65.1 Clinical Features
and Laboratory Investigations Leukoencephalopathy with vanishing white matter (VWM) has also been called childhood ataxia with central nervous system hypomyelination (CACH) and myelinopathia periaxialis diffusa.“Cree leukoen- cephalopathy” and “ovarioleukodystrophy” have both been found to be variants of VWM.
VWM is a disease with an autosomal recessive mode of inheritance. It has been shown to be one of the more prevalent leukoencephalopathies in chil- dren. Its incidence is similar to that of metachromat- ic leukodystrophy. The classical and most frequent variant has its onset in childhood, most often between the ages of 2 and 6 years. The disease is characterized by chronic progressive neurological deterioration with cerebellar ataxia, usually less prominent spastic- ity, and relatively mild mental decline. Optic atrophy with loss of vision may occur, but not in all patients.
Epilepsy is present in most patients, but is rarely a prominent feature. Characteristically, there are addi- tional episodes of major and rapid deterioration fol- lowing minor head trauma and especially febrile in- fections. Occasionally, these episodes are provoked by fright. During these episodes, patients rapidly lose motor faculties and become very hypotonic. Irritabil- ity, vomiting, and seizures usually progress to somno- lence and loss of consciousness. These episodes may end in coma. Death usually follows an episode of coma. If recovery occurs, it is usually incomplete.
Some patients have a more severe variant of the disease with onset within the first year of life and ear- ly demise. An example is found in so-called “Cree leukoencephalopathy,” a disease that was described among the Cree Indians. The onset of Cree leukoen- cephalopathy is between the ages of 3 and 9 months, and death occurs before the age of 2 years. Some (non-Cree) patients have an even more severe pheno- type with antenatal onset. In the third trimester of pregnancy, decreased fetal movements, oligohydram- nios, growth failure, and development of micro- cephaly occur. At birth, contractures may be seen.
From birth onwards or from soon after birth, there are increasing problems, with a rapid downhill course characterized by feeding problems, vomiting, failure to thrive, irritability, apathy, axial hypotonia, limb hypertonia or hypotonia, seizures, apneic episodes, coma, respiratory failure, and death within a few
months. In these infants evidence may be found of involvement of other organs, including cataract (oil droplet cataract), hepatosplenomegaly, kidney hy- poplasia, pancreas involvement, and ovarian dysgen- esis.
At the other end of the clinical spectrum are pa- tients who are completely normal until onset of the disease in adulthood. In some patients occasional seizures are the first sign of the disease. In other pa- tients, the disease starts with psychiatric symptoms.
Some patients slowly develop dementia. In other pa- tients motor deterioration dominates the clinical pic- ture. The episodes of major deterioration are usually less marked in patients with a later onset. Later onset most often implies a slower and more protracted dis- ease course, although unexpected rapid progression and death within a few months may also occur. In adult females with the disease, primary or secondary ovarian failure may occur.
Laboratory tests are unrevealing in VWM. The on- ly consistent abnormality ever demonstrated is mod- erately elevated CSF glycine. The CSF:serum glycine ratio is also elevated and may even be higher than 0.08. A ratio higher than 0.08 is thought to be indica- tive of nonketotic hyperglycinemia. It is not known whether CSF glycine is elevated in all patients with VWM and whether a normal level excludes the diagnosis. The glycine elevation is probably a non- specific finding related to ongoing excitatory brain damage. DNA testing is available for diagnostic con- firmation, carrier testing, and prenatal diagnosis.
65.2 Pathology
In VWM, the brain is generally of normal size and weight, but in a few cases it is slightly heavier or lighter than normal. The gyri are usually normal or atrophic. When the brain is removed from the skull, the rarefied and cystic white matter usually collapses.
On macroscopic examination, gray matter structures appear unaffected. The lesions are found primarily in cerebral white matter, with the cerebellum and brain stem much less severely involved. The cerebral white matter varies from gelatinous to cystic to frankly cavitary. The frontoparietal white matter, particularly deep and periventricular, appears to be more com- monly involved, with relative sparing of the temporal lobe. White matter areas that are characteristically
Leukoencephalopathy with Vanishing White Matter
Chapter 65
relatively spared include the optic system, corpus cal- losum, anterior commissure, and internal capsule.
