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 could be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour.
- 1 Diseases included in this category
- 2 Identified causes
- 3 Clinical situations inside standard MS
- 4 Controversy for the definition
- 5 See also
- 6 References
Diseases included in this category
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 including a special genetic variant named rapidly progressive multiple sclerosis.
- 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, currently is considered outside the scope of Multiple Sclerosis and inside the scope of Devic's disease, though it is uncertain if this applies to all cases. Also a variant affecting mainly the spinal cord and the cortex has been proposed
- 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
- 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 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.
- 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.
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 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.
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
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).
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 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
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
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
Oligoclonal negative MS
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
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 standarised 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 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".
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).
According to some pathologists, a more accurate pathological definition is required because clinical definitions have problems with differential diagnosis 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. Some authors instead speak about the biological disease vs. its clinical presentation. Anyway, the definition used in each case can be normally deduced from the context in any situation.
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