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Publicationdate: |
1-2-2007 |
This review is based on a
presentation given by Frederik Barkhof at the Neuroradiology teaching
course for the Dutch Radiology Society and was adapted for the
Radiology Assistant by Robin Smithuis.
This presentation will focus on the role of MRI in the diagnosis of
Multiple Sclerosis.
We will discuss the following subjects:
- Typical findings in MS
- Role of MR in the McDonald criteria of MS
- How to differentiate MS lesions from other white matter diseases
- The importance of the a priori chance for the
differential diagnosis of white matter lesions.
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Introduction
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Multiple white matter lesions. MS or vascular?
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One of the most common questions in daily
radiology practise, when we see an image like the one on the left is:
'Do we have to think of Multiple Sclerosis or are these white matter
lesions the result of small vessel disease, for instance in a
hypertensive patient or should we think of more uncommon diseases?
In order to be able to answer that question, we
have to realise that when we study white matter lesions (WMLs):
- Many neurological diseases can mimic MS both clinically and
radiologically.
- Most incidentally found WMLs will have a vascular origin.
- The list of possible diagnoses of WMLs is long.
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Multiple sclerosis
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Multiple sclerosis (MS) is the most common
inflammatory demyelinating disease of the central nervous system in
young and middle-age adults, but also affects older people.
According to the McDonald criteria for MS, the diagnosis requires
objective evidence of lesions disseminated in time and space.
As a consequence there is an important role for MRI in the diagnosis of
MS, since MRI can show multiple lesions (dissemination in space), some
of which can be clinically occult and MRI can show new lesions on
follow up scans (dissemination in time).
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Typical MRI findings in MS
MS has a typical distribution of WMLs.
This can be very helpfull in the differentiation from vascular lesions
(see Table).
Typical for MS is involvement of corpus callosum, U fibers, temporal
lobes, brainstem, cerebellum and spinal cord.
This pattern of involvement is uncommon in other diseases.
In small vessel disease there sometimes is involvement of the brainstem,
but it is usually symmetrical and central, while in MS it is
peripheral.
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Coronal PD image of a brain specimen with MS
involvement
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Even when a patient is clinically suspected of
MS, we still have to study the WMLs carefully to decide whether these
lesions are indeed suggestive of MS, and not incidental age-related
findings.
We will discuss this more in detail when we look at the MRI criteria in
the Mc Donald criteria for MS.
On the left a coronal PD image of a brain
specimen with MS involvement.
First look at the image and look for lesions that are specific for MS.
Than continue.
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Coronal PD image of a brain specimen with MS
involvement
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The lesions in the deep white matter (yellow
arrow) are non specific and can be seen in many diseases.
Typical for MS in this case is:
- Involvement of the temporal lobe (red arrow)
- Juxtacortical lesions (green arrow) - touching the cortex
- Involvement of the corpus callosum (blue arrow)
- Periventricular lesions - touching the ventricles
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LEFT: involvement of U-fibers in MS. RIGHT:
U-fibers are not involved in patient with hypertension.
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Juxtacortical lesions are specific for MS.
These are adjacent to the cortex. They must touch the cortex.
Do not use the word subcortical to describe this location, because that
is a less specific term, indicating a larger area almost reaching the
ventricles.
In small vessel disease these juxtacortical U-fibers are not involved
and there will be a dark band between the WML and the (also bright)
cortex (yellow arrow).
Temporal lobe involvement is also specific
for MS.
In hypertensive encephalopathy, the WMLs are located in the frontal and
parietal lobes, uncommonly in the occipital lobes and not in the
temporal lobes.
Only in CADASIL there is early involvement of the temporal lobes.
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Multiple WMLs with typical distribution of MS.
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First look at the images on the left.
Describe the lesions and decide which findings are typical for MS.
Typical findings for MS as seen in this case are:
- Multiple lesions adjacent to the ventricles (red arrow).
- Ovoid lesions perpendicular to the ventricles (yellow arrow).
- Multiple lesions in brainstem and cerebellum.
