Case record...Dilated Virchow-Robin spaces associated with leukoaraiosis http://yassermetwally.com http://yassermetwally.net

1. CASE OF THE WEEK
PROFESSOR YASSER METWALLY
CLINICAL PICTURE
CLINICAL PICTURE:
73 years old female patient, The patient is diabetic and hypertensive. The patient is presented clinically with mild
cognitive impairment. Apart from impairment of recent memory, clinical examination was normal. (To inspect the
patient's full radiological study, click on the attachment icon (The paper clip icon in the left pane) of the acrobat
reader then double click on the attached file) (Click here to download the attached file)
RADIOLOGICAL FINDINGS
RADIOLOGICAL FINDINGS:
Figure 1. Precontrast MRI T1. Virchow Robin spaces scattered in the region of the basal ganglia and thalamus. The
signal intensity of these spaces is identical to that of the CSF. (Type I VR spaces)

2. Figure 2. Precontrast MRI T2. Virchow Robin spaces scattered in the region of the basal ganglia and thalamus. The
signal intensity of these spaces is identical to that of the CSF. Also notice the periventricular white matter changes
(Leukoaraiosis) (Type I VR spaces)
Figure 3. Precontrast MRI FLAIR images. Virchow Robin spaces scattered in the region of the basal ganglia and
thalamus. The signal intensity of these spaces is identical to that of the CSF. Also notice the periventricular white
matter changes (Leukoaraiosis) (Type I VR spaces)

3. Figure 4. MRI T2 images showing
Vircho Robin spaces scsttered in the
region of the midbrain. (Type III VR
spaces)
Virchow-Robin (VR) spaces surround the walls of vessels as they course from the subarachnoid space through the
brain parenchyma. Small VR spaces appear in all age groups. With advancing age, VR spaces are found with
increasing frequency and larger apparent sizes. At visual analysis, the signal intensity of VR spaces is identical to
that of cerebrospinal fluid with all magnetic resonance imaging sequences. Dilated VR spaces typically occur in
three characteristic locations: Type I VR spaces appear along the lenticulostriate arteries entering the basal ganglia
through the anterior perforated substance. Type II VR spaces are found along the paths of the perforating
medullary arteries as they enter the cortical gray matter over the high convexities and extend into the white matter.
Type III VR spaces appear in the midbrain. Occasionally, VR spaces have an atypical appearance. They may
become very large, predominantly involve one hemisphere, assume bizarre configurations, and even cause mass
effect. Knowledge of the signal intensity characteristics and locations of VR spaces helps differentiate them from
various pathologic conditions, including lacunar infarctions, cystic periventricular leukomalacia, multiple sclerosis,
cryptococcosis, mucopolysaccharidoses, cystic neoplasms, neurocysticercosis, arachnoid cysts, and neuroepithelial
cysts.
Type I VR spaces Appear along the lenticulostriate arteries entering the basal ganglia through the anterior
perforated substance.
Type II VR spaces Are found along the paths of the perforating medullary arteries as they enter the cortical
gray matter over the high convexities and extend into the white matter.
Type III VR spaces Appear in the midbrain.
DIAGNOSIS:
DIAGNOSIS: ENLARGED VIRCHOW-ROBIN SPACES (PERIVASCULAR SPACES) ASSOCIATED WITH
MICROVASCULAR BRAIN DISEASE (LEUKOARAIOSIS)
DISCUSSION
DISCUSSION:
The Virchow-Robin (VR) space is named after Rudolf Virchow (German pathologist, 1821–1902) (1) and Charles
Philippe Robin (French anatomist, 1821–1885) (2). VR spaces, or perivascular spaces, surround the walls of vessels
as they course from the subarachnoid space through the brain parenchyma. VR spaces are commonly seen at
magnetic resonance (MR) imaging and may sometimes be difficult to differentiate from pathologic conditions.

