0:00

Up till now,

0:01

we've been talking about demyelinating

0:03

disorders where we have normal white

0:06

matter that is being destroyed

0:07

by various disease processes.

0:09

When we refer to dysmyelinating disorders,

0:12

we're usually talking about white matter

0:14

diseases in which the white matter

0:15

was never good from birth,

0:17

or that there is a process that is leading

0:21

to the abnormal formation of white matter.

0:25

With regard to the dysmyelinating

0:27

disorders, these are very uncommon causes.

0:31

They're very uncommon diseases. However,

0:33

among them,

0:34

the most common is metachromatic

0:36

leukodystrophy and adrenal leukodystrophy,

0:39

and we're going to emphasize those two

0:41

as representatives of dysmyelinating

0:43

disorders. Nonetheless,

0:45

you see that there are quite a number of

0:47

various entities here that are listed that

0:50

can lead to abnormal white matter

0:52

formation or hypomyelination,

0:55

in which the white matter never

0:57

forms normally. In addition,

0:59

there are other metabolic disorders that

1:02

will lead to abnormal development

1:05

or creation of white matter.

1:06

So we're going to lump all of these under

1:08

the dysmyelinating disorders.

1:11

As I mentioned,

1:13

metachromatic leukodystrophy is thought

1:15

to be one of the most common of

1:17

the dysmyelinating disorders.

1:18

And like many of these disorders,

1:21

there is often a very young infantile

1:25

version. There's a childhood version,

1:27

and there's an adult version of

1:29

metachromatic leukodystrophy.

1:30

And along with that,

1:31

you may see varying severity

1:33

of this disease.

1:34

This disease is associated with diffuse

1:37

abnormal white matter signal and something

1:40

that we call a tigroid appearance of

1:43

the periventricular white matter.

1:45

By tigroid appearance,

1:46

you'll see that there are tiny little dots

1:48

within the white matter that is likened

1:51

to the tiger stripes, if you will.

1:54

This particular disorder is due

1:56

to arylsulfatase deficiency,

1:58

which is an enzyme that is required

2:00

to make the myelin sheath.

2:02

The patient's symptoms include

2:03

gait disturbance, strabismus,

2:05

various eye problems,

2:07

as well as speech disturbance and absence

2:10

of making milestones as a child.

2:13

The key to metachromatic leukodystrophy

2:16

is this tigroid appearance on MRI,

2:18

as well as relative sparing

2:20

of the U fiber.

2:21

So it's much more of a central

2:23

white matter disease.

2:24

Let's look at it on slides.

2:26

Here we have a T1-weighted scan to the

2:29

left and a T2-weight scan

2:31

on the right-hand side.

2:33

And what one sees is a symmetric white

2:35

matter abnormality that is, in general,

2:39

sparing the U fibers.

2:41

By central, I mean,

2:43

that is in a periventricular zone.

2:45

Here's our ventricles.

2:47

But doesn't go out to the far

2:49

periphery of the brain.

2:51

It stays in this central area

2:55

by the tigroid appearance.

2:56

What I'm referring to are these little

2:58

dots that you're seeing in.

2:59

That white matter,

3:04

that is what is referred to

3:06

as the tigroid appearance.

3:08

And sometimes it's better demonstrated

3:10

at other times,

3:11

but generally around the frontal

3:14

horns in particular,

3:15

you may see these little dots of darker

3:19

signal amidst the bright signal,

3:21

which is the tigroid appearance.

3:24

This is from a radiographics article that

3:29

was demonstrating metachromatic

3:30

leukodystrophy and the tigroid

3:33

stripes of that entity.

3:36

So again,

3:37

this is from radiographics in 2002.

3:40

But what one is seeing are these little

3:42

dots of bright signal intensity within the

3:46

central white matter. As you can see,

3:48

maybe on the left side,

3:49

better than the right.

3:50

Absence of involvement of the periphery,

3:53

the subcortical U fibers.

3:55

And on the section that's

3:57

a little bit lower,

3:58

maybe this is a little bit more of the

4:00

tigroid striped look of the somewhat

4:05

spared myelin amidst the bright

4:08

signal intensity.

4:09

Abnormal myelin of metachromatic

4:11

leukodystrophy in keeping with

4:14

our use of abbreviations,

4:18

people will write down often MLD for this

4:22

entity, metachromatic leukodystrophy, MLD.

4:26

Among the other dysmyelinating disorders,

4:29

there are some that are associated

4:30

with macrocephaly,

4:32

and those are Canavan's disease and

4:35

Alexander's disease. Fortunately,

4:38

Canavan's disease is an entity that is

4:41

a diagnosis that can be made with the

4:43

combination of MR Spectroscopy.

4:46

Because of the N-acetyl aspartate

4:49

peak changes,

4:51

those that are involving the posterior

4:53

white matter somewhat selectively

4:56

are adrenoleukodystrophy and

4:58

adrenomyelodystrophy.

5:01

Let's take a look at those.

5:03

So, of those, we mentioned,

5:04

Canavan's disease.

5:05

Canavan's disease tends to have

5:08

a macrocephalia, large head.

5:10

In a child with a frontal predilection

5:14

for involvement.

5:16

It favors the subcortical U fibers,

5:19

and that makes it a distinction from

5:21

metachromatic leukodystrophy,

5:23

which you recall, I was saying,

5:24

has a more central involvement.

5:27

This is due to that deficiency of

5:29

N-acetylaspartylase enzyme that is

5:32

required for normal white

5:33

matter development.

5:37

This is a patient who has that

5:39

entity of Canavan's disease.

5:42

And let's distinguish it from

5:44

metachromatic leukodystrophy.

