Brain Pathology ISSN 1015-6305
MINI-SYMPOSIUM: Pathology of Genetics of (non-CAA) Cerebral Microvascular Disease
Neuroimaging of Cerebral Small Vessel Disease Noriko Salamon David Geffen School of Medicine, UCLA Health System, Los Angeles, CA.
Keywords MRI Imaging, White Matter, Vascular Anatomy. Corresponding author: Noriko Salamon, MD, PhD, David Geffen School of Medicine, UCLA Health System, 757 Westwood Plaza Suite 1621D, Los Angeles, CA 90095 (E-mail: [email protected]) Received 14 July 2014 Accepted 14 July 2014 Published Online Article Accepted 20 August 2014 doi:10.1111/bpa.12179
INTRODUCTION Neuroimaging plays an important role in the diagnosis of ischemic brain disease. Magnetic resonance imaging (MRI) is able to identify both acute and chronic infarction and ischemia, and magnetic resonance angiography (MRA) is a major modality of choice for atherosclerotic disease of the intra- or extracranial vessels. Hereditary small vessel diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have recently gained great interest as the most common heritable cause of stroke and vascular dementia in adults. MRI shows some characteristic pattern of abnormality different from other type of ischemic disease that may precede clinical symptoms (9). Many other forms of hereditary small vessel disease including with subcortical infarcts and leukoencephalopathy (CADASIL); hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS); cerebroretinal vasculopathy (CRV); and pseudoxanthoma elasticum (PXE) also demonstrates MRI findings, but many radiologists are not familiar with these findings; therefore, these conditions are probably underdiagnosed (16). Central nervous system vasculitis is categorized, in part, by the affected vessel size (11). Stenosis, dilatation or occlusion of the large- or medium-sized arteries (more than 0.5 mm of diameter) can be easily evaluated with MRA (14). However, cerebral microvascular diseases, which involve smaller caliber white matter arterioles, are difficult to assess even by conventional angiography. When smaller, precapillary vascular disease is suspected in conditions such as CADASIL, Susac syndrome or HERNS; the role of MRA may be limited. In this review, the current status of neuroimaging for small vessel disease characteristics will be discussed, including differential diagnosis and limitations of the various neuroimaging methods.
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
ANATOMY OF CEREBRAL MICROVASCULAR DISEASE Vascularization of the white matter Human brain is vascularized by two internal carotid arteries and two vertebral arteries with anterior, middle and posterior arteries. The arteries to the cortex give branches from the pial surface and then penetrate to the cortical layers. The pial vessels are surrounded by cerebrospinal fluid (CSF) and give smaller branches to the deep white matter. The space around the penetrating artery called Virchow–Robin space is easily identified by MRI using T2 or fluid-attenuated inversion recovery (FLAIR) sequences. Extra-axial cerebral artery caliber is in the range of 2–4 mm. The diameter of arteries becomes much smaller after penetrating the cortical surface. The vessels within the white matter measure less than 0.1 mm (14). The deep white matter arteries run straight through the white matter with some branching. Anastomosis has been found around the ventricular wall at the terminals of the deep white matter arteries (15). Nonaka et al found that there are adventitial sheaths and large adventitial spaces in the subcortical and deep white matter arteries, which are not seen in the arteries of the cerebral cortex (15). Understanding the anatomy of the microstructure of the white matter vascularization will be important to evaluate the cerebral microvascular disease. Unfortunately, current imaging modalities limit visualization of the microvasculature. Visualization of the vessels extends to 0.5 mm in diameter vessels in conventional angiography. However, stenosis or occlusion of the affected vasculature is detectable only in vessels of greater than 1 mm in diameter (15) (Figure 1). 519
Neuroimaging of Small Vessel Disease
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IMAGING MODALITIES TO DETECT MICROVASCULAR DISEASE MRI MRI has been a leading imaging modality useful in the diagnosis of stroke and vascular disease. Diffusion-weighted imaging (DWI), T1, T2, FLAIR and gradient echo imaging (GRE) are the most helpful.
DWI DWI is sensitive for detecting acute infarction including in the deep white matter or in the brain stem.
T2 and FLAIR Figure 1. Coronal slice (autopsy) specimen after injection of barium sulfate into the internal carotid artery. The density of arteries running within the central white matter is sparse.
