Neuroradiology

, Volume 49, Issue 5, pp 393–409

Idiopathic inflammatory-demyelinating diseases of the central nervous system

Authors

    • Magnetic Resonance Unit (I.D.I.), Department of RadiologyVall d’Hebron University Hospital
  • A. Rovira Gols
    • UDIAT, Diagnostic CentreParc Taulí University Institute - UAB
  • J. Río Izquierdo
    • Neuroimmunology Unit, Department of NeurologyVall d’Hebron University Hospital
  • M. Tintoré Subirana
    • Neuroimmunology Unit, Department of NeurologyVall d’Hebron University Hospital
  • X. Montalban Gairin
    • Neuroimmunology Unit, Department of NeurologyVall d’Hebron University Hospital
Review

DOI: 10.1007/s00234-007-0216-2

Cite this article as:
Cañellas, A.R., Gols, A.R., Izquierdo, J.R. et al. Neuroradiology (2007) 49: 393. doi:10.1007/s00234-007-0216-2

Abstract

Idiopathic inflammatory-demyelinating diseases (IIDDs) include a broad spectrum of central nervous system disorders 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 secondary 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, Baló’s concentric sclerosis, Schilder’s disease, and acute disseminated encephalomyelitis; (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 Devic’s 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 sclerosisMagnetic resonance imagingBrain 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 disorders 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 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 Baló’s concentric sclerosis (BCS), Schilder’s 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 syndromes 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 immunomodulatory treatment.

Some IIDDs have a restricted topographical distribution, such as Devic’s 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 clinically isolated 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., demonstration of dissemination in space and time, the two key factors 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 inflammation, 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. Immunomodulatory 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 immunosuppressive (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 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 paraparesis, and less frequently, progressive cerebellar, brainstem, 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 accumulating 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 abnormalities and the severity of the clinical disease [24].

Because patients with PPMS may have less inflammation 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.
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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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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)

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, disseminated throughout the hemispheric white matter and brainstem (Fig. 3) [28]. The lesions may show enhancement, and perilesional edema is often present. A similar imaging pattern is also seen in ADEM.
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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 the lesions are persistent, whereas others are new. The patient died 5 months after symptom onset

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 Baló-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.

Schilder’s 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 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. Several imaging findings can help to suggest the diagnosis of SD: large and relatively symmetrical involvement of both brain hemispheres, incomplete ring enhancement, minimal mass effect, low signal on diffusion-weighted MR images, and sparing of the brainstem (Fig. 4) [34, 35].
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Fig. 4

Schilder’s 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)

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].
Table 1

Proposed criteria for Schilder’s 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

Baló’s 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 myelinated 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 enhancement and decreased diffusivity is frequent in the outer rings (inflammatory edge) of the lesion [42, 43] (Fig. 6). This MR imaging Baló pattern may be isolated, multiple or mixed with typical MS-like lesions.
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Fig. 5

Baló’s 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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Fig. 6

Baló-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)

Although BCS was initially described as an acute, monophasic and rapidly fatal disease, thus resembling MD, there is strong evidence that large Baló-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 inflammatory response to viral or bacterial infections and vaccinations [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].
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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

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Fig. 8

Acute disseminated encephalomyelitis. T2-W MR images obtained in an 8-month-old boy with ADEM show diffuse, symmetrical, hyperintense basal ganglia lesions (upper row) that had completely disappeared 1 month later (lower row)

As ADEM is commonly a monophasic disease, the focal lesions would be expected to appear and mature simultaneously, and therefore, have the same appearance on contrast-enhanced MR images, resolve or remain unchanged, 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 appearance 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, it is 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 or relapsing) [54]. According to these new proposals monophasic 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 manifestation 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.
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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 disseminated encephalomyelitis ADEM and multiple sclerosis MS

 

ADEM

MS

Age

≤10

>10

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

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 cyclophosphamide 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 hemorrhages, better shown on T2*-weighted sequences, can be seen in the peripheral white matter (Fig. 10) [60, 61].
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Fig. 10

Acute hemorrhagic leukoencephalitis (Hurst encephalitis). Axial FLAIR MR image (a) shows an extensive abnormal signal affecting the periventricular and subcortical white matter, and the T2-W gradient-echo MR image (b) shows acute hemorrhage visualized as markedly hypointense foci within the white matter lesions

Tumefactive or pseudotumoral IIDDs

Infrequently, IIDDs present as single or multiple focal lesions that may be clinically and radiographically indistinguishable 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.

In some cases, pseudotumoral IIDDs represent the first clinical 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 pseudotumoral 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].
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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

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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

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 images, with the open border facing the gray matter of the cortex 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 pseudotumoral IIDDs from brain tumors are conflicting. Some authors 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 recognition system [71].

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 develop into 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 monosymptomatic 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 the diagnosis, 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 demyelination 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].
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Fig. 13

Optic neuritis. a Coronal fat-suppressed T2-W fast spin-echo MR image shows subtle hyperintensity within the right optic nerve (arrow). b Coronal fat-suppressed T1-W MR image after gadolinium administration shows obvious enhancement of the right optic nerve as compared with the normal contralateral nerve (arrow)

Brainstem inflammatory-demyelinating syndrome

Brainstem inflammatory-demyelinating syndrome is frequently the first clinical manifestation of MS, although this condition can also 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 symptomatic 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.
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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)

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 pathogenesis 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.
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Fig. 15

Bickerstaff encephalitis. 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

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 also be the first manifestation of MS or Devic’s 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 (asymmetrical 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].
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Fig. 16

Partial acute transverse myelitis. Small ovoid-enhancing lesion within the cervical spinal cord (a) associated with subclinical demyelinating periventricular lesions in the brain (b). This clinical and MR imaging pattern indicates a high risk of converting to clinically definite MS

Initial assessment of ATM requires spinal MR examination to exclude extra-axial compressive lesions and noninflammatory 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].
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)

IIDDs with a restricted topographical distribution

Devic’s neuromyelitis optica

Devic’s 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 simultaneously or sequentially within a varying period of time (weeks or years), without clinical involvement of other regions of the CNS. This selective and aggressive involvement 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 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 (20–40%) than in MS patients (80–90%) [73, 96, 97].
https://static-content.springer.com/image/art%3A10.1007%2Fs00234-007-0216-2/MediaObjects/234_2007_216_Fig17_HTML.gif
Fig. 17

Devic’s 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)

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 are shown in Table 5.
Table 4

Revised diagnostic criteria for definite Devic’s (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 (Paty’s diagnostic criteria)

NMO-IgG seropositive status

Paty’s 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 Devic’s (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

<1 segment, marginal

>3 segments, central

CSF cells

<50, lymphocytes

>50, PMN

CSF oligoclonal bands

Usually +

Usually -

NMO-IgG

<10%

>70%

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 (azathioprine, 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 restricted to the cord and brainstem, sparing the cerebral 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. For this 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.

Copyright information

© Springer-Verlag 2007