Idiopathic Inflammatory Disease of the Cns

8/3/2019 Idiopathic Inflammatory Disease of the Cns

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REVIEW

Idiopathic inflammatory-demyelinating diseases

of the central nervous system

A. Rovira Caellas & A. Rovira Gols & J. Ro Izquierdo &

M. Tintor Subirana & X. Montalban Gairin

Received: 10 November 2006 /Accepted: 18 January 2007 / Published online: 28 February 2007# Springer-Verlag 2007

Abstract Idiopathic inflammatory-demyelinating diseases

(IIDDs) include a broad spectrum of central nervous systemdisorders that can usually be differentiated on the basis of

clinical, imaging, laboratory and pathological findings.

However, there can be a considerable overlap between at

least some of these disorders, leading to misdiagnoses or

diagnostic uncertainty. The relapsing-remitting and second-

ary progressive forms of multiple sclerosis (MS) are the most

common IIDDs. Other MS phenotypes include those with a

progressive course from onset (primary progressive and

progressive relapsing) or with a benign course continuing for

years after onset (benign MS). Uncommon forms of IIDDs

can be classified clinically into: (1) fulminant or acute

IIDDs, such as the Marburg variant of MS, Bals concentric

sclerosis, Schilders disease, and acute disseminated enceph-

alomyelitis; (2) monosymptomatic IIDDs, such as those

involving the spinal cord (transverse myelitis), optic nerve

(optic neuritis) or brainstem and cerebellum; and (3) IIDDs

with a restricted topographical distribution, including

Devics neuromyelitis optica, recurrent optic neuritis and

relapsing transverse myelitis. Other forms of IIDD, which

are classified clinically and radiologically as pseudotumoral,can have different forms of presentation and clinical courses.

Although some of these uncommon IIDDs are variants of

MS, others probably correspond to different entities. MR

imaging 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.

Precise classification of these disorders may have relevant

prognostic and treatment implications, and might be helpful

in distinguishing them from tumoral or infectious lesions,

avoiding unnecessary aggressive diagnostic or therapeutic

procedures.

Keywords Multiple sclerosis . Magnetic resonance

imaging . Brain diseases

Introduction

Idiopathic inflammatory-demyelinating diseases (IIDDs)

represent a broad spectrum of central nervous system

disorders that can be differentiated on the basis of severity,

clinical course and lesion distribution, and imaging,

laboratory and pathological findings [14]. This spectrum

includes monophasic, multiphasic, and progressive disor-

ders ranging from highly localized forms to multifocal or

diffuse variants.

Relapsing-remitting and secondary progressive (SP)

multiple sclerosis (MS) are the most common forms of

IIDD [5]. MS can also have a progressive course from

onset (primary progressive and progressive relapsing MS),

or a benign course with minimal or no disability for years

after disease onset (benign MS) [68]. Fulminant forms of

Neuroradiology (2007) 49:393409

DOI 10.1007/s00234-007-0216-2

A. R. Caellas (*)

Magnetic Resonance Unit (I.D.I.), Department of Radiology,

Vall dHebron University Hospital,Pg. Vall dHebron 119-129,

Barcelona 08035, Spain

e-mail: [email protected]

A. R. Gols

UDIAT, Diagnostic Centre, Parc Taul University Institute - UAB,

Sabadell, Spain

J. R. Izquierdo : M. T. Subirana: X. M. Gairin

Neuroimmunology Unit, Department of Neurology,

Vall dHebron University Hospital,

Barcelona, Spain


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IIDD include a variety of disorders that have in common

the severity of the clinical symptoms, an acute clinical

course and atypical findings on MR imaging. The most

classic fulminant IIDD is Marburg disease (MD), although

Bals concentric sclerosis (BCS), Schilders disease (SD)

and acute disseminated encephalomyelitis (ADEM) can

also present with acute and severe attacks.

Monosymptomatic IIDD, such as transverse myelitis,optic neuritis (ON) and brainstem demyelinating syn-

dromes are commonly the first manifestation of MS,

although a significant percentage of patients never develop

the disease. Patients who have these monofocal syndromes

and brain lesions consistent with demyelination on MR

images have an 88% chance of developing clinically

definite MS over the subsequent 14 years, as compared

with 19% of such patients with normal brain MR imaging

findings [9]. Hence, brain MR imaging is essential to target

patients at high risk of early development of MS, an

important factor when selecting patients for early immuno-

modulatory treatment.Some IIDDs have a restricted topographical distribution,

such as Devics neuromyelitis optica (NMO), recurrent ON

and relapsing transverse myelitis (RTM), which can have a

monophasic or, more frequently, a relapsing course. Other

forms of IIDD occasionally present as a focal lesion that

may be clinically and radiographically indistinguishable

from a brain tumor [1]. It is difficult to classify these

tumefactive or pseudotumoral lesions within the spectrum

of IIDDs. In some patients the course is monophasic and

self-limited, in others the tumefactive plaque is the first

manifestation or appears during a typical relapsing form of

MS, and rarely the tumefactive lesions have a recurrent

course (recurrent tumor-like lesions).

