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Radiología. 2012;54(4):321---335

www.elsevier.es/rx

UPDATE IN

Hyperintense punctiform images in the : A diagnostic approachଝ

a,∗ b b

S. Medrano Martorell , M. Cuadrado Blázquez , D. García Figueredo ,

a a

S. González Ortiz , J. Capellades Font

a

Servicio de Radiodiagnóstico, Hospital del Mar/IDIMAR-CRC Mar, Barcelona, Spain

b

Servicio de Radiodiagnóstico, Hospital de Granollers, Barcelona, Spain

Received 30 January 2011; accepted 4 September 2011

KEYWORDS Abstract The presence of hyperintense punctiform images in the white matter in T2-weighted

magnetic resonance (MR) sequences is a very common finding and is occasionally a diagnostic

White matter;

challenge for the radiologist.

Magnetic resonance;

Leukoaraiosis; The present article attempts, using an anatomical approach to the brain circulation, as well as

from histopathology correlation studies, to simplify the task of interpreting these images from

Multiple sclerosis;

CADASIL; the description of the three main patterns of hyperintense punctiform images in the white

Vasculitis matter: vascular pattern, which corresponds to microvascular lesions; perivascular pattern,

which represents inflammatory of which the paradigm is ; and a non-

specific pattern, which has to be a microvascular disease.

From the various semiological elements in the MR images, a predominant pattern can be

determined in each case and, in this way, helps in the differential diagnosis.

© 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVE Imágenes puntiformes hiperintensas en la sustancia blanca: una aproximación

Sustancia blanca; diagnóstica

Resonancia

magnética; Resumen La presencia de múltiples imágenes puntiformes hiperintensas en la sustancia blanca

Leucoaraiosis; (IPHSB) en las secuencias de resonancia magnética (RM) ponderadas en T2 es un hallazgo muy

frecuente y, en ocasiones, un reto diagnóstico para el radiólogo.

Esclerosis múltiple;

CADASIL; Este artículo pretende, a través de una aproximación a la anatomía de la microcircu-

Vasculitis lación cerebral, así como a estudios de correlación anatomopatológica, simplificar la tarea de

interpretación de estas imágenes a partir de la descripción de tres principales patrones de pre-

sentación de IPHSB: patrón vascular (PV), que corresponde a lesiones microvasculares, patrón

perivascular (PpV), que representa a la enfermedad inflamatoria cuyo paradigma es la esclerosis

múltiple (EM), y patrón inespecífico (PI), que suele deberse a enfermedad microvascular.

ଝ

Please cite this article as: Medrano Martorell S, et al. Imágenes puntiformes hiperintensas en la sustancia blanca: una aproximación

diagnóstica. Radiología. 2012;54:321---35. ∗

Corresponding author.

E-mail address: [email protected] (S. Medrano Martorell).

2173-5107/$ – see front matter © 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

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322 S. Medrano Martorell et al.

A partir de varios elementos semiológicos en las imágenes de RM se puede determinar un

patrón predominante en cada caso y, de este modo, acotar el diagnóstico diferencial.

© 2011 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

Introduction matter, although with shorter course than that of the pial

arteries.

There is a second terminal system of cortical and

The interpretation of multiple hyperintense punctate

subependymal arteries (lenticulostriated and thalamic per-

images in the white matter in T2-weighted sequences, which

forating arteries) that supplies the (BG).

are daily reported at magnetic resonance imaging (MRI) of

The superficial and deep arteriolar systems (pial pen-

adult brains, plays a major role in the routine practice

etrating arteries and subependymal arteries) hardly anas-

of neuroradiologists.

tomose with each other. For this reason, the parenchyma

A parallelism can be established between the commonly

1 located on the bordering zone between the superficial and

used term unidentified bright objects (UBO) and the term

the deep vasculature is less vascularized. In contrast, the

hyperintense punctate images in the white matter (HPIWM),

U-fibres are more and better vascularized than the rest of

which is presented in this paper. Accordingly, HPIWM is a

2,3

the white matter and BG (Fig. 1A).

semiological entity revealing at least five solitary hyper-

intense foci of up to 1 cm in diameter on T2-weighted

sequences, with or without confluent lesions with an overall

Venous microvascular system

diameter >1 cm.

The main goal of this paper is to simplify the radiol-

The cerebral venules, also known as medullary venules, are

ogist’s task when dealing with cases of HPIWM, so that

divided into two large groups: superficial medullary venules,

radiologists can categorize the findings under a predominant

which are short venous channels draining to the cortical sur-

pattern and make a more accurate diagnosis. This paper pro-

face from about 1 or 2 cm below the cerebral cortex; and

poses three main HPIWM patterns based on the semiological

the deep medullary venules, which are longer channels that

characteristics: a vascular pattern (VP), which represents

drain perpendicularly to the ventricular surface towards

microvascular involvement (usually arteriolar); a perivas-

the subependymal veins. There is a third group including

cular pattern (PvP), which represents inflammatory disease

transcerebral venules, less abundant and that connect both

(particularly ); and a non-specific pat- 2,4

systems (Fig. 1B).

tern (NsP), which usually represents microvascular disease.

