Multiple Sclerosis and Other Idiopathic Inflammatory-Demyelinating Diseases

CHAPTER 43 Multiple Sclerosis and Other Idiopathic Inflammatory-Demyelinating Diseases

Idiopathic inflammatory-demyelinating diseases (IIDDs) represent a broad spectrum of central nervous system (CNS) disorders that can be differentiated on the basis of severity, clinical course, and lesion distribution, as well as imaging, laboratory, and pathologic findings. The spectrum includes monophasic, multiphasic, and progressive disorders ranging from highly localized forms to multifocal or diffuse variants.

Relapsing-remitting and secondary progressive multiple sclerosis (MS) are the two most common forms of IIDDs.1 MS can also have a progressive course from onset (primary progressive and progressive relapsing MS). Some patients have a benign course with minimal or no disability years after onset (benign MS). Fulminant forms of IIDDs include a variety of disorders that have in common the severity of the clinical symptoms, an acute clinical course, and atypical findings on MRI. The classic fulminant IIDD is Marburg disease. Balo’s concentric sclerosis, Schilder’s disease, and acute disseminated encephalomyelitis (ADEM) can also present as acute and severe attacks.

Monosymptomatic IIDD, such as transverse myelitis, optic neuritis, and brain stem demyelinating syndromes are commonly the first manifestation of MS, although a percentage of patients never actually develop the disease. Patients with monofocal clinical syndromes and MRI evidence of brain lesions consistent with demyelination have an 88% chance of developing clinically definite MS over the subsequent 14 years, whereas clinically similar patients with normal brain MRIs have less than a 20% chance of such progression.2 Hence, brain MRI is essential to target patients at high risk of early development of MS to select them for early immunomodulatory treatment.

Some IIDDs have a restricted topographic distribution, such as Devic’s neuromyelitis optica (NMO), recurrent optic neuritis, and relapsing transverse myelitis, which can have a monophasic or, more frequently, a relapsing course. Other types of IIDDs occasionally present as a focal lesion that may be clinically and radiographically indistinguishable from a brain tumor. It is difficult to classify these tumefactive or pseudotumoral lesions within the spectrum of IIDDs. Some cases have a monophasic, self-limited course, whereas in others the tumefactive plaque is the first manifestation or appears during a typical relapsing form of MS. MRI of the brain and spine is the imaging technique of choice for diagnosing these disorders, and, together with the clinical and laboratory findings, can accurately classify them.


Multiple sclerosis is a chronic, persistent inflammatory-demyelinating disease characterized pathologically by areas of inflammation, demyelination, axonal loss, and gliosis scattered throughout the CNS. MS has a predilection for the optic nerves, brain stem, spinal cord, and cerebellar and periventricular white matter.

Relapses and progression are the two major clinical phenomena of prototypic MS. Relapses are considered the clinical expression of acute focal or multifocal inflammatory demyelination disseminated in the CNS. Remission of symptoms early in the disease is likely the result of remyelination, resolution of inflammation, and compensatory mechanisms such as redistribution of axolemmal sodium channels and cortical plasticity. These recovery mechanisms are less effective after recurrent attacks.

In parallel with the demyelinating episodes there may be damage to the exposed axons, leading to transection of the axons and retrograde neuronal degeneration. This process can be irreversible and is responsible for the accrual of disability that occurs as the disease progresses. Later in the disease, flares of inflammatory activity occur less frequently but the neurodegenerative process continues inexorably.


MS is one of the most common neurologic disorders and the second cause of disability in Western countries in young white adults. It is relatively common in Europe, the United States, Canada, New Zealand, and parts of Australia but rare in Asia and in the tropics and subtropics of all continents. Within regions having a temperate climate, the incidence and prevalence of MS increase with latitude, both north and south of the equator. Multiple sclerosis is twice as common in women as in men; men have a tendency for later disease onset with a poorer prognosis. The incidence of MS is low in childhood, increases rapidly after the age of 18, reaches a peak between 25 and 35, and then slowly declines, becoming rare at 50 and older.3 The disease affects approximately 1 million people between 17 and 65 years of age worldwide.

