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Magnetic resonance findings in leucodystrophies and MS.

Classification of Leucoencephalopathies

The term 'leucoencephalopathies' encompasses disorders mainly involving the brain white matter. Hereditary leucoencephalopathies, often called leucodystrophies, can be separated into three categories: 1) metabolic leucoencephalopathies caused by defects in gene coding for enzymes or proteins involved in the cell metabolism, and for which the diagnosis is currently based on biochemical analysis of plasma and urines samples; 2) leucodystrophies caused by defects in gene coding for proteins not directly involved in metabolic pathways and for which the diagnosis is directly based on gene testing; and 3) leucoencephalopathies without any known biochemical abnormalities or mutated genes.

Most of the leucodystrophies are recessive. X-linked inheritance strongly suggests adrenomyeloneuropathy, Fabry disease, pre-mutation X-fragile diagnosis; dominant inheritance suggests cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), collagen type IV (Col IV) mutation, Nasu-Hakola disease (NHD), adult-onset autosomal dominant leucodystrophies (ADLD) and Alexander disease diagnosis. White matter diseases could be also diagnosed on the vascular or non-vascular involvement.

Vascular Origin

Vascular leucoencephalopathies are caused by cerebral microvascular disease, most often related to risk factors such as smoking, hypertension, diabetes, migraine or cardiovascular embolic disease. MR patterns consist of small-size infarcts, involving basal ganglia, internal capsule and brainstem (Figure 1). Microvascular disease is also occasionally related to genetic conditions.

Leucoencephalopathy Due to Notch3 Mutation

One of the most frequently described genetic vascular leucoencephalopathies is CADASIL. (1) It is an autosomal dominant condition, causing recurrent subcortical strokes, subcortical dementia, migraine with aura, and depression. The mutated gene Notch3 was mapped to the long arm of chromosome 19. (2) Neuroimaging findings consist of both focal lacunar infarcts and diffuse white matter ischaemic changes known as leucoaraiosis, seen as high-intensity signal on T2-weighted MR imaging. Lacunae are located in the thalamus, basal ganglia, internal capsule and brainstem (central pons). Leucoaraiosis typically involves the periventricular area, mainly in the posterior regions, typically sparing the subcortical U-fibres (Figure 2). In addition, Gradient Echo sequences often show hypointense lesions, resulting from cerebral microhaemorrhages. (3,4)

Recently, more specific MR findings have been described, such as involvement of the anterior part of the temporal pole, the external capsule, and the corpus callosum. (5) In the presence of these findings, it is sometimes possible to suspect CADASIL at the outset and to avoid, thereby, a false diagnosis of MS. These MR lesions represent different consequences of the underlying angiopathy.


Leucoencephalopathy Due to Col IV Mutation

The occurrence of leucoencephalopathy, lacunar lesions, micro- and macrohaemorrhages, porencephaly, cataract, infantile-onset hemiparesis and retinal arteriolar tortuosity in the presence of a positive family history has been recently related to mutation of the Col IV A1 gene. (6,7)

TREX 1 Leucoencephalopathies

Recently, a dominant vascular leucoencephalopathy was related to mutation of the TREX1 gene. It is characterized by retinal vasculopathy and brain leucoencephalopathy. (8)


Non-vascular Leucodystrophies

These conditions can be related to inborn errors of metabolism or genetic leucodystrophies. Main causes of leucodystrophies with identified enzyme deficiency are summarized in Tables 1 and 2.

It is difficult to discuss in detail the MR aspect of all inherited metabolic leucodystrophies. However, common radiological aspects often seen are:

* Symmetrical white matter hyperintensities on T2 sequences

* Diffuse and extensive radiological abnormalities

* Absence of gadolinium (Gd) enhancement

* Selective involvement of the white matter substance, i.e. frontal or parietal lobes, corticospinal fibres, corpus callosum

* Involvement of U-fibres in some cases

* Absence of small ovoid lesions

* Brainstem or cerebellar involvement.