4. Knowledge of their signal intensity characteristics and localization helps in this differentiation, which is important
for correct patient management.
 Anatomy
VR spaces surround the walls of arteries, arterioles, veins, and venules as they course from the subarachnoid space
through the brain parenchyma (Fig 1) (1–5). Electron microscopy and tracer studies have given insight into the
location of VR spaces and clarified that the subarachnoid space does not communicate directly with the VR spaces
(3–5).
Figure 1. Photomicrograph (original magnification, x20; hematoxylin-
eosin stain) of a coronal section through the anterior perforated
substance shows two arteries (straight arrows) with surrounding VR
spaces (curved arrows).
Arteries in the cerebral cortex are coated by a layer of leptomeninges that is subtended from the pia mater; by this
anatomic arrangement, the VR spaces of the intracortical arteries are in direct continuity with the VR spaces
around arteries in the subarachnoid space (Fig 2). The lack of a similar coating of leptomeningeal cells around veins
in the cerebral cortex suggests that VR spaces around veins are in continuity with the subpial space (4).
Figure 2. Drawing shows a cortical
artery with a surrounding VR space
crossing from the subarachnoid and
subpial spaces through the brain
parenchyma. The magnified view
on the right shows the anatomic
relationship between the artery, VR
space, subpial space, and brain
parenchyma.
In contrast to arteries in the cerebral cortex, arteries in the basal ganglia are surrounded by not one but two distinct
coats of leptomeninges, separated by a VR space that is continuous with the VR space around arteries in the
subarachnoid space. The inner layer of leptomeninges closely invests the adventitia of the vessel wall. The outer
layer abuts on the glia limitans of the underlying brain and is continuous with the pia mater on the surface of the
brain and the anterior perforated substance. Veins in the basal ganglia have no outer layer of leptomeninges
(similar to cortical veins), which suggests that their VR spaces are continuous with the subpial space (5).
Interstitial fluid within the brain parenchyma drains from the gray matter of the brain by diffusion through the
extracellular spaces and by bulk flow along VR spaces. There is evidence from tracer studies and from pathologic

5. analysis of the human brain that VR spaces carry solutes from the brain and are, in effect, the lymphatic drainage
pathways of the brain (6).
 Dilated VR Spaces
Dilatation of VR spaces was described by Durant-Fardel (7) in 1843. These dilatations are regular cavities that
always contain a patent artery. The mechanisms underlying expanding VR spaces are still unknown. Different
theories have been postulated: segmental necrotizing angiitis of the arteries or another unknown condition causing
permeability of the arterial wall (8–10), expanding VR spaces resulting from disturbance of the drainage route of
interstitial fluid due to cerebrospinal fluid (CSF) circulation in the cistern (11,12), spiral elongation of blood vessels
and brain atrophy resulting in an extensive network of tunnels filled with extracellular water (9,13), gradual leaking
of the interstitial fluid from the intracellular compartment to the pial space around the metarteriole through the
fenestrae in the brain parenchyma (14), and fibrosis and obstruction of VR spaces along the length of arteries and
consequent impedance of fluid flow (5).
 Prevalence
Small VR spaces (<2 mm) appear in all age groups. With advancing age, VR spaces are found with increasing
frequency and larger apparent size (>2 mm) (15). Some studies found a correlation between dilated VR spaces and
neuropsychiatric disorders (16–19), recent-onset multiple sclerosis (MS) (20), mild traumatic brain injury (21), and
diseases associated with microvascular abnormalities (22).
The prevalence of VR spaces at MR imaging is also dependent on the applied technique. Heavier T2-weighted
imaging results in better visualization of VR spaces (23). In addition, the use of thinner sections will demonstrate
more VR spaces as well (15,24). Also, high-field-strength MR imaging is expected to have an increased clinical
impact in the near future; the current magnetic field (1.5 T) is likely to be switched to 3 or 4 T. The anticipated
higher signal-to-noise ratio at higher magnetic field strengths may successfully improve spatial resolution and image
contrast (25–27), leading to better visualization (and increased prevalence) of VR spaces on MR images.
 Appearance at MR Imaging
 Signal Intensity Characteristics
Visually, the signal intensities of the VR spaces are identical to those of CSF with all pulse sequences. However,
when signal intensities are measured, the VR spaces prove to have significantly lower signal intensity than the CSF-
containing structures within and around the brain (28), a finding consistent with the fact that the VR spaces
represent entrapments of interstitial fluid. This difference in signal intensity can also be explained by partial volume
effects, since a VR space with accompanying vessel is smaller than the contemporary volume of a voxel on MR
images. VR spaces show no restricted diffusion on diffusion-weighted images because they are communicating
compartments. T1-weighted images with substantial flow sensitivity may show high signal intensity due to inflow
effects, thereby helping confirm that one is indeed dealing with VR spaces (29). VR spaces do not enhance with
contrast material. In patients with small to moderate dilatations of the VR spaces (2–5 mm), the surrounding brain
parenchyma generally has normal signal intensity (30,31).
 Locations and Morphology
Dilated VR spaces typically occur in three characteristic locations. The first type (type I) is frequently seen on MR
images and appears along the lenticulostriate arteries entering the basal ganglia through the anterior perforated
substance (Figs 3, 4) (15,32). Here, the tortuous lenticulostriate arteries change direction from a lateral to a
dorsomedial path and are grouped closely together. A proximal VR space, containing several vessels, is the resulting
physiologic finding (33).