Vascularization of the corpus callosum Corpus callosum is one of the major interhemispheric white matter fiber tracts, and vascularized by branches of the anterior and posterior cerebral arteries, including anterior communicating, pericallosal and posterior pericallosal arteries. Each branch gives rise to smaller vessels that supply the corpus callosum. One of the major vessels is the cingulocallosal artery; its diameter ranges between 0.15 and 0.6 mm (average, 0.25 mm). Posteriorly, the posterior pericallosal artery arising from the posterior cerebral artery supplies the splenium. Its diameter ranges between 0.4 and 1.0 mm (average 0.7 mm) (25) (Figure 2).
T2 and FLAIR sequences are sensitive tools for detecting white matter disease in general. With increasing resolution of MRI scanning over the past 20 years, the visualization of white matter disease and the perivascular spaces has significantly improved. Not all signal abnormalities visualized in MRI have clinical significance. One incidental imaging abnormality seen in MRI with unknown clinical significance is known as “unidentified bright objects (UBOs).” The distribution and location of disease is also important in differential diagnosis. When white matter abnormalities are seen in the periventricular region, these can be representative of demyelinating disease or ischemic changes. Demyelinating disease usually has an ovalshaped appearance at the border of the lesion. Ischemic changes are more irregular in shape. The immediate subcortical white matter, including U-fibers, is often affected by demyelinating disease but not by ischemic disease. Ischemic diseases are more often demonstrated in the central portion of the white matter. As seen in injection studies, the central portion of the white matter is sparsely vascularized and thus considered a watershed territory between periventricular and cortical surface collaterals in routine MRI studies, in which the slice thickness of axial imaging is 5 mm. Smaller infarcts may be overlooked using this slice thickness. Further study with thinner sections may be helpful in the case of microvascular disease or small brain stem infarcts (7). However, when the slice thickness is too thin (less than 2 mm), the signalto-noise ratio will decrease and imaging quality becomes poor. Signal-to-noise ratio is dependent on the voxel size, the number of averaging and the receiver bandwidth. Increasing number of averaging will increase the scanner time, which may lead to motion artifact with poor quality. To be able to obtain better resolution of subtle imaging findings, such as microvascular disease, optimal adjustment of balance with time and signal-to-noise ratio is challenging.
GRE
Figure 2. Sagittal slice specimen (autopsy brain, same preparation as Figure 1) highlights small branch arteries supplying the corpus callosum.
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GRE imaging is a sensitive tool to detect microhemorrhages (6). Hemosiderin staining of the brain tissue caused by microbleeding can cause susceptibility artifact. Small calcifications undetectable by computed tomography (CT) scan can be seen by GRE.
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
Salamon
Neuroimaging of Small Vessel Disease
A
B
Figure 3. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: same patient at ages 56 (A) and 66 years (B). Interval worsening of white matter high fluid-attenuated inversion recovery signal abnormality is noted, with more atrophy of the cerebrum. The ventricles are larger (at 66 years) because of progressive atrophy.
T1 T1-weighted imaging technique is useful to detect laminar necrosis. In tissue with laminar necrosis, linear high T1 signal is seen along the affected cortex, due to the accumulation of denatured proteins, lipid-laden macrophages in dying cells; it usually does not represent the presence of hemorrhage (19).
ROLE OF CT AND CT ANGIOGRAPHY (CTA) CT and CTA are of limited value in evaluating brain microangiopathic disease. CT is better at identifying vessel wall calcifications in the basal ganglia or cerebrum.
MRA
ROLE OF CONVENTIONAL ANGIOGRAM
Demaerel et al (4) retrospectively studied 14 young patients with clinical and/or radiological suspicion of cerebral vasculitis, using three-dimensional time-of-flight MRA compared with digital subtraction angiography (DSA). The sensitivity for detecting stenosis varied from 62% to 79% for MRA and from 76% to 94% for DSA. The specificity for detecting stenosis varied from 83% to 87% for MRA and from 83% to 97% for DSA (4). They concluded that DSA remains necessary even when MRA is normal or when less than three stenoses are seen.
Cerebral angiogram (DSA) is the “gold standard” for diagnosing central nervous system vasculitis (14). With microangiopathic disease, the angiogram may be normal: because the affected vessels are beyond the current limit of size resolution. In vasculitis affecting medium-sized vessels, for example, polyarteritis nodosa (PAN), sensitivity and specificity of the cerebral angiogram are 89% and 98% (14), respectively. The angiogram is indicated if there is any suspicion of another type of “medium-sized vessel” vasculitis, when the MRA is normal.