MS is usually not life shortening, but its socioeconomic importance is second only to trauma in young adults. The etiology of MS is still unknown, but it most likely results from an interplay between as yet unidentified environmental factors and susceptibility genes. Factors supporting a genetic influence include excess occurrence in Northern Europeans relative to indigenous populations from the same geographic location, familial aggregation, and lack of MS excess in adopted relatives of patients with MS.

The environmental epidemiology of MS is poorly understood. Although a direct causal link with diverse infectious agents has been suggested, such infectious agents may simply provide the appropriate milieu for the development of an autoreactive immune response directed against CNS myelin. Up to now, only Epstein-Barr virus (EBV) infection has been established as a strong, consistent risk factor. As compared with uninfected individuals, MS risk is about 10-fold higher among individuals who experienced an undiagnosed EBV infection in childhood and at least 20-fold higher among individuals who developed mononucleosis.3

Clinical Presentation

The clinical course of MS can follow different patterns over time but is usually characterized by acute episodes of worsening (relapses, bouts), gradual progressive deterioration of neurologic function, or a combination of both these features (relapsing MS). In a relatively small percentage of patients, the disease has a progressive course from onset without acute relapses (primary progressive MS).

Relapses or attacks typically present subacutely, with symptoms developing over hours to several days, persisting for several days or weeks, and then gradually abating. With time, the extent of recovery from these attacks often decreases, and baseline neurologic disability accumulates. The outcome in patients with relapsing forms of MS varies. About 50% of MS patients become dependent on a walking aid after 15 years of disease, whereas 10% remain free of any major disability after 25 years. The biologic basis of this variation in long-term clinical outcome is poorly understood. Neither symptom onset, nor gender, nor age at onset of symptoms predicts progression. However, increased attack frequency and poor recovery from attacks in the first year of clinical disease predict more rapid deterioration.4 The number of T2-weighted (T2W) lesions on brain MRI also predicts attack frequency and long-term disability.2

Relapsing-Remitting and Secondary Progressive Multiple Sclerosis

Relapsing forms account for 85% of all MS. This clinical form typically presents as an acute, clinically isolated syndrome attributable to a monofocal or multifocal CNS demyelinating lesion. The presenting lesion usually affects the optic nerve (optic neuritis), spinal cord (acute transverse myelitis), brain stem (typically an internuclear ophthalmoparesis), and cerebellum (clumsiness and gait ataxia).

Some patients have brief, recurrent, stereotypical phenomena (paroxysmal pain or paresthesia, trigeminal neuralgia, episodic clumsiness or dysarthria, and tonic limb posturing). Eventually, cognitive impairment, depression, vertigo, progressive quadriparesis and sensory loss, ataxic tremors, pain, sexual dysfunction, spasticity, bladder problems, and other manifestations of CNS dysfunction may become troublesome. Many MS patients describe fatigue that is worse in the afternoon. The onset of symptoms post partum, symptomatic worsening with increased body temperature (Uhthoff’s symptom), and pseudoexacerbation with fever are also frequent clinical features.

Over the following years, patients usually experience episodes of acute worsening of neurologic function, followed by variably complete recovery (relapsing-remitting course). Clinical and subclinical activity is frequent in this form. After several years of the relapsing-remitting course, more than 50% of untreated patients will develop progressive disability with or without occasional relapses, minor remissions, and plateaus (secondary progressive course).1

As long as the cause of MS remains unknown, causal therapy and effective prevention are not possible. Immunomodulatory drugs such as interferon-β, glatiramer acetate, mitoxantrone, and natalizumab can alter the course of the disease, particularly in the relapsing-remitting form, by reducing the number of relapses and the accumulation of lesions as seen on MRI, and by influencing the impact of the disease on disability. Patients with the secondary progressive form of MS, continuing relapses of activity, and pronounced progression of disability may also benefit from immunomodulatory or immunosuppressive therapy.