These ovoid lesions are also called Dawson
fingers.
They represent areas of demyelination along the small cerebral veins
that run perpendicular to the ventricles.
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SE PDW-image of the spinal cord in a patient
with MS
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First look at the spinal cord images on the left
Describe the lesions and decide which findings are typical for MS.
There are multipel lesions in the spinal cord.
This is another typical feature of MS .
By the way did you notice the lesion in the brainstem?
A spinal cord lesion together with a lesion in the cerebellum or
brainstem is very suggestive of MS.
Spinal cord lesions are uncommon in most other CNS diseases, with
exception of ADEM, Sarcoid, Lyme and SLE.
Notice that this image is a conventional (not
fast/turbo) proton density weighted image (PDWI).
Although these CSE PDW-images need more acquisition time to obtain the
same resolution compared toFSE/TSE images, they are crucial for studying
the myelum.
First on SE PDW-images the MS plaques show a better contrast than on FSE
images.
Secondly on SE PDW-images the CSF has a uniformly low signal intensity
(like CSF), which gives the MS lesions a good contrast against the
surrounding CSF and normal cord tissue.
Use a 512 matrix and cardiac gating for optimal results.
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LEFT: Typical Dawson finger with enhancement on
T1WI. RIGHT: Multiple lesions and edema around enhancing lesion on
T2WI.
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Dawson fingers
First look at the images on the left
Describe the lesions and decide which findings are typical for MS.
Typical findings for MS as seen in this case are:
- Ovoid lesions perpendicular to the ventricles (Dawson finger).
- Enhancing lesion.
- Multiple lesions adjacent to the ventricles.
Dawson fingers are typical for MS and are the
result of inflammation around penetrating venules.
These veins are perpendicular to the ventricular surface.
Enhancement is another typical finding in
MS .
This enhancement will be present for about one month after the occurence
of a lesion.
The simultaneous demonstration of enhancing and non-enhancing lesions in
MS is the radiological counterpart of the clinical dissemination in
time and space.
The edema will regress and finaly only the center will remain as a
hyperintense lesion on T2WI.
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Lymphocytic infiltration is seen surrounding a
small vein. These lymphocytes attack the myeline.
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On the left a specimen showing the perivenous
inflammation in MS.
MS starts as inflammation around these veins.
In the first four weeks of the inflammation there is enhancement with
gadolinium due to loss of blood brain barrier.
First there is homogeneous enhancement but this can change to ring
enhancement.
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Juxtacortical MS lesion located in the U-fiber.
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Juxtacortical lesions located in the
U-fibers are also very specific for MS.
You really have to look hard to notice them, because they are difficult
to differentiate from the hyperintense cortex.
The patient on the left not only has multiple periventricular lesions of
which some have the typical Dawson finger aspect (blue arrow), but
there also is a juxtacortical lesion.
The involvement of the U-fibers is best seen on the magnification view.
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T1WI: multiple enhancing lesions
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On the left a patient who was re-examined 3
months after the first clinical attack.
Describe the lesions and decide which findings are typical for MS.
Typical findings for MS as seen in this case are:
- Multiple enhancing lesions
- Many of these lesions 'touch the cortex' and must be located in
the U-fibers.
- These enhancing lesions all are new lesions, since Gadolinium
enhancement is only visible for about 1 month.
So this finding is proof of dissemination in time.
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LEFT: Single lesion on T2WI. RIGHT: Two new
lesions at 3 month follow up.
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New lesions on T2W images also indicate
dissemination in time.
The patient on the left had a follow up examination 3 months after the
first clinical event.
Notice how similar the positioning is.
This allows good comparison of the images.
Optimal positioning is discussed in the MRI protocol (see later).
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Mc Donald criteria for MS
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The McDonald criteria for MS were recommended in
2001 by an international panel and revised in 2005.
The diagnosis is either:
- MS : all criteria fullfilled
- possible MS : not all criteria fullfilled
- not MS : no criteria fullfilled
The McDonald criteria make use of the clinical
presentation and the advances of MR imaging.