To make a diagnosis, the predominant semiological pattern

should be considered together with the clinical manifesta-

tions of patient and the epidemiologic data.

The arterial system runs parallel to the venous system. The

perivascular space surrounds the wall of arteries and

Basic anatomy of brain microcirculation

arterioles (Virchow---Robin space) and veins and venules

(perivenular space) from the subarachnoid space along

The brain microcirculation consists of a vascular network

their intraparenchymatous course. The superficial or corti-

with a very complex anatomy that varies across subjects. To

cal arterioles are surrounded by one layer of leptomeninges

understand the HPIWM patterns suggested, the basic aspects

that separates the vascular surface from the periarteriolar

of brain microvascular anatomy will be addressed.

space. The parenchymatous surface of this space is limited

by the pia mater. The perivascular space of the penetrat-

Arterial microvascular system

ing arterioles of the BG is delimited by the two layers

of leptomeninges that surround their endothelium. Appar-

The cortical arteries cross the cerebral cortex and pen- ently there is direct communication of the superficial and

etrate the white matter perpendicularly to the cortical deep perivenular space with the subpial space, with no lep-

5,6

surface, forming the terminal pial or medullary arterioles tomeningeal layers separating them (Fig. 2).

up to 4 --- 5 cm long. Along their course, they give off short

cortical branches that supply the entire cerebral cortex

‘‘Normal’’ hyperintense punctate images

and the fibres of the juxtacortical white matter ( 3 --- 4 mm),

also called U-fibres. The cortical arteries establish multiple in the white matter

anastomoses, which provide the cerebral cortex with a rich

arteriolar network. When running deep into the white mat- The presence of a few hyperintense punctate foci in the

ter, pial arteries establish very few anastomoses cerebral white matter at MRI is a very common finding that

with the neighbouring pial arterioles, forming relatively can be regarded as insignificant in most of the cases. These

independent arteriolar metabolic units. bright dots, considered as normal, can be a manifestation

The deep subependymal arteries, which arise from the of dilated perivascular spaces or small gliotic or lacunar

choroid arteries, give off penetrating branches to the white ischemic foci.

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Hyperintense punctiform images in the white matter 323 A 1 B 1

2

2.1 1 2 6 4 4 2 3 5 3 2

1 5

1

Figure 1 Cerebral microcirculation. (A) Arterial microcirculation. 1: cortical arteries; 2: pial arteries; 2.1: short

branches; 3: subependymal arteries; 4: subependymal perforating arterioles; 5: lenticulostriated and thalamic perforating arterioles;

6: transcerebral arterioles. (B) Venous microcirculation. 1: cortical veins; 2: superficial medullary venules; 3: subependymal venules;

4: deep medullary venules.

Figure 2 Perivascular space. (A) Periarteriolar space of the pial arterioles surrounded by one leptomeningeal layer that separates

it from the subpial space (arrow). Periarteriolar space of lenticulostriated arterioles surrounded by two leptomeningeal layers

that separate it from the subpial space (arrowheads in the upper box and asterisks in the lower box); (B) perivenular space that

communicates with the subpial space (arrow); (C) photomicrographic detail of the perivascular Virchow---Robin space (arrows)

5

(courtesy of Dr. Susana Boluda).

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324 S. Medrano Martorell et al.

Figure 3 Perivascular spaces dilated in the (A), the semioval centre (B), and the mesencephalic region (C). T1

(shown) and FLAIR sequences demonstrate similar signal to that of the cerebrospinal fluid (D).

At conventional MRI, perivascular spaces appear dilated , as well as benign macrocephaly in the paediatric

15

(dPVS) in 13% of healthy adults and in only 3% of children population (Fig. 4).

7,8

between 20 months and 16 years of age. In a recent The appearance of ischemic-like lacunar foci in

multicentre observational study, cerebral MRI studies using the periventricular and subcortical white matter is a

high-resolution 3D sequences of 1818 healthy individuals physiological process because age is a cerebrovascular risk

16,17

aged over 65 (-free and with no history of cere- factor itself. Abnormalities of the white matter are

bral infarction) were reviewed. dPVS were detected in all almost ubiquitous (95%) in the population over the age of

18

patients and dPVS larger than 3 mm were detected in 65 years.

