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Radiología. 2012;54(4):321---335

www.elsevier.es/rx

UPDATE IN RADIOLOGY

Hyperintense punctiform images in the white matter: A diagnosticapproach�

S. Medrano Martorell a,∗, M. Cuadrado Blázquezb, D. García Figueredob,S. González Ortiza, J. Capellades Fonta

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

Received 30 January 2011; accepted 4 September 2011

KEYWORDSWhite matter;Magnetic resonance;Leukoaraiosis;Multiple sclerosis;CADASIL;Vasculitis

Abstract The presence of hyperintense punctiform images in the white matter in T2-weightedmagnetic resonance (MR) sequences is a very common finding and is occasionally a diagnosticchallenge for the radiologist.

The present article attempts, using an anatomical approach to the brain circulation, as well asfrom histopathology correlation studies, to simplify the task of interpreting these images fromthe description of the three main patterns of hyperintense punctiform images in the whitematter: vascular pattern, which corresponds to microvascular lesions; perivascular pattern,which represents inflammatory disease of which the paradigm is multiple sclerosis; 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 bedetermined in each case and, in this way, helps in the differential diagnosis.© 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVESustancia blanca;Resonanciamagnética;Leucoaraiosis;Esclerosis múltiple;

Imágenes puntiformes hiperintensas en la sustancia blanca: una aproximacióndiagnóstica

Resumen La presencia de múltiples imágenes puntiformes hiperintensas en la sustancia blanca(IPHSB) en las secuencias de resonancia magnética (RM) ponderadas en T2 es un hallazgo muyfrecuente y, en ocasiones, un reto diagnóstico para el radiólogo.

loaded from http://zl.elsevier.es, day 24/10/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

CADASIL; Este artículo pretende, a través de una aproximación a la anatomía de la microcircu- estudios de correlación anatomopatológica, simplificar la tarea de
lación cerebral, así como a Vasculitis
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, patrónperivascular (PpV), que representa a la enfermedad inflamatoria cuyo paradigma es la esclerosismúltiple (EM), y patrón inespecífico (PI), que suele deberse a enfermedad microvascular.

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

dx.doi.org/10.1016/j.rxeng.2011.09.001

http://www.elsevier.es/rx

mailto:[email protected]

322 S. Medrano Martorell et al.

A partir de varios elementos semiológicos en las imágenes de RM se puede determinar unpatrón predominante en cada caso y, de este modo, acotar el diagnóstico diferencial.© 2011 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

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Document downloaded from http://zl.elsevier.es, day 24/10/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

ntroduction

he interpretation of multiple hyperintense punctatemages in the white matter in T2-weighted sequences, whichre daily reported at magnetic resonance imaging (MRI) ofdult brains, plays a major role in the routine practicef neuroradiologists.

A parallelism can be established between the commonlysed term unidentified bright objects (UBO)1 and the termyperintense punctate images in the white matter (HPIWM),hich is presented in this paper. Accordingly, HPIWM is a

emiological entity revealing at least five solitary hyper-ntense foci of up to 1 cm in diameter on T2-weightedequences, with or without confluent lesions with an overalliameter >1 cm.

The main goal of this paper is to simplify the radiol-gist’s task when dealing with cases of HPIWM, so thatadiologists can categorize the findings under a predominantattern and make a more accurate diagnosis. This paper pro-oses three main HPIWM patterns based on the semiologicalharacteristics: a vascular pattern (VP), which representsicrovascular involvement (usually arteriolar); a perivas-

ular pattern (PvP), which represents inflammatory diseaseparticularly demyelinating disease); and a non-specific pat-ern (NsP), which usually represents microvascular disease.o make a diagnosis, the predominant semiological patternhould be considered together with the clinical manifesta-ions of patient and the epidemiologic data.

asic anatomy of brain microcirculation

he brain microcirculation consists of a vascular networkith a very complex anatomy that varies across subjects. Tonderstand the HPIWM patterns suggested, the basic aspectsf brain microvascular anatomy will be addressed.

rterial microvascular system

he cortical arteries cross the cerebral cortex and pen-trate the white matter perpendicularly to the corticalurface, forming the terminal pial or medullary arteriolesp to 4---5 cm long. Along their course, they give off shortortical branches that supply the entire cerebral cortexnd the fibres of the juxtacortical white matter (3---4 mm),lso called U-fibres. The cortical arteries establish multiplenastomoses, which provide the cerebral cortex with a richrteriolar network. When running deep into the white mat-er, pial arteries establish very few capillary anastomoses
ith the neighbouring pial arterioles, forming relatively
ndependent arteriolar metabolic units.The deep subependymal arteries, which arise from the

horoid arteries, give off penetrating branches to the white

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atter, although with shorter course than that of the pialrteries.

