Cerebrovasc Dis 2002;13(suppl 2):2130

Imaging of White Matter Lesions

Frederik Barkhof a Philip Scheltens b
Departments of a Radiology and b Neurology, Vrije University Medical Centre, Amsterdam, The Netherlands

Key Words White matter lesions W Magnetic resonance imaging

Abstract Magnetic resonance imaging (MRI) is very sensitive for the detection of white matter lesions (WML), which occur even in normal ageing. Intrinsic WML should be separated from physiological changes in the ageing brain, such as periventricular caps and bands, and from dilated Virchow-Robin spaces. Genuine WML are best seen with T2-weighted sequences such as long TR dual-echo spinecho or FLAIR (fluid-attenuated inversion recovery); the latter has the advantage of easily separating WML from CSF-like lesions. Abnormal T2 signal in MRI is not specific, and can accompany any change in tissue composition. In the work-up of WML in small vessel disease, magnetic resonance angiography can be used to rule out (concomitant) large vessel disease, and diffusionweighted MRI to identify new ischaemic lesions (amidst pre-existing old WML). The differential diagnosis of WML includes hereditary leukodystrophies and acquired disorders. The leukodystrophies that can present in adult age include metachromatic leukodystrophy, globoid cell leukodystrophy, adrenomyeloneuropathy, mitochondrial disorders, vanishing white matter, and cerebrotendinous xanthomatosis. These metabolic disorders typically present with symmetrical abnormalities that can be very diffuse, often with involvement of brainstem and cerebellum. Only the mitochondrial disorders tend to be more asymmetric and frequently involve the grey matter

preferentially. Among the acquired white matter disorders, hypoxic-ischaemic causes are by far the most prevalent and without further clinical clues there is no need to even consider the next most common disorder, i.e. multiple sclerosis (MS). Among the nonischaemic disorders, MS is far more common than vasculitis, infection, intoxication and trauma. While vasculitis can mimic small vessel disease, MS has distinctive features with preferential involvement of the subcortical U-fibres, the corpus callosum, temporal lobes and the brainstem/cerebellum. Spinal cord lesions are very common in MS, but do not occur in normal ageing nor in small vessel disease.
Copyright 2002 S. Karger AG, Basel

Introduction

Soon after its introduction, magnetic resonance imaging (MRI) was found to be more sensitive than computed tomography (CT) in the detection of (white matter) lesions of the brain (fig. 1). Following initial enthusiasm about the new diagnostic possibilities, like in multiple sclerosis (MS) [1], it was reported that clinically silent (incidental) magnetic resonance (MR) lesions could also be found in normal ageing and a variety of other diseases [2]. During a period of scepticism about the apparent lack of specificity of MR in the diagnosis of brain lesions, the term UBO (unidentified bright object) was employed to describe incidentally discovered brain abnormalities. In the second half of the 1980s, further studies on white matter lesions (WML) in a variety of diseases increased our

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2002 S. Karger AG, Basel 10159770/02/01360021$18.50/0 Accessible online at: www.karger.com/journals/ced

Dr. Frederik Barkhof Departments of Radiology and Neurology Vrije University Medical Centre PO Box 7057, NL1007 MB Amsterdam (The Netherlands) Tel. +31 20 444 0365, Fax +31 20 444 0397, E-Mail f.barkhof@vumc.nl

Fig. 1. Comparison of CT (left) and MRI (right) for the detection of WML in a patient with MS. Note how difficult the hyperintense lesions on MRI can be seen on CT, even in retrospect.

signal of white matter was determined by the high lipid content of myelin (compared with high signal of subcutaneous fat on T1-weighted MR images). The protons of those lipids, however, are firmly bound, and have broad resonances with very short T2 relaxation times, and therefore cannot be appreciated in conventional imaging techniques [5]. The lipid protons of myelin only indirectly determine image contrast, as they facilitate the relaxation of water protons bound to the macromolecular matrix of myelin. The interaction between free water in the small compartments between the myelin lamellae, with a radial repeat distance between myelin lamellae of 150 nm, and water bound to the membrane macromolecules, facilitates relaxation and shortens T1 and T2 relaxation times, leading to high signal on T1 and low signal on T2 sequences [6]. Magnetization transfer imaging can only indirectly visualize the contribution of myelin.

knowledge about the prevalence of incidental MR lesions and risk factors for such lesions. Improved image quality, newer MR techniques (including gadolinium enhancement), and knowledge about the shape, size and distribution of incidental MR lesions have provided further clues to the differential diagnosis of (incidental) MR lesions.