9

approximately one third of patients. dPVS appear as lin- There are different visual rating scales for age-related

ear or fusiform foci with similar signal to that of the white matter changes () showing a good cor-

19

cerebrospinal fluid in all sequences (Fig. 3). Small perivas- relation between them. One of the best known is the

20

cular spaces (<2 mm) have been regarded as an anatomic Fazekas scale, which was integrated in the ARWMC scale

7,8 21

variant, whereas larger (>2 mm) PVS have been associ- (age-related white matter changes), recommended when

6

ated with ageing, dementia, early inflammatory stages in lesions of the white matter are not to be quantified by

10 22

multiple sclerosis, and inflammatory reaction in traumatic CT or MRI. This is a four-grade rating scale for punctate

8

brain injury. A number of recent studies have concluded microvascular lesions in the white matter. Absence of lesions

that dPVS are associated with lacunar ischemic lesions, corresponds to grade 0; presence of non-confluent focal

and thus, this finding can be considered as an indica- lesions corresponds to grade 1; initially confluent lesions

11---13

tor of cerebral small vessel disease. As an exception, correspond to grade 2; diffuse confluent lesions correspond

perivascular spaces may be significantly dilated, typically to grade 3 (Fig. 5). Based on this scale, a lesion is consid-

in the mesencephalothalamic region. They can cause a sig- ered normal (attributed to ageing) and classified as grade 1,

nificant mass effect and and need to be grade 2 is considered abnormal in patients <75 years, and

23

distinguished from other tumefactive cystic lesions. These grade 2 is considered abnormal in any age group.

giant perivascular spaces are on many occasions incidentally There is a number of studies on pathologic and imaging

24---27

discovered and their presence not always correlates with correlation using magnetization transfer (MT) imag-

9,14

the clinical manifestations. Some studies have reported ing studies that compare magnetization transfer ratios

28---30

a poor association with different degrees of developmen- (MTR). These studies attempt to elucidate the nature of

tal delay, , behaviour anomalies, and nonspecific these lesions, and report differences between lesions in the

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Hyperintense punctiform images in the white matter 325

white matter lesions are essentially ischemic in nature due

24---30

to the senile degeneration of the microcirculation.

‘‘Abnormal’’ hyperintense punctate images

in the white matter

When the HPIWM is pathological, it may be indicative of

an acquired or inherited disease. Among the acquired dis-

eases of the white matter, microvascular hypoxicoischemic

disease is by far the most common, no matter whether

atherothrombotic, embolic or caused by cerebrovascular

risk factors (CVRFs). The acquired origin should be con-

sidered the first diagnostic option, even in the absence of

typical CVRFs, unless there are clinical and analytic evi-

dence suggestive of a different aetiology. Multiple sclerosis

(MS) is the second most common disorder, with vasculitis,

, intoxication, and trauma (among other causes)

31

trailing far behind. A large number of patients with a

very low vascular risk present with lesions of microvascular

appearance for which there is relatively often no alternative

or final diagnosis.

With respect to inherited disorders, leukodystrophic

are a group of rare diseases. Although they

usually occur in the paediatric age, they can present

in adult age. They are metabolic diseases that usu-

ally affect the white matter in a quite symmetric and

extensive (not punctate) manner, and usually damage the

Figure 4 Five-year old child with . Visualization of and the . An exception is mito-

dilated perivascular spaces is an incidental finding with a dubi- chondrial diseases, which cause more asymmetric lesions,

ous or unlikely clinical relevance. and normally affect the . In adults, the

most common are metachromatic , globoid

cell leukodystrophy, adrenomyeloneuropathy, mitochondrial

disorders, vanishing white matter, and cerebrotendinous

perivascular white matter and subcortical lesions. Outcomes

xanthomatosis.31

suggest that ageing induces anomalies in the ependymal

membrane, which causes filtration of the cerebrospinal

fluid. This filtration leads to and focal demyelinization Basic pathophysiology

of the parenchyma. In addition, subependymal penetrat-

ing microcirculation degenerates, which means that there is One possible mechanism of damage of the white matter

also a certain ischemic component associated, particularly is the primary involvement of an arteriole or cere-

in those cases in which periventricular leukoencephalopa- bral venule, which compromises the blood supply of

thy exhibits irregular borders. Apart from this, subcortical the parenchyma that depends on them, and induces a

0 1 2 3 No dots Very few dots Incipient confluence Significant confluence

(Normal) (Normal >65 years) (abnormal <75 years) (never normal)

Figure 5 ARWMC scale (age-related white matter changes) to assess punctate lesions in the white matter using computed

tomography and magnetic resonance.

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326 S. Medrano Martorell et al.