5:47

Here we have an old CT,

5:48

we have the MRI scan,

5:50

and as opposed to metachromatic

5:52

leukodystrophy,

5:53

we see that the white matter changes

5:54

go all the way out to the periphery.

5:56

This is our cortex. So this is.

5:59

Involvement of the subcortical U fibers

6:04

with Canavan's disease.

6:09

You notice also that the head

6:11

seems a little bit larger,

6:12

and that's not just due to magnification.

6:15

The patients have macrocephaly,

6:17

which is also seen in Alexander's disease.

6:20

As I mentioned,

6:21

the diagnosis of Canavan's disease can

6:25

be made with the combination of MR

6:28

Spectroscopy. So Canavan's disease,

6:31

we see again the involvement out to the

6:34

periphery of the white matter

6:36

in this patient

6:38

with involvement of the

6:39

subcortical U fibers.

6:41

But what we're also seeing here is

6:43

this large spike in the NAA.

6:47

Here we have creatinine and choline

6:49

peaks over here at three and 3.2.

6:51

But this very high spike in the NAA is due

6:56

to accumulation of N-acetyl aspartate,

6:59

because it's not being broken down by

7:01

that enzyme, N-acetylaspartylase,

7:04

that should be occurring in the

7:06

development of normal white matter.

7:11

Characteristic feature

7:13

of Canavan's disease,

7:15

along with the subcortical

7:17

U fiber involvement.

7:19

This is a credit to Peter Barker,

7:21

who's the head of our MR

7:22

Spectroscopies team.

7:24

Alexander's disease is the other of the

7:27

white matter dysmyelinating disorders

7:29

that has enlargement of the

7:32

head and macrocephaly,

7:34

but with the frontal predilection.

7:36

And this is also known as fibrinoid

7:39

leukodystrophy.

7:40

It too involves the U fibers.

7:43

Contrast that with this entity.

7:46

In this case,

7:47

we have a posterior predilection for

7:49

the white matter dysmyelination.

7:53

So here you see white matter involvement

7:56

of the posterior parietal

7:58

and occipital lobe.

8:00

You can see also the involvement of the

8:02

splenium here with abnormal signal

8:05

intensity and anointing effect.

8:08

On the Flare scan,

8:09

we actually see involvement to the

8:13

thalamus in the lateral geniculate body.

8:17

The lateral geniculate body is part of the

8:20

thalamus that is associated with

8:21

the visual apparatus. So,

8:23

as you could imagine,

8:24

with a person who has an occipital

8:26

and parietal lobe involvement,

8:28

as well as lateral geniculate involvement,

8:30

the clinical symptoms are usually

8:32

a visual disturbance,

8:34

and this is the entity of

8:35

adrenoleukodystrophy.

8:37

So adrenal leukodystrophy is characterized

8:39

by the posterior predilection,

8:42

the involvement of the lateral geniculate,

8:45

the extent to the subcortical U fibers,

8:49

not quite as severe as what we saw with,

8:53

for example, the Canavan's case,

8:55

but it does go out more peripherally than

8:57

what one would expect with

8:59

metachromatic leukodystrophy.

8:59

A dystrophy with adrenal leukodystrophy.

9:02

There is another characteristic feature

9:04

and that is contrast enhancement of the

9:07

leading edge of the dysmyelination.

9:10

So here we have a T2-weighted scan showing

9:12

the occipital lobe demyelinating

9:16

dysmyelinating process with on

9:20

post-gadolinium T1-weighted scan enhancement

9:23

along the leading edge of

9:24

the dysmyelination.

9:26

So we don't see it in the central

9:27

aspect of the dysmyelination,

9:28

but along the periphery of the

9:30

dysmyelination where you have white matter

9:33

breakdown and breakdown of

9:35

the blood-brain barrier.

9:37

This enhancement in a dysmyelinating

9:40

disorder is very uncommon except

9:43

in adrenoleukodystrophy.

9:46

Adrenoleukodystrophy is secondary to acyl

9:51

CoA synthetase deficiency

9:53

where you have no very

9:56

long-chain fatty acid breakdown.

10:01

Adrenal leukodystrophy was popularized in

10:05

the movie entitled Lorenzo's Oil and this

10:09

describes the patients with adrenal

10:13

leukodystrophy treated by Hugo Moser,

10:16

who is a physician at Johns Hopkins School

10:19

of Medicine, recently passed,

10:21

but used to work at the Kennedy

10:23

Krieger Institute.

10:24

And Hugo Moser was the person who

10:28

developed the diet that was sparing the

10:32

long-chain fatty acid diet for patients

10:35

who had adrenoleukodystrophy and it

10:38

miraculously led to improvement

10:41

in the patient's symptoms.

10:43

I shouldn't mention that the adrenal of

10:45

adrenal leukody is that these patients

10:47

typically have adrenal gland abnormalities

10:50

and hypoadrenalism in association with the

10:54

visual disturbance that's also associated

10:56

with adrenoleukody by virtue of the

10:59

occipital involvement. So again,

11:01

adrenoleukodystrophy treated

11:03

with Lorenzo's oil,

11:05

which is the

11:07

dietary manipulation advocated by Hugo

11:11

Moser for resolution of the symptoms or

11:14

improvement of the symptoms in patients

11:16

who have adrenoleukodystrophy. On Mr.

11:19

Spectroscopy,

11:20

the adrenoleukodystrophy shows the

11:23

breakdown of the white matter demonstrated

11:27

by a decrease in the

11:30

and the choline secondary to

11:34

the white matter breakdown.

11:36

As the patients are treated with

11:38

the dietary manipulation,

11:40

you find a return of the NAA to a more

11:44

normal height with the improvement

11:47

in the patient's symptoms.