When a patient presents with 2 or more attacks with clinical evidence of
2 or more neurological deficits, there is no need for additional
requirements to make the diagnosis of MS, because there is dissemination
in place and time.
In all other cases (less than 2 attacks or less than 2 clinical lesions)
there is a role for MRI to fullfill the diagnostic criteria by
demonstrating dissemination in space, in time or both.
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In the Mc Donald criteria the modified Barkhof
criteria for dissemination in place are used (Table on the left).
These criteria are very specific, because if you want to use MRI for the
diagnosis of MS, you have to make sure that the patient really has MS.
You do not want a patient to inject interferon daily if there is doubt
about the diagnosis.
At least 3 out of 4 of the Barkhof criteria need
to be present to fullfill the MRI criteria for MS.
These criteria were independently choosen and proved to be more specific
and accurate than criteria proposed by others for the prediction of
conversion of possible MS to definite MS (3).
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When patients present with only one symptom that
could be a first presentation of MS (possible MS), sometimes a follow up
MR is needed to prove that there is also dissemination in time in order
to fullfill the McDonald criteria.
The table on the left summarises the MR criteria for dissemination in
time.
Another way to prove dissemination in time is to await a second clinical
attack.
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MRI protocol
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Indications for MRI of the brain are:
- Clinically isolated syndrome suggestive of MS to prove
dissemination in time or space in order to fullfill the McDonald
criteria
- Patients with MS to determine the prognosis or reaction to
therapy
- To specify an atypical lesion in the spinal cord
Indications for MRI of the spinal cord are:
- Cord symptoms
- To gain specificity in case
of non-specific brain lesions
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MS Brain Protocol
At the start of the examination gadolinium is
given, because the longer you wait the more enhancement you will see on
the T1W images (MS lesions are not spontaneously bright on T1-weighted
images without contrast administration).
A scout with additional midsagittal T1WI is made for optimal and
constant positioning.
The sagittal FLAIR is ideal for detection of lesions in the corpus
callosum.
The PD/T2W scan is preferably conventional-SE and not TSE/FSE, because
on PD SE the CSF will be dark, enabling the visualisation of
juxta-ventricular and juxta-cortical lesions.
Finally the axial T1W-images are made after about 15 minutes to provide
optimal contrast enhancement.
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Coronal and midsagittal scout views are needed
for reproducible positioning of the slices, so you are able to compare
follow up studies.
Use the coronal scout to plan the true midsagittal image parallel to the
falx and other midline structures.
On a true midsagittal image a line is drawn through the hypophysis and
the roof of the fourth ventricle (fastigium).
This is called the HYFA: hypophysis-fastigium line.
Subsequently the slices are positioned with the middle slice at the
lower border of the splenium of the corpus callosum.
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MS Spinal cord Protocol
Gadolinium is not necessary when only the spinal
cord is examined.
Contrary to the brain there will only rarely be enhancement in the cord.
Only when other diagnoses are considered (e.g. sarcoid) Gd is
necessary.
The most diagnostic sequence is the conventional SE PDW, because this is
the most sensitive technique.
FLAIR should NOT be used in the spinal cord and will only demonstrate
10% of the lesions.
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Prevalence and a priori
chance
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When we look at the prevalence of the white
matter diseases, you will notice that there are enormous differences.
Heriditary diseases are extremely uncommon as individual diseases, but
as a group they are not that uncommon, but still far more uncommon than
MS.
If we look at the prevalence of Lyme's disease, which is a rather
popular disease at the moment, than we will notice that it still is a
very uncommon disease despite of all the serological tests that are
being performed nowadays.
When incidental WMLs are found, these are usually
the result of small vessel disease, since up to 50% of patients that
get an MR examination for whatever reason, will have WMLs of vascular
origin.
They are more common in older people and in patients with vascular risk
factors like atherosclerosis, high blood pressure, high cholesterol,
diabetes, amyloid angiopathy, hyperhomocysteinemia, atrial fibrillation
etc.
