years of age, and multiple microhaemorrhages at the lobar corticomedullary junction are often associated with larger lobar haemorrhages.35 Chronic hypertensive microhaemorrhages are more commonly found in the in the deep non-lobar grey and white matter, including the thalamus, basal ganglia, cerebellum, and pons, compared to the randomly distributed CHs. Neurovasculitis is often accompanied by ischaemic infarcts while CHs have no such association. The diagnosis of diffuse axonal injury is usually made on a clinical background of severe head trauma; typically, microhaemorrhages are located in the cerebral greyewhite matter junction, splenium of the corpus callosum, and dorsolateral brainstem. Rarely, haemorrhagic micrometastasis can mimic multiple CH, but the history of a primary neoplasm is often helpful for differentiation.36 Since cerebral CH is a diagnosis of exclusion, in ambiguous cases, a negative digital subtraction angiography (since CH is angiographically occult) may be necessary to exclude arterio-venous malformation (Fig 8).
Natural history, bleeding risk, and treatment options CHs located in the cortex or white matter of the cerebral hemispheres are classified as superficial lesions.37 These lesions typically follow a more benign course with surgery usually reserved for patients with intractable epilepsy. Deep lesions located in the brainstem, cerebellar nuclei, basal ganglia, and thalamus have a higher haemorrhagic rate (4.1% per patient-year annually compared to 0.4% for superficial lesions) and may be clinically devastating due to their close proximity to eloquent structures.1,10,37e40 However, surgery itself carries a risk of neurological deficit. Radiosurgery provides an attractive alternative for such cases, but results have been equivocal, and the risk of radiation-induced complications means its role in management is still controversial.12 Zabramski type I and II lesions are also noted to be at a higher risk of bleeding than type III and IV lesions.9
Spinal CHs CNS CHs can occur anywhere within the cerebral hemispheres, the cerebellum, brain stem, or spinal cord. CHs have also rarely been described within the spinal epidural space and these lesions can manifest clinically due to spinal cord compression. Intramedullary spinal CH (SCH) is rare, comprising less than 5% of CHs, manifesting with focal
Figure 9 CH of the brain and spinal cord. (a) Sagittal, T2-weighted MRI image of the cervical spine shows a “popcorn” lesion (arrow) with hypointense rim typical of intramedullary spinal CH (SCH). A second, similar “popcorn” (arrowhead) is noted intracranially in the midbrain, prompting a formal MRI study of the brain. (b) GRE, T2*-weighted MRI image showing multiple hypointense CH.
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neurological deficits or as progressive myelopathy.13,41e44 They most commonly involve the thoracic cord segments, presenting with progressive myelopathy or focal neurological deficit. The MRI features of SCH are similar to cerebral CH, with typical “popcorn” appearance of haemosiderin ring of low signal intensity surrounding mixed signal intensity on T1 and T2-weighted images (Fig 9). Similar to cerebral CHs, GRE images may be more sensitive in detection.41 However, in atypical situations, such as active haemorrhage, spinal angiography may be required when the suspicion of a spinal AVM or fistula persists. Patients with SCHs tend to have multiple other malformations elsewhere in the neuraxis, and also a higher association with familial cavernomatosis.42 Therefore, in the radiological assessment (typically of the cervical spine) of patients with suspected SCH, the imaged portion of the brain in the field of view should be systematically reviewed to detect other lesions (Fig 9a). CH may also be associated with venous angiomas, vertebral and soft-tissue haemangiomas, and detection of these lesions may help to strengthen the diagnosis.43 The presence of supporting evidence of multiple cerebral CHs and possible familial cavernomatosis may suggest the diagnosis without resorting to invasive diagnostic procedures. Hence, screening of the entire neuraxis may be helpful if a haemorrhagic intramedullary spinal lesion is detected.42 SCH has a higher rate of recurrent haemorrhage than cerebral CH (1.6% compared to 0.5 to 1% per year),44 but due to morbidity, operative management is still controversial: whether asymptomatic SCH should be removed is still a matter of debate.45
Conclusion CH may be detected incidentally on cross-sectional imaging studies of the brain and spine. They usually do not pose a diagnostic dilemma when they manifest as characteristic “mulberry” or “popcorn” lesions with heterogeneous centres containing blood products of various ages and a hypointense haemosiderin rim on T2-weighted MRI images. The presence of multiple lesions, such as occurs in familial cavernous haemangiomatosis, as well as the presence of one or more DVA within the brain are helpful in increasing the diagnostic certainty about the nature of the lesions.