There is a second terminal system of cortical andubependymal arteries (lenticulostriated and thalamic per-orating arteries) that supplies the basal ganglia (BG).

The superficial and deep arteriolar systems (pial pen-trating arteries and subependymal arteries) hardly anas-omose with each other. For this reason, the parenchymaocated on the bordering zone between the superficial andhe deep vasculature is less vascularized. In contrast, the-fibres are more and better vascularized than the rest ofhe white matter and BG2,3 (Fig. 1A).

enous microvascular system

he cerebral venules, also known as medullary venules, areivided into two large groups: superficial medullary venules,hich are short venous channels draining to the cortical sur-

ace from about 1 or 2 cm below the cerebral cortex; andhe deep medullary venules, which are longer channels thatrain perpendicularly to the ventricular surface towardshe subependymal veins. There is a third group includingranscerebral venules, less abundant and that connect bothystems2,4 (Fig. 1B).

erivascular space

he arterial system runs parallel to the venous system. Theerivascular space surrounds the wall of arteries andrterioles (Virchow---Robin space) and veins and venulesperivenular space) from the subarachnoid space alongheir intraparenchymatous course. The superficial or corti-al arterioles are surrounded by one layer of leptomeningeshat separates the vascular surface from the periarteriolarpace. The parenchymatous surface of this space is limitedy the pia mater. The perivascular space of the penetrat-ng arterioles of the BG is delimited by the two layersf leptomeninges that surround their endothelium. Appar-ntly there is direct communication of the superficial andeep perivenular space with the subpial space, with no lep-omeningeal layers separating them (Fig. 2).5,6

‘Normal’’ hyperintense punctate imagesn the white matter

he presence of a few hyperintense punctate foci in theerebral white matter at MRI is a very common finding that
an be regarded as insignificant in most of the cases. Theseright dots, considered as normal, can be a manifestationf dilated perivascular spaces or small gliotic or lacunarschemic foci.

Hyperintense punctiform images in the white matter 323

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Figure 1 Cerebral microcirculation. (A) Arterial microcirculation. 1: cortical arteries; 2: pial arteries; 2.1: shortbranches; 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 separatesit from the subpial space (arrow). Periarteriolar space of lenticulostriated arterioles surrounded by two leptomeningeal layersthat separate it from the subpial space (arrowheads in the upper box and asterisks in the lower box); (B) perivenular space thatcommunicates with the subpial space (arrow); (C) photomicrographic detail of the perivascular Virchow---Robin space (arrows)(courtesy of Dr. Susana Boluda).5



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

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shown) and FLAIR sequences demonstrate similar signal to tha

At conventional MRI, perivascular spaces appear dilateddPVS) in 13% of healthy adults and in only 3% of childrenetween 20 months and 16 years of age.7,8 In a recentulticentre observational study, cerebral MRI studies using

igh-resolution 3D sequences of 1818 healthy individualsged over 65 (dementia-free and with no history of cere-ral infarction) were reviewed. dPVS were detected in allatients and dPVS larger than 3 mm were detected inpproximately one third of patients.9 dPVS appear as lin-ar or fusiform foci with similar signal to that of theerebrospinal fluid in all sequences (Fig. 3). Small perivas-ular spaces (<2 mm) have been regarded as an anatomicariant,7,8 whereas larger (>2 mm) PVS have been associ-ted with ageing,6 dementia, early inflammatory stages inultiple sclerosis,10 and inflammatory reaction in traumaticrain injury.8 A number of recent studies have concludedhat dPVS are associated with lacunar ischemic lesions,nd thus, this finding can be considered as an indica-or of cerebral small vessel disease.11---13 As an exception,erivascular spaces may be significantly dilated, typicallyn the mesencephalothalamic region. They can cause a sig-ificant mass effect and hydrocephalus and need to beistinguished from other tumefactive cystic lesions. Theseiant perivascular spaces are on many occasions incidentally
iscovered and their presence not always correlates withhe clinical manifestations.9,14 Some studies have reported
poor association with different degrees of developmen-al delay, headaches, behaviour anomalies, and nonspecific

ci(t

he cerebrospinal fluid (D).

