Inflammatory demyelinating diseases of the central nervous system

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Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) because the unknown etiology of some of them, and sometimes known as borderline forms of multiple sclerosis,[1] is a collection of multiple sclerosis variants, sometimes considered different diseases,[2][3] but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.[4][5]

Multiple Sclerosis could be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour.[6]

Diseases included in this category[edit]

The list of these diseases depends of the author, but usually are included:

  • multiple sclerosis, normally defined by the dissemination in time and space of demyelinating lesions, with two (or sometimes three) clinical presentations:
    • Relapsing-Onset multiple sclerosis, the most known and extended variant, normally consisting of two distinct clinical phases (Remitent-Recidivant, RRMS, and Secondary Progressive, SPMS)
    • Progressive-Onset MS, most known as Primary progressive MS[7] including a special genetic variant named rapidly progressive multiple sclerosis.[8]
    • Optic-spinal MS, or opticospinal, clinical and pathological variant of multiple sclerosis which often include visual symptoms and have a more severe course than typical MS. Though multiple scars (scleroses) are present in CNS, and they comply with the dissemination criteria, and sometimes is classified as clinically definite multiple sclerosis,[9] currently is considered outside the scope of Multiple Sclerosis and inside the scope of Devic's disease,[10] though it is uncertain if this applies to all cases.[11] Also a variant affecting mainly the spinal cord and the cortex has been proposed[12][13]
  • Neuromyelitis optica (NMO), and its associated "spectrum of disorders" (NMOSD), currently considered a common syndrome for at least three separated diseases:[14]
  • CRION (Chronic relapsing inflammatory optic neuritis): A distinct clinical entity from other inflammatory demyelinating diseases including multiple sclerosis (MS), neuromyelitis optica-immunoglobulin G (NMO-IgG) spectrum disease, and idiopathic relapsing optic neuritis.[17]
  • Acute disseminated encephalomyelitis or ADEM, a closely related disorder in which a known virus or vaccine triggers autoimmunity against myelin.
  • Acute hemorrhagic leukoencephalitis, possibly a variant of Acute disseminated encephalomyelitis
  • Balo concentric sclerosis, an unusual presentation of plaques forming concentrenic circles, which can sometimes get better spontaneously.
  • Schilder disease or diffuse myelinoclastic sclerosis: is a rare disease that presents clinically as a pseudotumoural demyelinating lesion; and is more common in children.[18][19]
  • Marburg multiple sclerosis, an aggressive form, also known as malignant, fulminant or acute MS.
  • Tumefactive multiple sclerosis: lesions whose size is more than 2 cm, with mass effect, oedema and/or ring enhancement[20][21]
  • Solitary sclerosis: This variant has been recently proposed (2012) by Mayo Clinic researches.[22] though it was also reported by other groups more or less at the same time.[23][24] It is defined as isolated demyelinating lesions which produce a progressive myelopathy similar to primary progressive MS, and is currently considered a synonym for tumefactive multiple sclerosis.[25]

Some inflammatory conditions are associated with the presence of the scleroses.[26] Optic neuritis (monophasic and recurrent) and Transverse myelitis (monophasic and recurrent)

As MS is an active field for research, the list is not closed or definitive. For example, some diseases like Susac's syndrome (MS has an important vascular component[27]), leukoaraiosis, myalgic encephalomyelitis (aka chronic fatigue syndrome)[28] or autoimmune variants of peripheral neuropathies like Guillain-Barré syndrome or progressive inflammatory neuropathy could be included assuming the autoimmune model. Also Leukodystrophy (which see) and its sub-conditions: Adrenoleukodystrophy and Adrenomyeloneuropathy could be in the list. Venous induced demyelination has also been proposed as a hypothetical MS variant produced by CCSVI. Recent research has identified some possible new variants, like the possibility to separate primary progressive MS, PPMS, after recent findings seem to point that it is pathologically a very different disease.[29][30] Also a KIR4.1 multiple sclerosis variant was reported in 2012[31] and later reported again,[32] which could be considered a different disease (as Devic disease did before), and can represent up to a 47% of the MS cases. Finally, there exist some reports of an aquaporine-related multiple sclerosis, related to vegetal aquaporine proteins.[33]

