Idiopathic inflammatory-demyelinating diseases of the central nervous system
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- Cañellas, A.R., Gols, A.R., Izquierdo, J.R. et al. Neuroradiology (2007) 49: 393. doi:10.1007/s00234-007-0216-2
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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.
KeywordsMultiple sclerosisMagnetic resonance imagingBrain diseases
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 [1–4]. 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 . 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) [6–8]. 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 . 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 . 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.
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 . The morphological hallmarks are demyelination, inflammation, gliosis and axonal damage, although heterogeneity of the lesion pathology has been recognized .
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 .
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 . 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 . After a second, different clinical relapse that indicates a process disseminated in time, the diagnosis of clinically definite MS is established . 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) . 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 .
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 . 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 . Patients with PPMS tend to be older than those with the more common relapsing form, and are as likely to be male as female . The most common presentation by far is slowly progressing spastic paraparesis, and less frequently, progressive cerebellar, brainstem, visual, hemiplegic and cognitive syndromes .
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 . 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 .
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 .
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 [6–8].
Fulminant forms of IIDD
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 . 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 .
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.
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 .
Proposed criteria for Schilder’s disease 
Clinical symptoms and signs often atypical for the early course of MS
CSF normal or atypical for MS
Bilateral large areas of demyelination of cerebral white matter
No fever, viral or mycoplasma infection, or vaccination preceding the neurological symptoms
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 .
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 . 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.
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 . 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) . 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) . 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.
Clinical, biological and radiological differences between acute disseminated encephalomyelitis ADEM and multiple sclerosis MS
male = female
male > female
fluctuate over 3 months
separated by >1 month
Large MRI lesions
CSF white blood cell count >50
CSF oligoclonal bands
First-line treatment for ADEM is intravenous high-dose corticosteroids , 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 .
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) . 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.
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 .
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 .
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 .
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 .
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 . 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 .
Brainstem inflammatory-demyelinating syndrome
Acute transverse myelitis
Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction . 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.
Diagnostic criteria for idiopathic ATM 
Development of spinal cord 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.
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 .
Revised diagnostic criteria for definite Devic’s (NMO) 
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
Clinical, biological and radiological differences between Devic’s (NMO) nueromyelitis optica and multiple sclerosis (MS)
Optic nerve/spinal cord
Slight to moderate
Spinal cord MRI
<1 segment, marginal
>3 segments, central
CSF oligoclonal bands
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, 101–103].
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. , 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 .
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 . 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 .
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.
The authors thank Celine L. Cavallo for English language support.
Conflict of interest statement
We declare that we have no conflict of interest.