pilepsy, as well as benign macrocephaly in the paediatricopulation15 (Fig. 4).

The appearance of ischemic-like lacunar foci inhe periventricular and subcortical white matter is ahysiological process because age is a cerebrovascular riskactor itself.16,17 Abnormalities of the white matter arelmost ubiquitous (95%) in the population over the age of5 years.18

There are different visual rating scales for age-relatedhite matter changes (leukoaraiosis) showing a good cor-

elation between them.19 One of the best known is theazekas scale,20 which was integrated in the ARWMC scaleage-related white matter changes),21 recommended whenesions of the white matter are not to be quantified byT or MRI.22 This is a four-grade rating scale for punctateicrovascular lesions in the white matter. Absence of lesions

orresponds to grade 0; presence of non-confluent focalesions corresponds to grade 1; initially confluent lesionsorrespond to grade 2; diffuse confluent lesions correspondo grade 3 (Fig. 5). Based on this scale, a lesion is consid-red normal (attributed to ageing) and classified as grade 1,rade 2 is considered abnormal in patients <75 years, andrade 2 is considered abnormal in any age group.23

There is a number of studies on pathologic and imaging
orrelation24---27 using magnetization transfer (MT) imag-ng studies that compare magnetization transfer ratiosMTR).28---30 These studies attempt to elucidate the nature ofhese lesions, and report differences between lesions in the

Hyperintense punctiform images in the white matter

Figure 4 Five-year old child with headache. Visualization ofdilated perivascular spaces is an incidental finding with a dubi-

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One possible mechanism of damage of the white matter


ous or unlikely clinical relevance.

perivascular white matter and subcortical lesions. Outcomessuggest that ageing induces anomalies in the ependymalmembrane, which causes filtration of the cerebrospinalfluid. This filtration leads to gliosis and focal demyelinizationof the parenchyma. In addition, subependymal penetrat-ing microcirculation degenerates, which means that there is
also a certain ischemic component associated, particularlyin those cases in which periventricular leukoencephalopa-thy exhibits irregular borders. Apart from this, subcortical
ibt

0No dots(Normal)

1Very few dots

(Normal >65 years) (

Figure 5 ARWMC scale (age-related white matter changes) to atomography and magnetic resonance.

325

hite matter lesions are essentially ischemic in nature dueo the senile degeneration of the microcirculation.24---30

‘Abnormal’’ hyperintense punctate imagesn the white matter

hen the HPIWM is pathological, it may be indicative ofn acquired or inherited disease. Among the acquired dis-ases of the white matter, microvascular hypoxicoischemicisease is by far the most common, no matter whethertherothrombotic, embolic or caused by cerebrovascularisk factors (CVRFs). The acquired origin should be con-idered the first diagnostic option, even in the absence ofypical CVRFs, unless there are clinical and analytic evi-ence suggestive of a different aetiology. Multiple sclerosisMS) is the second most common disorder, with vasculitis,nfection, intoxication, and trauma (among other causes)railing far behind.31 A large number of patients with aery low vascular risk present with lesions of microvascularppearance for which there is relatively often no alternativer final diagnosis.