MRI Technique for White Matter Pathology

Normal White Matter

This discussion will be restricted to normally myelinated adult white matter. The signal of unmyelinated white matter and the patterns of development of myelin are a complex and fascinating subject, but are beyond the scope of this review [3]. A key point in the process of normal myelination is the formation of myelin according to preset functional patterns, whereby the water content of white matter is reduced from approximately 90% at birth to around 70% in the adult brain. The macroscopic appearance of the medulla of the adult brain parenchyma is white due to the presence of large amounts of myelin. Histologically, myelin sheaths consist of bilayers of membranes, formed by oligodendrocytes. Chemically, the major constituents of myelin membranes are lipids (especially cholesterol, cerebrosides) and proteins (especially proteolipid protein and myelin basic protein) [4]. On T1-weighted sequences, e.g. inversion recovery (IR), or T1-weighted spin-echo (SE), white matter has high signal, while on T2-weighted sequences, signal of white matter is low. It was initially thought that the

The most commonly used technique to demonstrate WML is a SE sequence with a long TR and long TE, often referred to as T2-weighted SE. Use of a relatively short TR (e.g. ! 3,000 ms) saturates species with a very long TR such as CSF, which facilitates detection of WML near CSF spaces. Intermediately long TEs (e.g. 4060 ms) are used to optimize the T2 contrast between lesions and surrounding white matter (fig. 2). Recent developments include fast (or turbo) SE, which essentially is a SE sequence with after each excitation pulse several refocusing pulses producing multiple echoes per TR. Prior to each echo, a new phase-encoding gradient step is applied, thereby filling the K-space faster than with conventional SE (one phase-encoding step per TR). In fast SE the TE varies throughout the K-space, and is centred around what is called an effective TE. The image contrast of fast SE is slightly different, with typical high signal of fat and CSF. Most studies suggest that fast SE performs equally well as conventional SE in detecting WML [7]. The disadvantages of fast SE include insensitivity to susceptibility effects (e.g. blood-breakdown products, iron deposition and flow effects in vascular malformations) and high CSF signal, which interferes with detection of WML near CSF spaces. Gradient-echo (GE) sequences are sensitive to T2*, but due to the absence of a (180) refocusing pulse do not correct for field inhomogeneity. With regard to T2 abnormalities, they are inferior to SE sequences and should not be

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Fig. 2. Mildly T2-weighted (TE 30/TR 3,000 ms), also referred to as

Fig. 3. FLAIR images, obtained here in a patient with long-standing

proton-density images, are best suited to demonstrate WML. Using this sequence, WML not only have a higher signal than surrounding brain tissue, but also a higher signal than CSF.

arterial hypertension, have exquisite sensitivity for the detection of WML. Note the low signal of CSF, facilitating detection of small lacunes.

used to detect WML, but can be a useful adjunct in demonstrating susceptibility effects. For example, flow within a (vascular) lesions or deposition of iron or calcium will produce a strong susceptibility effect, which can be well appreciated on T2*-weighted sequences like GE. GE images are indispensable for the detection of microhaemorrhages in diffuse axonal injury. The contrast of GE sequences can be improved by applying an off-resonance presaturation pulse, producing magnetization transfer (MT) contrast. MT-prepared GE has a higher contrast between lesions and white matter [8]. The commonest form of pathology in hypoxic/ischaemic disease is mild perivascular demyelination, which will not significantly alter T1 contrast; in MS plaques, severe demyelination with gliosis occurs, leading to prolongation of T1 and occurrence of black holes. Only when frank infarction with cystic transformation occurs will hypoxic/ischaemic lesions become strongly hypointense on T1-weighted SE, but can then be differentiated from MS plaques, because they follow CSF signal on all sequences. A recently introduced technique is fluid-attenuated inversion recovery (FLAIR). This technique employs a very long inversion time to suppress CSF, which allows use of a long TE (100120 ms) without the disadvantage of producing high CSF signal. A combination with fast SE produces a relatively fast sequence (fast FLAIR) with the signal of WML being higher than white matter, grey matter and CSF [9]. The use of FLAIR is especially suited in

Fig. 4. Advanced MRI techniques include DWI (left) and MRA

(right). In this patient with right MCA infarction, the high signal on DWI indicates restricted Brownian movement due to cytotoxic oedema; the MRA shows occlusion of the right carotid, with poor filling of the MCA.