6. Figure 3. Bilateral type I VR spaces in a 6-year-old boy. (a) Axial proton-density–weighted image (repetition time
msec/echo time msec = 2375/100) shows hyperintense areas (arrows) in the anterior perforated substance on both
sides. (b) Axial fluid-attenuated inversion-recovery (FLAIR) image (6606/100) obtained at the same level shows that
these areas have CSF-like content (arrows). The signal intensity of the surrounding brain parenchyma is normal. (c,
d) Diffusion-weighted image (2574/81; b factor = 1000 sec/mm2) (c) and corresponding apparent diffusion
coefficient map (d) show no restricted diffusion in these areas (arrows)..
Figure 4. Bilateral type I VR spaces in a 53-year-old woman. Coronal T1-
weighted image (500/30) shows symmetrical hypointense areas (arrows) in the
anterior perforated substance.
The second type (type II) can be found along the path of the perforating medullary arteries as they enter the cortical
gray matter over the high convexities and extend into the white matter (Figs 5, 6) (15,32).

7. Figure 5. Type II VR spaces in a 73-year-old woman. (a) Axial proton-density–weighted image (2376/100) shows
multiple hyperintense foci in the centrum semiovale in both hemispheres. (b) On an axial FLAIR image (6614/100)
obtained at the same level, the VR spaces are seen as hypointense dots without any surrounding high signal
intensity. Note the two small lesions with a hypointense center and a hyperintense rim (arrows) in the left
hemisphere; these lesions are not VR spaces but old lacunar infarctions.
Figure 6. Type II dilated VR spaces in a 6-year-old boy. (a) Axial T2-weighted image (2620/100) shows linear to
punctate hyperintense areas around the occipital horns, especially on the left side (arrow). (b) FLAIR image
(7572/100) obtained at the same level shows no abnormal signal intensity (arrow), in accordance with the fact that
these areas are true VR spaces..
The third type (type III) appears in the midbrain. In the lower midbrain, VR spaces at the pontomesencephalic
junction surround the penetrating branches of the collicular and accessory collicular arteries (Figs 7, 8). They are
mainly located between the cerebral peduncles in the axial plane and correspond to the level of the tentorial margin
as seen in coronal sections. In the upper midbrain, where the VR spaces are visible at the mesencephalodiencephalic
junction, they appear along the posterior (interpeduncular) thalamoperforating artery or the paramedian
mesencephalothalamic artery and short and long circumferential arteries originating from the upper basilar artery
or proximal posterior cerebral artery (23,34,35).