A
B
Figure 4. 66-year-old woman with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy diagnosed 11 years ago. A. Axial gradient echo sequence demonstrates punctate foci of dark signal suggesting microbleeds (arrows). B. Axial fluid-attenuated inversion recovery sequence shows characteristic anterior temporal lobe white matter involvement (hyperintensity).
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
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Figure 5. Hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS): serial magnetic resonance imaging of a HERNS patient. Periventricular white matter disease was first thought to represent multiple sclerosis. There is extension of the disease with central lacunar infarct similar to that seen in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy case, shown in Figure 4.
Corpus callosum involvement is not as common as in Susac syndrome (see below). Thalamus and basal ganglia involvement is common. Basal ganglia and dentate nuclei may demonstrate low T2/FLAIR signal,
NEUROIMAGING IN GENETICALLY DETERMINED SMALL VESSEL DISEASES CADASIL CADASIL is an inherited microangiopathy caused by mutations in the Notch3 gene on chromosome 19 (12, 13, 24; see also article in this issue by H. Kalimo et al). MRI abnormalities can be seen in both symptomatic and nonsymptomatic patients. About 90% of subjects have white matter abnormalities visible on MRI. Periventricular white matter is more commonly involved than the peripheral white matter. T2/FLAIR abnormality may be seen in the basal ganglia or in the brain stem. One of the hallmarks of the disease is diffuse white matter high FLAIR signal intensity and small lacunar infarcts (Figure 4). Lacunar infarcts are mainly located within the centrum semiovale, thalamus, basal ganglia and pons (2, 3, 8, 17, 18, 20, 28). Differential diagnosis of these findings includes sporadic subcortical arteriosclerotic encephalopathy or chronic hypertensive ischemic disease. Because CADASIL is seen in younger patients than the population usually affected by chronic (hypertensive) ischemic disease, the other differential diagnosis is a demyelinating process such as multiple sclerosis (MS). The configuration of the white matter disease is more oval shaped in MS and irregular with white matter ischemia. Atherosclerotic/ arteriosclerotic ischemic disease and CADASIL can be differentiated with by age, family history and clinical symptomatology and presentation, and distribution of the white matter disease (1). In CADASIL, the white matter abnormality is more often seen in the temporal and temporo-polar regions compared with the atherosclerotic/arteriosclerotic ischemia (Figure 4B).
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Figure 6. Hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS): serial magnetic resonance images of a patient with HERNS. Tumor-like lesion in the right frontal lobe, developed when the patient was 27 years old (top two images). Nine years later, another lesion developed posteriorly, with mass-like enhancement (middle images). Two years later (bottom two images), the lesion became confluent but the mass effect had resolved. There is persistent periventricular enhancement.
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Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
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Neuroimaging of Small Vessel Disease
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Figure 7. Susac syndrome. A. Coronal T1. B. Axial T2. C. Sagittal T1. Multiple 3-mm foci are seen in the central portion of the corpus callosum, a characteristic feature of Susac syndrome.
which is interpreted as increased iron deposition that possibly resulted from axonal iron transport failure due to diffuse white matter damage. GRE shows susceptibility artifact in the thalamus or cerebellum (Figure 4A). Leptomeningeal enhancement is rare. No enhancement of the cerebral lesions is seen. Interval progression may be seen (Figure 3).
HERNS HERNS is described in 1997 with linkage analysis mapped the disease locus to chromosome 3p21 (10). (For a discussion of neuropathologic and genetic aspects of this syndrome and cerebroretinal vasculopathies, see Kolar et al in this issue.) The imaging findings show periventricular and deep white matter high T2 and FLAIR signal, which is progressive. Because the disease starts at a fairly young age, the MRI is often read as demyelinating disease (Figure 5). Indeed, as shown by Kolar et al, gross lesions in the cut brain can show remarkable similarity to demyelinating plaques of MS. The imaging characteristics are not, however, specific. Jen et al had MRI of three family members among a total of eight HERNS patients, with one autopsy (10). MRI of one of the patients (Figure 6) demonstrated a large white matter lesion with central enhancement. This mimics a neoplasm. A similar finding has also described in CRV patients. Three case reports showed extensive white matter lesions with mass effect noted, and with enhancement, mimicking tumefactive MS or glioma. Microbleeds have also been seen in one case (26).