the elderly population, where grey-white matter contrast is reduced, resulting in a homogeneous low background signal, from which WML lesions clearly stand out. One of the great advantages of FLAIR is the clear separation of WML from Virchow-Robin spaces and lacunes, all of which can be bright on (heavily) T2-weighted images (fig. 3). Several advanced imaging techniques can provide additional information in the work-up of WML (fig. 4). MR

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Fig. 5. Value of DWI images in detecting new ischaemic lesions. In this hypertensive patient, several old WML (upper panel) can be seen on FLAIR (left) that have normal diffusion (right). The lesion in the brainstem, coinciding with new onset abducens paresis, shows restricted diffusion leading to high signal on DWI (lower panel). Note that without DWI, the FLAIR images would not have been able to separate the lesions in time.

angiography (MRA) uses flow of protons as an intrinsic contrast agent and can be used to assess the patency of the major cerebral vessels, and determine (coexisting) large vessel disease. With the advent of echo-planar imaging, diffusion-weighted imaging (DWI) can now be routinely acquired in a short period of time, and provides valuable information about restriction of proton mobility, e.g. in fresh infarction. DWI is especially well suited to differentiate new ischaemic WML from pre-existing older WML with increased diffusion (fig. 5).

Normal Ageing Phenomena

Surprisingly little is known about the histopathologic correlates of WML on MR. One should realize that the commonly used T2-weighted sequences are rather sensitive for WML: almost any change in tissue composition will prolong T2 and produce hyperintense signal. High sensitivity is warranted when demonstration of any lesion is important, e.g. to demonstrate dissemination in space in a young person suspected of MS. In the elderly, however, aspecific tissue changes related to normal ageing

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Fig. 6. Virchow-Robin spaces (seen in this case around the anterior

commissure) have signal intensity similar to CSF on all sequences (proton density and T2 upper panel; T1 and FLAIR lower panel).

Fig. 7. Etat cribl in a patient with arterial hypertension. Note that on the heavily T2-weighted images (upper panel), both WML and lacunes have high signal, while on FLAIR (lower panel), WML are bright and lacunes are dark.

produce WML on T2-weighted MR images indistinguishable from clinically more relevant brain lesions. Areas of very mild oedema or demyelination increase T2 signal to the same degree as severely demyelinated lesions would; increased signal on T2-weighted images is aspecific per se. The normally present Virchow-Robin or perivascular CSF spaces frequently become dilated in normal ageing (and in certain very rare perivascular diseases such as mucopolysaccharoidosis type IV). Since dilated VirchowRobin spaces contain CSF they produce high signal on T2-weighted images. Virchow-Robin spaces can be recognized by their signal, which is isointense to CSF on all sequences and by their location (fig. 6). Use of a sequence

such as long TR SE with moderately long TR (! 3,000 ms) and moderately long TE (! 60 ms) will produce a CSF signal lower than brain and WML, while more heavily T2weighted techniques produce very high CSF signal. Virchow-Robin spaces are easily recognized on T1-weighted and FLAIR images by their very low CSF signal and are found in typical locations: at the base of the brain and at the vertex. At the base of the brain they are located around perforating lenticulostriate arteries and can be seen on transverse MR images especially around the anterior commissure; they should not be confused with lacunar infarcts [10]. At the vertex they are located around medullary arteries and veins. In extreme cases of dilatation the condition is sometimes refered to as tat cribl

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Fig. 8. In metachromatic leukodystrophy, white matter involvement

is seen with characteristic early involvement of the corpus callosum. In addition to the location of the lesions, the strict symmetry should prompt the diagnosis of this metabolic disorder.

the basis of a vasculopathy. As a rule of thumb, this will probably be true, given the high a priori chance. In addition, however, several MRI features may reinforce this notion, such as the presence of cortical infarcts, borderzone/watershed lesions, lacunes and multifocal basal ganglia lesions. Absence of gadolinium enhancement is an additional indicator of a hypoxic/ischaemic genesis. However, only rarely can a clue be given leading to a more specific diagnosis within the group of hypoxic/ischaemic disorders. Such clues include haemorrhage (amyloid angiopathy), cortical/subcortical lesions crossing vascular territories (mitochondrial diseases), increased CSF pulsations evidenced by increased CSF flow voids (normal pressure hydrocephalus), significant asymmetry of the WML (ipsilateral carotid disease), or involvement of the external capsule and temporal poles (CADASIL).