Identified causes[edit]

Though for the most of the cases these diseases are still idiopathic, recent researchs have found the causes for some of them, making them not idiopathic anymore. There are currently two identified auto-antibodies and a genetic variant. The autoantibodies are anti-AQP4 and anti-MOG so far[34] and the genetic variant is a mutation in the gene NR1H3.

anti-AQP4 spectrum[edit]

Originally found in neuromyelitis optica, this autoantibody has been associated with other conditions. Its current spectrum is as following:

anti-MOG spectrum[edit]

The presence of anti-MOG autoantibodies has been associated with the following conditions[38]

  • Some cases of aquaporin-4-seronegative neuromyelitis optica: NMO derived from an antiMOG associated encephalomyelitis,[39]
  • Some cases of acute disseminated encephalomyelitis, specially the recurrent ones (MDEM)[40]
  • Some cases of multiple sclerosis[38][41]
  • isolated optic neuritis or transverse myelitis[38]
  • Recurrent optic neuritis. The repetition of an idiopatic optic neuritis is considered a distinct clinical condition, and it has been found to be associated with anti-MOG autoantibodies[42]

The anti-mog spectrum in children is equally variated: Out of a sample of 41 children with MOG-antibodies 29 had clinical NMOSD (17 relapsing), 8 had ADEM (4 relapsing with ADEM-ON), 3 had a single clinical event CIS, and 1 had a relapsing tumefactive disorder. Longitudinal myelitis was evident on MRI in 76[percent]. It has also been noted that percentage of children with anti-mog antibodies respect a demyelinating sample is higher than for adults[43]

Rapidly progressive multiple sclerosis[edit]

A special genetic variant of progressive MS.[8] It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA. It is important to notice that this kind of MS was previously reported to be responsive to plasma exchange[44] and though there is no confirmation, it is expected to be classified as pattern II

Double positive NMO[edit]

Some NMO patients present double positive for autoantibodies to AQP4 and MOG. These patients have MS-like brain lesions, multifocal spine lesions and retinal and optic nerves atrophy.[45]

Clinical situations inside standard MS[edit]

Also inside standard MS different clinical courses can be separated.

Primary progressive variants[edit]

Some authors think since long ago that primary progressive MS should be considered a disease different from standard MS,[46][47] and it was also proposed that PPMS could be heterogeneous[48]

Clinical variants have been described. For example, Late Onset MS.[49] Since 2016, a special clinical variant of "rapidly progressive" MS has been found to be different from RRMS and other kinds of PPMS.[8] It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.


For the rest of the progressive cases, it has been found that the lesions are diffuse instead of the normal focal ones,[50] and are different under MR spectroscopy.[51][52] RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.[53]

Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like[54] Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS[55]

Recently, the hypothesis of PPMS being apart from RRMS/SPMS is taken further credibility due that it was shown that CSF from PPMS patients can carry the disease to other animals, producing neurodegeneration in mice[29]

Preclinical MS: CIS and CDMS[edit]

The first manifestation of MS is the so-called Clinically isolated syndrome, or CIS, which is the first isolated attack. The current diagnosis criteria for MS does not allow doctors to give an MS diagnosis until a second attack takes place. Therefore, the concept of "clinical MS", for an MS that can be diagnosed, has been developed. Until MS diagnosis has been established, nobody can tell whether the disease dealing with is MS.

Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS.[56] Preclinical MS refers to cases after the CIS but before the confirming second attack.[57] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[58]

RIS, subclinical and silent MS[edit]

Silent MS has been found in autopsies before the existence of MRI[59] showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases.[60] Currently a distinction is made between "silent" and subclinical.

In absence of attacks, sometimes a radiological finding suggestive of demyelination can be used to establish a pre-diagnosis of MS. This is often named "Radiologically Isolated Syndrome" (RIS). Cases before the first attack or CIS are subclinical in the sense that they do not produce clinical situations.

