MULTIPLE SCLEROSIS

Myelin and White Matter• The gray and white matter of the central nervous system (CNS)

differ not only in gross morphology but also in water content and macromolecular components, notably membrane lipids.

• Although the gray matter primarily contains neurons and their processes, the white matter is composed predominantly of myelinated bundles of axons

• The oligodendroglial cell membrane is the source of the myelin sheath, which is a tightly wrapped, multilayered membrane composed of a repeating structure characterized by lipid-cytoplasm-lipid-water and which ensheathes axons

.

• Cholesterol, galactocerebroside, sphingomyelin, and phospholipids are the lipids found in fully formed white matter and account for the stability and strength

• proteins are also embedded within the myelin, including proteolipid protein, myelin basic protein (MBP), 20,30-cyclic-nucleotide 30-phosphodiesterase, myelin-associated glycoprotein, and myelin/oligodendrocyte glycoprotein

• . Any process, including metabolic injury or ischemia, that changes the chemical composition of myelin will result in a less stable structure that is more susceptible to injury .

• Neuroglial cells, namely oligodendrocytes, astrocytes, and microglia, are primarily responsible for the maintenance or “well-being” of the white matter- by providing structural and nutritional support of neurons, regulating the extracellular environment, and acting as scavenger cells

Progression of Myelination

• Proximal pathways before distal (e.g., brainstem before supratentorial brain)

• Sensory (visual and auditory) before motor• Central white matter before peripheral• Posterior before anterior

Myelinated Regions at Birth (or Shortly After Birth)

• Dorsal brainstem• Inferior, superior cerebellar peduncles• Perirolandic region• Corticospinal tract• Central portion of centrum semiovale• Posterior limb of internal capsule to cerebral

peduncle• Ventrolateral thalamus• Optic nerve, chiasm, tract

Myelination and MR Findings

• The most commonly used marker for evaluating normal brain maturation on conventional MR is the progression of myelination.

• Myelination starts in the second trimester of gestation and continues into adulthood, beginning with the peripheral nervous system and then the spinal cord, the brainstem, and finally the supratentorial brain.

• Myelination of the brain evolves in a predictable sequential fashion over the first 2 postnatal years .

• Studies have suggested that the sequence of myelination has functional significance and is correlated with psychomotor development ..

• As white matter becomes myelinated, it appears hyperintense on T1-weighted and hypointense on T2-weighted images relative to gray matter

• it is known that the signal changes on T1-weighted MR parallel increases in certain lipids that occur during the formation of myelin from oligodendrocytes .

• The signal changes on T2-weighted MR have been presumed to be correlated with the period of maturation of the myelin sheath seen histologically as thickening and tightening of the spiral of myelin around the axon and loss of water

• During the first 6 months of life, T1-weighted images are most useful for evaluating the progression of myelination ..

• After 6 months of age, most cerebral white matter appears high in signal intensity on the T1-weighted images,

• beyond this time the T2-weighted images are generally relied on to further evaluate myelin progression .

• By 24 months of age, the process of myelination is essentially complete except for the terminal zones of myelination found in the occipital-parietal periventricular white matter.

• These regions appear as subtle, ill-defined areas of hyperintensity

CLASSIFICATION OF WHITE MATTER DISEASES

• “. From the pathologic point of view, white matter diseases can be classified into three major groups:

• primary demyelination,• secondary demyelination, • dysmyelination.

Primary demyelinating diseases are characterized by loss of normally formed myelin with relative preservation of axons

Multiple sclerosis Classic (Charcot type) Acute (Marburg type) Diffuse cerebral sclerosis (Schilder type) Concentric sclerosis (Balò type) Neuromyelitis optica (Devic type)

Inflammatory demyelinating pseudotumor

Secondary demyelination - Demyelination associated with a known etiology or a systemic disorder

preferential destruction of white matter (i.e., destruction of both axons and myelin

• Associated with infectious agents and/or vaccinations

• AssociateAssociated with physical/chemical agents or therapeuticprocedures

• Associated with nutritional/vitamin deficiency• Associated with genetic abnormality

• Dysmyelination is a pathologic process of the white matter characterized by defective formation or maintenance of myelin.

• Many of these dysmyelinating have known genetic defects regarding abnormal metabolism of myelin.

• These disorders also called leukodystrophies

Leukodystrophies

• X-linkedAdrenoleukodystrophyClassic typeAdrenomyeloneuropathyPelizaeus-Merzbacher disease

Autosomal recessiveVanishing white matter diseaseGloboid cell leukodystrophy (Krabbe disease)Canavan disease (spongy degeneration of the brain)Metachromatic leukodystrophyCockayne syndromea

Aicardi-Goutière syndromea

Neonatal adrenoleukodystrophy

Pattern of inheritance unknownAlexander disease

• Multiple sclerosis - is the most common inflammatory demyelinating disease of the central nervous system in young and middle-age adults.

