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 for some people is a syndrome more than a single disease.[6] It can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour.[7] Multiple sclerosis also has a prodromal stage in which an unknown underlying condition, able to damage the brain, is present, but no lesion has still developed.

Diseases included in this category

Apart of the standard multiple sclerosis, defined by the dissemination in time and space of demyelinating lesions, with different clinical presentations (Relapsing-Onset or Progressive-Onset)[8] including a special genetic variant named rapidly progressive multiple sclerosis.[9] there are a long list of similar diseases. It depends of the author, but usually are included:

Some inflammatory conditions are associated with the presence of scleroses in the CNS.[33] 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 Autoimmune GFAP Astrocytopathy, Susac's syndrome (MS has an important vascular component[34]), leukoaraiosis, myalgic encephalomyelitis (aka chronic fatigue syndrome)[35] 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.[36][37]

Also an OPA1 variant [38] and aKIR4.1 multiple sclerosis variant was reported in 2012[39] and later reported again,[40] which could be considered a different disease (as Devic's disease did before), and can represent up to a 47% of the MS cases. Finally, there exist some reports by Drs. Aristo Vojdani, Partha Sarathi Mukherjee, Joshua Berookhim, and Datis Kharrazian of an aquaporine-related multiple sclerosis, related to vegetal aquaporine proteins.[41]

Identified causes

Though for the most of the cases these diseases are still idiopathic, recent research has 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[42] 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[46]

  • Some cases of aquaporin-4-seronegative neuromyelitis optica: NMO derived from an antiMOG associated encephalomyelitis,[47]
  • Some cases of acute disseminated encephalomyelitis, specially the recurrent ones (MDEM)[48]
  • Some cases of multiple sclerosis[46][49][14]
  • isolated optic neuritis or transverse myelitis[46]
  • 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[50]

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[51]

Rapidly progressive multiple sclerosis

This is a specially aggressive clinical course of progressive MS[9] 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.[52]

It is important to notice that this kind of MS was previously reported to behave different that the standard progressive course,[53] being linked to Connexin 43 autoantibodies with pattern III lesions (distal oligodendrogliopathy)[54] and being responsive to plasma exchange[55]

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.[56]

The correlation between this genetic mutation and MS was challenged but in 2018 has been replicated by an independent team.[57] Notice that this results do not refer to general MS.

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.[58]

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,[59][60] and it was also proposed that PPMS could be heterogeneous[61]

Clinical variants have been described. For example, Late Onset MS.[62] Since 2016, a special clinical variant of "rapidly progressive" MS has been found to be different from RRMS and other kinds of PPMS.[9] 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,[63] and are different under MR spectroscopy.[64][65] RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.[66]

Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like[67] Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS[68]

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[36] and that Normal Appearing White Matter (NAWM) structure is also different[69]

The predominant lesions in PPMS are slowly expanding lesions with T cells, microglial, and macrophage-associated demyelination in close similar to pattern I demyelination[70]

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.[71] Preclinical MS refers to cases after the CIS but before the confirming second attack.[72] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[73]

CIS itself is sometimes considered itself as a disease entity, different from MS. Even if they share the same underlying condition CIS is not MS given that it lacks the presence of lesions.[74] Approximately 84% of the subjects with CIS experience a second clinical demyelinating event and are diagnosed with clinically definite MS (CDMS) within 20 years.

RIS, subclinical and silent MS

Silent MS has been found in autopsies before the existence of MRI[75] showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases.[76] Currently a distinction is made between "silent" and subclinical.

In absence of attacks, sometimes a radiological finding suggestive of demyelination (T2 hyperintensities[77]) 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).[78]

It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives,[79] suggesting a wider scope for the "silent MS" term.

In these cases Interleukin-8 is a risk for clinical conversion.[80] 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[81]

It is also under investigation whether MS has a prodrome, i.e. a stage in which the disease exists with non-specific symptoms. Some reports point to a prodrome of several years for RRMS and decades for PPMS.[82]

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.[83] 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[84]

The aggressive course is associated to grey matter damage and meningeal inflammation, and presents a special intrathecal (meninges and CSF) inflammatory profile.[85]

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[86]

Pediatric MS patients tend to have active inflammatory disease course with a tendency to have brainstem / cerebellar presentations at onset. Due to efficient repair mechanisms at early life, pediatric MS patients tend to have longer time to reach EDSS 6 but reach it at earlier age.[87]

Oligoclonal negative MS

Around 95% of MS cases present oligoclonal bands in CSF.[88] Nevertheless, there are cases of real MS that do not have them. It is suspected to be immunogenetically different.[89] Their evolution is better than standard MS patients[90]

Oligoclonal IgM positive MS

Also an interesting subset is the oligoclonal positive MS with immunoglobulin M Bands (IgM-Bands), which accounts for a 30-40% of the MS population and has been identified as a predictor of MS severity.[91]

IgM-positive MS has been reported to have a poor response to interferon-beta but a better response to glatimer acetate instead[92]

Controversy for the definition

Currently there is no single diagnosis test for MS that is 100% sensitive and specific.[93][94] To have such a thing would require a standardised definition of the disease, which currently does not exist.[95] 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[96]

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 given that other diseases produce similar lesions, it is also required that those lesions cannot be explained by any other known disease.

This open definition present problems.[97] For example, before the discovery of anti-AQP4 in 2006, most optic-spinal MS patients were classified rightfully as MS. Currently they are classified as NMO. Both diagnosis are correct even though the definition has not (apparently) changed.

According to some pathologists, a pathological definition is required because clinical definitions have problems with differential diagnosis[98] and they always use a pathological definition on articles about post-mortem retrospective diagnosis, but for practitioners that need a diagnosis as soon as possible 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).[95][99]

Both definitions lead to different results. For example, confluent subpial cortical lesions are the most specific finding for MS, being exclusively present in MS patients.[100] but can only be detected post-mortem by an autopsy[101] Therefore, any other diagnosis method will have false positives.

At this moment, pathological and clinical definitions are currently used by each of their supporters and the relationship among them is not well documented.[95]

Other meanings of MS

There is no known etiology for MS and therefore no etiology-based definition is possible. Therefore, all meanings for the words "Multiple Sclerosis" are somehow diffuse.

The pathological definition based on proven dissemination in time and space has problems. For example, it leaves situations like RIS (radiologically isolated syndrome) outside the MS spectrum because the lack of proof, even in the case that this condition later could shown the same pathogenic conditions than MS cases.[102]

Besides, usually the term "multiple sclerosis" is used to refer to the presence of the unknown underlying condition that produces the MS lesions instead to the mere presence of the lesions. The term MS is also used to refers to the process of developing the lesions.[103]

Some authors instead speak about the biological disease vs. its clinical presentation.[104]

Anyway, the precise meaning in each case can be normally deduced from the context.

CIS and conversion to MS

The 2010 revision of the McDonald criteria[105] allows the diagnosis of MS with only one proved lesion (CIS). Consistently, the later revision for the MS phenotypes in 2013 was forced to consider CIS as one of the MS phenotypes.[106]

Therefore, the former concept of "Conversion from CIS to MS", that was declared when a patient had a second MS attack, does not apply anymore. More accurate is now to speak about conversions from the CIS phenotype to other MS phenotype.[107]

See also

References

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