References 1. Del Curling OD, Kelly DL, Elster AD, et al. An analysis of the natural history of cavernous angiomas. J Neurosurg 1991;75:702e8. 2. Brunereau L, Labauge P, Tournier-Lasserve E, et al. Familial form of intracranial cavernous angioma: MR imaging findings in 51 families. French soc neurosurg. Radiology 2000;214:209e16. 3. Russell DS, Rubinstein IJ. Pathology of tumors of the nervous system. 5th ed. Baltimore: Williams and Wilkins; 1989. 730e736. 4. Ogilvy CS, Moayeri N, Golden JA. Appearance of a cavernous hemangioma in the cerebral cortex after a biopsy of a deep lesion. Neurosurgery 1993;33:307e9. 5. Larson J, Ball WS, Bove KE, et al. Formation of intracerebral cavernous haemangiomas after radiation treatment for central nervous system neoplasia in children. J Neurosurg 1998;88:51e6.
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6. Pozzati E, Giangaspero F, Marliani F, et al. Occult cerebrovascular malformations after irradiation. Neurosurgery 1996;39:677e84. 7. Mazza C, Scienza R, Beltramello A, et al. Cerebral cavernous haemangiomas (cavernomas) in the pediatric age-group. Child Nerv Sys 1991;7:139e46. 8. Rutka JT, Brant-Zawadzki M, Wilson CB, et al. Familial cavernous malformations. Diagnostic potential of magnetic resonance imaging. Surg Neurol 1988;29:467e74. 9. Zabramski JM, Washer TM, Spetzler RF, et al. The natural history of familial cavernous malformations. Results of an ongoing study. J Neurosurg 1994;80:422e32. 10. Robinson J, Awad IA, Masaryk TJ, et al. Pathological heterogeneity of angiographically occult vascular malformations of the brain. Neurosurgery 1993;33:547e54. 11. Di Tullio Jr MV, Stern WE. Hemangioma calcificans. Case report of an intraparenchymatous calcified vascular hematoma with epileptogenic potential. J Neurosurg 1979;50:110e4. 12. Rivera PP, Willinsky RA, Porter PJ. Intracranial cavernous malformations. Neuroimaging Clin N Am 2003;13:27e40. 13. Weinzierl MR, Krings T, Korinth MC, et al. MRI and intraoperative findings in cavernous haemangiomas of the spinal cord. Neuroradiology 2004;46:65e71. 14. 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;19:51e7. 15. Wilms G, Demaerel P, Robberecht W, et al. Coincidence of developmental venous anomalies and other brain lesions: a clinical study. Eur Radiol 1995;5:495e500. 16. Atlas SW, Mark AS, Grossman RI, et al. Intracranial hemorrhage: gradient-echo MR imaging at 1.5 T. Comparison with spin-echo imaging and clinical applications. Radiology 1988;168:803e7. 17. Reichenbach JR, Venkatesan R, Yablonskiy DA, et al. Theory and application of static field inhomogeneity effects in gradient-echo imaging. J Magn Reson Imaging 1997;7:266e79. 18. Santhosh K, Kesavadas C, Thomas B, et al. Susceptibility weighted imaging: a new tool in magnetic resonance imaging of stroke. Clin Radiol 2009;64:74e83. 19. Haacke EM, Xu Y, Cheng YC, et al. Susceptibility weighted imaging (SWI). Magn Reson Med 2004;52:612e8. 20. Tong KA, Ashwal S, Obenaus A, et al. Susceptibility-weighted MR imaging: a review of clinical applications in children. AJNR Am J Neuroradiol 2008;29:9e17. 21. Wu Z, Mittal S, Kish K, et al. Identification of calcification with MRI using susceptibility-weighted imaging: a case study. J Magn Reson Imaging 2009;29:177e82. 22. Labauge P, Laberge S, Brunereau L, et al. Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Soc Fra Neurochir. Lancet 1998;352:1892e7. 23. Zhang J, Clatterbuck R, Rigamonti D, et al. Mutations in KRIT1 in familial cerebral cavernous malformations. Neurosurgery 2000;46:1272e9. 24. Labauge P, Denier C, Bergametti F, et al. Genetics of cavernous angiomas. Lancet Neurol 2007;6:237e44. 25. Dubovsky J, Zabramski J, Kurth J, et al. A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995;4:453e8. 26. Ueno H, Naka H, Ohshita T, et al. Association between cerebral microbleeds on T2*-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke. AJNR Am J Neuroradiol 2008;29:1483e6. 27. Koennecke HC. Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 2006;66:165e71. 28. Fazekas F, Kleinert R, Roob G, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathyrelated microbleeds. AJNR Am J Neuroradiol 1999;20:637e42. 29. Willinsky R, Harper W, Wallace MC, et al. Follow-up MR of intracranial cavernomas: the relationship between between haemorrhagic events and morphology. Interv Neuroradiol 1996;2:127e35. 30. Reyns N, Assaker R, Louis E, et al. Intraventricular cavernomas: three cases and a review of the literature. Neurosurgery 1999;44: 648e53.