The subcortical arcuate fibers also tend to be spared, but not consistently. In the brain stem the central tegmental tract at the level of the pons is often in- volved in a bilateral and symmetrical distribution.
Microscopically, the grossly affected white matter shows myelin pallor, thin myelin sheaths, vacuolation, myelin loss, cystic change, and rarely active demyeli- nation. Lipophages containing myelin breakdown products are rare. There is no significant inflammato- ry response (lymphocytes, plasma cells, neutrophils, eosinophils). The gray matter is generally spared or greatly preserved in comparison to white matter.
However, astrocytosis and microgliosis of the overly- ing cortex may be found. Subtle mineralization of the basal ganglia has been observed. While axonal loss is complete in areas of cavitation, the less involved areas demonstrate a more variable loss of axons. Some- times the axonal loss is as severe as the myelin loss, but in other cases or areas axons are relatively spared.
Myelin sheaths are abnormal and vary from pale to thin to vacuolated. Vacuolated myelin is noted in pre- served areas, often near the cystic to cavitated lesions.
The vacuoles are bordered by material staining posi- tive with Luxol fast blue or with myelin basic protein, suggesting that these vacuoles reflect intramyelinic edema. Ultrastructural studies have revealed some myelin vacuoles suggestive of intramyelinic edema.
However, a re-evaluation of the vacuolated white mat- ter following the recognition of “foamy” oligodendro- cytes has raised questions about how much vacuola- tion of white matter is related to intramyelinic edema and how much is due to the presence of these vacuo- lated oligodendrocytes. The radiating stripes within the rarefied white matter, seen on MRI, seem to corre- late with blood vessels accompanied by reactive as- trocytes.
Different types of glia are involved in the disease process. In and around the areas that are cavitated, oligodendrocytes demonstrate marked losses, al- though they are still relatively high in number as compared to other types of cells. In areas that are bet- ter preserved an increase in apparently mature oligo- dendrocytes is seen, most consistently in the arcuate fibers, other regions bordering the cystic to cavitated lesions, anterior commissure, the internal capsule, and the corpus callosum. Oligodendrocytes may have an abnormal appearance and look vacuolated or
“foamy.” At the ultrastructural level the vacuoles are membranous structures associated with mitochondr- ial membranes, and, in places, contiguous with myelin lamellae. These oligodendrocytes also combine many mitochondria, proteolipid protein mRNA, and finger- print structures – the latter two attributes also noted in nonvacuolated oligodendrocytes. Positive staining for both proliferative markers (Ki-67), antiapoptotic
markers (bcl2, survivin), and proapoptotic markers (bac, bax, TUNEL, and activated caspase-3) has been found in oligodendrocytes. There is a trend that in early-onset devastating encephalopathy, loss of oligo- dendrocytes dominates with enhanced staining for apoptosis markers, whereas in older patients with longstanding disease, proliferation of oligodendro- cytes dominates with striking increases in their num- bers. There is a meager to moderate response by as- trocytes and microglial cells in this disease, even in areas near the cavitation. Only scant lipophages are seen, and the astrocytes appear to be dysmorphic with blunt, broad processes rather than their typical delicate arborizations.
65.3 Pathogenetic Considerations
VWM is related to defects in translation initiation factor eIF2B. eIF2B consists of five nonidentical sub- units (eIF2Ba, eIF2Bb, eIF2Bg, eIF2Bd, and eIF2Be), all of which are encoded by different genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively) located on different chromosomes (12q24.3, 14q24, 1p34.1, 2p23.3, and 3q27, respectively). Mutations in any of these genes can independently cause the dis- ease.
