Multiple Sclerosis - Updated version

Diagnosis and differential diagnosis

Frederik Barkhof and Robin Smithuis

Amsterdam University Medical Center and University College London and Alrijne Hospital Leiderdorp, the Netherlands

Publicationdate

This article is an updated version of the 2013 article and focusses 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.

There is an important role for MRI in the diagnosis of MS, since MRI can show multiple lesions - dissemination in space, many of which are clinically occult already at the time of first presentation, and MRI can show new lesions on follow up scans - dissemination in time, much earlier than new symptoms develop. 

Introduction

* In elderly subject of those with cardiovascular risk factors it is better to look for at least 3 periventricular lesions

McDonald criteria

Multiple sclerosis is the most common inflammatory demyelinating disease of the central nervous system in young and middle-age adults, but may also affect older people.

The diagnosis of MS requires elimination of more likely diagnoses and demonstration of dissemination of lesions in space and time.

Dissemination in Space

One or more T2 hyperintense lesions characteristic of MS in two or more of four areas of the CNS (Magnims criteria): cortical or juxtacortical, periventricular, infratentorial and spinal cord.

Dissemination in time

Simultanious presence of enhancing and non-enhancing lesions or a new T2 hyperintense or new enhancing lesion on a follow up scan

Click for larger view

Typical locations of MS lesions
This is a coronal T2 image of a brain specimen with MS involvement. The lesions in the deep white matter (yellow arrow) are nonspecific and can be seen in many diseases.

Typical for MS in this case is:

  • Involvement of the temporal lobe (red arrow)
  • Juxtacortical lesions (green circle) - touching the cortex (no intervening WM)
  • Involvement of the corpus callosum (blue arrow)
  • Periventricular lesions – in direct contact with the ventricles


An early diagnosis of MS allows treatment to start earlier and improves prognosis. This does carry the risk of a false positive diagnosis when MRI findings are misinterpreted.

MS phenotypes

Relapsing-remitting (RR)
A multiple sclerosis course characterised by relapses with stable neurological disability between episodes. 85% of cases, F>M.

Secondary progressive (SP)
65% of relapsing-remitting disease becomes secondary progressive.

Primary progressive (PP)
10-15%, M=F

Atypical presentations
Marburg, Schilder, Balo, Devic, tumefactive MS (open-ring sign)

Clinically isolated syndrome (CIS)
A monophasic clinical episode with patient-reported symptoms and objective findings reflecting a focal or multifocal inflammatory demyelinating event in the CNS, developing acutely or subacutely, with a duration of at least 24 h, with or without recovery, and in the absence of fever or infection.

Radiologically isolated syndrome (RIS)
MRI findings strongly suggestive of multiple sclerosis in a patient with no neurological manifestations or other clear-cut explanation.

MR findings in MS

LEFT: involvement of U-fibers in MS. RIGHT: U-fibers are not involved in patient with hypertension.

Juxtacortical lesions

Juxtacortical and cortical lesions are specific for MS.
They are adjacent to the cortex and must touch the cortex (yellow circle).

In small vessel disease the U-fibers are typically spared and on T2 and FLAIR there will be a dark band of normal WM between the WML and the bright cortex (white circle).

Do not use the word subcortical to describe this location, because that is a less specific term, indicating a larger area of white matter almost reaching the ventricles.

Juxtacortical MS lesion located in the U-fiber.

You really have to look hard to notice juxtacortical lesions  because they are difficult to differentiate from the hyperintense cortex.

Temporal lobe involvement

Temporal lobe involvement is also specific for MS.

In hypertensive encephalopathy, the WMLs mostly found 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.

LEFT: Typical Dawson finger with enhancement on T1WI. RIGHT: Multiple lesions and edema around enhancing lesion on T2WI.

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 fingers).
  • 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.

Symmetrical brainstem lesions in SVD (left) compared to typical asymmetrical MS lesions (right)

Brainstem lesions

Here we see typical differences in vascular brainstem lesions compared to MS.

The image on the left is an axial T2 weighted image illustrating typical vascular brainstem involvement, with a central involvement of the transverse pontine fibers.

The image on the right is an axial T2 weighted image of the brainstem of an MS-patient, showing typical peripherally located white matter lesions, often in or near the trigeminal tract, or bordering the 4th ventricle.

