Inflammatory demyelinating diseases of the central nervous system

From Wikipedia, the free encyclopedia
Jump to: navigation, search

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 could be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour.[6]

Diseases included in this category[edit]

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[7] including a special genetic variant named rapidly progressive multiple sclerosis.[8]
    • 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,[9] currently is considered outside the scope of Multiple Sclerosis and inside the scope of Devic's disease,[10] though it is uncertain if this applies to all cases.[11] Also a variant affecting mainly the spinal cord and the cortex has been proposed[12][13]
  • Neuromyelitis optica (NMO), and its associated "spectrum of disorders" (NMOSD), currently considered a common syndrome for at least three separated diseases:,[14] 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.[15]
  • Anti-MOG associated spectrum, often clinically presented as an anti-MOG autoimmune encephalomyelitis,[16][17] but can also appear as negative NMO or atypical multiple sclerosis[18]
  • 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.[19]
  • 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.[20][21]
  • 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[22][23]
  • Solitary sclerosis: This variant has been recently proposed (2012) by Mayo Clinic researches.[24] though it was also reported by other groups more or less at the same time.[25][26] 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.[27]

Some inflammatory conditions are associated with the presence of scleroses in the CNS.[28] 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 Susac's syndrome (MS has an important vascular component[29]), leukoaraiosis, myalgic encephalomyelitis (aka chronic fatigue syndrome)[30] 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.[31][32]

Also an OPA1 variant[33] and aKIR4.1 multiple sclerosis variant was reported in 2012[34] and later reported again,[35] 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.[36]

Identified causes[edit]

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[37] and the genetic variant is a mutation in the gene NR1H3.

anti-AQP4 spectrum[edit]

Originally found in neuromyelitis optica, this autoantibody has been associated with other conditions. Its current spectrum is as following:

anti-MOG spectrum[edit]

The presence of anti-MOG autoantibodies has been associated with the following conditions[41]

  • Some cases of aquaporin-4-seronegative neuromyelitis optica: NMO derived from an antiMOG associated encephalomyelitis,[42]
  • Some cases of acute disseminated encephalomyelitis, specially the recurrent ones (MDEM)[43]
  • Some cases of multiple sclerosis[41][44][18]
  • isolated optic neuritis or transverse myelitis[41]
  • 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[45]

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[46]

Rapidly progressive multiple sclerosis[edit]

This is a specially aggressive clinical course of progressive MS[8] 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.[47]

It is important to notice that this kind of MS was previously reported to behave different that the standard progressive course,[48] being linked to Connexin 43 autoantibodies with pattern III lesions (distal oligodendrogliopathy)[49] and being responsive to plasma exchange[50]

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.[51]

Double positive NMO[edit]

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.[52]

Clinical situations inside standard MS[edit]

Also inside standard MS different clinical courses can be separated.

Primary progressive variants[edit]

Some authors think since long ago that primary progressive MS should be considered a disease different from standard MS,[53][54] and it was also proposed that PPMS could be heterogeneous[55]

Clinical variants have been described. For example, Late Onset MS.[56] Since 2016, a special clinical variant of "rapidly progressive" MS has been found to be different from RRMS and other kinds of PPMS.[8] 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,[57] and are different under MR spectroscopy.[58][59] RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.[60]

Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like[61] Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS[62]

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[31]

Preclinical MS: CIS and CDMS[edit]

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.[63] Preclinical MS refers to cases after the CIS but before the confirming second attack.[64] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[65]

RIS, subclinical and silent MS[edit]

Silent MS has been found in autopsies before the existence of MRI[66] showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases.[67] 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.

If a second radiological event appears without clinical consequences, the clinical situation is named "Silent MS" (Okuda criteria).[68]

It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives,[69] suggesting a wider scope for the "silent MS" term.

In these cases Interleukin-8 is a risk for clinical conversion.[70] 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[71]

Aggressive multiple sclerosis[edit]

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.[72] 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[73]

Pediatric and pubertal MS[edit]

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[74]

Oligoclonal negative MS[edit]

Around 95% of MS cases present oligoclonal bands in CSF.[75] Nevertheless, there are cases of real MS that do not have them. It is suspected to be immunogenetically different.[76] Their evolution is better than standard MS patients[77]

Controversy for the definition[edit]

Currently there is no single diagnosis test for MS that is 100% sensitive and specific.[78][79] To have such a thing would require a standarised definition of the disease, which currently does not exist.[80] 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[81]

Pathological and clinical definitions[edit]

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".[82]

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).[80][82]

According to some pathologists, a more accurate pathological definition is required because clinical definitions have problems with differential diagnosis[83] 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[edit]

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.[84] Some authors instead speak about the biological disease vs. its clinical presentation.[85] Anyway, the definition used in each case can be normally deduced from the context in any situation.

