Normal, myelinated white matter has a low signal on proton density, T2-weighted and FLAIR images, whereas the signal is high on T1-weighted images (figure 235.1-1). CSF has a high signal on T2-weighted images and a low signal on proton density, FLAIR and T1-weighted images (figure 235.1-1). Abnormal white matter has a high signal on proton density, T2-weighted and FLAIR images and a low signal on T1-weighted images (figure 235.1-2). Cystic white matter has the signal behavior of CSF, different from abnormal white matter on proton density and FLAIR images (figure 235.1-2).
Normal axial T2-weighted (a) and FLAIR (b), and sagittal T1-weighted (c) images of a 3-year-old child. On T2-weighted (a) and FLAIR (b) images, cortex, basal ganglia and thalami are gray; myelinated white matter structures are dark-gray. CSF is white on T2-weighted images and black on FLAIR images. On T1-weighted images (c), cortex is gray, myelinated white matter is white and CSF is black.
MR images of a 2-year-old patient with VWM. The axial T2-weighted images (a, b) show the diffuse abnormality of the cerebral white matter (a). The globus pallidus (a), cerebellar white matter (b), middle cerebellar peduncles (b), central tegmental tracts in the pontine tegmentum (b) and pyramidal tracts in the basis of the pons (b) also have an abnormal signal. The axial FLAIR images (c, d) show that all cerebral white matter is abnormal, part having a high signal and part a low signal, similar to CSF, indicative of cystic degeneration. Within the rarefied and cystic white matter, dots and stripes are seen, indicative of remaining tissue strands (c, d). The sagittal T1-weighted image (e) shows a pattern of radiating stripes within the abnormal white matter, representing the remaining tissue strands. Axial diffusion-weighted images (f) show a high signal, suggestive of restricted diffusion, in the directly subcortical white matter, corpus callosum and internal capsule. The remainder of the white matter has a low signal, suggesting increased diffusion (f). The ADC map (g) confirms the decreased diffusion in the areas mentioned with low ADC values (40-60), and increased diffusion in the remainder of the white matter with high ADC values (160-220). NB Normal myelinated white matter has ADC values of approximately 70–90 × 10−5 mm2/sec.
MRI of the brain is usually diagnostic in the classical variant of VWM. It shows a diffuse signal abnormality of the cerebral white matter (figure 235.1-2).11,12,28 The abnormal white matter has a high signal on T2-weighted images and a low signal on T1-weighted images. Proton density and FLAIR images, however, reveal that part of the white matter has a high signal, whereas part of the white matter has an intermediate to low signal, which is the signal behavior of rarefied or cystic white matter (figure 235.1-2).11,12,28 T1-weighted, FLAIR and PD images often show a radiating, stripe-like pattern within the rarefied and cystic white matter, suggesting the presence of better preserved tissue strands (figure 235.1-2).11,12,28 The cystic areas usually do not have well-delineated borders.
The inner rim of the corpus callosum is typically affected (figure 235.1-3).11,12,28 The U-fibers, the outer rim of the corpus callosum, the internal capsule and anterior commissure are typically, but not invariably spared (figure 235.1-4).11,12,28 The cerebellar white matter is often also mildly abnormal in signal, but without evidence of swelling, white matter rarefaction and cystic degeneration (figure 235.1-2).11,12,28 The cerebral and cerebellar cortices have a normal appearance. Especially during episodes of rapid neurological deterioration signal abnormalities may be observed in the thalami, basal ganglia and brain stem (figure 235.1-2) and these may revert during the period of clinical recovery12, unlike the cerebral and cerebellar white matter abnormalities. The globus pallidus may have a low signal intensity on T2 and T2*-weighted images, suggesting mineralization.12 The central tegmental tracts in the pons (figure 235.1-2) have been reported as particularly involved in VWM11,12, but it has been recognized that this is a nonspecific finding, observed in other conditions as well.
The axial FLAIR image of a 15-year-old boy with recent onset disease (a) shows extensive cerebral white matter abnormalities, sparing the subcortical white matter. The inner rim of the corpus callosum is affected whereas the outer rim is better preserved. There is no evidence of white matter rarefaction. The axial FLAIR image of a 46-year-old woman (b), who has been symptomatic for approximately 10 years, shows the same with additional white matter atrophy. The axial FLAIR image of a 42-year-old man (c), who has been symptomatic for 18 years, shows the same picture as the previous patient, with additional cystic degeneration of the cerebral white matter. The cerebral white matter atrophy is more severe. In contrast, the axial FLAIR image of a 37-year-old woman (d), who has been symptomatic for 2 years, shows the classical picture, comparable to figures 2c and 2d.
The axial T1-weighted image of a 6-year-old patient demonstrates the relative sparing of the U-fibers, corpus callusom and internal capsule.
MRI shows that over time the cystic degeneration of the cerebral white matter is progressive. In the end-stage, all white matter substance has disappeared between ependymal lining and cortex; only a fluid-filled space remains (figure 235.1-5).11,12,28 It is not clear why the cerebral cortex does not collapse over the central structures, because there seems no white matter substance to support it, but the absent white matter may even look swollen with broadening of gyri (figure 235.1-5).11,12,28 Some patients with rapidly progressive total cerebral white matter degeneration demonstrate signs of increased intracranial pressure with progressive macrocephaly.33,34 Over time, atrophy of the cerebellum and brain stem ensues.11,12,28
The axial T2-weighted image of a 12-year-old boy (a) shows that all cerebral white matter is abnormal. The matching FLAIR image (b) shows that almost all cerebral white matter has disappeared. Surprisingly the absent white matter looks swollen with stretching of the overlying cortex in broad gyri.
