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, is a collection of multiple sclerosis variants, sometimes considered different diseases, but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.
Multiple Sclerosis for some people is a syndrome more than a single disease. It can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour. 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.
- 1 Diseases included in this category
- 2 Identified causes
- 3 Clinical situations inside standard MS
- 4 Controversy for the definition
- 5 CIS and conversion to MS
- 6 See also
- 7 References
Diseases included in this category
The list of these diseases depends of the author, but usually are included:
- Standard 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 including a special genetic variant named rapidly progressive multiple sclerosis.
- Neuromyelitis optica (NMO), and its associated "spectrum of disorders" (NMOSD), currently considered a common syndrome for at least three separated diseases:, mainly produced by AQP4 autoimmune channelopathy, though other variants exists, some with anti-MOG and some others idiopathic. Some researchers think that there could exist an overlapping between Anti-NMDA receptor encephalitis cases and neuromyelitis optica or acute disseminated encephalomyelitis.
- Anti-MOG associated spectrum, often clinically presented as an anti-MOG autoimmune encephalomyelitis, but can also appear as negative NMO or atypical multiple sclerosis
- Acute disseminated encephalomyelitis or ADEM, a closely related disorder in which a known virus or vaccine triggers autoimmunity against myelin. Around 40% of the ADEM cases are due to an "anti-MOG associated encephalomyelitis".
- 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.
- 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.
- 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
- Solitary sclerosis: This variant has been recently proposed (2012) by Mayo Clinic researches. though it was also reported by other groups more or less at the same time. 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.
- Multiple sclerosis with cavitary lesions: Atypical multiple sclerosis cases similar to vanishing white matter disease but etiologically different from both.
- Myelocortical multiple sclerosis (MCMS), proposed variant with demyelination of spinal cord and cerebral cortex but not of cerebral white matter  Several atypical cases could belong here:
- Early reports of MCMS
- Atypical Optic-spinal MS, or opticospinal. While opticospinal MS now is considered inside Neuromyelitis optica, it is uncertain if this applies to all cases.
- Pure spinal multiple sclerosis: Patients with clinical and paraclinical features suggestive of cord involvement of multiple sclerosis (MS)-type albeit not rigidly fulfilling the McDonald criteria
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), leukoaraiosis, myalgic encephalomyelitis (aka chronic fatigue syndrome) 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.
Also an OPA1 variant  and aKIR4.1 multiple sclerosis variant was reported in 2012 and later reported again, 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.
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 and the genetic variant is a mutation in the gene NR1H3.
Originally found in neuromyelitis optica, this autoantibody has been associated with other conditions. Its current spectrum is as following:
- Seropositive Devic's disease, according to the diagnostic criteria described above
- Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis
- Asian optic-spinal MS - this variant can present brain lesions like MS.
- Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease
- Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem
- Some cases of tumefactive multiple sclerosis
The presence of anti-MOG autoantibodies has been associated with the following conditions
- Some cases of aquaporin-4-seronegative neuromyelitis optica: NMO derived from an antiMOG associated encephalomyelitis,
- Some cases of acute disseminated encephalomyelitis, specially the recurrent ones (MDEM)
- Some cases of multiple sclerosis
- isolated optic neuritis or transverse myelitis
- 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
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
Rapidly progressive multiple sclerosis
This is a specially aggressive clinical course of progressive MS 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.
It is important to notice that this kind of MS was previously reported to behave different that the standard progressive course, being linked to Connexin 43 autoantibodies with pattern III lesions (distal oligodendrogliopathy) and being responsive to plasma exchange
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.
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.
Clinical situations inside standard MS
Also inside standard MS different clinical courses can be separated.
Primary progressive variants
Clinical variants have been described. For example, Late Onset MS. Since 2016, a special clinical variant of "rapidly progressive" MS has been found to be different from RRMS and other kinds of PPMS. 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, and are different under MR spectroscopy. RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.
Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS
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 and that Normal Appearing White Matter (NAWM) structure is also different
The predominant lesions in PPMS are slowly expanding lesions with T cells, microglial, and macrophage-associated demyelination in close similar to pattern I demyelination
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. Preclinical MS refers to cases after the CIS but before the confirming second attack. After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).
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. 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 showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases. Currently a distinction is made between "silent" and subclinical.
In absence of attacks, sometimes a radiological finding suggestive of demyelination (T2 hyperintensities) 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.
It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives, suggesting a wider scope for the "silent MS" term.
In these cases Interleukin-8 is a risk for clinical conversion. 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
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.
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. 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
The aggressive course is associated to grey matter damage and meningeal inflammation, and presents a special intrathecal (meninges and CSF) inflammatory profile.
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
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.
Around 95% of MS cases present oligoclonal bands in CSF. Nevertheless, there are cases of real MS that do not have them. It is suspected to be immunogenetically different. Their evolution is better than standard MS patients
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.
IgM-positive MS has been reported to have a poor response to interferon-beta but a better response to glatimer acetate instead
Controversy for the definition
Currently there is no single diagnosis test for MS that is 100% sensitive and specific. To have such a thing would require a standardised definition of the disease, which currently does not exist. 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
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. 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 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).
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. but can only be detected post-mortem by an autopsy 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.
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.
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.
Some authors instead speak about the biological disease vs. its clinical presentation.
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 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.
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.
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