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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: alex.rovira@idi-cat.org
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
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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
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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%
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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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