• A significant body of information suggests a viral etiology in genetically susceptible individuals .

• However, there has been no confirmed isolation of a conclusive and unequivocal infective agent at autopsy or biopsy of MS plaques

• MS is characterized by a variety of clinical courses and disease patterns.

• Most MS cases are categorized into the classic form, or Charcot type

• Most patients initially present in the third and fourth decades,

• The incidence of MS is two to three times higher in females than in males, and it is quite uncommon in children, with only 0.3% to 0.4% of all cases occurring during the first decade.

The first clinical symptom is

• often impaired or double vision; • other common complaints include weakness,

numbness, tingling, and gait disturbances.• As the disease progresses, loss of sphincter

control, blindness, paralysis, and dementia may develop.

• Patients rarely experience pain with MS, except that associated with eye movement in association with optic neuritis

The clinical course of classic MS is highly variable. four temporal patterns of multiple sclerosis .

• Most patients (80% to 85%) experience a relapsing-remitting course of exacerbations (attacks) and remissions of neurologic deficits separated by stable periods.

• . About 10% to 15% of the cases have a nonremitting progressive course and have been termed primary-progressive MS .

• Less than 5% of patients start off with a primary progressive course but develop discrete exacerbations and are categorized under the progressive- relapsing MS

• Patients exhibiting the chronic-progressive pattern typically have more severe spinal cord involvement.

• Late in the classic form of the disease, severe neurologic disability with cognitive impairment is common, regardless of the overall time course of the progression .

• MS in this group, especially in infants or children younger than 5 years, may have unusual clinical and imaging features.

• Seizures have been reported to occur more frequently than in adults.

• In addition to these clinical patterns, patients may be monosymptomatic, in which the presentation consists of a single episode of a neurologic deficit

• These patients are included in the clinically isolated syndrome category, such as optic neuritis, transverse myelitis, or brainstem syndrome

PATHOLOGY• Characteristic pattern of distribution of plaques in

brains affected by MS is widely recognized, considerable variation is noted from patient to patient

• For unknown reasons, there is a distinct propensity for involvement of certain regions of white matter, most notably the periventricular white matter , optic nerves, brainstem, and spinal cord

• The characteristic susceptibility of the periventricular regions to MS plaques is not uniform; however, most plaques are seen anatomically related to subependymal veins

• About 50% occur in a periventricular distribution, predominantly near the angles of the lateral ventricles .

• The periaqueductal region and the floor of the fourth ventricle are also frequently involved

• MS plaques are typically situated within white matter, gray matter lesions are not uncommon on pathologic examination

• Typically, these lesions go through different stages, including an

• acute “active” stage,• followed by a subacute stage with plaques with

radially expanding “active rims” and plaques with “smoldering rims,”

• finally reach the “inactive” gliotic stage

Imaging

• MR has fundamentally changed the clinical evaluation of patients with MS.

• The sensitivity of MR to MS lesions far exceeds that of the clinical examination and any other imaging modality (e.g., computed tomography [CT] .

• MR is not specific for the diagnosis of MS because white matter lesions that mimic those of MS may be detected in both normal volunteers and patients harboring other pathologic conditions, some of which have nothing to do with demyelinating disease per se.

• Moreover, conventional MR can be normal in up to 25% of patients with a proven clinical diagnosis

• . For these reasons, MR imaging cannot be the sole criterion for the diagnosis of MS but must be included with clinical and laboratory findings

MS Brain Protocol

Indications for MRI of the brain are:

• Clinically isolated syndrome suggestive of MS to prove dissemination in time or space in order to fulfill the McDonald criteria

• Patients with MS to determine the prognosis or response to therapy

• To specify an atypical lesion in the spinal cord

• 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).

• A scout with additional mid-sagittal T1WI is made for optimal and constant positioning.

• 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.

.• Finally the axial T1W-images are made after about 15 minutes

to provide optimal contrast enhancement

Magnetic Resonance Findings• typically presenting as scattered foci of varying

size demonstrating high signal intensity on T2-weighted images

• MS lesions are frequently situated in the periventricular white matter, internal capsule, corpus callosum, pons, and but may be found throughout the myelinated white matter and within gray matter

• . Plaques located in the immediate periventricular region may be difficult to appreciate on T2-weighted image

• proton density– weighted images or fluid-attenuated inversion recovery (FLAIR) images usually better define periventricular lesions.

• MS plaques have a propensity to occur in the periventricular region

• commonly appear as linear or ovoid lesions oriented perpendicular to the lateral ventricle (Dawson fingers),

• MR appearance of MS lesions is highly variable and certainly not specific .