See also[edit]

References[edit]

  1. ^ Fontaine B (2001). "[Borderline forms of multiple sclerosis]". Rev. Neurol. (Paris) (in French). 157 (8–9 Pt 2): 929–34. PMID 11787357. 
  2. ^ Wingerchuk DM, Lucchinetti CF (2007). "Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis". Curr. Opin. Neurol. 20 (3): 343–50. doi:10.1097/WCO.0b013e3280be58d8. PMID 17495631. 
  3. ^ Poser CM, Brinar VV (October 2007). "Disseminated encephalomyelitis and multiple sclerosis: two different diseases - a critical review". Acta Neurol. Scand. 116 (4): 201–6. doi:10.1111/j.1600-0404.2007.00902.x. PMID 17824894. 
  4. ^ Weinshenker B, Miller D (1998). "Multiple sclerosis: one disease or many?". In Thompson AB, Siva A, Kesselring J. Frontiers in Multiple Sclerosis (2nd ed.). London: Taylor & Francis Group. pp. 37–46. ISBN 1-85317-506-4. 
  5. ^ Hartung HP, Grossman RI (May 2001). "ADEM: distinct disease or part of the MS spectrum?". Neurology. 56 (10): 1257–60. doi:10.1212/WNL.56.10.1257. PMID 11376169. 
  6. ^ Quintana FJ, Patel B, Yeste A, Nyirenda M, Kenison J, Rahbari R, Fetco D, Hussain M, O'Mahony J, Magalhaes S, McGowan M, Johnson T, Rajasekharan S, Narayanan S, Arnold DL, Weiner HL, Banwell B, Bar-Or A (2014). "Epitope spreading as an early pathogenic event in pediatric multiple sclerosis". Neurology. 83 (24): 2219–26. doi:10.1212/WNL.0000000000001066. PMC 4277672Freely accessible. PMID 25381299. 
  7. ^ Bruno Brochet, Neuropsychiatric Symptoms of Inflammatory Demyelinating Diseases, Springer international, Switzerland 2015, ISBN 3319184644, 9783319184647
  8. ^ a b c Wang Z, et al. (2016). "Nuclear Receptor NR1H3 in Familial Multiple Sclerosis". Neuron. 90 (5): 948–954. doi:10.1016/j.neuron.2016.04.039. PMC 5092154Freely accessible. PMID 27253448. 
  9. ^ Kalanie H, Kholghie Y, Shamsai GR, Ghorbani M (January 2009). "Opticospinal multiple sclerosis in Iran". J. Neurol. Sci. 276 (1–2): 130–2. doi:10.1016/j.jns.2008.09.038. PMID 18962726. 
  10. ^ Kira J (October 2008). "Neuromyelitis optica and asian phenotype of multiple sclerosis". Ann. N. Y. Acad. Sci. 1142 (1): 58–71. Bibcode:2008NYASA1142...58K. doi:10.1196/annals.1444.002. PMID 18990121. 
  11. ^ Matsushita T, Isobe N, Matsuoka T, Shi N, Kawano Y, Wu XM, Yoshiura T, Nakao Y, Ishizu T, Kira JI (2009). "Aquaporin-4 autoimmune syndrome and anti-aquaporin-4 antibody-negative opticospinal multiple sclerosis in Japanese". Mult. Scler. 15 (7): 834–47. doi:10.1177/1352458509104595. PMID 19465451. 
  12. ^ Vignos, Megan C. A HISTOPATHOLOGICAL AND MAGNETIC RESONANCE IMAGING ASSESSMENT OF MYELOCORTICAL MULTIPLE SCLEROSIS: A NEW PATHOLOGICAL VARIANT, http://orcid.org/0000-0002-8329-7764
  13. ^ Hendrickson, M., Chang, A., Fisher, E., Staugaitis, S., Fox, R., Mork, S., & Trapp, B. (2013, October). Myelocortical multiple sclerosis: a subgroup of multiple sclerosis patients with spinal cord and cortical demyelination. In MULTIPLE SCLEROSIS JOURNAL (Vol. 19, No. 11, pp. 366-366). 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND: SAGE PUBLICATIONS LTD.
  14. ^ Weinshenker Brian G (2014). "The two faces of neuromyelitis optica". Neurology. 82 (6): 466–467. doi:10.1212/WNL.0000000000000114. PMID 24415570. 
  15. ^ Gahr M, Lauda F, Wigand ME, Connemann BJ, Rosenbohm A, Tumani H, Reindl M, Uzelac Z, Lewerenz J (2015). "Periventricular white matter lesion and incomplete MRZ reaction in a male patient with anti-N-methyl-D-aspartate receptor encephalitis presenting with dysphoric mania". BMJ Case Rep. 2015: bcr2014209075. doi:10.1136/bcr-2014-209075. PMID 25917068. 
