Inflammatory demyelinating diseases of the central nervous system

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

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

Some inflammatory conditions are associated with the presence of scleroses in the CNS.[28] 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[29]), leukoaraiosis, myalgic encephalomyelitis (aka chronic fatigue syndrome)[30] 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.[31][32]

Also an OPA1 variant[33] and aKIR4.1 multiple sclerosis variant was reported in 2012[34] and later reported again,[35] 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.[36]

Identified causes

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[37] and the genetic variant is a mutation in the gene NR1H3.

anti-AQP4 spectrum

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

anti-MOG spectrum

The presence of anti-MOG autoantibodies has been associated with the following conditions[41]

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[46]

Rapidly progressive multiple sclerosis

This is a specially aggressive clinical course of progressive MS[8] that has been found to be caused by a special genetic variant. 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.[47]

It is important to notice that this kind of MS was previously reported to behave different that the standard progressive course,[48] being linked to Connexin 43 autoantibodies with pattern III lesions (distal oligodendrogliopathy)[49] and being responsive to plasma exchange[50]

In very rapidly progressive multiple sclerosis the use of immunosuppressive therapy (mitoxantrone/cyclophosphamide), rituximab, autologous haematopoietic stem cell therapy or combination therapy should be considered carefully.[51]

Double positive NMO

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.[52]

Clinical situations inside standard MS

Also inside standard MS different clinical courses can be separated.

Primary progressive variants

Some authors think since long ago that primary progressive MS should be considered a disease different from standard MS,[53][54] and it was also proposed that PPMS could be heterogeneous[55]

Clinical variants have been described. For example, Late Onset MS.[56] 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,[57] and are different under MR spectroscopy.[58][59] RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.[60]

Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like[61] Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS[62]

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[31] and that Normal Appearing White Matter (NAWM) structure is also different[63]

Preclinical MS: CIS and CDMS

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 do 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 one is dealing with is MS.

Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS.[64] Preclinical MS refers to cases after the CIS but before the confirming second attack.[65] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[66]

RIS, subclinical and silent MS

Silent MS has been found in autopsies before the existence of MRI[67] showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases.[68] 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).[69]

It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives,[70] suggesting a wider scope for the "silent MS" term.

In these cases Interleukin-8 is a risk for clinical conversion.[71] 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[72]

It is also under investigation wether MS has a prodrome, i.e. a stage in which the disease exists with non-specific symptoms.

Aggressive multiple sclerosis

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.[73] According to these definition aggressive MS would be a subtype of RRMS. Other authors disagree and define aggressive MS by the accumulation of disability, considering it as a rapidly disabling disease course[74]

Pediatric and pubertal MS

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[75]

Oligoclonal negative MS

Around 95% of MS cases present oligoclonal bands in CSF.[76] Nevertheless, there are cases of real MS that do not have them. It is suspected to be immunogenetically different.[77] Their evolution is better than standard MS patients[78]

Controversy for the definition

Currently there is no single diagnosis test for MS that is 100% sensitive and specific.[79][80] To have such a thing would require a standardised definition of the disease, which currently does not exist.[81] The most commonly used definition, based in the McDonald criteria, focuses in the presence and distribution of the lesions, not in the underlying condition that produces them. Therefore, even twins with the same underlying condition can be classified different[82]

Pathological and clinical definitions

McDonald criteria propose a clinical diagnosis based on a pathological definition, saying that the focus for diagnosis "remains on the objective demonstration of dissemination of lesions in both time and space" (DIT and DIS), but pointing to a clinical diagnosis by saying "Though 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".[83]

Nevertheless, MS is often regarded as a pure clinical entity, defined simply by a positive result in the standard clinical case definition being then named "clinically definite MS" (CDMS, Poser) or simply "MS" (McDonald).[81][83]

According to some pathologists, a more accurate pathological definition is required because clinical definitions have problems with differential diagnosis[84] but at this moment, pathological and clinical definitions are currently used by each of their supporters and the relationship among them is not well documented.

Definition based on cause

There is no agreement if the term "multiple sclerosis" should refer to the presence of the scars in CNS tissue or to the unknown underlying condition that produces those scars. The second would be an cause based definition but it is currently not available.

On the other hand, a pathological definition based in dissemination in time and space would leave situations like RIS (radiologically isolated syndrome) outside the MS spectrum, even in the case that this condition shares the same pathogenic condition than MS cases.

The term MS sometimes also refers to the process of developing the lesions.[85] Some authors instead speak about the biological disease vs. its clinical presentation.[86] Anyway, the definition used in each case can be normally deduced from the context in any situation.

See also

References

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