• anatomic distribution of the lesions should not be considered key to the diagnosis because “exceptional” locations are commonly encountered.

• However, the corpus callosum is a region that is especially vulnerable to demyelination in MS, possibly due to its intimate neuroanatomic relationship to the lateral ventricular roofs and to small penetrating vessels.

• Studies have shown focal areas of high signal intensity on T2-weighted images in the inferior aspect of the corpus callosum (callosal–septal interface) in up to 93% of MS patients

• . Sagittal T1-weighted images also nicely depict these lesions as focal areas of thinning of the inferior aspect of the corpus callosum

• MS lesions typically decrease in size over time and leave a smaller residual plaque.

• MS plaques may enhance after the administration of intravenous contrast , reflecting transient abnormality of the blood–brain barrier.

• The enhancement patterns are extremely variable and may appear homogeneous, ringlike, or nodular.

• Treatment with steroids may also be associated with a marked reduction in lesion enhancement and morphology .

• Contrast enhancement may be used to add specificity to the finding of multiple hyperintensities on T2-weighted images because the finding of enhancing along with nonenhancing lesions is quite common in MS (

• Although quite commonly large MS lesions have very little mass effect, masslike lesions (tumefactive MS) that may mimic a tumor on imaging

• Perfusion MR techniques may also be useful to increase the confidence of the noninvasive diagnosis of tumefactive MS .

• Typically there is evidence of decreased perfusion within the lesion in comparison with contralateral, normal-appearing brain parenchyma.

• MS can also appear as very subtle diffuse hyperintensity in the white matter

• Increasing hypointensity of MS plaques on T1-weighted images has been correlated with increased demyelination and axonal loss on pathology .

• These lesions may approach the signal intensity of CSF, referred to as “black holes,” and have been shown to be correlated more closely with clinical disability

• Peripheral lesional high signal intensity on T1-weighted images is frequently encountered, suggesting the presence of paramagnetic material and likely corresponds to the presence of free radicals in the macrophage layer forming the margin of an acute plaque.

• MS lesions may also display clearly defined rings within or surrounding plaques of demyelination

• Atrophy is common with progression of disease, usually manifested by ventricular enlargement and thinning of the corpus callosum,

• increased iron deposition is concomitantly found in the basal ganglia, thalami, cortex, and subcortical white matter

• . Rare reports are even found in the literature of meningeal enhancement (93) and hemorrhagic MS lesions

Revised Magnetic Resonance Imaging Criteria for the Diagnosis of Multiple SclerosisMagnetic resonance abnormality and

dissemination in spaceDissemination in time

At least one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium- enhancing lesion

Detection of gadolinium enhancement at least 3 mo after the onset of the initial clinical event, if not at the site corresponding to the initial event

At least one infratentorial lesion At least one juxtacortical lesion At least three periventricular lesions

Detection of a new T2 lesion if it appears at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event

A spinal cord lesion can be considered equivalent to a brain infratentorial lesion

Three of the following

• One of the most common questions in daily radiology practice 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, as 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.

• MS has a typical distribution of WMLs.This can be very helpful in differentiating them from vascular lesions .Typical for MS

• involvement of corpus callosum,• U-fibers,• temporal lobes,• brainstem,• cerebellum • 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 periphera

• 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

arrow) - touching the cortex• Involvement of the corpus

callosum (blue arrow)• Periventricular lesions -

touching the ventricles

• 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.

DAWSON FINGERS

• 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.

• .

• Enhancement is another typical finding in MS.This enhancement will be present for about one month after the occurrence 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 finally only the center will remain as a hyperintense lesion on T2WI

Juxtacortical lesions

• located in the U-fibers are also very specific for MS.

• The involvement of the U-fibers is best seen on the magnification view.

Variants

• Acute MS (Marburg type)- occurs as an infrequent variety of MS, most commonly in younger patients.

• It is often preceded by fever and typically has inexorable rapid progression to death within months.

• This fulminant form of MS has also been seen as a terminal event in classic MS.

• Pathologic findings of extensive myelin destruction, severe axonal loss, and early edema are seen

• Neuromyelitis optica (Devic type) -is a syndrome of acute onset of optic neuritis and transverse myelitis that develop at approximately the same time and dominate the clinical picture

• . This condition has a different pathogenesis from most of the other MS types related to the fact that demyelination is antibody dependent and complement mediated

• . Approximately 50% of these patients die within several months

• . The relationship of Devic syndrome to MS is controversial; indeed, other acute demyelinating disorders, including acute disseminated encephalomyelitis, can affect optic nerves and spinal cord

• Schilder type, or myelinoclastic diffuse

• refers to an entity consisting of extensive, confluent, asymmetric demyelination of both cerebral hemispheres with involvement of the brainstem and cerebellum. It is usually

• seen in children presenting with seizures, signs of pyramidal tract involvement, ataxia, and psychiatric symptomatology.