  16. ^ Pröbstel AK et al. Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. J Neuroinflammation. 2015 Mar 8;12(1):46.
  17. ^ Spadaro Melania; et al. (2015). "Histopathology and clinical course of MOG-antibody-associated encephalomyelitis". Annals of Clinical and Translational Neurology. 2 (3): 295–301. doi:10.1002/acn3.164. PMC 4369279Freely accessible. PMID 25815356. 
  18. ^ a b Spadaro M, et al. (2016). "Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis". Neurol Neuroimmunol Neuroinflamm. 3 (5): e257. doi:10.1212/NXI.0000000000000257. 
  19. ^ Rossman I (2015). "An 8 Year Old Girl with Chronic Inflammatory Optic Neuritis (CRION): the Youngest Reported Case to Date". Neurology. 84 (14): Supplement P7.015. 
  20. ^ Garrido C, Levy-Gomes A, Teixeira J, Temudo T (2004). "[Schilder's disease: two new cases and a review of the literature]". Rev Neurol (in Spanish). 39 (8): 734–8. PMID 15514902. 
  21. ^ Afifi AK, Bell WE, Menezes AH, Moore SA (1994). "Myelinoclastic diffuse sclerosis (Schilder's disease): report of a case and review of the literature". J. Child Neurol. 9 (4): 398–403. doi:10.1177/088307389400900412. PMID 7822732. 
  22. ^ Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S, Thomsen K, Mandrekar J, Altintas A, Erickson BJ, König F, Giannini C, Lassmann H, Linbo L, Pittock SJ, Brück W (July 2008). "Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis". Brain. 131 (Pt 7): 1759–75. doi:10.1093/brain/awn098. PMC 2442427Freely accessible. PMID 18535080. 
  23. ^ Given CA, Stevens BS, Lee C (1 January 2004). "The MRI appearance of tumefactive demyelinating lesions". AJR Am J Roentgenol. 182 (1): 195–9. doi:10.2214/ajr.182.1.1820195. PMID 14684539. 
  24. ^ Schmalstieg WF, Keegan BM, Weinshenker BG (Feb 2012). "Solitary sclerosis: progressive myelopathy from solitary demyelinating lesion". Neurology. 78 (8): 540–4. doi:10.1212/WNL.0b013e318247cc8c. PMID 22323754. 
  25. ^ Lattanzi S (2012). "Solitary sclerosis: Progressive myelopathy from solitary demyelinating lesion". Neurology. 79 (4): 393; author reply 393. doi:10.1212/01.wnl.0000418061.10382.f7. PMID 22826546. 
  26. ^ Ayrignac X, Carra-Dalliere C, Homeyer P, Labauge P (2013). "Solitary sclerosis: progressive myelopathy from solitary demyelinating lesion. A new entity?". Acta Neurol Belg. 113 (4): 533–4. doi:10.1007/s13760-013-0182-x. PMID 23358965. 
  27. ^ Jiménez Arango JA, Uribe Uribe CS, Toro González G (2013). "Lesser-known myelin-related disorders: Focal tumour-like demyelinating lesions". Neurologia. 30 (2): 97–105. doi:10.1016/j.nrl.2013.06.004. PMID 24094691. 
  28. ^ O'Connor P, Marriott J (2010). "Differential Diagnosis and Diagnostic Criteria for Multiple Sclerosis: Application and Pitfalls" (PDF). In Hohlfeld R, Lucchinetti CF. Multiple sclerosis 3 (1st ed.). Philadelphia: Saunders Elsevier. ISBN 978-1-4160-6068-0. 
  29. ^ Minagar A, Jy W, Jimenez JJ, Alexander JS (2006). "Multiple sclerosis as a vascular disease". Neurol. Res. 28 (3): 230–5. doi:10.1179/016164106X98080. PMID 16687046. 
  30. ^ "Chronic Fatigue Syndrome - Symptoms, Diagnosis, Treatment of Chronic Fatigue Syndrome". Health Information. New York Times. The following test results... are seen consistently...: Brain MRI showing swelling in the brain or destruction of part of the nerve cells (demyelination) 