With respect to inherited disorders, leukodystrophiciseases are a group of rare diseases. Although theysually occur in the paediatric age, they can presentn adult age. They are metabolic diseases that usu-lly affect the white matter in a quite symmetric andxtensive (not punctate) manner, and usually damage therainstem and the cerebellum. An exception is mito-hondrial diseases, which cause more asymmetric lesions,nd normally affect the grey matter. In adults, theost common are metachromatic leukodystrophy, globoid

ell leukodystrophy, adrenomyeloneuropathy, mitochondrialisorders, vanishing white matter, and cerebrotendinousanthomatosis.31

asic pathophysiology

s the primary involvement of an arteriole or cere-ral venule, which compromises the blood supply ofhe parenchyma that depends on them, and induces a

2Incipient confluenceabnormal <75 years)

3Significant confluence

(never normal)

ssess punctate lesions in the white matter using computed


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

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athological process and the adjacent parenchymatous lesion. Dith multiple sclerosis.

esion. White matter microvascular disease encompasses wide range of conditions: hypoxia-ischemia, granuloma-ous or nongranulomatous inflammation, infection, diseaseaused by substance deposit, toxins, metabolic disease,raumatism, etc. Another possible pathophysiological mech-nism of leukoencephalopathy is cell infiltration oreposition of pathologic substances in the perivascularpace that can also manifest radiologically as focal lesionsn the white matter. They have a non-infectious inflamma-ory aetiology (as is the case of MS or other demyelinatingiseases, some types of vasculitis, and some granulomatousiseases), an atypical infectious aetiology (Lyme’s disease,ryptococcosis, parenchymatous cysticercosis), a metabolicetiology (mucopolysaccharidosis) or a traumatic aetiologydiffuse axonal injury). Both pathophysiological mechanismsay co-occur in one same disease.White matter disease can be approached by taking into

ccount the anatomy of cerebral microcirculation and itsnterstitium, specifically by determining the most affectedlements in the different leukoencephalopathic groups. Inhis respect, our goal is to get insights into the pathophysi-logy of the disease underlying the HPIWM by identifyinghe predominant semiological pattern. Three main pat-erns can be defined on the basis of several semiologicallements:

A vascular pattern (VP) or microvascular pattern, whichis usually caused by an arteriolar lesion, and is the mostprevalent (Fig. 6A).

A perivascular pattern (PvP), which is usually causedby perivascular inflammation, among other less commoncauses. The paradigm of this pattern is MS, for which anautoimmune perivenular inflammation has been reported
that causes demyelinization32 (Fig. 6B).
A non-specific pattern (NsP), when neither of the previouspatterns can be identified, and which is normally causedby microvascular disease.

itll

elinating layer caused by perivenular inflammation in a patient

emiological elements in hyperintense punctateesions in the white matter

or the radiologic approach of a case of HPIWM, theemiological elements to be analysed are distribution andocation, shape, size, enhancement after contrast admin-stration, presence of haemorrhage or microhaemorrhage,nd grey matter involvement. Description of each of theselements may help identify one of the three semiologicalatterns suggested, thus facilitating an adequate differen-ial diagnosis for each case.

istribution and locationPIWM may present with a predominantly supratentorial,

nfratentorial or supra- and infratentorial distribution. Ashall be shown below, the presence of lesions with an essen-ially supratentorial distribution generally suggests smallessel disease as a first option, which favours a VP (Fig. 7).his suggestion is further supported by a predominantlyrontoparietal distribution.

Supratentorial distribution concerns four large areas:ubcortical area, periventricular area, deep area, and cor-us callosum (Fig. 8).

A subcortical lesion can be located either in directontact with the cerebral cortex (juxtacortical) thus affect-ng subcortical U-fibres of the white matter, or can beocated inside these fibres, which would not be affected.n this latter case, the lesion is classified as sub-U subcor-ical. A sub-U subcortical lesion suggests a VP,33 whereas auxtacortical lesion is more suggestive of a PvP, which is typ-cally associated with MS (a PvP is present in one third of MSases).34

A lesion will be regarded as periventricular when it is
n contact or virtually in contact (closer than 1 cm)35 withhe ependymal surface. Both microvascular and perivascularesions can have a periventricular location, the shape of theesion being the key semiological element.


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TemporalOccipital

Central

Peripheral

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

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infratentorial involvement with peripheral distribution suggestsdistribution suggests a vascular pattern.