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31. Sarwar M, McCormick WE. Intracerebral venous angioma: case report and review. Arch Neurol 1978;35:323e5. 32. Lee RR, Becher MW, Benson ML, et al. Brain capillary telangiectasia: MR imaging appearance and clinicohistopathologic findings. Radiology 1997;205:797e805. 33. Barr RM, Dillon WP, Wilson CB. Slow-flow vascular malformations of the pons: capillary telangiectasias? AJNR Am J Neuradiol 1996;17: 71e8. 34. Castillo M, Morrison T, Shaw JA, et al. MR imaging and histologic features of capillary telangiectasia of the basal ganglia. AJNR Am J Neuroradiol 2001;22:1553e5. 35. Chao CP, Kotsenas AL, Broderick DF. Cerebral amyloid angiopathy: CT and MR imaging findings. RadioGraphics 2006;26:1517e31. 36. Blitstein MK, Tung GA. MRI of cerebral microhemorrhages. AJR Am J Roentgenol 2007;189:720e5. 37. Porter P, Willinsky R, Harper W, et al. Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 1997;87:190e7. 38. Chahine LM, Berg MJ. Clinical reasoning: cerebral cavernous malformations. Neurology 2009;73:44e9.
39. 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;72:351e5. € m L. Deep and brainstem cavernomas: 40. Mathiesen T, Edner G, Kihlstro a consecutive 8-year series. J Neurosurg 2003;99:31e7. 41. Hegde AN, Mohan S, Lim CCT, et al. Spinal cavernous malformations: MRI and associated findings. in press. 42. Visheteh AG, Zabramski JM, Spetzler RF. Patients with spinal cord cavernous haemangiomas are at an increased risk for multiple neuraxis cavernous malformations. Neurosurgery 1999;45:30e3. 43. Clatterbuck RE, Cohen B, Gailloud P, et al. Vertebral hemangiomas associated with familial cerebral cavernous malformation: segmental disease expression. Case report. J Neurosurg 2002;97:227e30. 44. Santoro A, Piccirilli M, Brunetto GM, et al. Intramedullary cavernous angioma of the spinal cord in a pediatric patient, with multiple cavernomas, familial occurrence and partial spontaneous regression: case report and review of the literature. Childs Nerv Syst 2007;23:1319e26. 45. Kondziella D, Brodersen P, Laursens H, et al. Cavernous hemangioma of the spinal corddconservative or operative management? Acta Neurol Scand 2006;114:287e90.