Primary Progressive and Progressive-Relapsing Multiple Sclerosis

Primary progressive forms comprise approximately 10% of MS cases. This form of MS begins as a progressive disease with occasional plateaus and relapses and temporary minor improvements. Progressive-relapsing MS follows a progressive course like primary progressive MS but shows clear acute relapses that may or may not be followed by full recovery.1

As compared with patients with the more common relapsing form of MS, patients with primary progressive MS tend to be older, show more rapid progression from onset, and are as likely to be male as female. The most common presentation by far is slowly progressing spastic paraparesis and, less frequently, progressive cerebellar, brain stem, visual, hemiplegic, and cognitive syndromes.5

According to the 2010 McDonald criteria (Table 43-1),6 a diagnosis of primary progressive MS can be established if patients show insidious neurologic progression for at least 1 year associated with MS-like abnormalities on brain and/or spinal MRI, and/or oligoclonal bands on cerebrospinal fluid (CSF) study. In patients who present with progressive spastic paraparesis, it is mandatory to exclude structural or metabolic causes of myelopathy by appropriate laboratory studies and spinal MRI.

TABLE 43-1 Diagnosis of MS with Disease Progression from Onset

CSF, cerebrospinal fluid.

From Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2010; 69:292–302.

Compared with patients with the more frequent relapsing forms of MS, patients with primary progressive MS have smaller T2 lesion loads, smaller T2 lesions, slower rates of new lesion formation, and minimal gadolinium enhancement on brain MRI, despite their accumulating disability. The presence of extensive cortical damage, diffuse white matter tissue damage, and prevalent involvement of the spinal cord may partially explain this discrepancy between the MRI abnormalities and the severity of the clinical disease (Fig. 43-1).

Because patients with primary progressive MS may have less inflammation than those with relapsing MS, they may be less likely to respond to immunomodulatory therapies.

Benign Multiple Sclerosis

Benign MS accounts for about 20% of all cases of MS. These patients remain fully functional in all neurologic systems for at least 15 years after the onset of the disease. Factors that predict a benign course include onset with optic neuritis, female gender, onset before the age of 40, absence of pyramidal signs at presentation, duration of first remission more than 1 year, and only one exacerbation in the first 5 years after disease onset. Nevertheless, the form designated “benign” MS is often transient, because 50% to 70% of patients originally considered to have benign MS show significant clinical worsening or a shift to a secondary progressive disease course by 10 years after the baseline examination.

Patients with benign MS have few new or enlarging lesions on serial brain MRI studies, and such lesions that occur have a lower incidence of enhancement after use of a contrast agent (Fig. 43-2), as compared with the typical relapsing-remitting forms of MS associated with progressive disability (Fig. 43-3). Prediction of a benign MS course may have an impact on the decision to initiate immunomodulatory medication, because this treatment may be unnecessary or might at least be postponed for many years.

Multiple Sclerosis Variants

Marburg Disease

Marburg disease (also termed malignant MS) is a rare, acute MS variant that occurs predominantly in young adults. It is characterized by a confusional state, headache, vomiting, gait unsteadiness, and hemiparesis. This entity has a rapidly progressive course with frequent, severe relapses leading to death or severe disability within weeks to months, mainly from brain stem involvement or mass effect with herniation. Most of the patients who survive subsequently develop a relapsing form of MS. Because Marburg disease is often preceded by a febrile illness, this disease may also be considered a fulminant form of ADEM if it has a monophasic course. At the time of the clinical presentation, it can be difficult to find good predictors of whether the patient will follow a fulminant course, develop mild or severe MS, or even develop MS at all.

Pathologically, lesions of Marburg disease are more destructive than those of typical MS or ADEM and are characterized by massive macrophage infiltration, acute axonal injury, and tissue necrosis. Despite the destructive nature of these lesions, areas of remyelination are often observed. Neuropathologic studies suggest that this fulminant form of MS is often associated with deposition of immunoglobulins and pronounced complement activation at sites of active myelin destruction, which may support plasma exchange or mitoxantrone as treatment options when high-dose corticosteroids are not effective.

In Marburg disease, MRI typically shows multiple focal T2 lesions of varying size, which may coalesce to form large white matter plaques disseminated throughout the hemispheric white matter and brain stem (Fig. 43-4). Perilesional edema is often present. The lesions may show enhancement. A similar imaging pattern is also seen in ADEM.