If a second radiological event appears without clinical consequences, the clinical situation is named "Silent MS" (Okuda criteria).[61]

It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives,[62] suggesting a wider scope for the "silent MS" term.

In these cases Interleukin-8 is a risk for clinical conversion.[63] It has also been proposed that always exists a subclinical phase in the beginning of every MS case, during which the permeability of the BBB can be used for diagnosis[64]

Aggressive multiple sclerosis[edit]

Relapsing-Remitting MS is considered aggressive when the frequency of exacerbations is not less than 3 during 2 years. Special treatment is often considered for this subtype.[65] According to these definition aggressive MS would be a subtype of RRMS. Other authors disagree and define aggressive MS by the accumulation of dissability, considering it as a rapidly disabling disease course[66]

Pediatric and pubertal MS[edit]

MS cases are rare before puberty, but they can happen. Whether they constitute a separate disease is still an open subject. Anyway, even this pubertal MS could be more than one disease, because early-onset and late-onset have different demyelination patterns[67]

Oligoclonal negative MS[edit]

Around 95% of MS cases present oligoclonal bands in CSF.[68] Nevertheless, there are cases of real MS that do not have them. It is suspected to be immunogenetically different.[69] Their evolution is better than standard MS patients[70]

Controversy for the definition[edit]

Clinical vs. pathological definitions[edit]

There is no agreement if MS should refer to a clinical course or to a pathological condition. Even assuming a pathological definition it is not clear if MS should refer to the presence of scars in CNS tissue or to the underlying condition that produces them, characterized by some yet unknown biomarkers.

Probably the most implicitly used definition is pathological, and can be found in the McDonald criteria proposal. This author state that "The focus remains on the objective demonstration of dissemination of lesions in both time and space". Therefore, they point out to a pathological underlying definition. Nevertheless, they say "MS is a clinical entity and therefore should be diagnosized with clinical and paraclinical criteria".[71] Currently the McDonald criteria are considered the clinical case definition of MS.

Given the non-specificity of the McDonald underlying definition, based on dissemination in time and space regardless of the lesions nature, other authors consider that a more accurate pathological definition should be used.[72] According to Hans Lassmann, an improved pathological definition should be preferred because clinical definitions have problems with differential diagnosis.[73] Of course, using a pathological definition would not prevent performing clinical diagnosis, but would require to calibrate any diagnosis criteria against it.

McDonald et al. do not agree with this, and they remark on the clinical character of MS. They state that "Whereas it might be said that the only proved diagnosis of MS can be made upon autopsy, or occasionally upon biopsy, where lesions typical of MS can be directly detected through standard histopathological techniques, MS is essentially a clinical problem and can be diagnosed using clinical and paraclinical criteria""[71]

At this moment, both definitions are currently used by each of their supporters and the relationship among them is not well documented.

Current definitions[edit]

The list of diseases included in the MS-spectrum is not closed because no formal definition of MS is normally given. For example, the World Health Organization does not give any explicit definition with ICD-10 MS entry [1]. In ICD-9 it used to say "chronic disease characterized by presence of numerous areas of demyelination in the central nervous system with symptoms such as weakness, incoordination, paresthesis, and speech disturbances"[2].

The Unified Medical Language System also gives very loose definitions of MS [3]. The Medline medical dictionary defines it as "a demyelinating disease marked by patches of hardened tissue in the brain or the spinal cord and associated especially with partial or complete paralysis and jerking muscle tremor" [4]. It uses the anatomical hallmark of the lesions, but also imposes the existence of clinical problems (paralysis and jerking muscle tremor).

Assuming a definition as weak as the previous ones, several diseases could be included inside the MS-spectrum. Most authors use a definition for MS based in the dissemination of the lesions in time (DIT) and space (DIS)[74] These definitions refer to the lesions and their location, but not to the nature of the lesions and this kind of definition is potentially heterogeneous.

Besides while some pathologysts consider that MS is the presence of demyelinated and disseminated scars in the CNS tissue,[72] others consider that MS is the unknown underlying condition that produces those scars.[75] These subtle differences can affect statistics and the reader should be aware of the definition in which each paper is based.

See also[edit]

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