The deep region is located between the subcortical andperiventricular regions. The deep region is classified as bor-dering when located in a border zone between two vascularareas, which is indicative of a VP, or as non-bordering when
not clearly located in a border zone, which is indicative ofan NsP. The corpus callosum is a specific location as well,as in some other diseases, such as MS----typically in thecallosal-septal interface,34----in the Susac syndrome34,36,37
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Figure 8 Location: (1) juxtacortical; (2) sub-U subcortical; (3)(5) periventricular, and (6) corpus callosum. A predominantly juxtacoindicative of a vascular pattern (VP); the rest of locations favour a Vcause. Periventricular lesions may be indicative of a VP or a perivas

rivascular pattern. The infratentorial involvement with central

r in the cerebral autosomal dominant arteriopathy withubcortical infarcts and leukoencephalopathy (CADASIL),38

mong others.Infratentorial lesions can have a peripheral location, in

ontact with the surface of the parenchyma, or a centralocation, with no involvement of the surface. A centralesion is typically associated with a VP, whereas a peripheralesion is typically associated with a PvP34 (Fig. 7).

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5

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non-bordering deep subcortical; (4) bordering subcortical;rtical involvement or involvement of the corpus callosum is notP or a non-specific pattern, and thus, suggest a microvascular

cular pattern depending on the shape of the lesion.


Round, Punctate:Non-specific

Ovoid, Fusiform:PvP

Amorphous: Non-specific

ggest a perivascular pattern; the rest are non-specific.

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Not indicative of a vascular pattern


Figure 9 Morphology. Ovoid or fusiform lesions su

orphologyhere are several lesion types according to their shape:val or fusiform, punctate or roundish, and amorphousFig. 9). Punctate, roundish, and amorphous lesions are non-pecific, whereas oval or fusiform lesions usually have aistribution parallel to the cerebral microcirculation, andhus, they normally feature a PvP. Oval or fusiform periven-ricular lesions in a radial pattern and perpendicular to theongitudinal axis of the lateral ventricles are quite a com-on feature of MS. They are known as Dawson’s fingers,34

fter the neuropathologist James Dawson, who describednger-like venular and perivenular inflammatory cells in MSatients.39 Confluence of these lesions makes up a ridge-likeonfiguration, which is also associated with MS.34 CVRF-nduced microvascular periventricular leukoencephalopathyresents with typically more irregular borders.3,40

izeocalization of an isolated lesion (not several confluentesions) >10---15 mm in size is suggestive of a PvP (lacunarnfarctions are acknowledged to reach 15 mm).41 Smalleresions are non-specific, and can be indicative either of aicrovascular or a perivascular lesion (Fig. 10).

nhancement after contrast administrationlthough a non-specific finding, the absence of enhancementn leukoencephalopathic foci is suggestive of an inactivetage of the disease. In contrast, the active inflamma-ory stage of the disease usually involves an increase inermeability or absence of the blood---brain barrier andadolinium enhancement of the lesion. Punctate, peripheral
in complete or incomplete ring) or central (homogeneousr heterogeneous) contrast enhancement can be observed.nhancing patterns are generally a non-specific finding,xcept for peripheral incomplete ring-enhancement, which
Figure 10 Size. Lesions larger than 10---15 mm (not severalconfluent lesions) suggest a perivascular pattern (inflammation,infection).


Incomplete-ring enhancementtypical of MS

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

ed

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eral incomplete ring-enhancement favours a perivascular pattelesions showing typically associated incomplete ring-enhancem

has been reported as a finding typically associated withMS,34,36 and thus, suggestive of a PvP (Fig. 11).

When an image is suspicious of MS, the current diag-nostic criteria of the MAGNIMS (magnetic imaging in MS)42

group do not require gadolinium enhancement as part of thediagnosis for dissemination in space. However, one enhanc-ing lesion among non-enhancing lesions in the same MRI
study is enough to determine dissemination in time.
In the follow-up of the disease, many authors optfor contrast administration for the assessment of activeinflammation and response to treatment. The number of

H6op

Figure 12 Residual haemorrhage: (A) cortico-subcortical residuaganglia, brainstem, and cerebellum suggests AH, and (C) haemorrha

used by multiple sclerosis. Patient with multiple juxtacortical

nhancing lesions may also help predict the prognosis of theisease.34

aemorrhage or microhaemorrhaget MRI, images of microbleeding are associated with HPIWM

n at least 18% of the population over 60 years of age.
PIWM are present in over 95% of the population over5 years of age. These data provide further evidencef the mixed microvascular disease, which shares aathophysiological origin with white matter disease and
l haemorrhage suggests amyloid angiopathy; (B) in the basalge with a history of trauma suggests diffuse axonal injury.


