multiple sclerosis borderline

Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) due to the unknown etiology of some of them, are a heterogenous group of demyelinating diseases - conditions that cause damage to myelin, the protective sheath of nerve fibers - that occur against the background of an acute or chronic inflammatory process. IDDs share characteristics with and are often grouped together under Multiple Sclerosis. They are sometimes considered different diseases from Multiple Sclerosis, 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. As of 2019, three auto-antibodies have been found in atypical MS giving birth to separate diseases: Anti-AQP4 diseases, Anti-MOG and Anti-NF spectrums. A LHON-associated MS has also been reported, and in addition there have been inconclusive reports of TNF-α blockers inducing demyelinating disorders.

The subject is under intense research and the list of MS autoantibodies is expected to grow in the near future.

Separated variants

Several previous MS variants have been recently separated from MS after the discovery of a specific auto-antibody. Those autoantibodies are currently anti-AQP4, anti-MOG and some anti-Neurofascins.

The pathogenic mechanism is usually not related to the clinical course. Therefore, one given pathogenic underlying condition can yield several clinical diseases, and one disease can be produced by several pathogenic conditions.

These conditions can appear as Neuromyelitis optica (NMO), and its associated "spectrum of disorders" (NMOSD), currently considered a common syndrome for several separated diseases but with some still idiopathic subtypes. Some researchers think that there could exist an overlapping between Anti-NMDA receptor encephalitis cases and neuromyelitis optica or acute disseminated encephalomyelitis.

Anti-AQP4 spectrum

:See Anti-AQP4 diseases
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

Anti-MOG spectrum

:See Anti-MOG associated 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.

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 McDonalds-positive 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
** CRION ( Chronic relapsing inflammatory optic neuritis): A distinct clinical entity from other inflammatory demyelinating diseases. Some reports consider it a form of Anti-MOG encephalomyelitis and the most recent ones consider it the main phenotype of the anti-MOG spectrum

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 ercent It has also been noted that percentage of children with anti-mog antibodies respect a demyelinating sample is higher than for adults

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.

Anti-neurofascin spectrum

:See Anti-neurofascin demyelinating diseases
Some anti-neurofascin demyelinating diseases were previously considered a subtype of Multiple Sclerosis but now they are considered a separate entity, as it happened before to anti-MOG and anti-AQP4 cases. Around 10% of MS cases are now thought to be anti-Neurofascin disease in reality.

Anti-neurofascin autoantibodies have been reported in atypical cases of MS and CIDP, and a whole spectrum of Anti-neurofascin demyelinating diseases has been proposed.

Some cases of CIDP are reported to be produced by auto-antibodies against several neurofascin proteins. These proteins are present in the neurons and four of them have been reported to produce disease: NF186, NF180, NF166 and NF155.

Antibodies against Neurofascins NF-155 can also appear in MS and NF-186 could be involved in subtypes of MS yielding an intersection between both conditions.

Summarising, autoantibodies against several neurofascins can produce MS: neurofascin186 (NF186), neurofascin155 (NF155), contactin 1 (CNTN1), contactin associated protein 1 (CASPR1) and gliomedin. All of them nodal and paranodal proteins.

Demyelination associated with anti-TNF therapy

Several anti-TNF drugs like adalimumab are commonly prescribed by a number of autoimmune conditions. Some of them have been reported to produce a CNS-demyelination compatible with standard MS. Several other monoclonal antibodies like pembrolizumab, nivolumab and infliximab have been also reported to produce MS as an adverse event. Nevertheless, it is not so similar as reported in the previous references.

The reactions following Anti-TNF therapy have been diverse according to the source of the disease. Some of these cases can be classify as ADEM, using the confluent demyelination as barrier between both conditions.

In most cases, the damage fulfills all pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lassman/Lucchinetti system. Some lesions also showed Dawson fingers, which is supposed to be a MS-only feature.

These recent problems with artificial anti-TNF-α autoimmunity also point to the possibility of tumor necrosis factor alpha involvement in some multiple sclerosis variants.

LHON-associated MS

Also a previous subtype of MS associated to LHON has been described (LHON-MS) It is a presentation of LHON with MS-like CNS damage.

It used to satisfy McDonalds definition for MS, but after demonstration that LHON can produce this kind of lesions, the "no better explanation" requirement does not hold anymore. It is not due to auto-antibodies, but to defective mitochondria instead.

The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia. and the lack of muscular control.

Relapsing anti-NMDAR encephalitis

Atypical Anti-NMDA receptor encephalitis can appear in the form of relapsing optic neuritis.

Variants still idiopathic

Apart of the previously cited spectrums (Anti-AQP4 diseases, Anti-MOG, and Anti-NF) there is a long list of MS variants, with possibly different pathogenesis, which are still idiopathic and considered inside the MS-spectrum.