Translation of mRNA into polypeptides is one of the major energy-consuming processes in the cell and is therefore, not surprisingly, a tightly regulated process. The initiation phase, in which ribosomes are assembled on mRNA, is controlled via several differ- ent signaling pathways. Multiple so-called eukaryotic initiation factors (eIFs) are involved in translation initiation, and among them the guanine nucleotide exchange factor eIF2B plays a key regulatory role. A crucial step in translation initiation is the delivery by eIF2 of the initiator methionyl-transfer RNA (Met- tRNA
i) to the small ribosomal subunit. Upon recogni- tion of the start codon and binding of methionine to it, the eIF2-bound guanosine triphosphate (GTP) is hydrolyzed and eIF2 is released in its inactive guano- sine diphosphate (GDP)-bound form. In order to bind another Met-tRNA
iand initiate the production of another protein, active eIF2 must be regenerated by exchange of GDP for GTP. This step is catalyzed by eIF2B. The exchange of GDP for GTP by eIF2B is re- quired for each round of translation initiation. Thus, eIF2B is necessary for the production of all proteins in the body. Regulation of this step can control global rates of protein synthesis under diverse conditions.
Protein synthesis is markedly inhibited under a
variety of stress conditions and in the recovery phase
that follows. This response is part of a protective
mechanism of cells elicited by various stimuli, includ-
ing thermal, chemical, oxidative, or physical trauma,
called the cellular stress response or heat shock re-
sponse. Stress may lead to misfolding and denatura- tion of proteins, contributing to cell dysfunction and death. The inhibition of normal RNA translation dur- ing stress is thought to enhance cell survival by limit- ing the accumulation of denatured proteins and sav- ing cellular energy.
Inhibition of mRNA translation can be achieved through the modification of several initiation factors.
Most stress conditions, including heat stress, lead to activation of specific kinases that phosphorylate eIF2 on its a-subunit. In this phosphorylated form, eIF2 binds tightly with eIF2B and in this way is a competi- tive inhibitor of eIF2B, preventing the recycling of eIF2. The concentration of eIF2 usually exceeds that of eIF2B. Therefore, even modest levels of eIF2a phosphorylation can potentially lead to complete in- hibition of translation initiation and protein synthe- sis. In certain cell types, inactivation of eIF2B at 40–41 °C can be achieved without changes in eIF2a phosphorylation. eIF2B activity can also be regulated through other pathways, such as phosphorylation at different sites, which can enhance or suppress eIF2B activity.Whether these latter pathways are involved in the regulation of eIF2B activity under stress condi- tions is unclear.
The essential role of eIF2B, both in normal protein production and in its regulation under different con- ditions, including elevated temperature, is reflected by the evolutionary conservation of the complex and the nonviability of yeast null mutants for each of the subunits except eIF2Ba. In VWM patients, most mu- tations are missense mutations. So far, major muta- tions, which prevent the expression of full-length eIF2B subunits, have only been observed in the com- pound heterozygous state with a missense mutation as second mutation.
At a biochemical level, evidence has been provided that mutations reduce eIF2B activity. Certain muta- tions impair the ability to form the five-subunit eIF2B holocomplexes, leading to diminished eIF2B activity.
Point mutations in the catalytic domain, located at eIF2Be, impair its ability to bind eIF2. Some other mu- tations in eIF2Bb actually enhance eIF2 binding, also impairing eIF2B function.
The pathophysiology of VWM is still difficult to explain. Serious deteriorations often follow febrile in- fections and other forms of cellular stress. Inhibition of eIF2B via the phosphorylation of eIF2a is an im- portant mechanism for slowing down protein synthe- sis in response to, for example, the accumulation of unfolded proteins in the endoplasmic reticulum. This regulation of eIF2B is likely to be of particular impor- tance in preventing denatured proteins from accumu- lating during cellular stress and could provide a clue as to why VWM is exacerbated by episodes of infec- tion and trauma. There is evidence of activation of the
unfolded protein response in VWM. However, many aspects of the disease are poorly understood. eIF2B is ubiquitously expressed in all cells of the body. It is unclear why the brain is preferentially or selectively affected, whereas other organs are only involved in the most serious variants of the disease.