A fulminant course can also be present in acute IIDDs showing a tumefactive or Balo-like lesion.

Schilder’s Disease

Schilder’s disease is a rare acute or subacute disorder that can be defined as a specific clinicoradiologic presentation of IIDD. It commonly affects children and young adults. The clinical spectrum of Schilder’s disease includes psychiatric predominance, acute intracranial hypertension, intermittent exacerbations, and progressive deterioration. Imaging studies show large ring-enhancing lesions involving both hemispheres, sometimes symmetrically, and located preferentially in the parieto-occipital regions. These large, focal demyelinating lesions can resemble a brain tumor, an abscess, or even adrenoleukodystrophy. MR features that suggest possible Schilder’s disease include large and relatively symmetric involvement of both brain hemispheres, incomplete ring enhancement, minimal mass effect, restricted diffusivity, and sparing of the brain stem (Fig. 43-5).

Histopathologically, Schilder’s disease consistently shows well-demarcated demyelination and reactive gliosis with relative sparing of the axons. Microcystic changes and even frank cavitation can occur. The clinical and imaging findings usually show a dramatic response to corticosteroids.

Balo’s Concentric Sclerosis

Balo’s concentric sclerosis is thought to be a rare, aggressive variant of MS that can lead to death in weeks to months. The pathologic hallmarks of the disease are large demyelinated lesions showing a peculiar pattern of alternating layers of preserved and destroyed myelin. One possible explanation for the concentric alternating bands in this variant of MS may be that sublethal tissue injury is induced at the edge of the expanding lesion, which would then stimulate the expression of neuroprotective proteins to protect the rim of periplaque tissue from damage, thereby resulting in alternative layers of preserved and nonpreserved myelinated tissue.7

These alternating bands can be identified on T2W MRI, which typically shows concentric hyperintense bands corresponding to areas of demyelination and gliosis alternating with isointense bands corresponding to normal myelinated white matter (Figs. 43-6 and 43-7). This pattern can appear as multiple concentric layers (onionskin lesion), as a mosaic, or as a “floral” configuration. The center of the lesion usually shows no layering because of massive demyelination. Contrast enhancement and decreased diffusivity are frequent in the outer rings (inflammatory edge) of the lesion (see Fig. 43-7). On MRI this Balo pattern can be isolated, multiple, or mixed with typical MS-like lesions.

Although Balo’s concentric sclerosis was initially described as an acute, monophasic and rapidly fatal disease that resembled Marburg disease, large Balo-like lesions are frequently identified on MRI in patients with a classic acute or chronic MS disease course or in ADEM with a nonfatal course.

Tumefactive or Pseudotumoral IIDDs

Infrequently, IIDDs present as single or multiple focal lesions that can be clinically and radiographically indistinguishable from a brain tumor. This situation represents a diagnostic challenge and may require biopsy for definitive diagnosis, despite the clinical suspicion of demyelination. Given the hypercellular nature of these lesions, however, even the biopsy specimen may resemble a brain tumor. Large reactive astrocytes with fragmented chromatin (Creutzfeldt-Peters cells) are often present.

In some cases, pseudotumoral IIDDs are the first clinical and radiologic manifestation of MS. More commonly, tumefactive demyelinating plaques affect patients with a known diagnosis of MS (Fig. 43-8). In rare cases, pseudotumoral IIDDs have a relapsing course, with single or multiple pseudotumoral lesions appearing over time in different locations (Fig. 43-9).

On CT or MRI the pseudotumoral plaques usually present as large, single or multiple focal lesions within the cerebral hemispheres. Clues that can help to differentiate these lesions from a brain tumor are the relatively minor mass effect and the presence of incomplete ring-enhancement on gadolinium-enhanced T1-weighted (T1W) images, with the open border facing the gray matter of the cortex or basal ganglia (Fig. 43-10),8 sometimes associated with a rim of peripheral hypointensity on T2W sequences.


All the diagnostic criteria for establishing the diagnosis of MS proposed in the past 50 years are based on three main principles: (1) demonstration of disease dissemination in space (DIS); (2) demonstration of disease dissemination in time (DIT); and (3) reasonable exclusion of alternative explanations for the clinical presentation.