8. Figure 7. Type III VR space in a 25-year-old man. (a) Axial proton-density–weighted image (2620/100) shows a
hyperintense spot in the brainstem (arrow). (b) Axial FLAIR image (7292/120) obtained at the same level shows that
the spot has CSF-like content without abnormal surrounding signal intensity (arrow). These findings confirm that
the spot is a VR space.
Figure 8. Type III VR spaces in a 68-year-old man. (a) Axial proton-density–weighted image (2382/100) shows
multiple punctate hyperintense areas in the brainstem (arrow). (b) Close-up T2-weighted image (4615/120) clearly
shows the fine punctate pattern. (c) Axial FLAIR image (6609/100) shows the CSF-like content of the dots (arrow).
No surrounding high signal intensity is seen. The typical configuration and the fact that no high signal intensity is
seen on the FLAIR image confirm that the dots are VR spaces.
VR spaces are mostly seen as well-defined oval, rounded, or tubular structures, depending on the plane in which
they are intersected. They have smooth margins, commonly appear bilaterally, and usually measure 5 mm or less
(32).
 Atypical VR Spaces
It is reported that clusters of type II enlarged VR spaces may predominantly involve one hemisphere (36). There are
even reports that describe the solely unilateral appearance of enlarged VR spaces in the high convexity (37,38).
Occasionally, VR spaces appear markedly enlarged, cause mass effect, and assume bizarre cystic configurations that

9. may be misinterpreted as other pathologic processes, most often a cystic neoplasm. As most of these giant VR spaces
border a ventricle or subarachnoid space, reports of such cases (39–41) have offered an extensive differential
diagnosis that includes cystic neoplasms, parasitic cysts, cystic infarctions, nonneoplastic neuroepithelial cysts, and
deposition disorders such as mucopolysaccharidosis. Salzman et al (42) presented a series of 37 patients with giant
VR spaces. These spaces most often appear as clusters of variably sized cysts and are most common in the
mesencephalothalamic region (Fig 9), in the territory of the paramedial mesencephalothalamic artery, and in the
cerebral white matter. Giant VR spaces in the mesencephalothalamic region may cause hydrocephalus by direct
compression of the third ventricle or the sylvian aqueduct (Fig 9), requiring surgical intervention (8,11,42–47).
Figure 9. Giant VR spaces in the mesencephalothalamic region in a 19-year-old
man. (a, b) Axial (a) and sagittal (b) T2-weighted images (5970/120) show a
multicystic lesion in the mesencephalothalamic region. The lesion extends from
the left cerebral peduncle to the left thalamus. The content of the cysts is CSF-
like. The adjacent brain parenchyma has normal signal intensity. No solid
components are identified. (c) Axial gadolinium-enhanced T1-weighted image
(478/18) shows no enhancement. The process has caused obstruction of the
sylvian aqueduct, resulting in hydrocephalus. The size of the lesion and the
degree of hydrocephalus were unchanged compared with the appearance on
MR images obtained 2 years earlier
In one-half of cases, giant VR spaces that occur in the white matter may have surrounding signal intensity
abnormality on T2-weighted or FLAIR images (42). This may be viewed as a worrisome finding and in some cases
has prompted the performance of tissue biopsy. However, the abnormal signal intensity stems from reactive gliosis
surrounding the enlarged VR spaces and is not an ominous finding (47).
 Dilated Virchow-Robin spaces as a marker of microvascular brain disease
Virchow-Robin spaces (VRSs) are perivascular spaces that surround the perforating arteries that enter the brain.
The spaces are normally microscopic, but when dilated, they may be seen on MR images. Even in the normal brain,
some VRSs are usually seen in the area of the substantia innominata at the level of the anterior commissure, and a
small number of dilated spaces may also be seen in the basal ganglia (BG) in up to 60% of individuals. Virchow-
Robin Spaces can be identified by a combination of their typical location and their signal intensity characteristics.
They are classically described as isointense to CSF on images obtained with all pulse sequences, and they are round