Susac syndrome Susac syndrome was first described by John D. Susac in 1975, with the observation of two patients who presented with the clinical triad of encephalopathy, branch retinal artery occlusion and hearing loss. This syndrome affects only precapillary arterioles and is probably related to an autoimmune mediated process (5, 20–23). Not all the triad is present in all cases and the MRI can help guide the clinical diagnosis. The MRI of Susac syndrome shows characteristic features, with involvement of the corpus callosum (Figure 7). The central portion of the corpus callosum is involved and the distribution of the area of abnormality is different from that seen in demyelinating disease. The lesions usually measure 3–7 mm, suggesting occlusion of small precapillary arterioles that are under 0.1 mm (100 μm in diameter) in the corpus callosum. The lesions may be “snowball like” at the early phase,
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
and extend through the entire corpus callosum. The signal change can become smaller in later phases, when atrophy of the corpus callosum is often seen. The cerebral white matter lesions are also small and multifocal and frequently demonstrate enhancement of the parenchymal lesions (70%). Leptomeningeal enhancement is seen in 33% of cases, although cranial nerve enhancement is commonly not seen. There is involvement of basal ganglia or thalamus in 70% of the cases (20, 22, 23). DWI can be used to assess evolution of the disease (27). White matter volume loss is also observed over time. Subcortical lacunar lesions are also seen and may involve U-fibers. GRE microbleeds are seen in the thalamus and cerebellum, and subjects are at high risk for hemorrhage. Most of the case reports show no abnormality on MRA.
SUMMARY Neuroimaging of cerebral small vessel vascular disease is often nonspecific and the diagnosis is challenging; clinical and family history is pivotal in interpreting neuroimaging findings. Hereditary small vessel diseases have recently gained significant interest, and MRI is a sensitive tool to detect white matter abnormality. Characteristic MRI features are seen in Susac syndrome, HERNS and CADASIL. Many patients may have been mistakenly diagnosed as other white matter diseases such as MS or even brain neoplasms. It is important to recognize these diseases as the differential diagnosis, and multidisciplinary approach is crucial to promptly reaching the correct diagnosis. MRA and conventional angiogram is still of limited use in evaluating the affected vascular change. Studying hereditary endothelial cell damage causing progressive small vessel infarctions in these diseases may lead to better understanding of small vessel vascular disease.
REFERENCES 1. Auer D, Putz B, Gossl C, Elbel GK, Gasser T, Dichgans M (2001) Differential lesion patterns in CADASIL and sporadic subcortical srteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 218:443–451. 2. Chabriat H1, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A et al (1998) Patterns of MRI lesions in CADASIL. Neurology 51:452–457. 3. Davous P (1998) CADASIL: a review with proposed diagnostic criteria. Eur J Neurol 5:219–233. 4. Demaerel P, De Ruyter N, Maes F, Velghe B, Wilms G (2004) Magnetic resonance angiography in suspected cerebral vasculitis. Eur Radiol 14:1005–1012.
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5. Egan RA, Nguyen TH, Gass DM, Rizzo JF, Tivnan J, Susac JO (2003) Retinal arterial wall plaques in Susac syndrome. Am J Ophthalmol 135:483–486. 6. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, Hartung HP (1999) Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol 20:637–642. 7. Figueiredo G, Brockmann C, Boll H, Heilmann M, Schambach SJ, Fiebig T et al (2012) Comparison of digital subtraction angiography, micro-computed tomography angiography and magnetic resonance angiography in the assessment of the cerebrovascular system in live mice. Clin Neuroradiol 22:21–28. 8. Glusker P, Horoupian DS, Lane B (1998) Familial arteriopathic leukoencephalopathy: imaging and neuropathologic findings. AJNR Am J Neuroradiol 19:469–475. 9. Gunda B, Chabriat H, Bereczki D (2011) Cadasil and other hereditary small vessel diseases of the brain—increasingly diagnosed conditions underlying familial ischaemic stroke and dementia. Ideggyogy Sz 64:88–100. 10. Jen J, Cohen AH, Yue Q, Stout JT, Vinters HV, Nelson S, Baloh RW (1997) Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology 49:1322–1330. 11. Jennette JC, Falk RJ (2007) Nosology of primary vasculitis. Curr Opin Rheumatol 19:10–16. 12. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and vascular dementia. Nature 383:707–710. 13. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C et al (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350:1511–1515. 14. Kueker W (2007) Cerebral vasculitis: imaging signs revisited. Neuroradiology 49:471–479. 15. Nonaka H, Akiba M, Hatori T, Nagayama T, Zhang Z, Ihara F (2003) Microvasculature of the human cerebral white matter: arteries of the deep white matter. Neuropathology 23:111–118. 16. Pavlovic AM, Zidverc-Trajkovic J, Milovic MM, Pavlovic DM, Jovanovic Z, Mijajlovic M et al (2005) Cerebral small vessel disease in pseudoxanthoma elasticum: three cases. Can J Neurol Sci 32:115–118.