Contents lists available at SciVerse ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
CNS cavernous haemangioma: “popcorn” in the brain and spinal cord A.N. Hegde a, b, S. Mohan a, c, C.C.T. Lim a, d, * a
Department of Neuroradiology, National Neuroscience Institute, Singapore Department of Diagnostic Imaging, National University Hospital, Singapore c Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, USA d Department of Neurology, Duke NUS Graduate Medical School, Singapore b
article in formation Article history: Received 31 August 2011 Received in revised form 10 October 2011 Accepted 25 October 2011
Cavernous haemangiomas (CH) are relatively uncommon non-shunting vascular malformations of the central nervous system and can present with seizures or with neurological deficits due to haemorrhage. Radiologists can often suggest the diagnosis of CH based on characteristic magnetic resonance imaging (MRI) features, thus avoiding further invasive procedures such as digital subtraction angiography or surgical biopsy. Although typical MRI appearance combined with the presence of multiple focal low signal lesions on T2*-weighted images or the presence of one or more developmental venous anomaly within the brain can improve the diagnostic confidence, serial imaging studies are often required if a solitary CH presents at a time when the imaging appearances had not yet matured to the typical “popcorn” appearance. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Cavernous haemangiomas (CHs) are uncommon, angiographically occult vascular malformations of the central nervous system (CNS), with an incidence of 0.5 and 0.7% at autopsy and magnetic resonance imaging (MRI), respectively.1,2 CHs, also called cavernous malformation, cavernous angioma, or cavernoma, are composed of abnormally enlarged, discreet, thin-walled vascular structures within the parenchyma of the CNS. There is no brain parenchyma between the vascular channels, and the presence of blood products in various stages of degradation is responsible for the typical MRI signal characteristics of these lesions.3 Although the majority of CHs develop de novo, rare associations with viruses, pregnancy, family history, and previous irradiation have been described.4e6 * Guarantor and correspondent: C.C.T. Lim, Department of Neuroradiology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: þ(65) 63577021; fax: þ(65) 63581259. E-mail address: [email protected] (C.C.T. Lim).
Symptomatic cerebral CH typically come to clinical attention in the third to fifth decades of life with headaches, seizures, or focal neurological deficits. Clinical manifestations in the paediatric age group are similar to those in adults.7 There is no sex predilection. Cerebral CH is increasingly detected at computed tomography (CT) and MRI performed in asymptomatic patients as well as those with headache, seizures, or intracranial haemorrhage.8 Although the typical imaging appearances of CH have been well described in the literature, these lesions can pose a diagnostic dilemma for radiologists, especially when atypical appearing lesions are encountered in unusual locations, or following recent intralesional haemorrhage.9 Hence, radiologists should be familiar with typical and atypical features of CH of the brain and spinal cord.
Typical imaging appearances of cerebral CH At CT, typical cerebral CHs may be identified as focal hyperdense lesions with indistinct margins, containing
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2011.10.013
A.N. Hegde et al. / Clinical Radiology 67 (2012) 380e388
areas of blood or speckles of calcific density (Fig 1).10,11 These CT appearances are, however, non-specific and differential diagnosis such as granuloma, haemorrhage from other causes, vascular malformation, and neoplasm should be considered.12 Perifocal oedema and mass effect are not typical features of uncomplicated CH, and usually signify recent haemorrhage. MRI is the technique of choice for diagnosis of cerebral CHs,9 and they exhibit characteristic features that have been described as resembling
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a “mulberry” or “popcorn” appearance.9,13 This comprises a well-circumscribed, lobulate lesion with a reticulated core of heterogeneous signal intensity on both T1 and T2-weighted sequences; histologically, the central mixed signal intensity comprises thrombosis, fibrosis, calcification, and various blood breakdown products.9,12 In addition, there is also a characteristic peripheral ring of hypointensity, which corresponds to haemosiderin and iron deposition in the surrounding brain parenchyma11,12 (Fig 1). On contrast-enhanced MRI sequences, the appearances are variable with CH appearing as non-enhancing lesions or at most, demonstrating minimal enhancement.13 Gadolinium administration is generally not indicated in patients with a suspected CH unless the appearance is significantly atypical and the imaging differential diagnoses include other conditions such as infections and malignant neoplasms. Cerebral CH may also be associated with a nearby developmental venous anomaly (DVA, Fig 2). Studies have reported an incidence of CH in up to 33% of individuals with DVA and co-existence of DVA in 23% of patients with CHs.14,15 DVA comprise normal but variant venous vasculature (in contrast to CH, they are vascular anomalies and not abnormal malformations), and their synchronous presence can increase the diagnostic confidence for the adjacent cerebral CH.
