White Matter Disorders

The earliest pathologic finding is focal, high T2-intensity white matter changes followed by atrophic changes that lagged behind the white matter changes. In the advanced state, an almost total loss of white matter is evident, and the corpus callosum becomes thin.42 In the late stages, neuroimaging is nonspecific, with CT scanning showing diffuse atrophy and MR imaging showing patchy areas of prolonged relaxation time in the cerebral and cerebellar white matter.17

White Matter Disorders

Neuroimaging, combined with genetic and molecular biological analysis, has revolutionized the workup and understanding of metabolic disease. The high MR contrast between myelinated white matter and demyelinated or unmyelinated white matter, and between normal and damaged gray matter, has led to discovery of new patterns of tissue involvement.18,321,323 New white matter disorders, such as vanishing white matter disease321,326 and megalencephalic leukoencephalopathy with subcortical cysts,324 continue to be identified.

Abnormalities of white matter detected by MR imaging in metabolic disorders can be the result of many different processes, including inflammation, splitting (vacuolization) of myelin, and death of astrocytes or oligodendrocytes.18 For example, in Canavan disease and maple syrup urine disease, a splitting of myelin is assumed to be a toxic phenomenon because of abnormal metabolites.18 In X-linked adrenoleukodystrophy, myelin breakdown may be the result of its inherent instability or of triggering an inflammatory

microglial reaction.18 White matter injury in Tay–Sachs disease is attributed to a combination of hypomyelination, myelin loss secondary to axonal degeneration, and primary demyelination.322

In globoid cell leukodystrophy (Krabbe disease), the cytotoxic compound psychosine accumulates within oligodendrocytes after much of the brain has myelinated, causing cell death and breakdown of myelin sheaths maintained by the affected cells.18 In all of these disorders, MR imaging shows white matter that is extremely bright (hyperintense) when compared with gray matter on T2-weighted images and dark (hypointense) when compared with gray matter on T1-weighted images.18

Recently, a number of metabolic disorders called hypomyelinating disorders have been described, in which the principle finding is loss of myelin. In these disorders, white matter abnormalities are more subtle on MR imaging, being isointense to slightly hyperintense compared with gray matter on T1-weighted images and moderately hyperintense compared with gray matter on T2-weighted images. The prototypical hypomyelinating disease is Pelizaeus–Merzbacher disease. Other hypomyelination leukodystrophies include the Pelizaeus–Merzbacher-like disease (caused by mutations of GJA12 at chromosome 1q41–42), the 18q deletion syndrome (caused by deletion of the portio of the chromosome containing the gene for myelin basic protein, the other main structural protein of myelin), sialuria (also called Salla disease, caused by mutations of the SLC17A5 gene at 6q14– q15), hypomyelination with atrophy of the basal ganglia and cerebellum, trichothiodystrophy with photosensitivity, Cockayne’s syndrome, and hypomyelination with congenital cataracts.18,33

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder that is usually caused by mutations in the arylsulfatase A (ARSA) gene on chromosome 22q13.31. It is considered to be the most common white matter degeneration of childhood. Symptoms begin as a gait abnormality, usually in early childhood (1–2 years of age in the late infantile form and 5–10 years in the juvenile form). These children become progressively weak and, ultimately, bedridden and demented, with death usually occurring by age 10. A prominent feature of this condition is peripheral nerve involvement leading to decreased deep tendon reflexes.202,247

Neuro-ophthalmologic abnormalities include optic atrophy leading to delayed VEPs and strabismus. Rarely, nystagmus197 and a cherry red macula are seen.23 CT scanning reveals generalized atrophy and diffuse white matter lesions, with no enhancement after contrast. MR imaging demonstrates high-signal intensity lesions in the periventricular white matter on T2-weighted images.260 The peripheral white matter is spared until late in the disease179 (Fig. 10.7).

The condition is named for the appearance of the pathologically stored lipid material on light microscopy when stained with toluidine blue. Under these circumstances, the accumulated material stains brown or gold and demonstrates a birefringent character in samples of cerebral white matter.306 In addition to white matter involvement, some stored material is found in the cortex. The accumulation occurs in both neurons and glial cells. The condition also involves the deep cerebral nuclei and the spinal cord. The biochemical abnormality is an accumulation of sulfatides due to deficiency of arylsulfatase-a activity.303 The deficiency of this enzyme results in failure to break down and reutilize myelin. Several molecular forms of arylsulfatase-a exist and may account for the different phenotypes of metachromatic leukodystrophy.100

The enzyme activity can be assayed in urine or leukocytes. Ancillary studies may disclose elevated spinal fluid protein and a nonfunctioning gallbladder as assessed by cholecystogram.306 The heterozygous state (carriers) can be characterized by the enzymatic activity in white blood cells or fibroblasts.20 Late-onset forms of meta­chromatic leukodystrophy may respond to bone marrow transplantation.