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17. Rubio A, Rifkin D, Powers JM, Powers JM, Patel U, Stewart J et al (1997) Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol 94:247–254. 18. Sabbadini G, Francia A, Calandriello L, DiBiasi C, Trasimeni G, Guadi GF et al (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): clinical, neuroimaging, pathological and genetic study of a large Italian family. Brain 118:207–215. 19. Sawada H, Udaka F, Seriu N, Shindou K, Kameyama M, Tsujimura M (1990) MRI demonstration of cortical laminar necrosis and delayed white matter injury in anoxic encephalopathy. Neuroradiology 32:319–321. 20. Skehan SJ, Hutchinson M, MacErlaine DP (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AJNR Am J Neuroradiol 16:2115–2119. 21. Susac JO (1994) Susac’s syndrome: the triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology 44:591–593. 22. Susac JO, Hardimann JM, Selhorst LB (1979) Microangiopathy of the brain and retina. Neurology 29:313–316. 23. Susac JO, Murtagh FR, Egan RA, Berger JR, Bakshi R, Lincoff N et al (2003) MRI findings in Susac’s syndrome. Neurology 61:1783–1787. 24. Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H et al (1993) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 3:256–259. 25. Türe U, Yas¸argil MG, Krisht AF (1996) The arteries of the corpus callosum: a microsurgical anatomic study. Neurosurgery 39:1075–1084. 26. Weil S, Reifenberger G, Dudel C, Yousry TA, Schriever S, Noachtar S (1999) Cerebroretinal vasculopathy mimicking a brain tumor: a case of a rare hereditary syndrome. Neurology 53:629–631. 27. Xu MS, Tan CB, Umapathi T, Lim CC (2004) Susac syndrome: serial diffusion-weighted MR imaging. Magn Reson Imaging 22:1295–1298. 28. Yousry TA, Seelos K, Mayer M, Bruning R, Uttner I, Dichgans M et al (1999) Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). AJNR Am J Neuroradiol 20:91–100.
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
MINI-SYMPOSIUM: Pathology of Genetics of (non-CAA) Cerebral Microvascular Disease
Neuroimaging of Cerebral Small Vessel Disease Noriko Salamon David Geffen School of Medicine, UCLA Health System, Los Angeles, CA.
Keywords MRI Imaging, White Matter, Vascular Anatomy. Corresponding author: Noriko Salamon, MD, PhD, David Geffen School of Medicine, UCLA Health System, 757 Westwood Plaza Suite 1621D, Los Angeles, CA 90095 (E-mail: [email protected]) Received 14 July 2014 Accepted 14 July 2014 Published Online Article Accepted 20 August 2014 doi:10.1111/bpa.12179
INTRODUCTION Neuroimaging plays an important role in the diagnosis of ischemic brain disease. Magnetic resonance imaging (MRI) is able to identify both acute and chronic infarction and ischemia, and magnetic resonance angiography (MRA) is a major modality of choice for atherosclerotic disease of the intra- or extracranial vessels. Hereditary small vessel diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have recently gained great interest as the most common heritable cause of stroke and vascular dementia in adults. MRI shows some characteristic pattern of abnormality different from other type of ischemic disease that may precede clinical symptoms (9). Many other forms of hereditary small vessel disease including with subcortical infarcts and leukoencephalopathy (CADASIL); hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS); cerebroretinal vasculopathy (CRV); and pseudoxanthoma elasticum (PXE) also demonstrates MRI findings, but many radiologists are not familiar with these findings; therefore, these conditions are probably underdiagnosed (16). Central nervous system vasculitis is categorized, in part, by the affected vessel size (11). Stenosis, dilatation or occlusion of the large- or medium-sized arteries (more than 0.5 mm of diameter) can be easily evaluated with MRA (14). However, cerebral microvascular diseases, which involve smaller caliber white matter arterioles, are difficult to assess even by conventional angiography. When smaller, precapillary vascular disease is suspected in conditions such as CADASIL, Susac syndrome or HERNS; the role of MRA may be limited. In this review, the current status of neuroimaging for small vessel disease characteristics will be discussed, including differential diagnosis and limitations of the various neuroimaging methods.