In this review, we present the clinical and radiological

characteristics of the different forms of IIDDs, with special

emphasis on the more uncommon ones.

Multiple sclerosis

MS is the most common neurological disorder in young

adults of Caucasian origin and is considered the prototypic

form of IIDD. The etiology of MS is still unknown, but an

interplay between as-yet-unidentified environmental factors

and susceptibility genes appears most likely [10]. The

morphological hallmarks are demyelination, inflammation,

gliosis and axonal damage, although heterogeneity of the

lesion pathology has been recognized [11].

The clinical course of MS can follow a varying pattern

over time, but is usually characterized by either episodic

acute periods of worsening (relapses, bouts), gradual

progressive deterioration of neurological function, or a

combination of both these features [5].

Relapsing-remitting and secondary progressive multiple

sclerosis

Relapsing forms, which account for 85% of all MS cases,

correspond to the most frequent clinical course of MS. The

disease typically begins in the second or third decade of life

and has a female predominance of approximately 2:1 [12].

The relapsing forms typically present as an acute clinicallyisolated syndrome (CIS) attributable to a monofocal or

multifocal central nervous system demyelinating lesion,

which usually involves the optic nerve, the spinal cord or

the brainstem and cerebellum. In this situation, brain MR

scanning demonstrates subclinical lesions in 50% to 75% of

patients, indicating a process disseminated in space and a

high risk of developing MS within the following years [13].

After a second, different clinical relapse that indicates a

process disseminated in time, the diagnosis of clinically

definite MS is established [14]. According to the new

diagnostic criteria proposed by McDonald et al., demon-

stration of dissemination in space and time, the two keyfactors required to establish the diagnosis of MS, can also

be achieved with MR imaging [15, 16].

Over the following years, patients usually experience

episodes of acute worsening of neurological function,

followed by a varying degree of recovery (relapsing-remitting

course, RR). After several years of this RR course, in which

clinical and subclinical activity is frequent, more than 50% of

untreated patients will develop progressive disability with or

without occasional relapses, minor remissions, and plateaus

(SP course) [5]. During the SP course, lesion activity

decreases and destructive changes predominate over inflam-

mation, leading to an increase in the volume of hypointense

lesions on T1-weighted images and to progressive brain

atrophy. New and enlarging T2-weighted lesions are

commonly seen over the whole course of the disease,

increasing the total volume of T2-weighted lesions [17].

As long as the etiology of MS remains unknown, causal

therapy or effective prevention is not possible. Immuno-

modulatory drugs such as beta-interferon or glatiramer

acetate can alter the course of the disease, particularly in the

RR form, by reducing the number of relapses and the

accumulation of lesions as seen on MR images, and by

influencing the impact of the disease on disability [18].

Patients with the SP form of MS, with continuing relapse

activity and pronounced progression of disability, may also

benefit from immunomodulatory (interferon) or immuno-

suppressive (mitoxantrone) therapy [19, 20].

Primary progressive and progressive-relapsing multiple

sclerosis

In primary progressive MS (PPMS), which comprises

approximately 15% of MS cases, the illness begins as a

394 Neuroradiology (2007) 49:393409


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progressive disease with occasional plateaus and relapses,

and temporary minor improvements. Progressive-relapsing

MS progresses from onset as does PPMS, but shows clear

acute relapses that may or may not be followed by full

recovery [5]. Patients with PPMS tend to be older than

those with the more common relapsing form, and are as

likely to be male as female [21]. The most common

presentation by far is slowly progressing spastic para-

paresis, and less frequently, progressive cerebellar, brain-

stem, visual, hemiplegic and cognitive syndromes [22].

Surprisingly, brain MR imaging in these patients depicts

a lower load of T2-weighted lesions, smaller T2-weighted

lesions, and slower rates of new lesion formation with

minimal gadolinium enhancement, despite the accumulat-

ing disability of the patients, as compared to the more

frequent relapsing forms of MS [23]. It has been suggested

that the presence of extensive cortical damage, diffuse

white matter tissue damage at a microscopic level and

prevalent involvement of the spinal cord may partially

explain this discrepancy between the MR imaging abnor-

malities and the severity of the clinical disease [24].

Because patients with PPMS may have less inflamma-

tion than those with relapsing forms of MS, they may be

less likely to respond to immunomodulatory therapies [25].

Benign multiple sclerosis

Patients with benign MS, accounting for around 20% of all

MS patients, remain fully functional in all neurological

systems for at least 15 years after the onset of the disease.