It is becoming increasingly clear that there is some genotype–phenotype correlation. Some mutations are consistently, although not invariably, associated with a mild phenotype, whereas other mutations are consistently associated with a severe phenotype. One example is the Arg113His mutation in eIF2Be, which in the homozygous state is almost always associated with a late onset and slow progress. It is remarkable that histidine is normal at position 113 in mouse and rat. However, childhood-onset patients homozygous for the Arg113His mutation have been observed too.
The second example is the Arg195His in eIF2Be, the Cree leukoencephalopathy mutation, which in the homozygous state is invariably associated with an early onset and early death. There is also evidence for a correlation between decrease in guanine-nucleotide exchange factor (GEF) activity of eIF2B and the age at onset of the disease. Mutations with a more serious impact on eIF2B function seem to be associated with a more serious disease course. However, there is also major variation between patients carrying the same mutations and between affected siblings in the same family. So, environmental and other genetic factors influence the phenotype as well.
65.4 Therapy
There is presently no causal treatment for VWM, but certain preventive measures seem advisable. Particu- lar stress conditions should be avoided in patients with VWM: infections, high temperatures, and head trauma. Vaccinations to prevent infectious diseases are important. In the case of fever, it is essential to keep the temperature down with antipyretics, if nec- essary with cooling. It is important to be liberal with antibiotics. In children with frequent upper respirato- ry tract infections, daily low-dose antibiotics may be considered. Patients have reported deterioration after sun bathing. Playing for a long time in the full sun during hot weather may, therefore, be something to avoid. It is impossible to avoid the minor head trau- mas of daily life, but it is better to avoid certain types of physical contact sports. During episodes of major deterioration, corticosteroids have led to temporary improvements. However, this effect is not consistent and lasting beneficial effects have never been ob- served. Considering the potential adverse effects of steroids, in particular worsening of infections, their use during episodes of deterioration is not advocated.
65.4 Therapy 483
65.5 Magnetic Resonance Imaging
MRI of the brain shows extensive cerebral white mat- ter changes in VWM (Figs. 65.1–65.5). Over time, MRI shows evidence of disappearance of the affected white matter, which is replaced by fluid (Figs. 65.2 and 65.3).
On T
2-weighted images, abnormal white matter and cystic white matter both have a high signal intensity and cannot be distinguished. Proton-density or FLAIR images are necessary to demonstrate the white matter rarefaction and cystic degeneration. Abnor- mal white matter has a high signal on proton-density and FLAIR images, whereas cystic white matter has a low signal intensity, similar to the signal of CSF. Rar- efied white matter has an intermediate signal intensi- ty, not as low as CSF. Within the rarefied and cystic white matter a stripe-like pattern is visible, suggest- ing remaining tissue strands (Fig. 65.6). Heavily T
2- weighted images are as a rule not suitable to show the stripes, because these images do not allow distinction between the stripes of abnormal white matter and rarefied or cystic white matter, both appearing bright.
In exceptional cases, the stripes are dark on T
2- weighted images (Fig. 65.6). The U fibers are spared to a variable extent. In some patients a rim of subcor- tical white matter is spared, whereas in other patients the U fibers are abnormal (Fig. 65.7). The sparing of the U fibers is seen best on T
1-weighted images (Fig. 65.7). MRI has been performed in a few presymptomatic and oligosymptomatic individuals and in all persons diffuse cerebral white matter ab- normalities have been found, although initially not necessarily with evidence of rarefaction or cystic de- generation (Figs. 65.8 and 65.9). In the end stage of VWM all cerebral hemispheric white matter may have vanished, leaving a ventricular wall and cortex with little or nothing in between (Figs. 65.2 and 65.3). It is striking that although the white matter may be high- ly cystic, the brain does not collapse and rarely shows evidence of external atrophy. On the contrary, the cerebral white matter may have a (mildly) swollen appearance with broadening of gyri (Fig. 65.3). Even when there seems to be hardly any cerebral white matter left, there is a distance between ependymal lin- ing and the cortex, apparently filled with fluid. The lateral ventricles may be mildly to moderately dilated, but not seriously so.White matter swelling is predom- inantly seen in young children, whereas more serious atrophy is seen in teenagers and adults with VWM (Fig. 65.4).