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
ANATOMY OF CEREBRAL MICROVASCULAR DISEASE Vascularization of the white matter Human brain is vascularized by two internal carotid arteries and two vertebral arteries with anterior, middle and posterior arteries. The arteries to the cortex give branches from the pial surface and then penetrate to the cortical layers. The pial vessels are surrounded by cerebrospinal fluid (CSF) and give smaller branches to the deep white matter. The space around the penetrating artery called Virchow–Robin space is easily identified by MRI using T2 or fluid-attenuated inversion recovery (FLAIR) sequences. Extra-axial cerebral artery caliber is in the range of 2–4 mm. The diameter of arteries becomes much smaller after penetrating the cortical surface. The vessels within the white matter measure less than 0.1 mm (14). The deep white matter arteries run straight through the white matter with some branching. Anastomosis has been found around the ventricular wall at the terminals of the deep white matter arteries (15). Nonaka et al found that there are adventitial sheaths and large adventitial spaces in the subcortical and deep white matter arteries, which are not seen in the arteries of the cerebral cortex (15). Understanding the anatomy of the microstructure of the white matter vascularization will be important to evaluate the cerebral microvascular disease. Unfortunately, current imaging modalities limit visualization of the microvasculature. Visualization of the vessels extends to 0.5 mm in diameter vessels in conventional angiography. However, stenosis or occlusion of the affected vasculature is detectable only in vessels of greater than 1 mm in diameter (15) (Figure 1). 519
Neuroimaging of Small Vessel Disease
Salamon
IMAGING MODALITIES TO DETECT MICROVASCULAR DISEASE MRI MRI has been a leading imaging modality useful in the diagnosis of stroke and vascular disease. Diffusion-weighted imaging (DWI), T1, T2, FLAIR and gradient echo imaging (GRE) are the most helpful.
DWI DWI is sensitive for detecting acute infarction including in the deep white matter or in the brain stem.
T2 and FLAIR Figure 1. Coronal slice (autopsy) specimen after injection of barium sulfate into the internal carotid artery. The density of arteries running within the central white matter is sparse.
Vascularization of the corpus callosum Corpus callosum is one of the major interhemispheric white matter fiber tracts, and vascularized by branches of the anterior and posterior cerebral arteries, including anterior communicating, pericallosal and posterior pericallosal arteries. Each branch gives rise to smaller vessels that supply the corpus callosum. One of the major vessels is the cingulocallosal artery; its diameter ranges between 0.15 and 0.6 mm (average, 0.25 mm). Posteriorly, the posterior pericallosal artery arising from the posterior cerebral artery supplies the splenium. Its diameter ranges between 0.4 and 1.0 mm (average 0.7 mm) (25) (Figure 2).
T2 and FLAIR sequences are sensitive tools for detecting white matter disease in general. With increasing resolution of MRI scanning over the past 20 years, the visualization of white matter disease and the perivascular spaces has significantly improved. Not all signal abnormalities visualized in MRI have clinical significance. One incidental imaging abnormality seen in MRI with unknown clinical significance is known as “unidentified bright objects (UBOs).” The distribution and location of disease is also important in differential diagnosis. When white matter abnormalities are seen in the periventricular region, these can be representative of demyelinating disease or ischemic changes. Demyelinating disease usually has an ovalshaped appearance at the border of the lesion. Ischemic changes are more irregular in shape. The immediate subcortical white matter, including U-fibers, is often affected by demyelinating disease but not by ischemic disease. Ischemic diseases are more often demonstrated in the central portion of the white matter. As seen in injection studies, the central portion of the white matter is sparsely vascularized and thus considered a watershed territory between periventricular and cortical surface collaterals in routine MRI studies, in which the slice thickness of axial imaging is 5 mm. Smaller infarcts may be overlooked using this slice thickness. Further study with thinner sections may be helpful in the case of microvascular disease or small brain stem infarcts (7). However, when the slice thickness is too thin (less than 2 mm), the signalto-noise ratio will decrease and imaging quality becomes poor. Signal-to-noise ratio is dependent on the voxel size, the number of averaging and the receiver bandwidth. Increasing number of averaging will increase the scanner time, which may lead to motion artifact with poor quality. To be able to obtain better resolution of subtle imaging findings, such as microvascular disease, optimal adjustment of balance with time and signal-to-noise ratio is challenging.