Onset with ON, female sex, onset before the age of

40 years, absence of pyramidal signs at presentation,

duration of first remission more than 1 year, and only one

exacerbation in the first 5 years after onset of MS, are

predictors of a benign course. Nevertheless, the label

benign MS is often temporary, because 50% to 70% of

patients who were originally considered affected by this

clinical phenotype show significant clinical worsening or a

shift to a SP disease course at 10 years after the baseline

examination [68].

Patients with benign MS have few new or enlarging

lesions on serial brain MR imaging studies, and such

lesions that do occur have a lower incidence of contrast

enhancement (Fig. 1), as compared to the typical RR forms

of MS associated with progressive disability (Fig. 2).

Prediction of a benign MS course may have an impact on

the decision to initiate immunomodulatory medication, as

this treatment may be unnecessary or might at least be

postponed for many years.

Fig. 1 Benign multiple sclerosis. Serial, contrast-enhanced brain T1-

W (upper row) and T2-W (lower row) MR images in a patient with

benign MS. Note the small number of new lesions that appeared

during the 3-year follow-up and the very low incidence of contrast

enhancement (arrow in the baseline scan)

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Fulminant forms of IIDD

Marburg disease

MD is an acute variant of MS characterized by a

confusional state, headache, vomiting, gait unsteadiness,

and hemiparesis. This rare relapsing form of MS has a

rapidly progressive course with frequent, severe relapses

leading to death or severe disability within weeks to

months, mainly related to brainstem involvement [26].

Most of the patients who survive later develop a relapsing

form of MS. Pathologically the lesions are more destructive

than those of typical MS or ADEM and are characterized

by massive macrophage infiltration, acute axonal injury,

and necrosis [27].

The typical MR imaging appearance of MD is multiple

focal lesions of varying size on T2-weighted images that

may coalesce to form large white matter plaques, dissem-

inated throughout the hemispheric white matter and

brainstem (Fig. 3) [28]. The lesions may show enhance-

ment, and perilesional edema is often present. A similar

imaging pattern is also seen in ADEM.

Plasma exchange or mitoxantrone administration should

be considered as treatment options in these patients when

high-dose steroids are not effective [2931].

A fulminant course can also be present in acute IIDDs

showing a tumefactive or Bal-like lesion. Therefore, in the

literature, it is common to find patients with similar clinical

and radiological findings classified as having MD, BCS or SD.

Schilders disease

SD is a rare acute or subacute disorder that can be defined

as a specific clinical-radiological presentation of IIDD

commonly affecting children and young adults [32, 33].

The clinical spectrum of SD includes psychiatric predom-

inance, acute intracranial hypertension, intermittent exacer-

bations, and progressive deterioration. Imaging studies

show large ring-enhancing lesions involving both hemi-

spheres, sometimes symmetrically, and located preferential-

ly in the parieto-occipital regions. These large, focal

demyelinating lesions can resemble a brain tumor, an

abscess or even adrenoleukodystrophy. Several imaging

findings can help to suggest the diagnosis of SD: large and

Fig. 2 Relapsing form of multiple sclerosis. Serial contrast-enhanced

T1-W (upper row) and FLAIR (lower row) MR images of the brain in

a patient with a typical relapsing form of MS and progressive

disability. Note the new lesions that appear during this 3-year

follow-up, some of them showing gadolinium enhancement (arrows)



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relatively symmetrical involvement of both brain hemi-

spheres, incomplete ring enhancement, minimal mass

effect, low signal on diffusion-weighted MR images, and

sparing of the brainstem (Fig. 4) [34, 35].

Histopathologically, SD consistently shows well-demarcated

demyelination and reactive gliosis with relative sparing of the

axons, although microcystic changes and even frank cavitation

can occur [36, 37]. The clinical and imaging findings usually

show a dramatic response to steroids [38].

Poser et al. have proposed diagnostic criteria for SD that

emphasize the distinction from typical MS, ADEM, and

adrenoleukodystrophy (Table 1) [3].

Bals concentric sclerosis

BCS is thought to be a rare and aggressive variant of MS

leading to death in weeks to months. The pathological

hallmarks of the disease are large demyelinated lesions

characterized by a peculiar pattern of alternating layers of

preserved and destroyed myelin [39, 40].

A possible explanation for the formation of these

alternating bands of preserved and nonpreserved myelinat-

ed tissue concentric demyelination layers in this variant of

MS could be the induction of sublethal tissue injury at the

edge of the expanding lesion, which might stimulate the

expression of neuroprotective proteins that protect the rim

of periplaque tissue from damage [41].

These alternating bands can be identified on MR images.