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Figure 13 Grey matter involvement (basal ganglia). (A)lacunar porencephalic foci, which are likely associated withdilated Virchow---Robin spaces in a patient with uncontrolled AH.(B) Gelatinous cysts in the Virchow---Robin spaces of the lentic-ulostriated vasculature in a 30-year-old patient with AIDS, whofirstly presented with cryptococcosis.

Table 1 Semiological characteristics.

Vascular pattern- Not juxtacortical- Sub-U subcortical- Deep bordering- Periventricular irregular- Supra- > infratentorial- Supratentorial frontoparietal- Basal ganglia- No enhancement (if not acute) or mild enhancement

Perivascular pattern- Periventricular ovoid- Juxtacortical- Fusiform or ovoid- Dawson’s fingers- Supra- and infratentorial- Large lesions


30

icrobleeding.18 When a VP with foci of microbleedings observed in T2*, two pathologic entities are possible:rterial hypertension (AH) and amyloid angiopathy (AA).nvolvement of the deep region of the BG and infraten-orial involvement suggest hypertensive or arterioscleroticicroangiopathy, whereas a peripheral location in the cere-ral cortex or lobes of the bleeding is typically associatedith AA43 (Fig. 12).

Patients with vasculitis present with foci of cerebralleeding associated with white matter microvascular-likeesions and cortical ischemic lesions appearing at the onsetr secondary to infarct transformation.44

Another cause of HPIWM with residual bleeding is the dif-use axonal injury associated with a high-energy traumaticnjury. Residual foci of leukoencephalopathy with traces ofaemosiderin are detected at the grey matter-white matterorder, mainly located in the frontal lobe and typically inhe region of basal nuclei and in the splenium of the corpusallosum45 (Fig. 12).

rey matter involvementost HPIWM cases are associated with cortical lesions or

esions of the BG region.Co-presence of lesions in the cerebral cortex and multi-

le bright foci in the white matter is a non-specific finding.n patients with vasculitis-induced microvascular disease, its not uncommon to detect peripheral lesions with corti-al involvement, which usually represent areas of ischemicnfarction.44 However, they are not readily visualized in con-entional MRI sequences.34

GB involvement typically occurs in patients with hyper-ense or arteriosclerotic microangiopathy40 (Fig. 13), and isery rare in MS patients.34 In patients with acute dissem-nated encephalomielities (ADEM), who may present withesions indistinguishable from those of MS, the BG regionnd the spinal cord are usually affected.36,46 Diverse formsf vasculitis (systemic lupus erythematosus [SLE], Behcet’sisease, etc.) and neurosarcoidosis can affect the BG.44,47,48

mmunocompromised patients with cryptococcosis typicallyresent with gelatinous cysts in the perivascular space ofhe lenticulostriated and thalamic perforating arteriolesf the BG.49

ifferential diagnosis

he general features of each pattern can be defined byonsidering each of the semiological elements describedTable 1). An adequate differential diagnosis can be made bydentifying the predominant pattern and the specific aspectsf each case.

ascular pattern vascular pattern in microvascular hypoxic-ischemic dis-ase secondary to CVRFs (especially AH, dyslipidemia, andiabetes) is associated with a great number of lesionshat are normally identified in the majority of semiologi-
al findings described by this pattern. AH produces tracesf haemosiderin, which can be observed in T2*-weightedequences, particularly in the corpus striatum, thalami,erebellum, and brainstem (Fig. 14).
Non-specific pattern- Deep non-bordering- Amorphous, punctate, round


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

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the periventricular white matter; (B) involvement of the basal

subcortical U-fibres; (C) residual haemorrhage in the basal gang

As already mentioned, microvascular involvement in AAis associated with a VP, typically manifested as cortical fociof peripheral microhaemorrhage or areas of haemorrhage incerebral lobes18,50,51 (Fig. 15).