Fig. 10.7  Metachromatic leukodystrophy. This T2-weighted MR image shows prolongation of T2 relaxation time throughout cerebral white matter. Sparing of peripheral white matter (subcortical U fibers) is seen (arrow)

Canavan Disease (Spongy Degeneration

of Cerebral White Matter)

Canavan disease is an autosomal recessive disorder caused by aspartoacylase deficiency.302 This deficiency leads to increased concentration of N-acetylaspartic acid in brain and body fluids. The failure to hydrolyze N-acetylaspartic acid causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia early in life, which changes to spasticity, macrocephaly, head lag, and progressive mental retardation. Although Canavan disease is panethnic, it is most prevalent in the Ashkenazi Jewish population. Infants with Canavan disease may appear normal in the first few months after birth, only to become progressively irritable and hypotonic, with poor head control. After 6 months of age, the triad of hypotonia, head lag, and megalencephaly should lead one to consider this leukodystrophy. Children with Canavan disease develop optic atrophy, but they are still able to see and recognize their surroundings.209,302 As optic atrophy develops and vision loss progresses, nystagmus may be seen.

Canavan disease is inherited as an autosomal recessive trait, with a mutation in the gene that synthesizes aspartoacylase.209 High levels of urine N-acetylaspartic acid, often more than 50 times normal, are a specific test for the diagnosis of Canavan disease. CT or MR imaging of the head shows diffuse whitematter degeneration in Canavan disease.41 The aspartoacelylase gene has been cloned and localized to the short arm of chromosome 17 (17p13-ter).175,176 Aside from symptomatic

management of seizures, preliminary results with gene therapy have shown some promise in managing Canavan disease.195 Clinical improvement in one patient following treatment with lithium citrate (which decreases whole-brain levels of N-acetyl aspartate in a rat genetic model of Canavan disease) suggests that this treatment may also hold promise.169 Dietary supplementation with acetate has recently been suggested as treatment for Canavan disease.57,204

The clinical diagnosis of Canavan disease rests on progressive neurologic deterioration in a child with megalencephaly, optic atrophy, and seizures. The clinical picture is of a quiet, apathetic, fair-haired baby with a drooping head.246 Hypotonia and lack of head control usually become evident between the ages of 3 and 9 months. As in children with Alexander disease, progressive megalencephaly develops. Megalencephaly, spasticity, mental and motor retardation, and optic atrophy, with parenchymal cerebral degeneration, end in a decerebrate state.246 Many die in infancy, but some survive into adolescence. Studies have shown that aspartoacylase deficiency causes N-acetylasparic acid to accumulate and damage cerebral myelin, with excess N-acetylaspartate in plasma and urine.209

Pathologically, Canavan disease is characterized by the finding of a spongiform degeneration of cerebral white matter. The pathologic sine qua non of Canavan disease is vacuolization of the deep cortical layers and subcortical white matter. As tissue is lost, the ventricles may become enlarged (Fig. 10.8). Myelin sheaths decrease in size and, in the later stage, axonal loss is noted. Cortical neurons appear

normal early in the course of the disease, but neuronal loss may be seen in long-standing cases.102

Canavan disease, like the other spongy myelopathies such as Kearns–Sayre syndrome and myoclonic epilepsy with ragged red fibers (MERRF), shows preferential involvement of the subcortical white matter on pathological studies. This distinguishes it from Krabbe disease and metachromatic leukodystrophy, which spare peripheral white matter until late in the disease.17 Unlike other spongiform myelopathies, Canavan disease does not show pathological involvement of gray matter. This condition was once thought to be a mitochondrial disorder because of its clinical similarities to other mitochondrial encephalomyopathies.283

Krabbe Disease

Krabbe disease is an autosomal recessive disorder of sphingolipid metabolism that is caused by mutations in the galactosylceramide gene on chromosome 14q31.342 Prior to 6 months of age, infants display irritability, dysphagia, spasticity, mental deterioration, poor vision, and deafness, and generalized seizures. Intense optic atrophy ensues within the first months of life.45,141 On rare occasion, a cherry red spot has been reported.229 Patients generally die within the first few years of life. In terminal stages of this illness, the children are blind, deaf, and have opisthotonic posturing. CT shows periventricular hyperdensity that occurs concomitantly with decreased attenuation in white matter.17 MR imaging demonstrates white matter abnormalities in the form of nonspecific T1 and T2 prolongation in deep cerebral and cerebellar white matter, with a predilection for parietooccipital involvement (Fig. 10.9).16,98,342