Pseudotumefactive variants

Most atypical variants appear as tumefactive or pseudotumefactive variants (lesions whose size is more than , with mass effect, oedema and/or ring enhancement) Some cases of the following have shown anti-MOG auto-antibodies and therefore they represent MS cases only partially.
* 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". It includes Acute hemorrhagic leukoencephalitis, possibly a variant of Acute disseminated encephalomyelitis
* Marburg multiple sclerosis, an aggressive form, also known as malignant, fulminant or acute MS, currently reported to be closer to anti-MOG associated ADEM than to standard MS. and is sometimes considered a synonym for Tumefactive multiple sclerosis
* 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.
* Solitary sclerosis: This variant has been recently proposed (2012) by Mayo Clinic researchers. 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.

Atypical lesion location variants

Also the location of the lesions can be used to classify variants:

Myelocortical multiple sclerosis

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. See the early reports of MCMS<

AQP4-negative Optic-spinal MS

Real Optic-spinal MS (OSMS) without anti-AQP4 antibodies, has been consistently reported, and it is classified into the MS spectrum.

OSMS has its own specific immunological biomarkers The whole picture is under construction and several reports exists about overlapping conditions.

Pure spinal MS

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

LHON associated MS

LHON associated MS (LHON-MS), a presentation of LHON with MS-like CNS damage, and therefore a subtype of MS according to McDonalds definition.

Atypical OCB variants

Also different classifications by body fluid biomarkers is possible:
* Oligoclonal negative MS: Some reports point to the possibility of a different pathogenesis They represent around 5% of the cases which is suspected to be immunogenetically different. Their evolution is better than standard MS patients,
* Oligoclonal IgM 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. It has been reported to have a poor response to interferon-beta but a better response to glatimer acetate instead
* OCB's types: OCBs are made up of activated B-cells. It seems that the molecular targets for the OCB's are patient-specific.

Radiologically atypical variants

Inside well defined MS (Lesions disseminated in time and space with no other explanation) there are atypical cases based in radiological or metabolic criteria. A four-groups classification has been proposed:
* Tumefactive demyelinating lesion (TDL)-onset MS
* Acute disseminated encephalomyelitis (ADEM)-like MS
* Multiple sclerosis with cavitary lesions: Atypical multiple sclerosis cases similar to vanishing white matter disease but etiologically different from both. Lesions similar to vanishing white matter disease
* Leukodystrophy-like MS.

Other radiological classification of atypical lesions proposes the following four subtypes:
* infiltrative
* megacystic
* Baló-like
* ring-like lesions

Atypical clinical courses

In 1996, the US National Multiple Sclerosis Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis (ACCTMS) standardized four clinical courses for MS (Remitent-Recidivant, Secondary Progressive, Progressive-Relapsing and Primary progressive). Later, some reports state that those "types" were artificially made up trying to classify RRMS as a separate disease so that the number of patients was low enough to get the interferon approved by the FDA under the orphan drugs act. Revisions in 2013 and 2017 removed the Progressive-Relapsing course and introduced CIS as a variety/course/status of MS, establishing the actual classification (CIS, RRMS, SPMS and PPMS). Nevertheless, these types are not enough to predict the responses to medications and several regulatory agencies use additional types in their recommendations lide Highly active MS, Malignant MS, Aggressive MS or Rapidly progressive MS.

Highly Active MS

As of 2019, HAMS is defined as an RRMS phenotype with one or more of the following characteristics:

# DSS scale of 4 points at 5 years of onset of the disease
# Multiple relapses (two or more) with incomplete recovery in the ongoing year
# More than 2 brain magnetic resonance imaging (MRI) studies demonstrating new lesions or increase in the size of the lesions in T2, or lesions that enhance with gadolinium despite treatment (Clinical case 1 and 2).
# No response to treatment with one or more DMTs for at least one year.

There is a group of patients who have defined clinical and radiological risk factors that predict a behavior of greater risk of conversion to HAMS, without having the diagnostic criteria of HAMS in a first clinical attack have predictors of high risk.

Some other previous authors have used other definitions like:
* High activity according to 2017 definition of activity
* Rapid accumulation of physical and cognitive deficit, despite treatment with DMT's.
* Being eligible for immunoablative therapy followed by autologous haematopoietic stem cell transplantation (aHSCT) because of a) the failure of conventional treatment, b) frequent and severe (disabling) relapses, or c) MRI activity (new T2 or gadolinium-enhancing lesions).

Malignant MS

:See malignant multiple sclerosis

Occasionally, the term ‘malignant’ MS (MMS) has been used to describe aggressive phenotypes of MS, but this is another ambiguous term that—despite wide usage—means different things to different people.

In 1996, the US National MS Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis, “malignant MS” was also included, namely, “disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset.”

Many authors reserve the term malignant for fulminant forms of MS that deteriorate so rapidly from the outset as to be almost monophasic, and result in death within months to a few years. One such example is the Marburg variant of MS, which is classically characterized by extensive necrotic and/or tumefactive lesions with mass effect.

Despite recent (and increasing) emphasis on early detection of patients with aggressive MS, the original definition of MMS was not modified by the NMSS Advisory Committee in its latest publication in 2013 (Lublin et al., 2014).

Aggressive MS

Common to all definitions is the early, unexpected acquisition of disability followed by frequent relapses and highly active disease seen on MRI.

One definition can be based on EDSS score and the time to develop secondary progressive MS (SPMS) (Menon et al., 2013).

