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 As of 2014 several previous MS variants had been separated from MS after the discovery of a specific auto-antibody. Those autoantibodies were anti-AQP4, anti-MOG and some anti-Neurofascins. 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[percent]. 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.
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