Figure 6 (A) Pathophysiology of the vascular pattern. The picture features the mural and/or endoluminal microvascular lesion

that induces the ischemic lesion of the parenchyma. Note the mural hyalinization caused by hypertensive arteriopathy (arrow)

and the adjacent ischemic vacuolation (*); (B) pathophysiology of the perivascular pattern. The picture features a perivascular

pathological process and the adjacent parenchymatous lesion. Demyelinating layer caused by perivenular inflammation in a patient

with multiple sclerosis.

lesion. White matter microvascular disease encompasses Semiological elements in hyperintense punctate

a wide range of conditions: hypoxia-, granuloma- lesions in the white matter

tous or nongranulomatous inflammation, infection, disease

caused by substance deposit, , metabolic disease,

For the radiologic approach of a case of HPIWM, the

traumatism, etc. Another possible pathophysiological mech-

semiological elements to be analysed are distribution and

anism of leukoencephalopathy is cell infiltration or

location, shape, size, enhancement after contrast admin-

deposition of pathologic substances in the perivascular

istration, presence of haemorrhage or microhaemorrhage,

space that can also manifest radiologically as focal lesions

and grey matter involvement. Description of each of these

in the white matter. They have a non-infectious inflamma-

elements may help identify one of the three semiological

tory aetiology (as is the case of MS or other demyelinating

patterns suggested, thus facilitating an adequate differen-

diseases, some types of vasculitis, and some granulomatous

tial diagnosis for each case.

diseases), an atypical infectious aetiology (Lyme’s disease,

cryptococcosis, parenchymatous cysticercosis), a metabolic

aetiology (mucopolysaccharidosis) or a traumatic aetiology

Distribution and location

(diffuse axonal injury). Both pathophysiological mechanisms

HPIWM may present with a predominantly supratentorial,

may co-occur in one same disease.

infratentorial or supra- and infratentorial distribution. As

White matter disease can be approached by taking into

shall be shown below, the presence of lesions with an essen-

account the anatomy of cerebral microcirculation and its

tially supratentorial distribution generally suggests small

interstitium, specifically by determining the most affected

vessel disease as a first option, which favours a VP (Fig. 7).

elements in the different leukoencephalopathic groups. In

This suggestion is further supported by a predominantly

this respect, our goal is to get insights into the pathophysi-

frontoparietal distribution.

ology of the disease underlying the HPIWM by identifying

Supratentorial distribution concerns four large areas:

the predominant semiological pattern. Three main pat-

subcortical area, periventricular area, deep area, and cor-

terns can be defined on the basis of several semiological

elements: pus callosum (Fig. 8).

A subcortical lesion can be located either in direct

contact with the cerebral cortex (juxtacortical) thus affect-

ing subcortical U-fibres of the white matter, or can be

• A vascular pattern (VP) or microvascular pattern, which

located inside these fibres, which would not be affected.

is usually caused by an arteriolar lesion, and is the most

In this latter case, the lesion is classified as sub-U subcor-

33

prevalent (Fig. 6A).

tical. A sub-U subcortical lesion suggests a VP, whereas a

•

A perivascular pattern (PvP), which is usually caused

juxtacortical lesion is more suggestive of a PvP, which is typ-

by perivascular inflammation, among other less common

ically associated with MS (a PvP is present in one third of MS

34

causes. The paradigm of this pattern is MS, for which an cases).

autoimmune perivenular inflammation has been reported

A lesion will be regarded as periventricular when it is

32 35

that causes demyelinization (Fig. 6B).

in contact or virtually in contact (closer than 1 cm) with

•

A non-specific pattern (NsP), when neither of the previous

the ependymal surface. Both microvascular and perivascular

patterns can be identified, and which is normally caused

lesions can have a periventricular location, the shape of the

by microvascular disease.

lesion being the key semiological element.

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Hyperintense punctiform images in the white matter 327

FP Supra

Frontoparietal

Central

Temporal Occipital T

Infra

Peripheral

Figure 7 Distribution. A mainly supratentorial distribution with frontoparietal prevalence is typical of the vascular pattern. The

infratentorial involvement with peripheral distribution suggests a perivascular pattern. The infratentorial involvement with central

distribution suggests a vascular pattern.

The deep region is located between the subcortical and or in the cerebral autosomal dominant arteriopathy with

38

periventricular regions. The deep region is classified as bor- subcortical infarcts and leukoencephalopathy (CADASIL),

dering when located in a border zone between two vascular among others.

areas, which is indicative of a VP, or as non-bordering when Infratentorial lesions can have a peripheral location, in

not clearly located in a border zone, which is indicative of contact with the surface of the parenchyma, or a central

an NsP. The is a specific location as well, location, with no involvement of the surface. A central

as in some other diseases, such as MS----typically in the lesion is typically associated with a VP, whereas a peripheral

34 34,36,37 34

callosal-septal interface, ---- i n the Susac syndrome lesion is typically associated with a PvP (Fig. 7).