Interestingly, some leucodystrophies with known mutated genes have specific patterns of MR. The following section concerns these genetic leucodystrophies with highly specific MR patterns.

Megalencephalic Leucoencephalopathy with Subcortical Cysts

First described in 1995, megalencephalic leucoencephalopathy with subcortical cysts (MLC) is characterized by: 1) clinical symptoms: macrocephaly occurring in the first year of life, mild-to-moderate cognitive defects and progressive spasticity, leading to a progressive and slow handicap and epileptic seizures (in half of the cases); 2) neuroradiological findings (Figure 3): diffuse, symmetrical white matter lesions, with constant frontoparietal and anterotemporal subcortical cysts. (9-11) Histological analysis consists of spongiform white matter changes related to vacuoles between the outer lamellae of myelin sheaths, sparing the axons. These changes could be related to splitting of the myelin lamellae along the intraperiod line or incomplete compaction. (9)


MLC is observed worldwide. (12,13) A high incidence is seen in Northern India in the Agarwals population, (14) and in Turkey. (10,11) The mode of transmission is consistent with autosomal recessive inheritance. A first gene, mapped to 22qtel, (15) KIAA0027, named MLC1 (MIM no. 604004), was identified by Leegwater et al. (16) A founder effect was seen in some populations. (17) However, close to 20% of the patients are not linked to MLC1 gene mutations, (18,19) confirming the genetic heterogeneity.

Leucoencephalopathy with Brainstem and Spinal Cord Involvement and High Lactates

A new ataxic leucodystrophy with recessive inheritance was described by van der Knaap et al. in 2003, (20) characterized by a slowly progressive paraparesis, and proprioceptive and cerebellar ataxia with childhood onset. This entity was referred to as leucoencephalopathy with brainstem and spinal cord involvement and high lactate (LBSL). MR patterns in LBSL are characterized by extensive demyelination, involving corpus callosum, pyramidal fibres of corona radiata, posterior part of the internal capsules, brainstem (cerebellar peduncles, intraparenchymal and mesencephalic trigeminal nerves). The spinal cord is frequently also involved, especially with demyelination of lateral corticospinal tracts, dorsal columns and medial lemniscus. (21)

Demyelination can also involve white matter of the cerebellum. (22) MR spectroscopy patterns consist of a significant decrease in N-acetylaspartate, an increase in myoinositol, normal or mildly elevated choline, and elevated lactate within the white matter. However, a few patients with normal content of lactates have been described. (23,24) The mutated gene has been mapped to chromosome 1 and was recently identified as DARS2. This gene encodes mitochondrial aspartyl-tRNA synthetase resulting in reduced enzymatic activity of the mutant protein. (25)


NHD, also known as polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy (PLOSL/ MIM221770), is an autosomal recessive disease characterized by association of presenile dementia and destruction of bones. (26) Since the first descriptions in the 1970s, more than 150 cases have been reported from Japan, Finland and other countries. (27) First symptoms typically appear in the third decade, consisting of pain and swelling of the wrists and ankles, and extremity bone fractures related to minor trauma. Radiographs showed trabecular loss in the distal ends of the long bones and cystic alterations in the fingers and toes, sparing skull and axial skeleton. Cystic cavities contain fat cells and lipid membranes of 1-2 ?m thickness. (26) Neurological symptoms occurred 10 years later, including epileptic seizures, frontal-type dementia and choreiform movements. Frontal dysfunction was assessed by positron emission tomography studies. Death usually occurred 20 years later (mean age: 50). Progressive MR abnormalities can be seen: cerebral atrophy, increased bicaudate ratio and basal ganglia calcifications, with initially normal cerebral white matter. The end of the radiological evolution is characterized by a diffuse cerebral atrophy together with increased signal intensity of the cerebral white matter on T2-weighted images. The demyelination typically involves the entire white matter. Brain histopathology is characterized by frontal loss of myelin and nerve fibres, with axonal spheroids, lipid-loaded macrophages and extensive astrocytic reaction and gliosis. (26-29) In addition, reduction in size of basal ganglia, mainly caudate nuclei, is observed. Vascular alterations are consistently observed: they consist of concentric thickening of the vascular wall with narrowing or obliteration of the lumen of small arterioles and capillaries. Immunostaining for Col IV showed thickened and multiple basement membranes. Based on these changes, pathogenesis was explained by lipid metabolism abnormalities or vascular hypoplasia.