GRE
Figure 2. Sagittal slice specimen (autopsy brain, same preparation as Figure 1) highlights small branch arteries supplying the corpus callosum.
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GRE imaging is a sensitive tool to detect microhemorrhages (6). Hemosiderin staining of the brain tissue caused by microbleeding can cause susceptibility artifact. Small calcifications undetectable by computed tomography (CT) scan can be seen by GRE.
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
Salamon
Neuroimaging of Small Vessel Disease
A
B
Figure 3. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: same patient at ages 56 (A) and 66 years (B). Interval worsening of white matter high fluid-attenuated inversion recovery signal abnormality is noted, with more atrophy of the cerebrum. The ventricles are larger (at 66 years) because of progressive atrophy.
T1 T1-weighted imaging technique is useful to detect laminar necrosis. In tissue with laminar necrosis, linear high T1 signal is seen along the affected cortex, due to the accumulation of denatured proteins, lipid-laden macrophages in dying cells; it usually does not represent the presence of hemorrhage (19).
ROLE OF CT AND CT ANGIOGRAPHY (CTA) CT and CTA are of limited value in evaluating brain microangiopathic disease. CT is better at identifying vessel wall calcifications in the basal ganglia or cerebrum.
MRA
ROLE OF CONVENTIONAL ANGIOGRAM
Demaerel et al (4) retrospectively studied 14 young patients with clinical and/or radiological suspicion of cerebral vasculitis, using three-dimensional time-of-flight MRA compared with digital subtraction angiography (DSA). The sensitivity for detecting stenosis varied from 62% to 79% for MRA and from 76% to 94% for DSA. The specificity for detecting stenosis varied from 83% to 87% for MRA and from 83% to 97% for DSA (4). They concluded that DSA remains necessary even when MRA is normal or when less than three stenoses are seen.
Cerebral angiogram (DSA) is the “gold standard” for diagnosing central nervous system vasculitis (14). With microangiopathic disease, the angiogram may be normal: because the affected vessels are beyond the current limit of size resolution. In vasculitis affecting medium-sized vessels, for example, polyarteritis nodosa (PAN), sensitivity and specificity of the cerebral angiogram are 89% and 98% (14), respectively. The angiogram is indicated if there is any suspicion of another type of “medium-sized vessel” vasculitis, when the MRA is normal.
A
B
Figure 4. 66-year-old woman with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy diagnosed 11 years ago. A. Axial gradient echo sequence demonstrates punctate foci of dark signal suggesting microbleeds (arrows). B. Axial fluid-attenuated inversion recovery sequence shows characteristic anterior temporal lobe white matter involvement (hyperintensity).
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
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Figure 5. Hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS): serial magnetic resonance imaging of a HERNS patient. Periventricular white matter disease was first thought to represent multiple sclerosis. There is extension of the disease with central lacunar infarct similar to that seen in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy case, shown in Figure 4.
Corpus callosum involvement is not as common as in Susac syndrome (see below). Thalamus and basal ganglia involvement is common. Basal ganglia and dentate nuclei may demonstrate low T2/FLAIR signal,
NEUROIMAGING IN GENETICALLY DETERMINED SMALL VESSEL DISEASES CADASIL CADASIL is an inherited microangiopathy caused by mutations in the Notch3 gene on chromosome 19 (12, 13, 24; see also article in this issue by H. Kalimo et al). MRI abnormalities can be seen in both symptomatic and nonsymptomatic patients. About 90% of subjects have white matter abnormalities visible on MRI. Periventricular white matter is more commonly involved than the peripheral white matter. T2/FLAIR abnormality may be seen in the basal ganglia or in the brain stem. One of the hallmarks of the disease is diffuse white matter high FLAIR signal intensity and small lacunar infarcts (Figure 4). Lacunar infarcts are mainly located within the centrum semiovale, thalamus, basal ganglia and pons (2, 3, 8, 17, 18, 20, 28). Differential diagnosis of these findings includes sporadic subcortical arteriosclerotic encephalopathy or chronic hypertensive ischemic disease. Because CADASIL is seen in younger patients than the population usually affected by chronic (hypertensive) ischemic disease, the other differential diagnosis is a demyelinating process such as multiple sclerosis (MS). The configuration of the white matter disease is more oval shaped in MS and irregular with white matter ischemia. Atherosclerotic/ arteriosclerotic ischemic disease and CADASIL can be differentiated with by age, family history and clinical symptomatology and presentation, and distribution of the white matter disease (1). In CADASIL, the white matter abnormality is more often seen in the temporal and temporo-polar regions compared with the atherosclerotic/arteriosclerotic ischemia (Figure 4B).