T2-weighted images typically show concentric hypointense

bands corresponding to areas of demyelination and gliosis,

alternating with isointense bands corresponding to normal

myelinated white matter (Figs. 5 and 6). This pattern may

adopt a multilayered concentric (onion layers), mosaic, or

floral configuration. The center of the lesion usually shows

no layers due to massive demyelination. Contrast enhance-

ment and decreased diffusivity is frequent in the outer rings

(inflammatory edge) of the lesion [42, 43] (Fig. 6). This

Fig. 3 Marburg disease. Serial

T2-W and contrast-enhanced

T1-W MR images of the brain

obtained in a patient with a final

diagnosis of fulminant IIDD.

Note the presence of multiple

contrast-enhanced focal lesions

diffusely involving the cerebral

and cerebellar hemispheres and

the brainstem. Some of thelesions are persistent, whereas

others are new. The patient died

5 months after symptom onset



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MR imaging Bal pattern may be isolated, multiple or

mixed with typical MS-like lesions.Although BCS was initially described as an acute,

monophasic and rapidly fatal disease, thus resembling

MD, there is strong evidence that large Bal-like lesions

are frequently identified on MR images in patients with a

classical acute or chronic MS disease course, or in ADEM,

with a nonfatal course.

Acute disseminated encephalomyelitis

ADEM is a severe, acute, demyelinating disease of the

central nervous system, usually triggered by an inflamma-

tory response to viral or bacterial infections and vaccina-tions [44]. Patients commonly present with nonspecific

symptoms, including headache, vomiting, drowsiness, fever

and lethargy, all of which are relatively uncommon in MS[45, 46]. The course of ADEM is usually monophasic and

affects children more commonly than adults, with no

predilection for either sex. In general, the disease is self-

limiting and the prognostic outcome is favorable.

Unlike lesions in MS, ADEM lesions are often bilateral,

have poorly defined margins on MR images [45, 46], and

predominantly involve the subcortical white matter (Fig. 7),

thalami and basal ganglia [44, 47], particularly in children

(Fig. 8). The spinal cord can be also affected, usually with

large, tumefactive lesions [48, 49].

As ADEM is commonly a monophasic disease, the focal

lesions would be expected to appear and mature simulta-neously, and therefore, have the same appearance on

Fig. 4 Schilders disease. Serial brain MR images in a patient with

SD who later developed clinically definite MS. FLAIR images (upper

row) and contrast-enhanced T1-W images (lower row) were obtained

serially over 6 months. Note the progressive appearance of large

lesions in the posterior periventricular white matter. The 6-month scan

obtained during an episode of optic neuritis shows a new contrast-

enhancing lesion in the right frontal white matter (arrow)

Table 1 Proposed criteria for

Schilders disease [3] Criteria

1. Clinical symptoms and signs often atypical for the early course of MS

2. CSF normal or atypical for MS

3. Bilateral large areas of demyelination of cerebral white matter

4. No fever, viral or mycoplasma infection, or vaccination preceding the neurological symptoms

5. Normal serum concentrations of very long-chain fatty acids



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contrast-enhanced MR images, resolve or remain un-

changed, with no new lesions on follow-up MR images

[44, 50, 51]. Not infrequently, however, new lesions are

seen on follow-up MR images within the first month after

the initial attack. This explains the mixed pattern of

enhancing and non-enhancing lesions at the same time point. In addition, there may be a delay of more than

1 month between the onset of symptoms and the appear-

ance of lesions on MR images [52]. Therefore, a normal

brain MR scan obtained within the first days after the onset

of neurological symptoms suggestive of ADEM does not

exclude this diagnosis.

It has been demonstrated that one-third of patients with

ADEM will have relapses in the future (relapsing ADEM)

[53]. Despite efforts to improve the diagnostic accuracy, itis still impossible to predict which patients will suffer from

recurrent bouts.

Very recently the International Pediatric MS Study

Group proposed operational definitions for acquired central

nervous system demyelinating disorders of childhood,

which include the different forms of ADEM (monophasic

Fig. 7 Acute disseminated encephalomyelitis. Transverse T2-W MR

image obtained in a 6-year-old boy who presented with a multifocal

clinical syndrome associated with somnolence. Note the poorly

defined bilateral lesions that selectively involve the subcortical white

matter. This clinical and radiological pattern is very unusual for a first

episode of MS

Fig. 6 Bal-like IIDD lesion. Axial T2-W and contrast-enhanced T1-W MR images, and apparent diffusion coefficient map (ADC). Observe the

alternating concentric bands, decreased peripheral diffusivity (black arrow), and contrast enhancement (white arrow)

Fig. 5 Bals concentric sclerosis. T2-W MR image shows a large

focal lesion within the right frontal white matter. The striking

lamellated pattern of alternating bands of demyelination and relatively

normal white matter, reflecting either spared or remyelinated regions,

is clear



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or relapsing) [54]. According to these new proposals mono-

phasic ADEM is defined as a multifocal clinical syndrome in

patients without a history of a demyelinating event, which

includes encephalopathic symptoms such as behavioral

changes (e.g. irritability, lethargy) or altered consciousness

(somnolence, coma). Recurrent ADEM requires a second

ADEM attack more than 3 months after the initial event (one

or more months after steroid completion), involving the

same anatomic area. On the other hand multiphasic ADEM

requires a second ADEM attack with new areas of

involvement. Symptoms evolving up to 3 months after a

first ADEM attack should be considered part of it, and not a

recurrent or multiphasic ADEM.