10. or linear depending on the imaging plane, although their characteristics may vary from this pattern for a number of
reasons. First, the small size of the Virchow-Robin Spaces makes partial-volume effects common; therefore,
measured signal intensities seldom equal those seen in pure CSF, although the changes in signal intensity between
sequences are closely correlated. In addition, T1-weighted images with substantial flow sensitivity may show high
signal intensity due to inflow effects. Even if we allow for these effects, the measured signal intensity in the VRS
often slightly differs from that of true CSF. This finding has been attributed to the fact that Virchow-Robin Spaces
around intracerebral arteries may represent interstitial fluid trapped in the subpial or interpial space.
Pathologic dilatation of Virchow-Robin Spaces is most commonly associated with arteriolar abnormalities that arise
due to aging, diabetes, hypercholesterolemia, smoking, and hypertension and other vascular risk factors. This
dilatation forms part of a histologic spectrum of abnormalities, which include old, small infarcts (type 1 changes);
scars from small hematomas (type 2 changes); and dilatations of Virchow-Robin Spaces (type 3 changes) (74). The
presence of these abnormalities on histologic examination is believed to result from moderate-to-severe
microangiopathy characterized by sclerosis, hyalinosis, and lipid deposits in the walls of small perforating arteries
50 – 400 `im in diameter (74, 75). As the severity of the microangiopathy increases, microvessels demonstrate
increasingly severe changes, with arterial narrowing, microaneurysms and pseudoaneurysms, onion skinning, mural
calcification, and thrombotic and fibrotic luminal occlusions (74–76) Although microvascular disease is common,
few reliable surrogate imaging markers of its presence have been described. The extent and severity of deep white
matter (WM) and periventricular hyperintensity on T2-weighted images have been widely studied as potential
surrogate markers for small-vessel disease. However, the correlation between these abnormalities and clinical
characteristics, such as diagnosis, vascular risk factor, or neuropsychological deficit, is often poor (77).
Figure 10. MRI T2 (A), MRI FLAIR (B) and precontrast
MRI T1 (C) images showing dilated Virchow-Robin
Spaces associated with diffuse white matter changes
(leukoaraiosis)
 More details about etiology and pathogenesis of dilatation of Virchow-Robin Spaces
Virchow-Robin Spaces are potential perivascular spaces covered by pia that accompany arteries and arterioles as
they perforate the brain substance. Deep in the brain, the Virchow-Robin Spaces are lined by the basement
membrane of the glia limitans peripherally, while the outer surfaces of the blood vessels lie centrally. These pial
layers form the Virchow-Robin Spaces as enclosed spaces filled with interstitial fluid and separated from the