• Adult cases have aso been described .

• Typically, there is a rapid progression of disease over the course of 1 to 2 years, but the demyelinating process may be fulminant se..

• Concentric sclerosis (Balò type)

• IT is a very rare type of demyelinating disease in which large regions with alternating zones of demyelinated and myelinated white matter are found.

• The myelinated regions may reflect remyelination rather than spared normal myelin.

• This progressive disease is more often found in young patients and is more common in the Philippines.

• When encountered, Balò concentric sclerosis has a pathognomonic appearance on both pathology and MR

• Tumefactive MS• Tumefactive MS is a variant of

Multiple Sclerosis.

• The open-ring enhancement pattern with low signal T2 ring and low CBF are all indicative of demyelination.

EXTRA CEREBRAL LESIONS

Spinal cord.• MS lesions of the spinal cord are usually found in

combination with lesions in the brain; however, 5% to 24% of cases can be found in isolation

• MR studies have shown that cord abnormalities may be found in approximately 75% of MS patients and in an even higher proportion of patients with spinal cord symptoms

• Most lesions are found in the cervical region

• Axial T2-weighted images demonstrate the typical peripheral location of MS lesions commonly the dorsolateral aspect of the cord, where pial veins are adjacent to white matter .

• Involvement of both gray and white matter by MS plaques can be seen.

• Gadolinium contrast administration frequently demonstrates enhancement of acute spinal cord lesion

• The most typical enhancement pattern in demyelinating spinal cord lesions is a peripheral ringlike enhancement, although this is not always seen

• Enhancing MS plaques can be virtually indistinguishable from neoplastic lesions and other inflammatory lesions of the spinal cord particularly when the spinal cord is enlarged due to edema.

• Therefore, clinical correlation and often serial follow-up scanning are necessary to formulate a specific diagnosis,

Differential diagnosis of WMLs

DD multiple patchy lesions

• Borderzone infarctionKey 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.

• ADEMKey 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

• Lyme2-3mm 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)

• PMLProgressive 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 asymmetrical and bilateral.

• Metastases

Metastases are mostly surrounded by a lot of edema.

• Virchow Robin spaces

On the T2W image there are multiple high intensity lesionsMc location in the basal ganglia. basal ganglia, around atria, near

the anterior commissure and in the middle of the brainstem.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.

• Normal AgingIn 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.

Newer Techniques

• Proton MR spectroscopy has been studied by several investigators in MS

• Decreased levels of NAA have been reported in acute active and chronic plaques

• Serial MR spectroscopic studies have shown that the NAA level can be partially restored,

• The described reduced level in MS plaques does not imply irreversible damage. Instead, its recovery might be related to resolution of edema or recovery from sublethal neuroaxonal injury

• MT techniques have been applied to brain MR in an attempt to characterize MS lesions and to discern otherwise occult disease in normal-appearing brain parenchyma.

• This pulse sequence technique, which can be implemented on a conventional scanner, exploits differences in relaxation between immobilized water transiently bound to macromolecules and water protons not associated with macromolecules.

• The hypothesis underlying these investigations is that demyelination results in more free water compared with myelinated white matter or intact but edematous tissue.

• Selective suppression of immobilized water is accomplished by the application of an off-resonance saturation pulse, which saturates the broad resonance of protons bound to macromolecules.

• . Using this experimental design, it has been shown in some studies that MT ratios are higher in normal mature myelinated white matter than in gray matter.

• A slight decrease of the magnetization transfer ratio was noted in early inflammatory lesions without demyelination in models of experimental allergic encephalomyelitis.

• More pronounced reductions in MT ratios have been described in demyelinating lesions in experimental models (proportional to the degree of demyelination) and in patients with MS

• diffusion MR study showed that markedly hypointense nonenhancing lesions showed higher apparent diffusion coefficient (ADC) values than isointense nonenhancing lesions, indicating that quantitative diffusion data from MR imaging differs among MS lesions that appear different from each other on T1-weighted images.

• These quantitative diffusion differences imply microstructural differences, which may prove useful in documenting irreversible disease.

• A whole-brain diffusion MR histogram study also showed that MR diffusion histograms can quantify visible and occult cerebral lesion load in patients with MS

• Fiber tractography is another promising technique for evaluation of white matter abnormalities in MS patients, in particular in assessing the degree of axonal loss

• demonstrating fewer fibers in corticospinal tracts of patients with higher lesion loads