Other imaging appearances of cerebral CH
Figure 1 Typical cerebral CH. (a) Unenhanced, axial CT shows left periventricular hyperdensity with a few specks of calcific density without surrounding oedema. (b) T2-weighted MRI image reveals a reticulated hyperintensity surrounded by a rim of hypointensity typical of the “popcorn” or “mulberry” appearance of (Zabramski Type II) CH.
The MRI appearances of CH may vary depending on their size and the stage of evolution of the blood products, and not all will have the characteristic “popcorn” appearance. Zabramski et al.9 have proposed a classification system ranging from types I to IV for cerebral CHs based on MRI features on conventional spin-echo (SE) and gradientrecalled echo (GRE) sequences. The classification is as follows: (a) type I lesions are subacute haematomas dominated by intracellular methaemoglobin, and therefore, appear homogeneously hyperintense on T1-weighted images (Fig 3); (b) type II lesions have the classic heterogeneous “popcorn” appearance on both T1 and T2-weighted images (Fig 1), caused by a combination of intra- and extracellular methaemoglobin centrally within the lesion with a rim of haemosiderin in the surrounding brain parenchyma; (c) type III lesions are isointense to hypointense on both T1 and T2-weighted images because of the predominance of haemosiderin (Fig 4); (d) type IV lesions are tiny, punctate, foci of hypointensity on both T1 and T2-weighted sequences. Multiple type IV CHs (especially patients with familial cavernomatosis, see below) are best detected on GRE sequences (Fig 5). On T2*-weighted GRE images, the local magnetic field inhomogeneity caused by haemosiderin-containing blood products is accentuated (compared to spin-echo images), and focal dephasing of the MR signal makes the CH appear larger and more prominent due to this “blooming effect”.16,17 More recently, susceptibility-weighted imaging (SWI) has also been found to be sensitive for detecting small CH.18 SWI is a high-spatial-resolution, three-dimensional (3D)
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Figure 2 CH with DVA. (a) Axial, T2-weighted MRI image shows a small “popcorn” lesion of mixed signal intensity with hypointense rim in the right frontal lobe. (b) On the GRE, T2*-weighted MRI image, the lesion appears larger due to the “blooming effect” caused by local magnetic field inhomogeneity caused by paramagnetic blood products (see text). Multiple hypointense radiating/branching tributaries are noted around the CH. (c, d) After contrast medium injection, the vascular structures enhance, draining centripetally into a large collecting medullary vein (arrows) typical of the “Medusa head” pattern of DVA.
gradient-echo MRI technique that makes use of the phase information to accentuate and measure the susceptibility difference between tissues.19 The technique is exquisitely sensitive in the detection of intravascular venous deoxygenated blood as well as extravascular blood products such as CH (Fig 6).20 In addition, haemosiderin and calcification can be differentiated on the filtered phase images of SWI as they affect the phase in opposite directions.21
Familial cavernomatosis and cerebral CH Most cerebral CHs are sporadic in occurrence, with a familial form of this disease comprising about 10% of cases.22 Familial cavernomatosis has an autosomaldominant pattern of inheritance with incomplete
penetrance, and genetic analysis has identified mutations on chromosome 7 (including the Krit1 gene first described in Hispanic Americans).23e25 Multiple CHs is a characteristic feature of familial cavernomatosis, with 50e85% of familial cases showing multiplicity.2,9 GRE images are very sensitive to detect multiplicity of the tiny type IV CH that characterize familial disease (16e20 lesions per patient were detected in one study), and radiologists may play a useful role in suggesting the correct diagnosis2 (Figs 5,6). The MRI appearance of multiple focal areas of susceptibility may also be similar to other causes of microhaemorrhage, and the clinical presentation of the patient should be taken into account in making a radiological diagnosis.26e28 The higher incidence of de novo lesion formation and higher annual haemorrhage rate (4.3% per patient-year) in familial cavernomatosis usually means that greater
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Figure 3 Large CH in familial cavernomatosis. (a) Unenhanced, sagittal, T1-weighted image shows a well-defined mixed hyperintense/isointense lesion in the pons. (b) T2-weighted MRI image shows that in addition to the predominantly hyperintense pontine (Zabramski type I) CH, there are smaller low signal lesions (arrow) in the right cerebellar hemisphere and left temporal lobe (arrowheads). The patient’s father also had cerebral CH demonstrated on CT.