Often a dilated cavum septi pellucidi and cavum Vergae are present. The inner rim of the corpus callo- sum is usually involved (Figs. 65.8 and 65.9), and in later stages the corpus callosum becomes thin (Fig. 65.10). The posterior limb of the internal capsule is often involved, whereas the anterior limb of the in- ternal capsule is rarely involved. The anterior com-
missure is spared. The cerebellar white matter may have a normal (Fig. 65.4) or mildly abnormal signal (Figs. 65.1, 65.2 and 65.5). However, the process of rar- efaction and cystic degeneration appears to be re- stricted to the cerebral hemispheric white matter.
Over time, atrophy of the cerebellum and sometimes also the brain stem ensues. There are often signal ab- normalities in the midbrain and pons, and sometimes in the medulla (Figs. 65.2 and 65.5). Especially, the central tegmental tracts in the pontine tegmentum are often involved. Unlike the cerebral and cerebellar white matter abnormalities, the brain stem signal ab- normalities, when present, may improve again and even disappear. They seem to be particularly promi- nent during episodes of lowered consciousness (Figs. 65.2 and 65.5). MRI-visible spinal cord lesions are rare but may occur.
The cerebral and cerebellar cortex have a normal appearance. Most often, the basal ganglia and thala- mus also have a normal signal intensity, but particu- larly thalamus and globus pallidus lesions may occur (Figs. 65.2 and 65.5). Thalamus lesions may also im- prove and disappear all together. The globus pallidus may have a low signal intensity on T
2-weighted im- ages, suggesting mineralization (Figs. 65.4 and 65.5).
The above MRI description applies to the late-in- fantile, childhood, juvenile, and adult-onset disease (Figs. 65.1–65.10). The MRI picture may be much more difficult to diagnose in early-infantile VWM. In evidently affected neonates, the brain may only look immature with a gyral pattern that is too coarse for the gestational age of the child and with immature white matter having a high water content and little myelin, but little or no rarefaction (Figs. 65.11–65.13).
Over time, the cerebral white matter may look in- creasingly abnormal, rarefied, and cystic, as seen in the later-onset variants of the disease, but the cerebral white matter may also become highly atrophic, the ependymal lining (almost) touching the depth of the gyri (Fig. 65.13), very much unlike what is seen in the later-onset variants of the disease. In these severely affected infants, the brain as a whole is highly atroph- ic, including also the corpus callosum, cerebellum, and brain stem. In early-onset VWM, the cerebellar white matter may also become cystic.
Proton MRS shows stage-dependent abnormali- ties. In the initial stages, when there is little white mat- ter rarefaction, the white matter spectrum is relative- ly preserved. With ongoing rarefaction and cystic de- generation, the signals decrease, finally to disappear altogether. Finally, the spectrum is a CSF spectrum with some lactate and glucose and no or minor “nor- mal” peaks. The cortex spectrum remains well pre- served throughout.
A study using phosphorus MRS of the brain
(Blüml et al. 2003) revealed evidence for an altered
energy state of the residual cells in the cerebral white
matter. Nucleoside triphosphate and inorganic phos- phate were reduced, whereas phosphocreatine was elevated. The relative preservation of gray matter over white matter may have contributed to this observa-
tion, the nucleoside triphosphate to inorganic phos- phate ratio normally being lower in gray matter than in white matter. Of the metabolites involved in biosynthesis and catabolism of membrane phospho-
65.5 Magnetic Resonance Imaging 485
Fig. 65.1. The cerebral white matter is diffusely abnormal in this 3.5-year-old girl with VWM.The posterior limb of the inter- nal capsule is affected. The brain stem is intact. The cerebellar white matter has a mildly abnormal signal intensity.The FLAIR images (third row, left and middle) demonstrate that within the white matter that is abnormal on the T
2-weighted images there are areas with a low signal intensity, close or equal to the
signal intensity of CSF, consistent with white matter rarefac-
tion and cystic degeneration. Within these areas dots and
stripes with a high signal intensity are seen, consistent with re-
maining strands of abnormal tissue. The sagittal T
1-weighted
image (third row, right) shows a pattern of radiating stripes,
compatible with better preserved tissue strands
Fig. 65.2.