These principles were codified in 1983 by the Poser committee,9 which specified that the diagnosis of clinically definite MS could be based on either (1) occurrence of two attacks and clinical evidence of two lesions or (2) two attacks and clinical evidence of one lesion plus paraclinical evidence of a second lesion. MRI was not considered at that time because it was then a new, untested technique.

In 2001, new diagnostic criteria were published that incorporated a precisely defined role for MRI.10 These 2001 McDonald criteria integrated MRI criteria into their scheme to demonstrate dissemination of demyelinating lesions in space (Table 43-2). To demonstrate this principle, brain MR images must meet the Barkhof-Tintoré criteria, in which a threshold of at least three of the following four features must be achieved: (1) one gadolinium-enhancing lesion or nine T2 hyperintense lesions if gadolinium-enhancing lesions are not present, (2) at least one infratentorial lesion, (3) at least one juxtacortical lesion, and (4) at least three periventricular lesions. When three of these four parameters are not fulfilled, the presence of two or more subclinical lesions consistent with MS on brain MRI plus CSF detection of oligoclonal bands or a raised IgG index are required to demonstrate DIS. DIT can be demonstrated with MRI when new lesions have developed at least 3 months after the clinical onset. This can be a gadolinium-enhancing lesion on a scan obtained more than 3 months after a clinically isolated syndrome if it is not associated with the initial clinical event. When the scan shows no new enhancing lesion, a subsequent scan is required to demonstrate new T2 and/or gadolinium-enhancing lesions. This criterion requires between one and three MR images to be performed, with a minimum delay between symptom onset and the first scan of at least 3 months.

In 2005, a consensus revision of the McDonald criteria based on new evidence was proposed (see Table 43-2).13 Three major changes were introduced in the 2005 McDonald criteria. The first modification attempted to simplify the criteria for DIT. This was achieved by establishing the simple condition of demonstrating a new T2 lesion on a brain MR image at any time as compared with a reference scan done at least 30 days after the onset of the initial clinical event. The reason for selecting the 30-day time period was to exclude new T2 lesions occurring in the first few weeks after the onset of the first clinical episode, which would not be considered a new separate event. The second change proposed endeavored to better define the role of MRI of spinal cord lesions for demonstrating DIS.

A new version of the McDonald criteria (McDonald 2010)6 proposed new MR imaging criteria, in which demonstration of DIS requires the presence of at least one asymptomatic T2 lesion in two of the four locations defined as characteristic for MS: juxtacortical, periventricular, infratentorial, and spinal cord, while demonstration of DIT requires demonstration of a new T2 lesion on a follow-up scan irrespective of the timing of the baseline scan, or concomitant enhancing and non enhancing lesions on a scan performed at any time after symptoms onset11,12 (see Table 41-2). These criteria have shown similar (high) specificity for clinically definite MS and higher sensitivity when compared with the 2001 and 2005 McDonald criteria.

For optimal application of MRI criteria, scans must be technically adequate and well repositioned to permit fair comparisons between scans obtained at different times. Physicians involved in the diagnostic MRI evaluation must be provided with sufficient demographic and clinical information to properly interpret the imaging findings and be expert enough to recognize the full range of brain and spinal cord abnormalities that suggest the diagnosis of MS.


It is generally accepted that the sequence of events underlying the development of the inflammatory plaque in MS originates from a breach in the integrity of the blood-brain barrier via the interaction of integrins expressed on the surface of lymphocytes and adhesion molecules present on the endothelial surface of blood vessels. Genetic and environmental factors, such as a viral infection, may facilitate the entry of potentially pathogenic autoreactive T cells and antibodies into the CNS via bloodbrain barrier disruption. Local CNS factors upregulate the expression of endothelial adhesion molecules, which further enhances the movement of pathogenic cells into the CNS. Proinflammatory cytokines within the CNS activate resident and hematogenous macrophages, which contribute to tissue injury and demyelination.