The mutated gene (DAP12) was mapped to 19q13.1. It was recently identified, with a founder mutation in some populations, as in Finland. (27) Different types of mutations were found, including single base mutation or large deletions.

Genetic heterogeneity for this disorder has been established because one Swedish and one Norwegian family have been described who met diagnostic criteria for PLOSL criteria but do not have a DPA12 mutation. (30) Other reports described a second mutated gene, TREM2, possibly involved in this disease. (31)

The pathogenesis of PLOSL remains unclear. Two hypotheses have been proposed: 1) vascular damage with resultant blood--brain barrier breakdown and consequent ischaemia, resulting in oligodendroglial and axonal damage, including spheroid formation, and widespread loss of axons and myelin sheaths; and 2) abnormalities of systemic lipid metabolism, resulting in breakdown of the myelin sheaths. (32) Vascular origin is likely part of the mechanism of this disease.

Adult-onset Autosomal Dominant Leucodystrophy

Adult-onset autosomal dominant leucodystrophy (ADLD; OMIM = 169500) was first reported in an American-Irish kindred in 1984. (33) Symptoms onset is typically seen between the age of 50 and 60. Autonomic dysfunction (bladder and bowel dysfunction, orthostatic hypotension) is frequently preceded by cerebellar and pyramidal dysfunction.

On MRI, the signal-intensity changes are most prominent in the frontoparietal and cerebellar white matter (especially the peduncles). In advanced disease, abnormalities are also seen in the occipital and, to a lesser extent, temporal lobes. (34) Involvement of the entire corticospinal tract and corpus callosum is seen in all symptomatic subjects (Figure 4). Sparing or less severe alteration of the periventricular white matter is typical. Signal-intensity changes can often be seen in asymptomatic individuals, ranging from subtle changes in the upper part of the corticospinal tract to a more extensive involvement.

Due to clinical (especially the long-term evolution with a frequent survival rate of 20 years) and MR findings, a diagnosis of MS is often mistakenly made in these patients.

Neuropathology has been reported in three patients, who showed extensive loss of myelin, isolated and confluent patches, involving cerebrum and cerebellum white matter. Preservation of oligodendroglia and relative absence of astrogliosis in the demyelinated areas without any inflammation of the brain were regarded as unique features.


The gene that causes the disease is located on chromosome 5q31.6. (35) Identification of a tandem genomic duplication resulting in a copy of the gene encoding the nuclear lamina protein lamin B1 (LMNB1) was made in 2006. (36)

Alexander Disease

Alexander disease is a progressive, usually fatal, neurological disorder, mainly occurring in childhood. Onset of the disease is usually before the age of 2 years (72% of the published cases). (37) Symptoms include mental retardation, bulbar dysfunction, seizures, macrocephaly and spasticity, resulting in death usually by the age of 10 years. Histological findings consist of loss of myelin in the frontal lobes. Juvenile forms (age of onset: 2-12 years) are characterized by occurrence of bulbar symptoms and a slower evolution. More recently, a delayed onset (adulthood) form has been described, characterized by a slower progressive course, with ataxia and palatal myoclonus in absence of cognitive defect and macroencephaly. (38-40) Other phenotypes have been reported: oscillopsia, primary ovarian failure, thyroid hormone abnormalities, hypothermia, microcoria, dysautonomia and acute evolution of the disease with death occurring in less than 2 months. (41,42)

The prognosis depends on the age of onset: mean survival is close to 3.6 years in infantile onset, 8.1 in juvenile onset and 15.0 in adulthood onset.