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Figure 6. Hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS): serial magnetic resonance images of a patient with HERNS. Tumor-like lesion in the right frontal lobe, developed when the patient was 27 years old (top two images). Nine years later, another lesion developed posteriorly, with mass-like enhancement (middle images). Two years later (bottom two images), the lesion became confluent but the mass effect had resolved. There is persistent periventricular enhancement.
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Figure 7. Susac syndrome. A. Coronal T1. B. Axial T2. C. Sagittal T1. Multiple 3-mm foci are seen in the central portion of the corpus callosum, a characteristic feature of Susac syndrome.
which is interpreted as increased iron deposition that possibly resulted from axonal iron transport failure due to diffuse white matter damage. GRE shows susceptibility artifact in the thalamus or cerebellum (Figure 4A). Leptomeningeal enhancement is rare. No enhancement of the cerebral lesions is seen. Interval progression may be seen (Figure 3).
HERNS HERNS is described in 1997 with linkage analysis mapped the disease locus to chromosome 3p21 (10). (For a discussion of neuropathologic and genetic aspects of this syndrome and cerebroretinal vasculopathies, see Kolar et al in this issue.) The imaging findings show periventricular and deep white matter high T2 and FLAIR signal, which is progressive. Because the disease starts at a fairly young age, the MRI is often read as demyelinating disease (Figure 5). Indeed, as shown by Kolar et al, gross lesions in the cut brain can show remarkable similarity to demyelinating plaques of MS. The imaging characteristics are not, however, specific. Jen et al had MRI of three family members among a total of eight HERNS patients, with one autopsy (10). MRI of one of the patients (Figure 6) demonstrated a large white matter lesion with central enhancement. This mimics a neoplasm. A similar finding has also described in CRV patients. Three case reports showed extensive white matter lesions with mass effect noted, and with enhancement, mimicking tumefactive MS or glioma. Microbleeds have also been seen in one case (26).
Susac syndrome Susac syndrome was first described by John D. Susac in 1975, with the observation of two patients who presented with the clinical triad of encephalopathy, branch retinal artery occlusion and hearing loss. This syndrome affects only precapillary arterioles and is probably related to an autoimmune mediated process (5, 20–23). Not all the triad is present in all cases and the MRI can help guide the clinical diagnosis. The MRI of Susac syndrome shows characteristic features, with involvement of the corpus callosum (Figure 7). The central portion of the corpus callosum is involved and the distribution of the area of abnormality is different from that seen in demyelinating disease. The lesions usually measure 3–7 mm, suggesting occlusion of small precapillary arterioles that are under 0.1 mm (100 μm in diameter) in the corpus callosum. The lesions may be “snowball like” at the early phase,
Brain Pathology 24 (2014) 519–524 © 2014 International Society of Neuropathology
and extend through the entire corpus callosum. The signal change can become smaller in later phases, when atrophy of the corpus callosum is often seen. The cerebral white matter lesions are also small and multifocal and frequently demonstrate enhancement of the parenchymal lesions (70%). Leptomeningeal enhancement is seen in 33% of cases, although cranial nerve enhancement is commonly not seen. There is involvement of basal ganglia or thalamus in 70% of the cases (20, 22, 23). DWI can be used to assess evolution of the disease (27). White matter volume loss is also observed over time. Subcortical lacunar lesions are also seen and may involve U-fibers. GRE microbleeds are seen in the thalamus and cerebellum, and subjects are at high risk for hemorrhage. Most of the case reports show no abnormality on MRA.
SUMMARY Neuroimaging of cerebral small vessel vascular disease is often nonspecific and the diagnosis is challenging; clinical and family history is pivotal in interpreting neuroimaging findings. Hereditary small vessel diseases have recently gained significant interest, and MRI is a sensitive tool to detect white matter abnormality. Characteristic MRI features are seen in Susac syndrome, HERNS and CADASIL. Many patients may have been mistakenly diagnosed as other white matter diseases such as MS or even brain neoplasms. It is important to recognize these diseases as the differential diagnosis, and multidisciplinary approach is crucial to promptly reaching the correct diagnosis. MRA and conventional angiogram is still of limited use in evaluating the affected vascular change. Studying hereditary endothelial cell damage causing progressive small vessel infarctions in these diseases may lead to better understanding of small vessel vascular disease.
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