1 2

1

3

4 2 4 5 6 5

6

Figure 8 Location: (1) juxtacortical; (2) sub-U subcortical; (3) non-bordering deep subcortical; (4) bordering subcortical;

(5) periventricular, and (6) corpus callosum. A predominantly juxtacortical involvement or involvement of the corpus callosum is not

indicative of a vascular pattern (VP); the rest of locations favour a VP or a non-specific pattern, and thus, suggest a microvascular

cause. Periventricular lesions may be indicative of a VP or a perivascular pattern depending on the shape of the lesion.

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328 S. Medrano Martorell et al.

Round, Punctate: Non-specific

Ovoid, Fusiform: PvP

Amorphous: Non-specific

Figure 9 Morphology. Ovoid or fusiform lesions suggest a perivascular pattern; the rest are non-specific.

Morphology

>1.5 cm (one single lesion):

There are several lesion types according to their shape:

oval or fusiform, punctate or roundish, and amorphous

Not indicative of a vascular pattern

(Fig. 9). Punctate, roundish, and amorphous lesions are non-

specific, whereas oval or fusiform lesions usually have a

distribution parallel to the cerebral microcirculation, and

thus, they normally feature a PvP. Oval or fusiform periven-

tricular lesions in a radial pattern and perpendicular to the

longitudinal axis of the are quite a com-

34

mon feature of MS. They are known as Dawson’s fingers,

after the neuropathologist James Dawson, who described

finger-like venular and perivenular inflammatory cells in MS

39

patients. Confluence of these lesions makes up a ridge-like

34

configuration, which is also associated with MS. CVRF-

induced microvascular periventricular leukoencephalopathy

3,40

presents with typically more irregular borders.

Size

Localization of an isolated lesion (not several confluent

lesions) >10---15 mm in size is suggestive of a PvP (lacunar

41

infarctions are acknowledged to reach 15 mm). Smaller

lesions are non-specific, and can be indicative either of a

microvascular or a perivascular lesion (Fig. 10).

Enhancement after contrast administration

Although a non-specific finding, the absence of enhancement

on leukoencephalopathic foci is suggestive of an inactive

stage of the disease. In contrast, the active inflamma-

tory stage of the disease usually involves an increase in

permeability or absence of the blood---brain barrier and

enhancement of the lesion. Punctate, peripheral

Figure 10 Size. Lesions larger than 10---15 mm (not several

(in complete or incomplete ring) or central (homogeneous

confluent lesions) suggest a perivascular pattern (inflammation,

or heterogeneous) contrast enhancement can be observed.

infection).

Enhancing patterns are generally a non-specific finding,

except for peripheral incomplete ring-enhancement, which

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Hyperintense punctiform images in the white matter 329

Incomplete-ring enhancement

typical of MS

Figure 11 Enhancement following contrast administration. Absence of enhancement is a non-specific semiological finding. Periph-

eral incomplete ring-enhancement favours a perivascular pattern caused by multiple sclerosis. Patient with multiple juxtacortical

lesions showing typically associated incomplete ring-enhancement.

has been reported as a finding typically associated with enhancing lesions may also help predict the prognosis of the

34,36 34

MS, and thus, suggestive of a PvP (Fig. 11). disease.

When an image is suspicious of MS, the current diag-

42

nostic criteria of the MAGNIMS (magnetic imaging in MS)

group do not require gadolinium enhancement as part of the Haemorrhage or microhaemorrhage

diagnosis for dissemination in space. However, one enhanc- At MRI, images of microbleeding are associated with HPIWM

ing lesion among non-enhancing lesions in the same MRI in at least 18% of the population over 60 years of age.

study is enough to determine dissemination in time. HPIWM are present in over 95% of the population over

In the follow-up of the disease, many authors opt 65 years of age. These data provide further evidence

for contrast administration for the assessment of active of the mixed microvascular disease, which shares a

inflammation and response to treatment. The number of pathophysiological origin with white matter disease and

Figure 12 Residual haemorrhage: (A) cortico-subcortical residual haemorrhage suggests amyloid angiopathy; (B) in the basal

ganglia, brainstem, and cerebellum suggests AH, and (C) haemorrhage with a history of trauma suggests diffuse axonal injury.

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330 S. Medrano Martorell et al.

18

microbleeding. When a VP with foci of microbleeding

is observed in T2*, two pathologic entities are possible:

arterial (AH) and amyloid angiopathy (AA).

Involvement of the deep region of the BG and infraten-

torial involvement suggest hypertensive or arteriosclerotic

microangiopathy, whereas a peripheral location in the cere-

bral cortex or lobes of the bleeding is typically associated

43

with AA (Fig. 12).