Spinal cord lesions

Typical spinal cord lesions in MS are relatively small and peripherally located.
They are most often found in the cervical cord and are usually less than 2 vertebral segments in length.
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 the exception of ADEM, sarcoid, and NMOSD. 

PD-image of the spinal cord in a patient with MS

The images show multiple short-segment lesions in the spinal cord. 

On PDW-images the spinal cord 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.
A good alternative for PDW is STIR; make sure to have always 2 contrasts or 2 planes.

Enhancement on T1-image (left). Edema around lesion on T2-image (right)

Enhancement

Enhancement is another typical finding in MS.
The enhancement will be present for about one month after the occurrence of a lesion.
The edema around a new lesion will regress and finally only the center will remain as a hyperintense lesion on T2WI.

Tumefactive MS. Arrow indicates biopsy site.

Tumefactive MS

Tumefactive MS is a variant of Multiple Sclerosis.
On MRI it presents as a large intra-parenchymal lesion with usually less mass effect than would be expected for its size.
They may show some peripheral enhancement, often with an incomplete ring unlike gliomas or intraparenchymal abscesses, which typically have a closed-ring enhancement.

These T2W and T1W post-gadolinium images are of a 39-year-old male who presented with subacute onset of hemianopsia.
He was referred for biopsy to differentiate between a glioma or demyelination.

There is an intraparenchymal mass in the right temporal and occital lobe with a hypointense rim on T2, which only partially enhances (open-ring sign) on the postcontrast images.
There is surrounding edema, but relatively little mass effect.

This was a biopsy-proven demyelinating lesion.
The open-ring enhancement pattern with low signal T2 ring and low CBF are all indicative of demyelination.

MS Differential diagnosis

Introduction

The differential diagnosis of MS is extremely large and includes almost all white matter diseases.
In this chapter we will only deal with a limited number.

A broader differential diagnosis of white matter diseases is found here.

However there are some rules that we can follow.

If a patient is clinically suspected of having MS and the MR-images support that diagnosis, then you should not consider other uncommon diseases.

When we look at the prevalence of the white matter diseases, you will notice that there are enormous differences.

Hereditary diseases are extremely uncommon as individual diseases, but as a group they are not that uncommon, but still far more uncommon than MS.

CNS involvement in Lyme disease is extremely rare.

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.

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 small vessel disease and we have to follow the McDonald criteria.

Brainstem involvement in small vessel disease (left). Focal brainstem lesions in MS (right).

Small vessel disease

The differences between small vessel disease and MS are summarized in the 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 may be involvement of the brainstem, but it is usually symmetrical and central, while in MS it is peripheral.

Here a typical case of small vessel disease.

There is widespread white matter disease with a symmetrical distribution.
Notice that the corpus callosum is not involved.

Patient with NMO showing a longitudinally extensive cord lesion with marked swelling. Bilateral neuritis optica. The diagnosis was confirmed by an AQP4-AB titer of 1:1024.

Neuromyelitis Optica

A very important differential to keep in mind, especially in patients with a bilateral optic neuritis and myelitis, is Neuromyelitis Optica Spectrum Disorder (NMOSD), previously called Devic's Disease.
This is a demyelinating disease caused by antibodies against aquaporin or MOG in which the optic nerves and spinal cord are usually involved.

Think of NMO when there is longitudinally extensive myelitis (LETM defined as more than 3 vertebral segments) with low T1-signal intensity and swelling of the cord.
On axial images the lesions often involve the central of the cord.
This is unlike MS, in which the lesions are usually smaller and peripherally located.

Often there are a few T2-lesions in the brain.

Read more on NMO in the spinal cord...

Balo's Concentric Sclerosis

Balo's Concentric Sclerosis is an uncommon demyelinating disease.

It is characterized by alternative bands of demyelination and myelin preservation, with a laminated onion-skin configuration.

Here T2 and postcontrast T1W images showing a large lesion in the left hemisphere with alternating T2-hyperintense and isointense bands.

On the T1W images after gadolinium there is alternating linear enhancement. Note that the outermost band shows diffusion restriction.

There is a smaller, similar lesion on the right.

ADEM extensive involvement of the cortical and gray matter - including thalamus.