Studies with migraine patients have reportedmicrovascular-like HPIWM,52,53 predominantly frontalor located in the semioval centres54 (Fig. 16). A recentstudy with 780 participants confirms this association both inpatients with migraine headache and in patients presentingwith other headache disorders, especially tension-related headaches. Prevalence for tension-related andmigraine headaches was 34% and 32%, respectively,and both were much higher than prevalence for HPIWM inthe controls (7.4%).35 Migraine with aura has been shown
to have a stronger association with clinical or subclinicalischemic infarcts, particularly in the posterior circulationterritory (cerebellum, protuberance).54 Additionally, andirrespective of the headache type, the presence of cerebral
pc

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Figure 15 Vascular pattern: amyloid angiopathy. Significant chasupratentorial white matter with a vascular pattern (left). Gradienin the cortico-subcortical interface, predominantly posterior (arrowdetail of the mural arteriolar deposits of congophilic �-amyloid mat

ia and the subcortical white matter but no involvement of thebrainstem, and cerebellum.

bnormalities does not seem to be associated with cognitivempairment.35

Most blood vessels affected by vasculitis in the cen-ral nervous system present with HPIWM typical of a VP,ith a certain subcortical prevalence and associated withortical ischemic lesions and foci of intraparenchymatousleeding appearing at the onset or secondary to infarctransformation.44 Traces of peripheral microhaemorrhagean be found in the BG due to septic vasculitis50 andasculitis caused by vasoactive drugs, such as cocainend alkaloid derivatives, amphetamine, ephedrine andhenylpropanolamine44,50 (Fig. 17).

CADASIL integrates all features typical of VP associ-ted with bilateral temporal involvement of the anterior
oles, the external capsules, and the corpus callosum in theallosal-septal interface55---57 (Fig. 18).
In short, a leukoencephalopathy can be caused by HPIWMith VP if the patient presents with CVRFs. Otherwise, the

nges of microvascular disease in the fronto-parieto-occipitalt-echo sequences (centre) show punctate foci of hemosiderin), suggesting an underlying amyloid angiopathy. On the right,

ter.


Figure 16 Vascular pattern: migraine. In patients with migraine (generally with aura), it is common to find frontal punctatelesions 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 antibodies. She presented with punctate lesions in the supratentorial white matter with noi pastfi

dcde

PHfifi

itlho

F(a


nvolvement of the U-fibres (orange arrow) and some areas of andings suggested lupic vasculitis.

ifferential diagnosis focuses on other causes of microvas-ular abnormalities, such as AA, headache, toxic-metaboliciseases, some forms of vasculitis and CADASIL, among oth-rs.

erivascular patternPIWM with a perivascular pattern is suggestive of MS as therst diagnostic option. The most characteristic semiologicalndings are: juxtacortical and periventricular ovoid lesions

a

pn

igure 18 Vascular pattern: dominant autosomic cerebral arteCADASIL). 50-Year-old patient diagnosed with CADASIL with signsnd involvement of the anterior temporal poles (arrows).

cortico-subcortical temporoparietal infarct (red arrow). These

n the form of Dawson’s fingers, typically in contact withhe inferior aspect of the corpus callosum (callosal-septalesions) or adjacent to the anterior aspect of the temporalorn; peripheral infratentorial lesions adjacent to the floorf the fourth ventricle, in the middle cerebellar peduncles

34
nd in the brainstem (Fig. 19).If other clinical or analytic indications favour MS, the
atient is treated as having MS before the final diag-osis of dissemination in space and time, in consonance

riopathy with subcortical infarcts and leukoencephalopathy of microvascular disease in the supratentorial white matter


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

and

NLtd


son’s fingers (left and centre). Confluent lesions with a ridge-li(C) callosal-septal lesions; (D) peripheral infratentorial lesions;

with the MAGNIMS criteria.42 If the clinical setting isnot suggestive of MS, the differential diagnosis willinclude other diseases with a likely autoimmune aetiol-ogy, such as atypical MS, ADEM, SLE, Sjögren’s disease,
and sarcoidosis,47,48 infections such as Lyme’s disease58
and cryptococcosis,49 some forms of vasculitis, suchas Behcet’s disease,59 and metabolic diseases, such asmucopolysaccharidosis.6

dd

r

PvP

NsP

VP

VircNormal

• Not juxta

• U-subco

• Deep bo

• Perivent

• Supra- >

• Suprate

• Basal ga

• No enha

acute) or

enhancem

• Perivent

• Juxtaco

• Fusiform

(Dawson)