Five MR criteria were defined by van der Knaap et al. in 2001:43 cerebral white matter change with frontal preponderance; periventricular rim with high-signal T1 and low signal on T2-weighted images; 'periventricular garlands' (considered as typical); abnormalities of basal ganglia, thalami and brainstem; and contrast enhancement. (44)

In adulthood, MR findings consist of hypointense signals on T2 sequences involving grey matter, brainstem and cervical cord, with marked atrophy. Interestingly, frontal lobes are spared in these late onset forms. Histological findings (massive accumulation in the Rosenthal fibres) are shared between the different forms of the disease. Accumulation of fibres is mainly seen in subpial and subependymal regions in the juvenile forms, and in cerebellum and brainstem in the adulthood forms. Most of the cases are related to mutations in the gene encoding glial fibrillary acidic protein (GFAP), resulting in Rosenthal fibre deposition in astrocytes. (45,46) Both GFAP and LMNB1 are members of the intermediate filament superfamily. (47)

Childhood Ataxia with Central Nervous System Hypomyelination/ Leucoencephalopathy with Vanishing White Matter Syndrome (EIF2B-related Disorders)

The classic and most common variant of childhood ataxia with central nervous system (CNS) hypomyelination/leucoencephalopathy with vanishing white matter (CACH/VWM) has its onset in childhood, at age 2-6 years. It is characterized by chronic progressive neurological deterioration with cerebellar ataxia, milder spasticity and mental decline. The evolution is characterized by episodes of major and rapid deteriorations following different triggers, such as minor head trauma, febrile infections and acute fright. During these episodes, loss of motor faculties and hypotonia are observed, with coma and death in some cases. Recovery is usually incomplete, with neurological sequellae and occurrence of death in a few years. (48) Phenotypic variation has been described depending on the age of onset.

Decreased fetal movements, oligohydramnios, growth failure and microcephaly (48) are seen in antenatal forms. Soon after birth, rapid deterioration occurs in these patients, including vomiting, axial hypotonia, apnoeic episodes, respiratory failure, coma and death within a few months. (50,51)

Infantile CACH, also called 'Cree leucoencephalopathy', was described among the Cree Indians. (52) Onset is between 3 and 9 months of age and leads to a rapid death. Milder variants of the disease with an adolescent or adult onset have been recently described: asymptomatic forms, late onset (beginning at 40), isolated psychiatric symptoms or dementia. (53,54)

Primary or secondary ovarian failure can be encountered among females of all different disease severities. Ovarian atrophy can be found on abdominal echography. (55-57)

The MRI shows an abnormal signal of almost all of the cerebral white matter, but sparing the U-fibres. Serial MRs show progressive rarefaction and cystic degeneration of the affected white matter, which is replaced by water (Figure 5). This change is best seen on proton density and fluid-attenuated inversion recovery (FLAIR) sequences as regions of high-signal (demyelination) and hypointense signal (cystic degeneration). Increased diffusivity is found on diffusion-weighted sequences, corresponding to the cystic degeneration. Abnormal lesions never enhance following Gd administration. In addition, MR examination (notably on T1 sequences) can show a radiating, stripe-like pattern within the rarefied and cystic white matter, suggesting remaining tissue strands. (58)

There is no correlation between MR abnormalities and clinical symptoms, since patients with typical MR can be clinically or mildly asymptomatic. At the end of the evolution, the entire cerebral hemispheric white matter may have vanished.

Demyelination can sometimes involve the brainstem and cerebellar white matter, resulting in atrophy, but without cystic degeneration.

On macroscopic examination the cerebral white matter varies from gelatinous to cavitary. The frontoparietal white matter, particularly deep and periventricular, seems to be more commonly involved, with relative sparing of the temporal lobe, optic system, corpus callosum and internal capsule.