Pattern Recognition in Leukodystrophies

(fig. 7), and can be hard to distinguish from lacunar infarcts [11]. Although Virchow-Robin spaces have to be differentiated from WML and lacunes, strictu sensu they are associated with the same risk factors like hypertension, age, dementia, and are often found in association with incidental WML [12]. Another feature or normal ageing is the presence of periventricular high signal areas called bands and caps on T2-weighted MRI [13]. Histopathologically, those lesions are caused by loss of ependymal lining and mild subependymal glia accumulation [14, 15]. Although extensive perivascular signal abnormalities are associated with risk factors and should be differentiated from other entities, such as normal pressure hydrocephalus, small caps and pencil-like bands are probably a normal ageing phenomenon, and should not be interpreted as abnormal [13].

In contrast to the discontinuous nonsymmetrical distribution of WML in subcortical small vessel disease/ dementia, most leukodystrophies will present with a more or less symmetrical abnormality (except certain mitochondrial disorders) or be very diffuse (e.g. vanishing white matter [16]). Involvement of the brainstem and cerebellum occurs very frequently, with selective, symmetrical involvement of white matter tracts or nuclei suggesting a metabolic rather than an acquired cause. Several diseases will preferentially involve the corticospinal tracts (e.g. Krabbes disease [17]) or the cerebellum (cerebrotendinous xanthomatosis [18]), a pattern that is not found in ischaemia where the infratentorial regions are relatively spared. Other disorders may involve the supratentorial white matter in a pattern that is very unusual for ischaemia, such as extensive involvement of the corpus callosum in metachromatic leukodystrophy (fig. 8), or symmetric involvement of occipital lobes in adrenomyeloneuropathy.

Differentiating Small Vessel Ischaemic WML from Other Leukencephalopathies

In order to appreciate the appropriateness of the diagnosis of subcortical small vessel disease and other hypoxic-ischaemic vasculopathies, we need to have sufficient clinical data: neurological and psychiatric history, medical history, medication, surgical procedures and family history. In the absence of any clue in the clinical data, many WML are classified by radiologists as vascular, implying a presumed hypoxic-ischaemic pathogenesis on

Differentiating Ischaemic WML from Other Acquired Disorders

The list of differential diagnoses in WML in table 1 is long and probably incomplete. In a younger age group (! 50 years of age), the prevalence of MS is relatively high. Even in this age group, however, diagnostic MR criteria for MS are not very specific. Paty et al. [19] classify an MR scan as highly suggestive of MS when 4 or more

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Table 1. Differential diagnosis of acquired

WML on MRI

Hypoxic/ischaemic Hereditary Lipid metabolism: Familial hyperlipidaemia, cerebrotendinous xanthomatosis, angiokeratoma corporis diffusum (Fabrys disease) Amino acid metabolism: Phenylketonuria (PKU), hyperhomocystinaemia Mitochondrial: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), Kearns-Sayre syndrome Amyloid deposition: Cystatin C amyloid angiopathy (Icelandic), cerebral haemorrhage with amyloidosis (Dutch) Unknown: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL), moya-moya, Rendu-Osler-Weber, Neuman progressive subcortical sclerosis, antiphospholipid antibody syndrome Acquired Hypertension: Macroangiopathy, microangiopathy Hypotension: Borderzone infarcts, Binswangers disease Atherosclerosis: Idiopathic, diabetes mellitus (DM) Unknown origin: Alzheimers disease, major depression, normal pressure hydrocephalus, (familial) migraine Embolic: Cardiac, atheromatous, perioperative Wallerian degeneration Inflammatory Multiple sclerosis and variants Charcot type, Marburg type, Balos concentric sclerosis, diffuse sclerosis (m. Schilder), neuromyelitis optica (m. Devic) Peripheral inflammatory demyelinating diseases Fishers syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) Vasculitis Lupus erythematodes, Behets disease, giant cell arteritis, Sjgrens disease, polyarteritis nodosa Sarcoid Inflammatory bowel disease Infectious Protozoal Fungal Spirochetal Syphilis, neuroborreliosis (Lymes disease) Bacterial Viral Herpes simplex, HIV, progressive multifocal leukencephalopathy (PML), HTLV-1 (TSP) Postinfectious Acute demyelinating encephalomyelopathy (ADEM), subacute sclerosing postinfectious encephalitis (SSPE) Toxic-metabolic Central pontine myelinolysis (CPM), carbon monoxide (CO) intoxication, methotrexate (MTX) treatment, Marchiafavi-Bignami, funicular myelinolysis (B12 deficiency) Traumatic Radiation, contusion Unknown Erdheim-Chester disease, systemic histiocytosis