Contrast enhancement has not been observed.28 On diffusion-weighted images, the rarefied and cystic white matter demonstrates an increased diffusivity.45 Evidence of restricted diffusion may be present within the non-rarefied white matter, mainly in the U-fibers, corpus callosum and internal capsule (figure 235.1-2).
Several presymptomatic and mildly symptomatic individuals underwent MRI, which has thus far always revealed cerebral white matter abnormalities, although initially not necessarily with evidence of rarefaction or cystic degeneration.11,37
The white matter cystic degeneration is usually less complete in teenagers and adults with VWM (figure 235.1-3).29,37,41 In some of the patients with later onset, the MRI features are similar to those seen in patients with the classical variant of VWM29,37,38,41, whereas in others the cerebral white matter contains signal abnormalities, but is not rarefied or cystic, not even in the end stage (figure 235.1-3).29,37,41 Atrophy of the cerebral white matter is often present (figure 235.1-3).29,37,41 The resulting MRI picture is nonspecific, showing homogeneous or more patchy cerebral white matter abnormalities and atrophy with widening of the lateral ventricles and subarachnoid spaces.
The MRI picture is more difficult to interpret in antenatal onset VWM.16 In neonates the brain may only look immature (figure 235.1-6).16,42 The gyral pattern is too coarse for the gestational age of the child; the immature white matter has a high water content and little myelin, but shows little or no rarefaction. A striking finding is that the anterior temporal white matter is frequently swollen and may contain a cyst.16 Over time, the cerebral white matter may become increasingly abnormal, rarefied and cystic, as seen in the later-onset variants of the disease16, but the cerebral white matter may also become highly atrophic, the ependymal lining touching the depth of the gyri, unlike what is seen in the later onset variants of the disease (figure 235.1-6).16,42
Axial T2-weighted images of a VWM patient, obtained at 6 days (a) and 5 months (b). The initial MRI (a) shows broadening of gyri and a mildly swollen aspect of the cerebral white matter. Its signal intensity is normal for unmyelinated white matter. The follow-up MRI (b) shows an impressive atrophy of the cerebral white matter with highly dilated lateral ventricles. What remains of the white matter has too high a signal intensity, even for unmyelinated white matter.
Reproduced from Boltshauser E, Barth PG, Troost D, Martin E, Stallmach T. “Vanishing white matter” and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype. Neuropediatrics 33: 57, 2002; from Van der Knaap MS, van Berkel CGM, Herms J, et al. eIF2B Related Disorders: Antenatal Onset and Involvement of Multiple Organs. Am J Hum Genet 73: 1199, 2003; and from Van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol 5: 413, 2006.
In early infantile onset VWM, the MRI pattern is similar, but more severe than in the patients with the classical phenotype.16,46 The cerebral white matter is diffusely abnormal, has a swollen appearance and undergoes rapid cystic degeneration. In Cree encephalopathy, signal abnormalities of the globus pallidus, thalamus and large parts of the brain stem are typically present in addition to the diffuse cerebral white matter abnormalities.47
MRI criteria allow an MRI-based diagnosis of VWM in patients with a typical MRI.28 These criteria are not suitable for identifying unusual MRI variants, which are mainly seen in patients with neonatal, early infantile or adult VWM, and in the earliest stages of the disease at any age.
MRI Criteria for the Diagnosis VWM28
The cerebral white matter exhibits either diffuse or extensive signal abnormalities; only the immediately subcortical white matter may be spared.
Part or all of the abnormal white matter has a signal intensity close to or the same as CSF on proton density or FLAIR images, suggestive of white matter rarefaction or cystic destruction.
If proton density and FLAIR images suggest that all cerebral white matter has disappeared, there is a fluid-filled distance between ependymal lining and the cortex, but not a total collapse of the white matter.
The disappearance of the cerebral white matter occurs in a diffuse “melting away” pattern.
The temporal lobes are relatively spared, in the extent of the abnormal signal, degree of cystic destruction, or both.
The cerebellar white matter may be abnormal, but does not contain cysts.
There is no contrast enhancement.
Within the abnormal white matter there is a pattern of radiating stripes on sagittal and coronal T1-weighted or FLAIR images; on axial images, dots and stripes are seen within the abnormal white matter as cross-sections of the stripes.
Lesions within the central tegmental tracts in the pontine tegmentum.
Involvement of the inner rim of the corpus callosum, whereas the outer rim is spared.
Proton Magnetic Resonance Spectroscopy
Proton MRS shows stage-dependent abnormalities.8–12,48 In the initial stages, when there is little white matter rarefaction, the white matter spectrum is relatively preserved. With ongoing rarefaction and cystic degeneration, the signals decrease and eventually disappear altogether. Choline is relatively less decreased than other metabolites in the initial stages, suggesting enhanced membrane turnover.48 In the end stage, the spectrum is similar to that of CSF with some lactate and glucose and no or minor “normal” signals.8–12,48 This spectrum is not diagnostic for VWM in that it may be seen in any cystic white matter disease. The cortical spectrum remains well-preserved throughout the disease course.
A study on phosphorus MRS of the cerebral white matter revealed that of the metabolites involved in the biosynthesis and catabolism of membrane phospholipids, glycerophosphoethanolamine was reduced and phosphorylethanolamine was increased, whereas choline-containing phosphorylated metabolites were unchanged.49 It is difficult to interpret these findings, primarily because the composition of the remaining brain tissue in VWM is dramatically changed due to serious rarefaction and altered ratios of composing cells.