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Reporting
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If a patient is clinically suspected of having MS
and the MR-images support that diagnosis, than you should not consider
the possibility of Lyme's disease and neuro-SLE in the differential
diagnosis, because they have such a low prevalence.
There must be other ways to impress your collegues.
These diagnoses are only worth mentioning if there are clinical findings
that support these diagnoses.
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Consequently, it is not wise to put MS in the
differential diagnosis, if the clinician does not suspect the patient of
having MS and on the MR incidental WMLs are found.
The odds are against the diagnosis of MS, because vascular WMLs are
50-500 times more likely than MS plaques.
On the other hand if a patient is clinically suspected of having MS and
multiple WMLs are found, our major concern is the differential diagnosis
MS versus vascular disease and we have to follow the McDonald criteria.
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Differential diagnosis of
WMLs
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The differential diagnosis of white matter
lesions is extremely long.
In normal aging WMLs are seen, but most WMLs are acquired and of
hypoxic-ischemic origin.
The most common inflammatory disease is Multiple Sclerosis.
The most comon viral infections are PML and HIV.
Inherited diseases usually will have symmetrical abnormalities, so they
have to be differentiated from intoxication.
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DD multiple patchy lesions
On the left a collection of images with multiple
punctate and patchy lesions in the WM.
Some will be discussed in more detail.
There is no complete overlap between the images on the left and the text
on the right.
Borderzone infarction
Key finding: typically these lesions are located in only one hemisphere,
either in deep watershed area or peripheral watershed area. Case on the
left is infarction in deep watershed area.
ADEM
Key findings: Multifocal lesions in WM and basal ganglia 10-14 days
following infection or vaccination.
As in MS, ADEM can involve the spinal cord, U-fibers and corpus callosum
and sometimes show enhancement.
Different from MS is that the lesions are often large and in a younger
age group. The disease is monophasic.
Lyme
2-3mm lesions simulating MS in a patient with skin rash and
influenza-like illness.
Other findings are high signal in spinal cord and enhancement of CN7
(root entry zone).
Sarcoid
Sarcoid is the great mimicker. The distribution of lesions is quite
similar to MS.
PML
Progressive Multifocal Leukencephalopathy (PML) is a demyelinating
disease caused by JC virus in immunosuppressed patients.
Key finding: space-occupying, non enhancing WMLs in the U-fibers (unlike
HIV or CMV).
PML may be unilateral, but more often asymmetrical bilateral.
Virchow Robin spaces
Key finding: Bright on T2WI and dark on FLAIR.
Small vessel diease
WMLs in the deep white matter. Not located in corpus callosum,
juxtaventricular or juxtacortical.
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DD multiple enhancing
lesions
On the left a collection of images with multiple
enhancing lesions in the WM.
Some will be discussed in more detail.
There is no complete overlap between the images on the left and the text
on the right.
Vasculitis
Most diseases with vasculits are characterised by punctiform
enhancement.
Vasculitis in the brain is seen in SLE, PAN, Behcet, syphilis, Wegener,
Sjogren and Primary angiitis of CNS
Behcet
Behcet is more commony seen in Turkish patients.
Typicall findings are abrainstem lesions with nodular enhancement in the
acute phase
Metastases
Metastases are mostly surrounded by a lot of edema.
Borderzone infarction
A peripheral border zone infarction may enhance in the early phase.
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T2WI and FLAIR
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Virchow Robin spaces
First look at the images on the left and describe
the lesions.
Then continue.
On the T2W image there are multiple high
intensity lesions in the basal ganglia.
On the FLAIR image these lesions are dark, so they follow the intensity
of CSF on all sequences (they were hypointense ion the T1WI).
This signal intensity in combination with the location is typical for VR
spaces.
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FLAIR image
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Virchow Robin spaces are CSF spaces around
penetrating leptomeningeal vessels.
They are typically located in basal ganglia, around atria, near the
anterior commissure and in the middle of the brainstem.