11. surrounding brain and CSF . Dilatation of Virchow-Robin Spaces results in fluid filled perivascular spaces along the
course of the penetrating arteries.
Abnormal dilatation of Virchow-Robin Spaces is clinically associated with aging, dementia, incidental WM lesions,
and hypertension and other vascular risk factors (73). Pathologically, this finding is most commonly associated with
arteriosclerotic microvascular disease, which forms a spectrum of severity graded from 1 to 3 on the basis of
histologic appearances (74, 76). Grade 1 changes include increased tortuosity and irregularity in small arteries and
arterioles (74) Grade 2 changes include progress sclerosis, hyalinosis, lipid deposits, and regional loss of smooth
muscle in the vessel wall associated with lacunar spaces that are histologically seen to consist of three subtypes. Type
1 lacunes are small, old cystic infarcts; type 2 are scars of old hematomas; and type 3 are dilated Virchow-Robin
Spaces (79). Grade 3 microangiopathy represents the most severe stage and is especially related to severe chronic
hypertension. Typical changes described in lower grades are accompanied by fibrotic thickening vessel wall with
onion skinning, loss of muscularis and elastic lamina, and regional necrosis in the vessel walls. The brain
parenchyma contains multiple lacunae, and diffuse abnormality of myelin is present in the deep hemispheric white
matter.
Several mechanisms for abnormal dilatation of Virchow-Robin Spaces have been suggested (80,81). These include
mechanical trauma due to CSF pulsation or vascular ectasia (83), fluid exudation due to abnormalities of the vessel
wall permeability (82), and ischemic injury to perivascular tissue causing a secondary ex vacuo effect (83).
In the Western world, ischemic vascular dementia is seen in 8 –10% of cognitively impaired elderly subjects (84)
and commonly associated with widespread small ischemic or vascular lesions throughout the brain, with
predominant involvement of the basal ganglia, white matter, and hippocampus (84). Several groups have shown that
a severe lacunar state and microinfarction due to arteriolosclerosis and hypertensive microangiopathy are more
common in individuals with IVD than in healthy control subjects, and they have emphasized the importance of
small vascular lesions in the development of dementia (84, 85). On CT or MR imaging, white matter lesions are
commonly used as potential biomarkers of vascular abnormality. Many groups have suggested that simple scoring
schemes for white matter lesion load and distribution are useful in the diagnosis of vascular dementia (86,87,88,89).
Although white matter lesions are more severe in patients with vascular dementia (86), they are more prevalent in
all groups with dementia than in healthy control subjects.
Dilation of Virchow-Robin Spaces provides a potential alternative biomarker of microvascular disease (small vessel
disease). Virchow-Robin Spaces in the centrum semiovale were significantly more frequent in patients with fronto-
temporal dementia (FTD) than in control subjects (P .01). This finding is not associated with increases in basal
ganglionic Virchow-Robin Spaces and is closely correlated with measures of forebrain atrophy, suggesting that
these changes are probably representative of atrophy, which is more marked in this patient group than in those with
other dementing conditions (78).
SUMMARY
SUMMARY
 Pathologic Findings
Enlarged perivascular spaces, also known as Virchow-Robin spaces, are pial-lined interstitial fluid-filled structures
that accompany penetrating arteries and veins. They do not communicate directly with the subarachnoid space.
They are common, incidental, "leave me alone" lesions that should not be mistaken for more ominous disease. They
frequently appear in the inferior basal ganglia, clustering around the anterior commissure and surrounding the

12. lenticulostriate arteries as they superiorly course through the anterior perforated substance. Other common
locations include the midbrain, deep white matter, and subinsular cortex. They can also be found in the region of the
thalami, dentate nuclei, corpus callosum, and cingulate gyrus .
Microscopically, perivascular spaces consist of a single or double layer of invaginated pia. They are typically very
small or inapparent as they pass through the cortex, enlarging in the subcortical white matter. They are typically
not associated with gliosis in the surrounding parenchyma.
 Imaging
Prominent perivascular spaces are considered a normal variant. Most appear as smoothly demarcated fluid-filled
cysts, typically less than 5 mm in diameter, and often occur in clusters in the basal ganglia or midbrain. They are
isointense to CSF at all sequences, including FLAIR. Most show normal signal intensity in the adjacent brain; 25%
may have a small rim of slightly increased signal intensity. They do not enhance, cause focal mass effect, or restrict
on diffusion-weighted images. In older patients, basal ganglia perivascular spaces sometimes become prominent and
sievelike, a condition known as état criblé, or cribriform state.
Occasionally perivascular spaces may become very large and appear bizarre. They are probably caused by the
accumulation of interstitial fluid between the penetrating vessels and the pia. If interstitial fluid egress is blocked,
fluid accumulates and the perivascular spaces dilate . These lesions cause focal mass effect and occasionally even
hydrocephalus. Rarely, so-called giant or tumefactive perivascular spaces may be mistaken for more ominous
disease.
 Differential Diagnosis
Enlarged perivascular spaces are often mistaken for multiple lacunar infarcts, cystic neoplasms, and infectious
cysts. Lacunar infarcts can usually be distinguished from perivascular spaces since many exhibit adjacent
parenchymal hyperintensity (so-called état lacunaire). Cystic neoplasms rarely exhibit signal intensity exactly like
the CSF. Neurocysticercosis cysts may have a scolex (parasite head), and the cyst walls often enhance.
Neurocysticercosis cysts may be multiple but do not typically occur in clusters within the brain parenchyma.
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