disability may result. Hence there is a need for genetic counselling in the management of this form of the disease.22
Haemorrhagic complications and diagnosis of cerebral CH Cerebral CH may be complicated by intralesional haemorrhage. On CT or MRI it may be recognized as acute or
Figure 4 CH with surrounding blood products. (a) Unenhanced, axial, T1-weighted MRI image showing left temporal lobe hypointensity (arrow) without surrounding oedema. (b) However, T2-weighted and (c) fluid-attenuated inversion recovery MRI images show that the hypointense lesion (Zabramski type III) is surrounded by a larger area of low signal consistent with haemosiderin from previous bleeding.
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Figure 5 Multiple tiny CH in familial cavernomatosis. (a) Axial, T2-weighted MRI image shows only a few small foci of low signal intensity (arrows). (b) GRE, T2*-weighted MRI images reveal the full extent of multiple tiny hypointense lesions (Zabramski type IV) typical of familial cavernomatosis.
subacute blood products located outside the haemosiderin ring or an increase in lesion size by at least 20% in diameter on serial imaging. There is typically associated mass effect and perilesional oedema.29 The mass effect and oedema typically decrease over time and the lesion may return to its typical appearance on follow-up MRI (Fig 7). Rarely, haemorrhage from CH may result in superficial siderosis.29 Intraventricular CHs are rare, rapidly growing, haemorrhagic lesions that
Figure 6 CH on SWI. (a) Axial, GRE, T2*-weighted MRI image shows multiple hypointense lesions of varying sizes. (b) SWI reveals and accentuates even more lesions with local magnetic field inhomogeneity, including deoxygenated blood in the normal veins (arrowheads).
often mimic neoplasm. The characteristic hypointense rim on T2-weighted images may be absent in these lesions.30 On imaging, the diagnosis of CH is one of exclusion; other causes of a single haemorrhagic lesion, such as arteriovenous malformation, bland intraparenchymal haemorrhage, haemorrhagic infection, and neoplasm must be excluded.
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Figure 7 Symptomatic haemorrhage and oedema in CH. (a) Unenhanced, axial CT showing right frontal lobe hyperdensity with peripheral cerebral oedema (arrow) in a patient with seizures. (b) Corresponding T2-weighted MRI image confirms mixed signal intensity consistent with haemorrhage with cerebral oedema (arrow). Note the presence of multiple smaller CHs (arrowheads), which suggests the diagnosis of familial cavernomatosis and may help prevent unnecessary investigation and biopsy. (c) Eight years later, the cerebral oedema has resolved in the asymptomatic patient. The largest lesion shows alteration of the internal signal intensity and appearance of hypointense haemosiderin rim (arrow), and waxing and waning of the multiple smaller CHs (arrowheads).
Figure 8 CH: diagnosis of exclusion. (a) T1-weighted MRI image showing left temporal lobe hyperintensity in a patient with headache. (b) Corresponding T2-weighted MRI image shows mixed signal intensity consistent with blood products. (c) MR angiography shows no evidence of dilated feeding arteries or draining veins. (d) However, 3 years later, new bloodefluid level (arrow) was found when the patient complained of headache again. Digital subtraction angiography ruled out the possibility of small arteriovenous malformations. On MRI performed 7 years after the initial diagnosis (not shown), the bloodefluid level had resolved, and the CH had not increased in size in the asymptomatic patient.
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CH may sometimes be confused with capillary telangiectasias, which are also rare angiographically occult vascular malformations typically found in the pons.31 Capillary telangiectasias are nearly always asymptomatic and on contrast-enhanced MRI, they typically display a faint “brush-like” or “stippled” pattern of enhancement.32e34 The differential diagnosis of multiple small CH includes amyloid angiopathy, cerebral microhaemorrhages associated with chronic hypertension, neurovasculitis, and diffuse axonal injury. Cerebral amyloid angiopathy is typically found in patients over 60 years of age, and multiple microhaemorrhages at the lobar corticomedullary junction are often associated with larger lobar haemorrhages.35 Chronic hypertensive microhaemorrhages are more commonly found in the in the deep non-lobar grey and white matter, including the thalamus, basal ganglia, cerebellum, and pons, compared to the randomly distributed CHs. Neurovasculitis is often accompanied by ischaemic infarcts while CHs have no such association. The diagnosis of diffuse axonal injury is usually made on a clinical background of severe head trauma; typically, microhaemorrhages are located in the cerebral greyewhite matter junction, splenium of the corpus callosum, and dorsolateral brainstem. Rarely, haemorrhagic micrometastasis can mimic multiple CH, but the history of a primary neoplasm is often helpful for differentiation.36 Since cerebral CH is a diagnosis of exclusion, in ambiguous cases, a negative digital subtraction angiography (since CH is angiographically occult) may be necessary to exclude arterio-venous malformation (Fig 8).