On MR they follow the signal intensity of CSF on all sequences.
They are dark on FLAIR and PD unlike other WMLs.
Usually they are small except around the anterior commissure, where
perivascular spaces can be larger.
On the image on the left we see both very wide VR
spaces aswell as confluent hyperintense lesions in the WM.
This case nicely illustrates the difference between VR spaces and WMLs.
This is an extreme case and this condition is known as état criblé.
VR spaces enlarge with age and hypertension as a result of atrophy of
surrounding structures.
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Normal aging: Widening of sulci,
periventricular caps (arrow) and bands and some punctate WMLs in the
deep white matter.
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Normal Aging
In normal aging we can see:
- Periventricular caps and bands
- Mild atrophy with widening of sulci and ventricles
- Punctate and sometimes even confluent lesions in the deep white
matter (Fazekas I and II).
Periventricular caps are hyperintense regions
around the anterior and posterior pole of the lateral ventricles and are
associated with myelin pallor and dilated perivascular spaces.
Periventricular bands or 'rims' are thin linear lesions along the body
of the lateral ventricles and are associated with subependymal gliosis.
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White matter changes in Fazekas I, II and III.
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Normal Aging (2)
The clinical significance of white matter changes in aging has not been
fully elucidated.
There is a relationship between several cerebrovascular risk factors and
the presence of white matter changes.
One of the strongest risk factors however, apart from hypertension, is
that of age.
What is still considered normal depends on the
age of the patient.
These white matter changes are classified according to Fazekas (see
Fazekas classification in Addendum).
Mild (punctate WMLs: Fazekas I) and sometimes even moderate changes
(confluent WMLs: Fazekas II) in the deep white matter can be considered
normal in aging.
The severe form of white matter lesions (extensive confluent WMLs:
Fazekas III) however is never considered normal.
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SE T2WI: multiple WMLs in a hypertensive
patient.
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Vascular disease
First look at the images on the left and describe
the lesions.
Then continue.
The location of these white matter lesions is in
the deep white matter and it is important to notice that these lesions
are not juxtaventricular, not juxtacortical and not located in the
corpus callosum.
Unlike in MS, they do not touch the ventricles or the cortex.
Given the a priori greater chance of hypoxic-ischemic WM lesions, we
must conclude that these WMLs probably have a vascular origin.
Only if the clinical findings strongly direct us towards inflammatory,
infectious, toxic or other diseases, we should consider these
diagnoses.
Suggesting the diagnosis of MS in a patient with these MR findings and
with no clinical suspicion for MS would be unwise.
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The spinal cord in this patient was normal.
In a patient with vasculitis or ischemia the spinal cord is usually
normal, while in a MS patient in more than 90% of the cases it will be
abnormal (2).
If the differentiation between a vascular origine of WMLs and MS is
difficult for instance in an older patient who is suspected of MS, than a
MR of the spinal cord can be helpfull (2).
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Vascular disease (2)
When we go back to the first case that was shown, it is now very obvious
that this is vascular disease.
There is widespread disease in the deep white matter, but the U-fibers
and corpus callosum are not involved.
Ischemic WMLs present as lacunar infarcts,
watershed infarcts or diffuse hyperintens lesions within the deep white
matter.
Lacunar infarcts are due to arteriolar sclerosis of small penetrating
medullary arteries.
Watershed infarctions are the result of atherosclerosis of larger
vessels, for instance carotid obstruction or the result of
hypoperfusion.
Atherosclerotic brain changes are seen in 50% of patients older than 50
years.
They are found in normotensive patients, but more common in
hypertensives.
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Sarcoid
First look at the images on the left and describe
the lesions.
Then continue.
The distribution of lesions is quite similar to
MS.
Besides lesions in the deep WM, there are some juxtaiventricular lesions
and even Dawson finger-like lesions.
The final diagnosis was sarcoid.
Sarcoid has surpassed neurosyphilis as the great mimicker.
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Sarcoid (2)
On the left we see the coronal Gd-enhanced T1W images of this patient.