65.5 Magnetic Resonance Imaging 487
Fig. 65.3. The T
2-weighted (first row) and FLAIR images (sec- ond row) of a severely affected 2-year-old boy with VWM show the characteristic abnormalities. Note the large cavum septi pellucidi. Ten months later he has lost almost all functions. He is blind and has no intentional movements. The MRI was per- formed because he had papilledema at funduscopy.The FLAIR
images (third row) show that all cerebral white matter has van- ished. The lateral ventricles are mildly dilated, but the cerebral cortex has not collapsed over the central structures. On the contrary, the vanished white matter look swollen with broad- ening of gyri
Fig. 65.2. The T
2-weighted images of this 3-year-old girl with VWM (first two rows) show diffuse involvement of the cerebral white matter, posterior limb of the internal capsule, and cere- bellar white matter. Within the pons the central tegmental tracts and the pyramidal tracts are affected. The FLAIR image (first row, left) shows much more serious white matter rarefac-
tion and cystic degeneration than in the previous patient. Five months later (third and fourth rows), she is in coma. The FLAIR images (third row, left) show that the cerebral white matter is now largely cystic. The T
2-weighted images show that the globus pallidus, midbrain, and medulla now have an abnormal signal. The girl died soon after the MRI
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lipids, glycerophosphoethanolamine was reduced and phosphotidyl ethanolamine was increased, whereas choline-containing phosphorylated metabo- lites were unchanged. It is difficult to interpret these findings, most of all because the composition of the remaining brain tissue in VWM is dramatically
changed with serious rarefaction and altered ratios of composing cells. Why a defect in the regulation of protein synthesis would selectively affect ethanol- amine phospholipid metabolism and leave choline phospholipid metabolism unaffected is presently un- clear.
Fig. 65.4. This 18-year-old girl has a milder form of VWM. Al- though she has been symptomatic since the age of 4 years,she can still walk without support. The T
2-weighted images show diffuse white matter involvement with some atrophy, but the proton-density images (third row, left and middle) show that
the cerebral white matter is rarefied but not cystic. The FLAIR image (third row, right) shows the characteristic radiating stripes of better preserved tissue strands. The globus pallidus has a low signal intensity, probably related to mineralization.
The brain stem and cerebellar white matter are intact
65.5 Magnetic Resonance Imaging 489
Fig. 65.5. The girl illustrated in this figure presented for the first time at the age of 16, lapsed into coma and died after 4 months. The T
2-weighted images show the diffuse white mat- ter involvement, but the proton-density images (third row, left and middle) show that the white matter is rarefied but not cys- tic. This was confirmed at autopsy. Both the proton-density
and FLAIR (third row, right) images show evidence of some bet-
ter preserved tissue strands.The T
2-weighted images show sig-
nal abnormalities in the internal capsule, thalamus, midbrain,
basis of the pons, central tegmental tracts, middle cerebellar
peduncles, cerebellar white matter, and medulla
Fig. 65.6. The first row of images was obtained in a 5-year-old boy with VWM; the second row in a 6-year-old girl with VWM. In the boy the typical MRI features of VWM are seen with a pat- tern of radiating stripes on the sagittal T
1-weighted image (left), diffuse white matter abnormalities without evidence of stripes and dots on the axial T
2-weighted image (middle), whereas on the FLAIR image (right) the abnormal white matter has a high signal in some parts and a low signal in others, the latter compatible with rarefaction and cystic degeneration.