Patients with vasculitis present with foci of cerebral

bleeding associated with white matter microvascular-like

lesions and cortical ischemic lesions appearing at the onset

44

or secondary to infarct transformation.

Another cause of HPIWM with residual bleeding is the dif-

fuse axonal injury associated with a high-energy traumatic

injury. Residual foci of leukoencephalopathy with traces of

haemosiderin are detected at the grey matter-white matter

border, mainly located in the frontal lobe and typically in

the region of basal nuclei and in the splenium of the corpus 45

callosum (Fig. 12).

Grey matter involvement

Most HPIWM cases are associated with cortical lesions or

lesions of the BG region.

Co-presence of lesions in the cerebral cortex and multi-

ple bright foci in the white matter is a non-specific finding.

In patients with vasculitis-induced microvascular disease, it

is not uncommon to detect peripheral lesions with corti-

cal involvement, which usually represent areas of ischemic

44

infarction. However, they are not readily visualized in con-

34

ventional MRI sequences.

GB involvement typically occurs in patients with hyper-

40

tense or arteriosclerotic microangiopathy (Fig. 13), and is Figure 13 Grey matter involvement (basal ganglia). (A)

34

very rare in MS patients. In patients with acute dissem- lacunar porencephalic foci, which are likely associated with

inated encephalomielities (ADEM), who may present with dilated Virchow---Robin spaces in a patient with uncontrolled AH.

lesions indistinguishable from those of MS, the BG region (B) Gelatinous cysts in the Virchow---Robin spaces of the lentic-

36,46

and the are usually affected. Diverse forms ulostriated vasculature in a 30-year-old patient with AIDS, who

of vasculitis (systemic erythematosus [SLE], Behc¸et’s firstly presented with cryptococcosis.

44,47,48

disease, etc.) and can affect the BG.

Immunocompromised patients with cryptococcosis typically

Table 1 Semiological characteristics.

present with gelatinous cysts in the perivascular space of

the lenticulostriated and thalamic perforating arterioles

Vascular pattern

49

of the BG.

- Not juxtacortical

- Sub-U subcortical

- Deep bordering

Differential diagnosis

- Periventricular irregular

- Supra- > infratentorial

The general features of each pattern can be defined by

- Supratentorial frontoparietal

considering each of the semiological elements described

- Basal ganglia

(Table 1). An adequate differential diagnosis can be made by

- No enhancement (if not acute) or mild enhancement

identifying the predominant pattern and the specific aspects

of each case. Perivascular pattern

- Periventricular ovoid

- Juxtacortical

Vascular pattern

- Fusiform or ovoid

A vascular pattern in microvascular hypoxic-ischemic dis-

- Dawson’s fingers

ease secondary to CVRFs (especially AH, dyslipidemia, and

- Supra- and infratentorial

) is associated with a great number of lesions

- Large lesions

that are normally identified in the majority of semiologi-

cal findings described by this pattern. AH produces traces Non-specific pattern

of haemosiderin, which can be observed in T2*-weighted - Deep non-bordering

sequences, particularly in the corpus striatum, thalami, - Amorphous, punctate, round

cerebellum, and brainstem (Fig. 14).

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Hyperintense punctiform images in the white matter 331

Figure 14 Vascular pattern: cerebrovascular risk factors. Patients with AH showing: (A) foci of leukoencephalopathy confluent in

the periventricular white matter; (B) involvement of the basal ganglia and the subcortical white matter but no involvement of the

subcortical U-fibres; (C) residual haemorrhage in the basal ganglia, brainstem, and cerebellum.

As already mentioned, microvascular involvement in AA abnormalities does not seem to be associated with cognitive

35

is associated with a VP, typically manifested as cortical foci impairment.

of peripheral microhaemorrhage or areas of haemorrhage in Most blood vessels affected by vasculitis in the cen-

18,50,51

cerebral lobes (Fig. 15). tral present with HPIWM typical of a VP,

Studies with patients have reported with a certain subcortical prevalence and associated with

52,53

microvascular-like HPIWM, predominantly frontal cortical ischemic lesions and foci of intraparenchymatous

54

or located in the semioval centres (Fig. 16). A recent bleeding appearing at the onset or secondary to infarct

44

study with 780 participants confirms this association both in transformation. Traces of peripheral microhaemorrhage

50

patients with migraine headache and in patients presenting can be found in the BG due to septic vasculitis and

with other headache disorders, especially tension- vasculitis caused by vasoactive drugs, such as cocaine

related headaches. Prevalence for tension-related and and alkaloid derivatives, amphetamine, ephedrine and

44,50

migraine headaches was 34% and 32%, respectively, phenylpropanolamine (Fig. 17).

and both were much higher than prevalence for HPIWM in CADASIL integrates all features typical of VP associ-

35

the controls (7.4%). Migraine with aura has been shown ated with bilateral temporal involvement of the anterior

to have a stronger association with clinical or subclinical poles, the external capsules, and the corpus callosum in the

55---57

ischemic infarcts, particularly in the posterior circulation callosal-septal interface (Fig. 18).