Microscopically, the grossly affected white matter shows myelin pallor, thin myelin sheaths, vacuolation, myelin loss and cystic change. Lipophages containing myelin breakdown products are rare. The grey matter is generally spared or greatly preserved in comparison to white matter. Inflammatory infiltration is always absent. Importance of axonal loss is correlated with extension of cavitations. Sheaths are abnormal and vary from pale to thin to vacuolated. The radiating stripes seen on MRI appear to correlate with blood vessels accompanied by reactive astrocytes.

Increase of oligodendrocyte size is found in the areas of demyelination. The astrocytes are dysmorphic with blunt broad processes.

Five mutated genes EIF2B1-5 have been identified so far. (59-62) They encode the five subunits of eukaryotic translation initiation factor eIF2B (elF2B[alpha], [beta], [gamma], [delta] and [epsilon]). Two-thirds of the patients with VWM have mutations in EIF2B5 which is the largest subunit.

Demyelinating Diseases


By now, the MR patterns in MS are well established. They were initially described in the early 1980s by Lukes and colleagues, (63) and in 1997 Barkhof developed a system of classification that has been incorporated into the current international diagnostic criteria for MS. (63-65) These criteria for dissemination in space are defined as follows: 1) Either one Gd-enhancing lesion or nine T2-hyperintense lesions; 2) At least one infratentorial lesion; 3) At least one juxtacortical lesion; 4) At least three periventricular lesions.

Typical MS lesions are seen as >3 mm in diameter, periventricular with extensions (Dawson fingers) into the adjacent white matter, and ovoid morphology.

They involve corpus callosum, internal capsule, cerebellar peduncles and juxtacortical areas. Using FLAIR, the percentage of juxtacortical lesions in MS was 30%. Lesions in the cortex make up a substantial percentage of lesions in histopathological studies, up to 59% in one series. Their presence is related to myelinated axons extending well into the cortex, and contrasts with hypoxic/ischaemic diseases where the direct subcortical zone, containing the U-fibres, is typically spared. (63)

In addition, chronic T1 hypointense lesions ('black holes'), are often found in MS patients. They consist of focal areas of relatively severe tissue injury, including axonal injury, matrix destruction and myelin loss. Acute MS lesions also appear T1-hypointense as a result of transient oedema, although these are not true T1-black holes. T1 hypointensity may linger months after an acute event with such lesions evolving to isointensity (loss of oedema or repair) or persisting as chronic, permanent hypointensity. A true T1 black hole is a chronic hypointensity. These lesions cannot be determined with certainty on an MR image obtained on one occasion, because, by definition, a chronic black hole must persist for at least 6 months.

Other Inflammatory Disorders

Devic's Disease

Neuromyelitis optica (NMO, also known as Devic's disease) is an idiopathic, severe, demyelinating disease of the CNS that preferentially affects the optic nerve and spinal cord. MRI findings of the brain at the onset of NMO are typically normal in contrast to MS. They may show non-specific white matter lesions and optic nerve enhancement by Gd injection, during acute optic neuritis. An exception is brainstem lesions, which can occur in isolation or as a rostral extension of cervical myelitis (Figure 6).

During evolution of the disease, MR can find asymptomatic white substance lesions in 60% of the patients. Spinal cord involvement is quite different from MS myelitis: lesions are longitudinally extensive, and span three or more contiguous vertebral segments.

The presence of a highly specific serum autoantibody marker (NMO-IgG) differentiates NMO from MS. These antibodies react with the water channel aquaporin-4. (66)

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is considered as a monophasic demyelinating disease of the CNS. Young children and adolescents are most commonly affected. Numerous cases among adults and even elderly patients have been recently reported. (67)


MR Findings

MR findings are quite different from MS: frequent grey matter involvement (basal ganglia or cortical lesions), uncommon involvement of the corpus callosum, simultaneous enhancement of the lesions by Gd injection and importance of the oedema reaction (Figure 7).