First study these images, than continue.
There is punctate enhancement in the basal nuclei.
This is seen in sarcoid and can also be seen in SLE or other vasculitis.
Typical for sarcoid in this case is the leptomeningeal enhancement
(yellow arrow).
This is the result of granulomatous inflammation of the leptomeninges.
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Sarcoid (3)
Another typical finding in this same case is the linear enhancement
(yellow arrow).
This is due to inflammation along the Virchow Robin spaces.
This is also a form of leptomeningeal enhancement.
This explains why sarcoid has a similar distribution as MS, because the
Virchow Robin spaces follow the small penetrating veins, that are
involved in MS.
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Typical skin rash caused by spirochaet
transmitted by a tick.
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Lyme disease
Lyme disease is caused by a spirochaet (borrelia
Burgdorferi) that is transmitted by a tick.
It first causes a skin rash.
A few months later the spirochaet can infect the CNS and MS-like WMLs
are seen.
Clinically Lyme presents with acute CNS symptoms
(e.g.cranial nerve palsy) and sometimes transverse myelitis.
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MS like lesions in Lyme's disease.
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Lyme disease (2)
Key finding: 2-3mm lesions simulating MS in a patient with skin rash and
influenza-like illness.
Other findings are high signal in spinal cord and enhancement of CN7
(root entry zone).
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HIV
Key finding: Atrophy and symmetric
periventricular or more diffuse WMLs in AIDS patient
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Cadasil
Cadasil is short for cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukencephalopathy.
It is an herited small vessel disease.
Clinical clues: migraine, dementia and family history.
Key finding: subcortical lacunar infarcts with small cystic lesions and
leukencephalopathy in young adults.
Localisation in anterior temporal pole and external capsule have a high
specificity.
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Addendum
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2005 Revised McDonald MS
Diagnostic Criteria
In April, 2001, an international panel in
association with the NMSS of America recommended revised diagnostic
criteria for multiple sclerosis.
These new criteria have become known as the McDonald criteria after
their lead author.
They make use of advances in MRI imaging techniques and are intended to
replace the Poser Criteria and the Schumacher Criteria.
These criteria were revised in 2005 and listed in the table on the left.
An Attack is defined as:
- Neurological disturbance of kind seen in MS
- Subjective report or objective observation
- 24 hours duration, minimum
- Excludes pseudoattacks, single paroxysmal episodes
Time Between Attacks is defined as 30 days
between onset of event 1 and onset of event 2.
MRI Evidence Of Dissemination In Space is when
three out of four criteria are seen:
- 1 Gd-enhancing or 9 T2 hyperintense lesions if no Gd-enhancing
lesion
- 1 or more infratentorial lesions
- 1 or more juxtacortical lesions
- 3 or more periventricular lesions (1 spinal cord lesion can
replace a missing infratentorial lesion and contribute to the 9
T2-lesions)
MRI Evidence Of Dissemination In Time is defined
as:
- A Gd-enhancing lesion demonstrated in a scan done at least 3
months following onset of clinical attack at a site different from
attack
- or In absence of Gd-enhancing lesions at 3 month scan, follow-up
scan after an additional 3 months showing Gd-lesion or new T2 lesion.
Positive CSF is oligoclonal IgG bands in CSF (and
not serum) or elevated IgG index.
Positive visual evoced potentials (VEP) is delayed but well-preserved
wave form
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Fazekas classification
The Fazekas classification is used to describe
changes in the deep white matter.
Whenever you see these WMLs, try to describe them according to this
Fazekas classification:
- Fazekas I : small punctate lesions in the deep white matter.
- Fazekas II : larger WMLs that are beginning to become confluent.
- Fazekas III : extensive confluent WMLs.
Fazekas I is considered normal in aging.
Fazekas II is considered abnormal in patients < 75 Years.
Fazekas III is abnormal in any age group.
These WMLs are probably due to microangiopathy and seen more frequently
in patients with vascular risk factors .
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