54

territory (cerebellum, protuberance). Additionally, and In short, a leukoencephalopathy can be caused by HPIWM

irrespective of the headache type, the presence of cerebral with VP if the patient presents with CVRFs. Otherwise, the

Figure 15 Vascular pattern: amyloid angiopathy. Significant changes of microvascular disease in the fronto-parieto-occipital

supratentorial white matter with a vascular pattern (left). Gradient-echo sequences (centre) show punctate foci of hemosiderin

in the cortico-subcortical interface, predominantly posterior (arrow), suggesting an underlying amyloid angiopathy. On the right,

detail of the mural arteriolar deposits of congophilic ␤-amyloid matter.

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332 S. Medrano Martorell et al.

Figure 16 Vascular pattern: migraine. In patients with migraine (generally with aura), it is common to find frontal punctate

lesions in the subcortical white matter with no involvement of subcortical U-fibres (arrows).

Figure 17 Vascular pattern: vasculitis. 63-Year-old woman free of typical cerebrovascular factors with discrete hyperhomo-

cysteinemia and antiphospholipid . She presented with punctate lesions in the supratentorial white matter with no

involvement of the U-fibres (orange arrow) and some areas of a past cortico-subcortical temporoparietal infarct (red arrow). These

findings suggested lupic vasculitis.

differential diagnosis focuses on other causes of microvas- in the form of Dawson’s fingers, typically in contact with

cular abnormalities, such as AA, headache, toxic-metabolic the inferior aspect of the corpus callosum (callosal-septal

diseases, some forms of vasculitis and CADASIL, among oth- lesions) or adjacent to the anterior aspect of the temporal

ers. horn; peripheral infratentorial lesions adjacent to the floor

of the fourth ventricle, in the middle cerebellar peduncles

34

and in the brainstem (Fig. 19).

Perivascular pattern

If other clinical or analytic indications favour MS, the

HPIWM with a perivascular pattern is suggestive of MS as the

patient is treated as having MS before the final diag-

first diagnostic option. The most characteristic semiological

nosis of dissemination in space and time, in consonance

findings are: juxtacortical and periventricular ovoid lesions

Figure 18 Vascular pattern: dominant autosomic cerebral arteriopathy with subcortical infarcts and leukoencephalopathy

(CADASIL). 50-Year-old patient diagnosed with CADASIL with signs of microvascular disease in the supratentorial white matter

and involvement of the anterior temporal poles (arrows).

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Hyperintense punctiform images in the white matter 333

Figure 19 Perivascular pattern: multiple sclerosis (MS). (A) juxta-cortical lesions; (B) periventricular lesions in the form of Daw-

son’s fingers (left and centre). Confluent lesions with a ridge-like configuration in chronic MS and anterior temporal lesion (right);

(C) callosal-septal lesions; (D) peripheral infratentorial lesions; and (E) peripheral incomplete ring-enhancement.

42

with the MAGNIMS criteria. If the clinical setting is Non-specific pattern

not suggestive of MS, the differential diagnosis will Leukoencephalopathy can be caused by HPIWM with an NsP if

include other diseases with a likely autoimmune aetiol- the patient presents with CVRFs. Otherwise, the differential

ogy, such as atypical MS, ADEM, SLE, Sjögren’s disease, diagnosis firstly focuses on causes of atypical microvascular

47,48 58

and sarcoidosis, such as Lyme’s disease disease, and secondly, on uncommon causes of perivascular

49

and cryptococcosis, some forms of vasculitis, such disease.

59

as Behc¸et’s disease, and metabolic diseases, such as The summary chart in Fig. 20 suggests a diagnostic algo-

6

mucopolysaccharidosis. rithm to be used in an HPIWM case. This algorithm may help