To propagate the inflammatory cascade, T cells that have entered the CNS need to be activated by specific antigens, which requires the presentation of antigenic peptides in the context of major histocompatibility complex (MHC) molecules. Therefore the presence of the so-called trimolecular complex consisting of the T-cell receptor, the processed antigen, and the MHC molecule is needed to activate the T cells, which will ultimately orchestrate multiple cellular and humoral responses that result in tissue injury and formation of an acute inflammatory-demyelinating lesion.

MS is remarkably heterogeneous, particularly when one considers the inflammatory mechanisms leading to tissue damage, patterns of demyelination, oligodendrocyte survival, extent of remyelination, and degree of axonal injury. Luchinetti and colleagues grouped focal active MS plaques into four types, I through IV, on the basis of the pathogeneses of the lesions. All four types are characterized by T cell– and macrophagedominated inflammation:

The heterogeneous pathologic patterns have been related to specific MS variants. All patients with the Devic type of neuromyelitis optica have antibody-mediated tissue damage (type II), whereas all patients with the Balo type of concentric lesions have a distal oligodendrogliopathy (type III). Furthermore, primary oligodendrocyte degeneration (type IV) has only been found in patients with primary progressive MS disease.

In individual patients, this pathogenic heterogeneity disappears, because there is a striking homogeneity among lesions. For this reason it has been suggested that MS may represent a common name for different pathologic features.13 This hypothesis has important therapeutic implications because specific therapies can be targeted to specific mechanisms.


The pathologic hallmarks of MS lesions are (1) inflammation with T cells, B cells, and macrophages/microglia; (2) demyelination with oligodendrocyte loss during the chronic stage of the disease and varying degrees of remyelination; (3) axonal loss; and (4) gliosis with astrocyte proliferation and intense glial fiber production.

In general, MS plaques are centered on one or several medium-sized vessels and have a tendency to accumulate near the periventricular or outer surfaces of the brain and spinal cord. The lesions are usually round to oval but often show finger-like extensions in the periphery (Dawson’s fingers) that follow the path of a small- or medium-sized vessel. On gross inspection, the plaques appear as gray discolored areas with a firm tissue texture. Neuropathologically, focal MS lesions can be divided into chronic and active plaques.



Conventional MRI Techniques


MRI is the most sensitive imaging technique for detecting MS plaques throughout the brain and spinal cord. Proton density (PD)-weighted (PDW) or T2W MR images show areas of high signal intensity in the periventricular white matter in 98% of MS patients. MS plaques are generally round to ovoid and range from a few millimeters to more than 1 cm in diameter. They are typically discrete and focal at the early stages of the disease but become confluent as the disease progresses, particularly in the posterior hemispheric periventricular white matter (see Fig. 43-3). MS plaques tend to affect the deep white matter rather than the subcortical white matter, whereas small vessel ischemic lesions tend to involve the subcortical white matter more than the periventricular white matter. The total T2 lesion volume of the brain increases by 5% to 10% each year in the relapsing forms of MS.14

Both acute and chronic MS plaques appear bright on PDW and T2W sequences, reflecting their increased tissue water content. The signal increase indicates edema, inflammation, demyelination, reactive gliosis, and/or axonal loss in proportions that differ from lesion to lesion. The vast majority of MS patients have at least one ovoid periventricular lesion, whose major axis is oriented perpendicular to the outer surface of the lateral ventricles (Fig. 43-11). The ovoid shape and perpendicular orientation derive from the perivenular location of the demyelinating plaques (Dawson’s fingers).

MS lesions tend to affect specific regions of the brain, including the periventricular white matter situated superolateral to the lateral angles of the ventricles, the callososeptal interface along the inferior surface of the corpus callosum, the corticojuxtacortical regions, and the infratentorial regions. Focal involvement of the periventricular white matter in the anterior temporal lobes is typical for MS and rarely seen in other white matter disorders (Fig. 43-12). The lesions commonly found at the callososeptal interface are best depicted by sagittal fast-FLAIR images; so this sequence is highly recommended for diagnostic MRI studies (Fig. 43-13).

Jan 22, 2016 | Posted by in NEUROLOGICAL IMAGING | Comments Off on Multiple Sclerosis and Other Idiopathic Inflammatory-Demyelinating Diseases
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