Not infrequently an ADEM attack is the first manifes-

tation of the classical relapsing form of MS. In fact, 21% of

patients with ADEM develop MS after a mean follow-up

period of 2.36 years, and 27% after 5.64 years [55]. Hence,

ADEM is likely to be over-diagnosed on the basis of the

initial clinical presentation and MR findings. For this

reason, a presumptive diagnosis of ADEM mandates close

clinical and MR imaging follow-up (Fig. 9). The key

clinical, biological and MR imaging features that can help

differentiate ADEM from MS are shown in Table 2.

First-line treatment for ADEM is intravenous high-dose

corticosteroids [56], which, in non-responsive patients, is

followed by plasma exchange or immunoglobulins [57, 58].

Immunosuppressive agents, such as mitoxantrone or cyclo-

phosphamide should be considered as alternative therapies

if antiinflammatory treatment shows no clinical effect [59].

Acute hemorrhagic leukoencephalitis (Hurst encephalitis)

is an uncommon condition thought to be a hyperacute form

or the maximal variant of ADEM. The onset of this form of

ADEM can be very rapid, with fever, headache and a

decreasing level of consciousness. Death can occur within a

few days in severely affected patients. On MR images, large,

bihemispheric areas of demyelination with petechial hemor-

rhages, better shown on T2*-weighted sequences, can be

seen in the peripheral white matter (Fig. 10) [60, 61].

Tumefactive or pseudotumoral IIDDs

Infrequently, IIDDs present as single or multiple focal

lesions that may be clinically and radiographically indistin-

guishable from a brain tumor. This situation represents a

diagnostic challenge, which reasonably calls for a biopsy

despite the clinical suspicion of demyelination. However,

even the biopsy specimen may resemble a brain tumor

given the hypercellular nature of the lesions, which are

often associated with large protoplasmatic glial cells with

fragmented chromatin and abnormal mitosis (Creutzfeldt

cells) [62]. The presence of large numbers of infiltrating

macrophages in the setting of myelin loss and relative

axonal preservation should, however, confirm the diagnosis

of IIDD.

Fig. 8 Acute disseminated en-

cephalomyelitis. T2-W MR

images obtained in an 8-month-

old boy with ADEM show dif-

fuse, symmetrical, hyperintense

basal ganglia lesions (upper

row) that had completely disap-

peared 1 month later (lower

row)



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In some cases, pseudotumoral IIDDs represent the firstclinical and radiological manifestation of MS. More

commonly, tumefactive demyelinating plaques affect

patients with a known diagnosis of MS (Fig. 11). In this

situation, the pseudotumoral plaques do not usually imply a

diagnostic problem. In rare cases, pseudotumoral IIDDs

have a relapsing course, with single or multiple pseudotu-

moral lesions appearing over time in different locations

(Fig. 12). This form of IIDD may be a tumefactive,relapsing type of ADEM or early MS [63].

On CT or MR imaging the pseudotumoral plaques

usually present as large, single or multiple focal lesions

located in the brain hemispheres [64, 65]. 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 T1-weighted gadolinium-enhanced

Fig. 9 Serial T2-W MR images obtained in a young patient in whom

an initial diagnosis of ADEM was established. Note the development

of new symptomatic lesions within the middle cerebellar peduncle and

brainstem (arrows) 1 and 3 years after symptom onset, and the

complete disappearance of the subcortical supratentorial lesions

identified in the first image. A final diagnosis of clinically definite

MS was established

Table 2 Clinical, biological

and radiological differences

between acute disseminatedencephalomyelitis (ADEM)

and multiple sclerosis (MS)

ADEM MS

Age 10 years >10 years

Gender male = female male > female

Prior flu very frequent variable

Encephalopathy required rare

Attacks fluctuate over

3 months

separated by

>1 month

Large MRI lesions frequent rare

Longitudinal MRI resolution new lesions

CSF white blood cell count >50 frequent very rare

CSF oligoclonal bands variable frequent



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images, with the open border facing the gray matter of thecortex or basal ganglia (Fig. 11) [66, 67], sometimes

associated with a rim of peripheral hypointensity on T2-

weighted sequences [68].