ADEM

Acute Disseminated Encephalomyelitis (ADEM) is another important differential diagnosis of MS.

This is a monophasic, immune-mediated demyelinating disease which often presents in children following an infection or vaccination. Many of the have MOG antibodies.

On MRI there are often diffuse and relatively symmetrical lesions in the supra-and infratentorial white matter which may enhance simultaneously.

There often is preferential involvement of the cortical gray matter and the deep gray matter of the basal ganglia and thalami.

Here we have axial FLAIR and T2W-images of a young patient with ADEM - notice the extensive involvement of the cortical and gray matter, including thalamus.

Here another case of ADEM.

Notice the involvement of the basal ganglia and the middle cerebral peduncle.

Here another case of ADEM.

Notice the similarity to the other two cases.

The differences between ADEM and MS are summarized in the table.

Natalizumab-associated PML. Images were kindly provided by Bénédicte Quivron CH Jolimont, La Louvière, Belgium

Natalizumab-associated PML

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease caused by JC virus in immunosuppressed patients.

Natalizumab is a monoclonal antibody against α4-integrin approved for the treatment of multiple sclerosis due to a positive effect on clinical and magnetic resonance imaging (MRI) outcome measures.

A relatively rare but serious side effect of this drug is a higher risk of developing PML.

The diagnosis of PML according to diagnostic criteria is based on the clinical presentation, the identification of JCV DNA in the CNS (e.g., in the cerebrospinal fluid) and imaging findings preferably on MRI.

Compared to other PML populations such as HIV, the imaging findings in natalizumab-associated PML have been described as heterogeneous and fluctuating.

Key imaging signs are:

  • Focal or multifocal lesions in the supratentorial subcortical white matter involving the U-fibers and the cortical grey matter, less frequently posterior fossa and deep grey matter
    • T2-hyperintense (occasionally with small focal lesions in the vicinity of the main lesion)
    • T1-isointese or hypointense depending on the degree of demyelination
    • In approximately 30% of the patients PML lesions can show contrast enhancement.
    • High signal intensity on DWI particularly in the border of the lesions reflecting active infection and swelling of the white matter cells.

It can be difficult to differentiate progressive MS from natalizumab-associated PML.
See table for differences in imaging.

How to image natalizumab-associated PML:

  • FLAIR has the highest sensitivity in the detection of PML lesions
  • T2-weighted sequences can show certain aspects of PML lesions (eg, microcysts)
  • T1 with and without contrast is helpful to assess the degree of demyelination and signs of inflammation.
  • DWI is useful for the detection of active infection.

Further information: www.MS-PML.org

Differential diagnosis of WMLs

The differential diagnosis of white matter lesions is extremely long.
In normal ageing WMLs are seen, but most WMLs are acquired and of hypoxic-ischemic origin.
The most common inflammatory disease is Multiple Sclerosis.
The most common viral infections are PML and HIV.
Inherited diseases usually will have symmetrical abnormalities, so they have to be differentiated from intoxications.

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. In the case on the left the infarction is in the 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 Leukoencephalopathy (PML) is a demyelinating disease caused by JC virus in immunosuppressed patients.
Key finding: space-occupying, nonenhancing WMLs in the U-fibers (unlike HIV or CMV).
PML may be unilateral, but more often it is bilateral and asymmetrical.
Click here for more information.

Virchow Robin spaces
Key finding: Bright on T2WI and dark on FLAIR.

Small vessel disease
WMLs in the deep white matter. Not located in corpus callosum, juxtaventricular or juxtacortical.
In many cases there are also

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 vasculitis are characterized 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 commonly seen in Turkish patients.
Typical findings are brainstem lesions with nodular enhancement in the acute phase

Metastases
Metastases are mostly surrounded by a lot of edema.

Borderzone infarction
Peripheral border zone infarctions may enhance in the early phase.

T2WI and FLAIR

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.

FLAIR image

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 this image we see both very wide VR spaces as well 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 etat crible.
VR spaces enlarge with age and hypertension as a result of atrophy of surrounding structures.

Normal aging: Widening of sulci, periventricular caps (arrow) and bands and some punctate WMLs in the deep white matter.

Normal Aging

In normal ageing 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.

White matter changes in Fazekas I, II and III.