Virchow-Robin, aging (ARWMC I, ARWMC II >75 years) Normal

• Not juxtacortical With typical CVRFs: AH, DLP, • U-subcortical DM, etc. • Deep bordering • Periventricular irregular • Supra- > infratentorial VP • Supratentorial FP With no typical CVRFs: • Basal ganglia atypical CVRFs (, • No enhancement (if not pro-thrombotic states); migraine; amyloid acute) or mild angiopathy; vasculitis; CADASIL, etc. enhancement HPIWM • Periventricular ovoid Typical MS: ovoid (Dawson); • Juxtacortical enhancement (typical incomplete ring); supra- / infra-; corpus callosum; • Fusiform or ovoid PvP infra-peripheral (Dawson) • Supra- and infratentorial • Large lesions : atypical multiple sclerosis; ADEM; other diseases (SLE, Sjögren’s syndrome, etc.) With CVRFs Sarcoidosis • Profundo no Infections: Lyme, limítrofe cryptococcosis, etc. NsP • Amorphous, Vasculitis, other demyelinating punctate, Vasculitis (Behçet) round diseases, toxic-

metabolic diseases, etc. Mucopolysaccharidosis

Figure 20 Diagnostic algorithm of the hyperintense punctate images in the white matter (HPIWM), vascular pattern (VP), perivas-

cular pattern (PvP), and non-specific pattern (NsP). ARWMC: ARWMC scale (age-related white matter changes); CVRFs: cardiovascular

risk factors; AH: arterial hypertension; DLP: dyslipidemia; DM: diabetes mellitus; CADASIL: dominant autosomic cerebral arteriopathy

with subcortical infarcts and leukoencephalopathy; MS: multiple sclerosis.

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334 S. Medrano Martorell et al.

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8. Heier LA, Bauer CJ, Schwartz L. Large Virchow---Robin

This study proposes a practical and simple diagnostic

spaces: MR-clinical correlation. AJNR Am J Neuroradiol.

tool on the basis of three main semiological patterns of

1989;10:929---36.

hyperintense punctate images in the white matter: a vas-

9. Zhu YC, Dufouil C, Mazoyer B, Soumaré A, Ricolfi F, Tzourio C,

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et al. Frequency and location of dilated Virchow---Robin spaces

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Am J Neuroradiol. 2011;32:709---13.

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Authorship Dilatation of the Virchow---Robin space is a sensitive indicator of

cerebral microvascular disease: study in elderly patients with

dementia. AJNR Am J Neuroradiol. 2005;26:1512---20.

1. Responsible for the integrity of the study: SM.

13. Rouhl RP, van Oostenbrugge RJ, Knottnerus IL, Staals JE, Lodder

2. Conception of the study: SM, MC and DG.

J. Virchow---Robin spaces relate to cerebral small vessel disease

3. Design of the study: SM.

severity. J Neurol. 2008;255:692---6.

4. Acquisition of data: SM.

14. Salzman KL, Osborn AG, House P, Jinkins JR, Ditchfield A, Cooper

5. Analysis and interpretation of data: SM, MC, DG, JC and

JA, et al. Giant tumefactive perivascular spaces. AJNR Am J SG.

Neuroradiol. 2005;26:298---305.

6. Statistical analysis: N/A. 15. Bruna AL, Martins I, Husson B, Landrieu P. Developmental

7. Bibliographic search: SM, MC and DG. dilatation of Virchow---Robin spaces: a ? Pediatr

8. Drafting of the manuscript: SM, MC and DG. Neurol. 2009;41:275---80.

9. Critical review with intellectually relevant contrib- 16. Basile AM, Pantoni L, Pracucci G, Asplund K, Chabriat H, Erk-

injuntti T, et al. Age, hypertension, and lacunar stroke are the

utions: SM, MC, DG, JC and SG.

major determinants of the severity of age-related white matter

10. Approval of the final version: SM, MC, DG, JC and SG.

changes. The LADIS (Leukoaraiosis and in the Elderly)

study. Cerebrovasc Dis. 2006;21:315---22.

Conflicts of interests 17. Arana Fernández de Moya E. Demencias e imagen: lo básico.

Radiología. 2010;52:4---17.

18. Fisher M. The challenge of mixed . Ann

The author declares no conflicts of interests.

N Y Acad Sci. 2010;1207:18---22.

19. Pantoni L, Simoni M, Pracucci G, Schmidt R, Barkhof F, Inzitari

Acknowledgements D. Visual rating scales for age-related white matter changes

(leukoaraiosis) can the heterogeneity be reduced? Stroke.

2002;33:2827---33.

We would like to thank Susana Boluda, neuropathologist at

20. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR

the Unit of Neuropathology of Bellvitge Hospital, for pro-

signal abnormalities at 1.5 T in Alzheimer’s dementia and nor-

viding the microphotographs of pathological correlation;

mal aging. AJR Am J Roentgenol. 1987;149:351---6.

Dolores Cocho, neurologist at the Unit of of

21. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjö-

Granollers Hospital, for providing the databases of repre- gren M, et al. A new ratings scale for age-related white matter

sentative cases; and illustrator Txomin Medrano for the changes applicable to MRI and CT. Stroke. 2001;32:1318---22.

anatomy illustrations. 22. Hachinski V, Ladecola C, Petersen RC, Breteler MM, Nyenhuis DL,

Black SE, et al. National institute of neurological disorders and

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