Data on the literature regarding the diagnostic value

of proton MR spectroscopy for differentiating pseudotu-

moral IIDDs from brain tumors are conflicting. Someauthors have shown that there are not enough spectral

differences that allow a precise diagnosis in individual

cases [69, 70], while others have demonstrated that this

discrimination is possible using a computer pattern recog-

nition system [71].

Fig. 11 Tumefactive form of RR MS. Serial brain T2-W MR images

(upper row) and contrast-enhanced T1-W MR images (lower row)

obtained in a patient with a RR form of MS. Note the initial increase,

and posterior decrease in size of the right frontal lobe pseudotumoral

lesion, which has almost disappeared on the 12-month scan. These

lesions frequently show an open ring-enhancing pattern of contrast

uptake, with the open margin facing the gray matter (arrows). This

pseudotumoral lesion was asymptomatic

Fig. 10 Acute hemorrhagic leu-

koencephalitis (Hurst encephali-

tis). Axial FLAIR MR image (a)

shows an extensive abnormal

signal affecting the periventric-

ular and subcortical white mat-

ter, and the T2-W gradient-echo

MR image (b) shows acute

hemorrhage visualized as mark-

edly hypointense foci within thewhite matter lesions



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In infrequent cases, pseudotumoral IIDDs have a

fulminant course that does not respond to high doses of

steroids. Plasma exchange should be considered as a

treatment option in these patients [72].

Monosymptomatic IIDDs

Optic neuritis

ON, either papillitis or retrobulbar neuritis, is characterized

by rapid deterioration of vision in one or both eyes that is

sometimes associated with retrobulbar pain and usually

recovers spontaneously within a few weeks after onset.

Although ON can have an isolated and monophasic course,

it can also be the first manifestation of MS or Devic s NMO

[13, 73]. Recurrent forms of ON are more likely to developinto MS, while severe visual loss, presence of papillitis, and

bilateral involvement indicate a low-risk profile for the

development of MS [74].

Brain MR imaging is mandatory in patients who present

with ON for the first time, as the presence of asymptomatic

focal lesions (>50% of patients) indicates a high risk of

developing MS [13]. As compared to other monosymptom

atic IIDDs, patients with ON have a higher percentage of

normal brain MR studies at presentation and a lower rate

of conversions to MS [13].

Optic nerve MR imaging is not necessary to confirm thediagnosis, unless there are atypical clinical features (no

response to steroids, long-standing symptoms). In this case,

brain and optic nerve MR imaging should be performed to

rule out a noninflammatory cause of the visual symptoms

[75]. Typical MR imaging findings in acute or subacute ON

include focal thickening and hyperintensity on T2-weighted

fat-suppressed or STIR sequences and intense enhancement

of the nerve sheath on contrast-enhanced T1-weighted fat-

suppressed sequences (Fig. 13) [7678], reflecting demy-

elination and inflammation. In patients with established

MS, STIR sequences can also detect subclinical signal

abnormalities within the optic nerve, which probably reflect predominantly demyelination [79].

Brainstem inflammatory-demyelinating syndrome

Brainstem inflammatory-demyelinating syndrome is frequent-

ly the first clinical manifestation of MS, although this condition

Fig. 12 Tumefactive relapsing course. Serial contrast-enhanced CT and T1-W MR images obtained in a 10-year-old girl who experienced several

acute relapses over a period of several years, related to pseudotumoral bihemispheric lesions

Fig. 13 Optic neuritis. a Coro-

nal fat-suppressed T2-W fast

spin-echo MR image shows

subtle hyperintensity within the

right optic nerve (arrow).

bCoronal fat-suppressed T1-WMR image after gadolinium a

dministration shows obvious

enhancement of the right optic

nerve as compared with the

normal contralateral nerve

(arrow)



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canalso continue as a monophasic disease [80, 81]. The risk of

progression to MS is increased if oligoclonal bands are

present on CSF analysis and disseminated brain lesions are

seen on MR images (>75% of patients) [13]. The symptom-

atic brainstem lesions tend to be located in the peripheral

areas of the pons, including the floor of the IVth ventricle or

in the middle cerebellar peduncles, with relative sparing of

the central pontine white matter (Fig. 14). The lesions can

have any size and pseudotumoral lesions are rarely found.

Bickerstaff encephalitis is a rare form of acute brainstem

syndrome considered to be a form of ADEM, in which

inflammation appears to be confined to the brainstem [82].

This syndrome, which has a benign prognosis, is due to

localized encephalitis in the brainstem, commonly preceded

by a febrile illness [83]. T2-weighted MR images usually

show an extensive high signal intensity lesion involving the

midbrain, the pons and sometimes the thalamus [84, 85].