No consensus exists on the speed of progression or degree of disability sufficient for aggressive MS, but some assume that reaching an EDSS score of 6 points probably represents an upper limit beyond which the risk-benefit ratio for an aggressive treatment is unfavourable.

Pragmatically, AMS has been defined as any type of MS that is associated with repeated severe attacks and accelerated accrual of disability—put more simply, "rapidly progressive" MS.

Rapidly progressive multiple sclerosis

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.

Under research

Some auto-antibodies have been found consistently across different MS cases but there is still no agreement on their relevance:
* HEPACAM: A cross-reactivity between HepaCam (GlialCam) and EBNA1 has been reported as of 2022 on 25% of MS cases
* Anti-kir4.1: A KIR4.1 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
* Anoctamin 2: Auto-antibodies against anoctamin-2 (ANO-2), one of the ion-channel proteins, have been reported consistently since 2013
** This finding is not universal. Most of the MS patients do not show auto-antibodies against ANO-2. Therefore, this points toward an ANO2 autoimmune sub-phenotype in MS.
** Later reports point towards a mimicry between ANO-2 and EBV-EBNA-1 protein
* Anti-NMDAR autoantibodies: There is an overlap between cases of Anti-NMDA receptor encephalitis and MS, NMO and ADEM. It also could be a confusion with Anti-NMDA receptor encephalitis in the early stages but there are also anti-NMDAR reported cases that evolve to McDonalds MS
* Anti-Flotilin spectrum: The proteins Flotillin 1 and flotillin 2 have been recently identified as target antigens in some patients with multiple sclerosis. First 14 cases were reported together in the first report, and 3 new cases were reported later inside a cohort of 43 patients.
* Mutations in GJB1 coding for connexin 32, a gap junction protein expressed in Schwann cells and oligodendrocytes, that usually produce Charcot-Marie-Tooth disease. In some cases also MS (as defined by McDonalds criteria) can appear in these patients.
* Also an OPA1 variant exists.
* There exist some reports by Drs. Aristo Vojdani, Partha Sarathi Mukherjee, Joshua Berookhim, and Datis Kharrazian of an aquaporin-related multiple sclerosis, related to vegetal aquaporin proteins.
* Auto-antibodies against histones have been reported to be involved.
* Anti-AQP1 could be involved in atypical MS and NMO
* N-type calcium channel antibodies can produce cognitive relapses mimicking MS related cognitive decline, and may coexist with MS.
* MLKL-MS: Mixed lineage kinase domain like pseudokinase (MLKL) related MS - A preliminary report has pointed out evidence of a novel neurodegenerative spectrum disorder related to it.

Other auto-antibodies can be used to stablish a differential diagnosis from very different diseases like Sjögren syndrome which can be separated by Anti–Calponin-3 autoantibodies.

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

In general, NMO-like spectrum without known auto-antibodies is considered MS. Principal component analysis of these cases show 3 different kinds of antibody-negative patients. The metabolite discriminators of RRMS and Ab-NMOSD suggest that these groupings have some pathogenic meaning.

As MS is an active field for research, the list of auto-antibodies is not closed nor definitive. For example, some diseases like Autoimmune GFAP Astrocytopathy or variants of CIDP that affects the CNS (CIDP is the chronic counterpart of Guillain–Barré syndrome) could be included. Autoimmune variants peripheral neuropathies or progressive inflammatory neuropathy could be in the list assuming the autoimmune model for MS, together with a rare demyelinating lesional variant of trigeminal neuralgia and some NMDAR Anti-NMDA receptor encephalitis.

Venous induced demyelination has also been proposed as a hypothetical MS variant produced by CCSVI, Susac's syndrome and Neuro-Behçet's disease (MS has an important vascular component), myalgic encephalomyelitis (aka chronic fatigue syndrome).

Also leukoaraiosis can produce lesions disseminated in time and space, condition usually sufficient in the MS definition. Maybe two sub-conditions of Leukodystrophy: Adrenoleukodystrophy and Adrenomyeloneuropathy could be in the list. Specially interesting is X-linked adrenoleukodystrophy (X-ALD or CALD).

Genetic types

Different behaviour has been reported according to the presence of different HLA genes.

HLA DRB3*02:02 patients

In HLA DRB3 cases, autoimmune reactions against the enzyme GDP-L-fucose synthase has been reported The same report points that the autoimmune problem could derive from the gut microbiota.

HLA-DRB1*15:01 has the strongest association with MS.

HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 are associated with independent MS susceptibility and HLA-DQβ1 position 9 with phenylalanine had the strongest effect on MS susceptibility.

Another possible type is one with auto-antibodies against GDP-L-fucose synthase. In HLA- DRB3*02:02 patients, autoimmune reactions against the enzyme GDP-L-fucose synthase has been reported The same report points that the autoimmune problem could derive from the gut microbiota.

Rapidly progressive multiple sclerosis

:See malignant 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.

Primary progressive variants

Some researchers propose to separate primary progressive MS from other clinical courses. PPMS, after recent findings seem to point that it is pathologically a very different disease.

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

Clinical variants have been described. For example, Late Onset MS. 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.