Within the rarefied white matter of the centrum semiovale,
dots with a high signal intensity are seen, consistent with
transections of strands of abnormal white matter. In the girl an
unusual pattern is seen. The sagittal (left) and axial (middle)
T
2-weighted images show the diffuse abnormality of the cere-
bral white matter.Within the abnormal white matter a pattern
of dark radiating stripes is seen, apparently representing
strands of normal tissue. The FLAIR image (right) shows some
white matter rarefaction in the parietal area. Images of the sec-
ond patient courtesy of Dr. T. Polster, Gilead Pediatric Center,
Bielefeld, Germany
65.5 Magnetic Resonance Imaging 491
Fig. 65.7. The first row of images originates from a 9-year-old girl with VWM, the second row from a 16-year-old girl with VWM. The T
2-weighted (middle) and FLAIR or proton-density
(right) images reveal the characteristic features of VWM.The IR
image (left) shows that the U fibers are spared in the first
patient, whereas they are affected in the second patient
Fig. 65.9. A 13-year-old girl has a history of complicated mi- graines,but no abnormalities at neurological examination.She has a DNA-confirmed diagnosis of VWM. These FLAIR images show abnormalities in the periventricular and deep white
matter and inner rim of the corpus callosum with sparing of all subcortical white matter. There is no evidence of white matter rarefaction. Courtesy of Dr. M. D’Hooghe, Department of Neu- rology, Sint-Jan General Hospital, Brugge, Belgium
Fig. 65.8. This 18-year-old university student presented with a single seizure and had no abnormalities at neurological ex- amination. She has a DNA-confirmed diagnosis of VWM. The T
2-weighted images (first row) show diffuse involvement of the
cerebral white matter and the inner rim of the corpus callo-
sum. The FLAIR images (second row) do not show evidence of
white matter rarefaction. Courtesy of Dr. E Storey, Neurogen-
etics Clinic, Royal Melbourne Hospital, Parkville, Australia
65.5 Magnetic Resonance Imaging 493
Fig. 65.10. A 49-year-old man with a history of presenile dementia and motor problems. His MRI is typical for VWM and the diagnosis was DNA-confirmed. Note the thin corpus callosum. From Prass et al. (2001), with permission
Fig. 65.11. The VWM patient in this figure had an antenatal onset of symptoms with decreased fetal movements and oligohydramnios. At birth she had dislocated hips and was hy- potonic. She followed a rapidly downhill course with in- tractable seizures, feeding difficulties, hypotonia, apathy, and finally coma and respiratory failure.At physical examination oil droplet cataracts and hepatosplenomegaly were found. She died at 8 months.The left (T
2-weighted) and middle (FLAIR) im-
ages were obtained at the age of 3 months and revealed most
of all an immature brain with failure of myelination and insuf-
ficient gyral development.The FLAIR image shows some white
matter rarefaction. The right image was obtained at 6 months
and revealed more prominently abnormal cerebral white mat-
ter with additional involvement of the globus pallidus and the
right thalamus. From van der Knaap et al. (2003), with permis-
sion
Fig. 65.12. This figure shows the images of two siblings with antenatal onset of VWM and death at the ages of 3.5 and 4 months, respectively.The first row of images was obtained at 1 month in a girl; the second row shows the follow-up images ob- tained at 4 months. The third row shows the images of her af- fected brother, obtained at 3 months. The images obtained at 1 month reveal an immature brain with failure of myelination and insufficient gyration. Note the swelling of the anterior temporal white matter, which contains a cyst. The images ob-
tained at 3 and 4 months revealed more prominent abnormal- ities of the cerebral white matter. Myelination and gyration have not progressed. There is white matter volume loss with enlargement of the lateral ventricles. Note the swollen and cystic anterior temporal white matter. The cerebellum is small and the brain stem looks atrophic. Courtesy of Dr. R. van Coster, Department of Pediatric Neurology, C. Hooft University Hospi- tal, Gent, Belgium
Fig. 65.13. A patient with antenatal onset of VWM underwent MRI at the ages of 5 days (first and second rows) and 5 months (third and fourth rows). Initially, the brain has an immature appearance with coarse gyri and cerebral white matter with a high water content. The inferior horns of the lateral ventricles are dilated. On follow-up, most of the cerebral white matter has disappeared, but, unlike the typical appearance of vanish-
ing white matter, the ependyma touches the cortex. The later- al ventricles are now highly dilated. There is a cyst in the ante- rior temporal region. The remaining cerebral white matter looks highly abnormal and swollen. The cerebellum has be- come highly atrophic. The brain stem is also thin. From Boltshauser et al. (2002) and van der Knaap et al. (2003), with permission
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