The clinical outcome is good, and parallels resolution of the

lesions on MR imaging (Fig. 15) [83, 86]. The pathogen-

esis of Bickerstaff encephalitis is uncertain; however, the

absence of CSF oligoclonal bands and resolution of the

clinical symptoms and lesions on MR imaging suggest an

inflammatory origin and make demyelination unlikely.

Acute transverse myelitis

Acute transverse myelitis (ATM) is a focal inflammatory

disorder of the spinal cord, resulting in motor, sensory, and

autonomic dysfunction [87]. ATM can be idiopathic or

develop in the context of viral, bacterial, fungal or parasitic

infections, as well as in the course of systemic autoimmune

diseases. Although ATM can be a monophasic disease, it can

Fig. 14 Brainstem syndrome. Axial T2-W MR images at the posterior

fossa. Examples of typical demyelinating brainstem lesions located a

in the right brachium pontis (arrow), b in the left margin of the pons

in a patient with a first trigeminal branch sensory disturbance (arrow),

and c in the floor of the IVth ventricle in a patient with internuclear

ophthalmoplegia (arrow)

Fig. 15 Bickerstaff encephali-

tis. Initial axial FLAIR MR

image (a) shows an extensive

increased signal area in the

brainstem that has fully resolved

in a follow-up study (b)

obtained 2 months later



13/17

also be the first manifestation of MS or Devics NMO or

(rarely) have a recurrent course restricted to the spinal cord(RTM). Approximately one-third of patients recover with few

or no sequelae, one-third are left with a moderate degree of

permanent disability, and one-third have severe disabilities.

Patients who develop MS after ATM are more likely to

have asymmetrical clinical findings, predominantly sensory

symptoms with relative sparing of motor systems (asym-

metrical or partial ATM), nontumefactive lesions on MR

images extending over fewer than two spinal segments

[88], an abnormal appearance brain MR images (>75% of

patients with asymmetrical ATM) (Fig. 16) [13], and CSF

oligoclonal bands [80]. Fast STIR sequences seems to be

better than fast spin-echo sequences for detecting these

demyelinating spinal cord lesions [89, 90].

Initial assessment of ATM requires spinal MR examination

to exclude extra-axial compressive lesions and noninflamma-

tory spinal cord lesions (ischemia, radiation myelopathy).

Brain MR imaging and visual evoked potentials are needed to

determine whether there is demyelination elsewhere in the

neuroaxis, which would define the process as multifocal and

indicate a diagnosis of ADEM or a high risk of developing

MS. In the setting of unifocal idiopathic ATM, clinical and

biological features suggesting an infectious disease or a

systemic inflammatory disease should be ruled out prior to

establishing the diagnosis of primary ATM (Table 3) [87].

IIDDs with a restricted topographical distribution

Devics neuromyelitis optica

Devics NMO is an uncommon, acute, severe IIDD that can

be considered a distinct disease rather than a variant of MS.

NMO is characterized by severe unilateral or bilateral ON

and complete transverse myelitis which occur simulta-

neously or sequentially within a varying period of time(weeks or years), without clinical involvement of other

regions of the CNS. This selective and aggressive involve-

ment is now recognized to typically evolve as a relapsing

disorder that results in severe residual injury with each

attack due to considerable myelin destruction and axonal

loss [91, 92]. Clinical features alone are insufficient to

diagnose NMO; CSF analysis and MR imaging are usually

required to confidently exclude other disorders.

Spinal cord MR imaging shows extensive cervical or

thoracic tumefactive myelitis, involving more than three

vertebral segments on sagittal and much of the cross-

section on axial T2-weighted images, which sometimes

enhance with gadolinium for several months [73]. These

spinal cord lesions can progress to atrophy and necrosis,

leading to syrinx-like cavities on T1-weighted images

(Fig. 17). Brain MR imaging may demonstrate unilateral

or bilateral optic nerve enhancement during acute ON, but,

in contrast to MS, white matter lesions are, at least in the

early stages, absent or few, and nonspecific [73, 91, 93] and

magnetization transfer ratio values are normal in the

normal-appearing white matter [94, 95]. Over years of

Fig. 16 Partial acute transverse

myelitis. Small ovoid-enhancing

lesion within the cervical spinal

cord (a) associated with sub-

clinical demyelinating periven-

tricular lesions in the brain (b).

This clinical and MR imaging

pattern indicates a high risk of

converting to clinically definite

MS

Table 3 Diagnostic criteria for idiopathic ATM [87]

Criteria

Development of spinal cord symptoms

Bilateral signs/symptoms

Clearly defined sensory level

Exclusion of extra-axial compressive etiology (MRI)

Presence of spinal cord inflammation (MR or CSF)

Symptom progression within the first days

No history of optic neuritis

No brain abnormalities (MRI)



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follow-up, serial studies may reveal an increasing number

of cerebral white matter lesions but fewer than 10% ever

meet MR imaging criteria for MS. In children unusual

white matter, basal ganglia and hypothalamic lesions are

sometimes found. CSF pleocytosis (>50 leucocytes/mm3)

and blood brain barrier damage are often present, while

oligoclonal bands are seen less frequently (2040%) than

in MS patients (8090%) [73, 96, 97].