Clumps of globoid and epithelioid cells and cerebral white matter are the characteristic pathological abnormality in Krabbe disease. Cortical atrophy and overall loss of brain mass may also be noted. The lipid accumulation in this disease is due to deficiency of the enzyme galactocerebroside beta galactosidase, which results in the storage of large amounts of galactocerebroside (galactosyl ceramide), which is toxic to oligodendroglial cells.306 Banked cord blood and bone marrow transplantation are effective treatments for infantile Krabbe disease, but only if given in the presymptomatic stage.

Pelizaeus–Merzbacher Disease

Figure 10.8  Canavan disease. T2-weighted MR image shows diffuse increased signal intensity in deep white matter with multifocal round areas of higher signal intensity, suggesting vacuolar changes (arrow). Courtesy of Charles M. Glasier, M.D.

Pelizeus–Merzbacher disease is a rare X-chromosomal neurodegenerative disorder that affects primarily the white matter of the CNS and is caused by mutations of the proteolipid protein 1 gene (PLP1), which codes for proteolipid protein (PLP), one

Fig. 10.9  Krabbe disease. T2-weighted MR image showing diffusely increased signal intensity in deep white matter. Courtesy of Charles M. Glasier, M.D.

of the major structural proteins of myelin.18 Point mutations have been found in 10–25% of cases, but most affected patients have duplications of the gene,159,287 which has been mapped to Xq21.1.207 Duplication of the PLP gene, probably results in the accumulation of PLP within the oligodendrocytes, with resultant impaired cell function, and early oligodendrocyte death, resulting in impaired myelin formation. A rare autosomal recessive form of Pelizaeus-Merzbacher-like disease caused by GJA12 mutations can be present in girls.18,144a

Clinically, the syndrome presents with nystagmus, hypotonia, progressive spastic quadriparesis of varying degrees, ataxia, and developmental delay associated with diffuse leukoencephalopathy.281,298 Carrier females may or may not manifest symptoms.207 The pathological hallmark is patchy demyelination with preservation of islands of normal myelin, resulting in a tigroid appearance of stained sections of white matter on light microscopy. Pelizaeus–Merzbacher disease has its onset in the first few months of life, beginning with nystagmus310 and head tremor and progressing to ataxia, limb tremor, and choreoathetosis. Trobe et al314 have described distinctive elec- tro-oculographic characteristics of nystagmus in this condition, consisting of an elliptical pendular nystagmus that may be superimposed or interposed with upbeat nystagmus.314 Early in the course of this disease, nystagmus may be associated with head nodding and may simulate spasmus nutans. Patients may have saccadic dysmetria and other cerebellar signs such as truncal titubation.193 Optic atrophy and seizures occur later. Intellectual function is relatively preserved, but a mild dementia may occur. Most of these patients die in the second decade of life or during early adulthood, and most are male. A connatal form is more severe with death in the first few years of life.276

Fig. 10.10  Pelizaeus–Merzbacher disease. This T2 MR image in 7-year-old child shows severe loss of myelin. Myelin should appear dark in image. Courtesy of A. James Barkovich, M.D.

Neuroimaging in Pelizaeus–Merzbacher disease shows a lack of myelination without evidence of a white matter destructive process (Fig. 10.10).17,284,294,327 The finding of white matter abnormalities in a child thought to have spasmus nutans should raise suspicion of this disorder.

Cockayne Syndrome

Cockayne syndrome is an autosomal recessive disorder related to the transcription-coupled repair pathway.88 It is a progressive neurological disorder characterized in infancy by growth failure (cachectic dwarfism), deficient neurological development, progressive retinal degeneration, and sensitivity to sunlight without propensity to cancer.88 It is also characterized by premature aging, dementia, worsening vision and hearing, endocrinopathies, progressive spasticity, ataxia, peripheral neuropathy, weakness, osteopenia, kyphosis, and joint contractures.258 Two genes for Cockayne syndrome have been identified.206,295,315,316 Complementation groups on a gene on chromosome 5q12 account for 20% of cases, while those on a gene on chromosome 10q11 account for 80% of cases.258 Type I, the “classical” type, has an onset in the postnatal period, while type II, the “severe” type, occurs before birth and usually results in death by 6 or 7 years.233