Natural history, bleeding risk, and treatment options CHs located in the cortex or white matter of the cerebral hemispheres are classified as superficial lesions.37 These lesions typically follow a more benign course with surgery usually reserved for patients with intractable epilepsy. Deep lesions located in the brainstem, cerebellar nuclei, basal ganglia, and thalamus have a higher haemorrhagic rate (4.1% per patient-year annually compared to 0.4% for superficial lesions) and may be clinically devastating due to their close proximity to eloquent structures.1,10,37e40 However, surgery itself carries a risk of neurological deficit. Radiosurgery provides an attractive alternative for such cases, but results have been equivocal, and the risk of radiation-induced complications means its role in management is still controversial.12 Zabramski type I and II lesions are also noted to be at a higher risk of bleeding than type III and IV lesions.9
Spinal CHs CNS CHs can occur anywhere within the cerebral hemispheres, the cerebellum, brain stem, or spinal cord. CHs have also rarely been described within the spinal epidural space and these lesions can manifest clinically due to spinal cord compression. Intramedullary spinal CH (SCH) is rare, comprising less than 5% of CHs, manifesting with focal
Figure 9 CH of the brain and spinal cord. (a) Sagittal, T2-weighted MRI image of the cervical spine shows a “popcorn” lesion (arrow) with hypointense rim typical of intramedullary spinal CH (SCH). A second, similar “popcorn” (arrowhead) is noted intracranially in the midbrain, prompting a formal MRI study of the brain. (b) GRE, T2*-weighted MRI image showing multiple hypointense CH.
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neurological deficits or as progressive myelopathy.13,41e44 They most commonly involve the thoracic cord segments, presenting with progressive myelopathy or focal neurological deficit. The MRI features of SCH are similar to cerebral CH, with typical “popcorn” appearance of haemosiderin ring of low signal intensity surrounding mixed signal intensity on T1 and T2-weighted images (Fig 9). Similar to cerebral CHs, GRE images may be more sensitive in detection.41 However, in atypical situations, such as active haemorrhage, spinal angiography may be required when the suspicion of a spinal AVM or fistula persists. Patients with SCHs tend to have multiple other malformations elsewhere in the neuraxis, and also a higher association with familial cavernomatosis.42 Therefore, in the radiological assessment (typically of the cervical spine) of patients with suspected SCH, the imaged portion of the brain in the field of view should be systematically reviewed to detect other lesions (Fig 9a). CH may also be associated with venous angiomas, vertebral and soft-tissue haemangiomas, and detection of these lesions may help to strengthen the diagnosis.43 The presence of supporting evidence of multiple cerebral CHs and possible familial cavernomatosis may suggest the diagnosis without resorting to invasive diagnostic procedures. Hence, screening of the entire neuraxis may be helpful if a haemorrhagic intramedullary spinal lesion is detected.42 SCH has a higher rate of recurrent haemorrhage than cerebral CH (1.6% compared to 0.5 to 1% per year),44 but due to morbidity, operative management is still controversial: whether asymptomatic SCH should be removed is still a matter of debate.45
Conclusion CH may be detected incidentally on cross-sectional imaging studies of the brain and spine. They usually do not pose a diagnostic dilemma when they manifest as characteristic “mulberry” or “popcorn” lesions with heterogeneous centres containing blood products of various ages and a hypointense haemosiderin rim on T2-weighted MRI images. The presence of multiple lesions, such as occurs in familial cavernous haemangiomatosis, as well as the presence of one or more DVA within the brain are helpful in increasing the diagnostic certainty about the nature of the lesions.
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