Diagnosis of white matter lesions is a frequent question for clinicians. Asymmetrical lesions, basal ganglia and brainstem involvement are indicative of vascular disorder. Acquired diseases are more frequent than genetic pathologies. CADASIL, Col IV and TREX1 mutations are recently identified genes of familial vascular leucoencephalopathies. Extensive and symmetrical demyelination, sparing grey matter and absence of Gd enhancement are indicative of a non-vascular leucodystrophy. Specific MR patterns has been observed for CACH/VWM, MLC, LBSL, ADLD and Alexander diseases.


Conflict of Interest

No conflicts of interest were declared in relation to this article.

Key Points

* The two more frequent inherited vascular leucoencephalopathies are related to Notch3 and Col IV mutations

* Cavitory leucoencephalopathies mainly consist of CACH/VWM and MLC1

* Mutated genes of CACH are EIF2B1-5 with a peculiar common mutation in adults (R113H)

* Lamin B1 mutations are associated with a dominant inherited leucodystrophy

* MR patterns can distinguish MS diagnosis from genetic leucodystrophies: absence of gadolinium enhancement, symmetric hyperintense signals and brainstem involvement argue to a genetic disorder

Received: 17 June 2008

Accepted: 5 August 2008


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P Labauge

Department of Neurology, CHU Montpellier-Nimes, Nimes, France

Address for Correspondence

Pierre Labauge MD, PhD, Department of Neurology, CHU Montpellier-Nimes, 30 029 Nimes Cedex, France E-mail:
Table 1: Main adult leucoencephalopathies

 Metabolic disorders Corresponding
 with white matter enzyme deficiency

 Adre noleucodystrophy C 26/24
 Krabbe disease Galacto cerebroside
 Homocystinury [beta]-galactosidase
Cerebrotendinous xanthomatosis Homocystinury increase
 Refsum disease Cholestanol increase
 [alpha]/[beta] mannosidosis Phytanic acid increase
 Metachromatic leucodystrophy [alpha]/[beta] mannosidose decrease
 Gangliosidosis GM1 Arylsulphatase A decrease
 Gangliosidosis GM2 Galactocerebrosidase deficiency
 Sandhoff disease Galactosidase deficiency
 Gaucher disease Hexosaminidase A deficiency
 Fabry disease Hexosaminidase A and B deficiency
 Niemann-Pick dis ease Glucosidase deficiency
 (types A and B) Galactosidase A deficiency
 Sphingomyelinase deficiency

 with gene mutation

 CADASIL (Notch3)
 Col IV muta tion (Col VI)
 CACH syndrome (EIF2B1-5)
 ADLD (Lamine B1)
 Alexander dis ease G (FAP)
Premutation X fragile (GAA)

Table 2: Leucoencephalopathy and leucodystrophies

 Vascular metabolism
 leucoencephalopathy markers

High-intense signals
 Ovoid - -
 Thalami + -
 Caude nuclei + -
 Internal capsules + -
 Brainstem + -
 Medium pons + -
 Cerebellar peduncles - -

 Pyramidal - -

 Trigeminal nerves - -
 Extensive + +
 Symmetrical + +
 Periventrciular + +
 External capsules + -
 Corpus callosum + +/-
 Anterior temporal + +

Cystic - -

Gradient echo sequences

 Microbleeds + -

 leucodystrophy MS

High-intense signals
 Ovoid - +
 Thalami - -
 Caude nuclei - -
 Internal capsules - +
 Brainstem - -
 Medium pons - -
 Cerebellar peduncles LBSL +
 LaminB1 -
 Pyramidal LBSL -
 LaminB1 -
 Trigeminal nerves LBSL
 Extensive + -
 Symmetrical + -
 Periventrciular + +
 External capsules - +
 Corpus callosum +/- +
 Anterior temporal - -

Cystic CACH -
Gradient echo sequences

 Microbleeds - -
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Article Details
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Title Annotation:MR in Leucodystrophies and MS
Author:Labauge, P.
Publication:The International MS Journal
Article Type:Report
Geographic Code:4EUFR
Date:Jul 1, 2009
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