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Fig. 9. In MS, brain images (upper panel) show typical ovoid lesions around the ventricle, in the corpus callosum, and the infratentorial region. Spinal cord images show multiple demyelinating lesions on both proton-density (left) and heavily T2-weighted (right) images.

lesions are present, or 3, one of which is located around the ventricles. Fazekas et al. [20] have developed criteria that are probably more specific (combination of infratentorial, periventricular and large (1 6 mm) lesions). In the criteria of Barkhof et al. [21] additional features include the presence of a juxtacortical lesion and gadoliniumenhancing lesions (fig. 9). In MS, virtually every lesion goes through an acute inflammatory phase with gadolinium enhancement. By contrast, chronic ischaemia evolves slowly and will therefore not exhibit a phase of enhancement. Gadolinium enhancement will most likely be present however, in those rare hypoxic/ischaemic diseases that have stroke-like features, such as MELAS (mitochondrial encephalomyopathy, lactate acidosis and stroke-like episodes), amyloid angiopathy and CADASIL.

There are numerous additional features of MS lesions that will alert the expert reader. Since MS lesions are located around venules [22], their shape is characteristically not round but oval and the majority are found around the lateral ventricles and in the corpus callosum. It is commonly believed that lesions in the corpus callosum do not occur as frequently in hypoxic/ischaemic diseases [23], due to the unique double blood supply to the corpus callosum; however, this is not universally true (fig. 10). Other features typical for MS are the presence of lesions in the temporal and occipital lobes. Lesions in the basal ganglia are relatively less common, and are never cystic (as in lacunes). In contrast to the perivenular distribution of MS, hypoxic/ischaemic diseases may be dominated by arterial anatomy. Lesions involving vascular territories can either be cortical infarcts, basal ganglia lesions (including lacunar infarcts), or watershed/borderzone abnormalities. Diseases associated with macroangiopathy typically produce cortical infarcts, while microangiopathy and thromboembolic disease are more likely to produce basal ganglia or deep white matter abnormalities. CADASIL is characterized by lesions in the external capsule and temporal pole [24]. Chronic ischaemia can produce watershed and borderzone lesions in addition to typical subcortical WML. As a rule of thumb, the direct subcortical zones, containing the corticocortical association or U-fibres, are spared in hypoxia, since they receive blood from both the cortical branches and the medullary arteries. By contrast, MS lesions are frequently seen at the corticomedullary junction. A developing, but very interesting field in this respect is spinal cord imaging. Using phased-array coils, the whole cord can now be imaged with high resolution, revealing abnormalities in 8090% of MS patients, often without accompanying neurological symptoms or signs. By contrast, patients with hypoxic-ischaemic disease do not show cord abnormalities (fig. 11). Furthermore, incidental WML do not occur with ageing, a finding that is in sharp contrast to brain MRI. The prevalence of cord abnormalities in other inflammatory disorders is probably lower than in MS; especially in those patients without spinal cord symptoms, cord abnormalities do not seem to occur. The finding of asymptomatic cord lesions therefore is highly suggestive of MS [25]. The CNS abnormalities seen in vasculitis and related disorders may be extremely difficult to differentiate from hypoxic-ischaemic vasculopathies, especially those disorders that affect the small vessels. Both tend to affect the basal ganglia in a patchy way, sometimes with cystic

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Fig. 10. In contrast to MS, the corpus callosum is usually spared in hypoxic-ischaemic WML (upper panel). In some

cases of severe subcortical arteriosclerotic encephalopathy however, quite extensive lesions in the corpus callosum can be seen, including lacunar infarcts (lower panel).

Fig. 11. Proton-density (left) and heavily T2-weighted (right) spinal cord images obtained with a phased-array coil, using cardiac gating and 3 mm slice thickness. In normal ageing, incidental lesions are not found in the cord (in contrast to the brain). In patients with hypertension and hypoxicischaemic WML, the spinal cord is completely normal (same patient as in figure 2). By contrast, MS patients show spinal cord lesions in over 80% of cases.

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transformation. Cortical lesions can occur in both, and since both are caused by ischaemia, recent lesions can be demonstrated using DWI. In vasculitis, these cortical infarctions are more likely to be multiple, and the brainstem and cerebellum are more frequently involved. MR

angiography may be normal in both. Probably most useful is the application of an intravenous contrast agent, showing leptomeningeal enhancement in vasculitis, which in granulomatous disorders, like sarcoid, can be extremely extensive and extend into the Virchow-Robin spaces.

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