A serum autoantibody marker for NMO (NMO-IgG) has

been recently identified. This autoantibody, with a reported

sensitivity of 73% and specificity of 91% for NMO, may be

helpful in distinguishing this form of IIDD from MS [93,

98] and may predict relapse and conversion to NMO in

patients presenting with a single attack of longitudinally

extensive myelitis [99].

Wingerchuk et al. recently reported a revised set of

criteria for diagnosing NMO [100]. These new criteria

remove the absolute restriction on CNS involvement

beyond the optic nerves and spinal cord and emphasize

the specificity of longitudinally extensive spinal cord

lesions on MR images and NMO-IgG seropositive status

(Table 4). The key clinical, biological and MR imaging

features that can help to differentiate NMO from MS areshown in Table 5.

Early, accurate diagnosis of NMO is important because it

carries a poorer prognosis than MS and can determine the

start of early, appropriate treatment, which may differ from

that of early MS. High-dose corticosteroids, plasma

exchange and immunosuppressive medication (azathio-

prine, rituximab) seem to be effective treatment for NMO

[56, 94, 101103].

Recurrent optic neuritis

ON may have a recurrent course (recurrent ON, RON)without events referable to other parts of the central nervous

system [104, 105]. By strict application of MS criteria,

including the criteria of McDonald et al. [15], RON affecting

both nerves could be considered MS. However, if RON is

not considered MS by definition, the risk of developing

classical MS or NMO is uncertain. Severe visual loss in the

first episode and early relapses indicate a high-risk profile for

developing NMO, whereas the presence of subclinical white

matter lesions on T2-weighted MR images indicate a high-

risk profile for developing MS [106].

Relapsing transverse myelitis

RTM occurs in MS, NMO and other conditions, including

systemic lupus erythematosus and herpes simplex infection

[107, 108]. Recurrent myelopathy also occurs in anti-

phospholipid antibody syndrome and spinal arteriovenous

malformation. Idiopathic RTM is characterized by recurrent

attacks of inflammatory demyelination and necrosis re-

stricted to the cord and brainstem, sparing the cerebral

Fig. 17 Devics neuromyelitis optica. Sagittal T2-W and T1-W MR

images of the cervicodorsal spinal cord show a long syrinx-like spinal

cord lesion extending to the lower medulla (arrows)

Table 4 Revised diagnostic criteria for definite Devics (NMO) [100]

Definite NMO:

Optic neuritis

Acute myelitis

At least two of three supportive criteria:

Contiguous MRI spinal cord lesion on MR images extending over

3 vertical segments

Brain MRI findings do not meet diagnostic criteria for multiple

sclerosis (Patys diagnostic criteria)

NMO-IgG seropositive status

Patys criteria: presence of four or more white matter lesions or three

lesions when one is periventricular [109].

Table 5 Clinical, biological and radiological differences between

Devics (NMO) nueromyelitis optica and multiple sclerosis (MS)

MS NMO

Topography Any Optic nerve/spinal cord

Relapses Slight to moderate Severe

Brain MRI Abnormal Normal/nonspecific

Spinal cord MRI 3 segments, central

CSF cells 50, PMN

CSF oligoclonal

bands

Usually + Usually -

NMO-IgG 70%



15/17

hemispheres and optic nerves [108]. A normal brain on MR

imaging, absence of CSF oligoclonal bands, extensive

myelitis with MR imaging signal abnormalities extending

over three vertebral segments and a poor prognosis are

characteristic features of idiopathic RTM. This rare form of

IIDD should be considered a distinct disorder from MS that

shares clinical, radiological and pathological features with

NMO, with the exception of optic nerve involvement. Forthis reason, some authors consider this disorder a restricted

variant of NMO [108].

Conclusion

Idiopathic inflammatory demyelinating diseases represent a

wide spectrum of disorders with relatively specific clinical,

laboratory and imaging findings. Although some of these

disorders are variants of MS, others probably correspond to

different entities. Accurate classification of these disorders

may have relevant prognostic and treatment implications,

and might be helpful in distinguishing them from tumoral

or infectious lesions, avoiding unnecessary aggressive

diagnostic or therapeutic procedures.

Acknowledgements The authors thank Celine L. Cavallo for

English language support.

Conflict of interest statement We declare that we have no conflict

of interest.

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Idiopathic Inflammatory Disease of the Cns