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:

  1. Mild - punctate WMLs: Fazekas I)
  2. Moderate - confluent WMLs: Fazekas II - in the deep white matter can be considered normal in aging.
  3. Severe - extensive confluent WMLs: Fazekas III - always abnormal.
SE T2WI: multiple WMLs in a hypertensive patient.

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, should we 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.

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 origin of WMLs and MS is difficult for instance in an older patient who is suspected of MS, than an MR of the spinal cord can be helpful (2).

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 hyperintense 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.

Sarcoid

First look at the images 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.

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.

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 to MS: the Virchow Robin spaces follow the small penetrating veins, which are involved in MS.

Typical skin rash caused by spirochete transmitted by a tick.

Lyme disease

Lyme disease is caused by a spirochete (borreliaBurgdorferi) that is transmitted by a tick.
It first causes a skin rash.
A few months later the spirochete 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.

MS like lesions in Lyme's disease.

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).

Natalizumab-associated PML. Images were kindly provided by Bénédicte Quivron CH Jolimont, La Louvière, Belgium.

Natalizumab-associated PML

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease caused by JC virus in immunosuppressed patients.

Natalizumab is a monoclonal antibody against α4-integrin approved for the treatment of multiple sclerosis due to a positive effect on clinical and magnetic resonance imaging (MRI) outcome measures.

A relatively rare but serious side effect of this drug is a higher risk of developing PML.

The diagnosis of PML according to diagnostic criteria is based on the clinical presentation, the identification of JCV DNA in the CNS (e.g., in the cerebrospinal fluid) and imaging findings preferably on MRI.

Compared to other PML populations such as HIV, the imaging findings in natalizumab-associated PML have been described as heterogeneous and fluctuating.

Key imaging signs are:

  • Focal or multifocal lesions in the supratentorial subcortical white matter involving the U-fibers and the cortical grey matter, less frequently posterior fossa and deep grey matter
    • T2-hyperintense (occasionally with small focal lesions in the vicinity of the main lesion)
    • T1-isointese or hypointense depending on the degree of demyelination
    • In approximately 30% of the patients PML lesions can show contrast enhancement.
    • High signal intensity on DWI particularly in the border of the lesions reflecting active infection and swelling of the white matter cells.

It can be difficult to differentiate progressive MS from natalizumab-associated PML.
See table for differences in imaging.

How to image natalizumab-associated PML:

  • FLAIR has the highest sensitivity in the detection of PML lesions
  • T2-weighted sequences can show certain aspects of PML lesions (eg, microcysts)
  • T1 with and without contrast is helpful to assess the degree of demyelination and signs of inflammation.
  • DWI is useful for the detection of active infection.

For further information please see: www.MS-PML.org

HIV

Key finding: Atrophy and symmetric periventricular or more diffuse WMLs in AIDS patient

Cadasil

Cadasil is short for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy.
It is an inherited small vessel disease.
Clinical clues: migraine, dementia and family history.

Key finding: subcortical lacunar infarcts with small cystic lesions and leukoencephalopathy in young adults.
Localizations of the WMLs in the anterior temporal pole and external capsule have a high specificity.

MRI protocol

MS Brain Protocol

Indications for MRI of the brain are:

  • Clinically isolated syndrome suggestive of MS to show dissemination in time or space in order to fulfill the McDonald criteria
  • Patients with MS to determine the prognosis or response to therapy
  • To screen for opportunistic infections in patients receiving immunosuppressive treatment (for example development of Progressive Multifocal Leukoencephalopthy in patients using natalizumab).


Gadolinium is administered at the start of the examination 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).

The sagittal FLAIR is ideal for detection of lesions in the corpus callosum and the 3D sequence allows for better detection of smaller and juxtacortical lesions.
The T2W scan is preferably conventional SE or FSE.

* You may choose for dual contrast or dual plane images

MS Spinal cord Protocol

Indications for MRI of the spinal cord are:

  • Cord symptoms
  • To gain specificity in case of non-specific brain lesions


Gadolinium is less relevant when only the spinal cord is examined and is only administered when other diagnoses are considered (e.g. sarcoid) .

The most sensitive sequence is the PD or STIR.
FLAIR should not be used in the spinal cord as it will only demonstrate 10% of the lesions.