• Supra- a

• Large le

• Profundo nolimítrofe• Amorphous, punctate, round

HPIWM

Figure 20 Diagnostic algorithm of the hyperintense punctate imagcular pattern (PvP), and non-specific pattern (NsP). ARWMC: ARWMC srisk factors; AH: arterial hypertension; DLP: dyslipidemia; DM: diabetewith subcortical infarcts and leukoencephalopathy; MS: multiple scl

nfiguration in chronic MS and anterior temporal lesion (right);(E) peripheral incomplete ring-enhancement.

on-specific patterneukoencephalopathy can be caused by HPIWM with an NsP ifhe patient presents with CVRFs. Otherwise, the differentialiagnosis firstly focuses on causes of atypical microvascular
isease, and secondly, on uncommon causes of perivascularisease.
The summary chart in Fig. 20 suggests a diagnostic algo-ithm to be used in an HPIWM case. This algorithm may help

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

cortical

rtical

rdering

ricular irregular

infratentorial

ntorial FP

nglia

ncement (if not

mild

ent

ricular ovoid

rtical

or ovoid

nd infratentorial

sions

With CVRFs

Vasculitis, otherdemyelinatingdiseases, toxic-metabolic diseases, etc.

With typical CVRFs: AH, DLP,DM, etc.

With no typical CVRFs:atypical CVRFs (hyperhomocysteinemia,pro-thrombotic states); migraine; amyloidangiopathy; vasculitis; CADASIL, etc.

Typical MS: ovoid (Dawson);enhancement (typical incomplete ring);supra- / infra-; corpus callosum;infra-peripheral

Autoimmune disease:atypical multiple sclerosis;ADEM; other diseases (SLE,Sjögren’s syndrome, etc.)

Sarcoidosis

Vasculitis (Behçet)

Infections: Lyme,cryptococcosis, etc.

Mucopolysaccharidosis

es in the white matter (HPIWM), vascular pattern (VP), perivas-cale (age-related white matter changes); CVRFs: cardiovasculars mellitus; CADASIL: dominant autosomic cerebral arteriopathy

erosis.

3

mn

C

Tthcpadetmm

A

1

C

T

A

WtvDGsa

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2


34

ake an adequate differential diagnosis once the predomi-ant pattern has been identified.

onclusions

his study proposes a practical and simple diagnosticool on the basis of three main semiological patterns ofyperintense punctate images in the white matter: a vas-ular pattern, a perivascular pattern, and a non-specificattern. These patterns are established based on thenatomy of cerebral microcirculation. Identifying the pre-ominant semiological pattern enables to narrow down thetiological diagnosis. Most bright dots visualized at MRI ofhe brain have a vascular aetiology. MS is the most com-on cause of PvP. An NsP is more likely to be an atypicalanifestation of vascular aetiology.

uthorship

1. Responsible for the integrity of the study: SM.2. Conception of the study: SM, MC and DG.3. Design of the study: SM.4. Acquisition of data: SM.5. Analysis and interpretation of data: SM, MC, DG, JC and

SG.6. Statistical analysis: N/A.7. Bibliographic search: SM, MC and DG.8. Drafting of the manuscript: SM, MC and DG.9. Critical review with intellectually relevant contrib-

utions: SM, MC, DG, JC and SG.0. Approval of the final version: SM, MC, DG, JC and SG.

onflicts of interests

he author declares no conflicts of interests.

cknowledgements

e would like to thank Susana Boluda, neuropathologist athe Unit of Neuropathology of Bellvitge Hospital, for pro-iding the microphotographs of pathological correlation;olores Cocho, neurologist at the Unit of Neurology ofranollers Hospital, for providing the databases of repre-entative cases; and illustrator Txomin Medrano for thenatomy illustrations.

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