  31. ^ a b Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA (2014). "Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice". Exp. Neurol. 261: 620–32. doi:10.1016/j.expneurol.2014.07.020. PMID 25111532. 
  32. ^ Ulloa Bianca; Alahiri Marwan; Liu Ying; Sadiq Saud (2015). "Cerebrospinal Fluid Haptoglobin (Hp) Levels are elevated in MS patients with progressive disease". Neurology. 84 (14): 213. 
  33. ^ Yu-Wai-Man P1, Spyropoulos A2, Duncan HJ3, Guadagno JV2, Chinnery PF4. A multiple sclerosis-like disorder in patients with OPA1 mutations , Ann Clin Transl Neurol. 2016 Jul 19;3(9):723-9. doi: 10.1002/acn3.323. eCollection 2016
  34. ^ Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A, Bennett JL, Korn T, Hemmer B (2012). "Potassium channel KIR4.1 as an immune target in multiple sclerosis". N. Engl. J. Med. 367 (2): 115–23. doi:10.1056/NEJMoa1110740. PMC 5131800Freely accessible. PMID 22784115. 
  35. ^ Schneider R (2013). "Autoantibodies to Potassium Channel KIR4.1 in Multiple Sclerosis". Front Neurol. 4: 125. doi:10.3389/fneur.2013.00125. PMC 3759297Freely accessible. PMID 24032025. 
  36. ^ Vojdani A, Mukherjee PS, Berookhim J, Kharrazian D (2015). "Detection of antibodies against human and plant aquaporins in patients with multiple sclerosis". Research abs. 2: 1378. doi:10.13070/ev.en.2.1378. 
  37. ^ Kazutoshi Sato Douglas; et al. (Feb 2014). "Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders". Neurology. 82 (6): 474–481. doi:10.1212/WNL.0000000000000101. 
  38. ^ Li Y, Xie P, Lv F, et al. (2008). "Brain magnetic resonance imaging abnormalities in neuromyelitis optica". Acta Neurol. Scand. 118 (4): 218–25. doi:10.1111/j.1600-0404.2008.01012.x. PMID 18384459. 
  39. ^ Wingerchuk, Dean (2006). "Neuromyelitis Optica (Devic's Syndrome)" (PDF). 2006 Rare Neuroimmunologic Disorders Symposium. Retrieved 2007-01-05. 
  40. ^ Ken Ikeda et al. Repeated Non-enhancing Tumefactive Lesions in a Patient with a Neuromyelitis Optica Spectrum Disorder. Internal Medicine Vol. 50 (2011) No. 9 P 1061-1064, 2011/05/01, http://doi.org/10.2169/internalmedicine.50.4295
  41. ^ a b c Reindl M, Di Pauli F, Rostásy K, Berger T (Aug 2013). "The spectrum of MOG autoantibody-associated demyelinating diseases". Nat Rev Neurol. 9 (8): 455–61. doi:10.1038/nrneurol.2013.118. PMID 23797245. 
  42. ^ Spadaro Melania; et al. (2015). "Histopathology and clinical course of MOG-antibody-associated encephalomyelitis". Annals of Clinical and Translational Neurology. 2 (3): 295–301. doi:10.1002/acn3.164. PMC 4369279Freely accessible. PMID 25815356. 
  43. ^ M. Baumann, E.M. Hennes, K. Schanda, M. Karenfort, B. Bajer-Kornek, K. Diepold, B. Fiedler, I. Marquardt, J. Strautmanis, S. Vieker, M. Reindl, K. Rostásy. Clinical characteristics and neuroradiological findings in children with multiphasic demyelinating encephalomyelitis and MOG antibodies. European Journal of Paediatric Neurology, Volume 19, Supplement 1, May 2015, Pages S21, Abstracts of the 11th EPNS Congress. 22 May 2015. doi:10.1016/S1090-3798(15)30066-0
  44. ^ Jarius S, Metz I, König FB, Ruprecht K, Reindl M, Paul F, Brück W, Wildemann B. Screening for MOG-IgG and 27 other anti-glial and anti-neuronal autoantibodies in 'pattern II multiple sclerosis' and brain biopsy findings in a MOG-IgG-positive case. Mult Scler. 2016 Feb; pii: 1352458515622986.
  45. ^ Chalmoukou K; et al. (2015). "Recurrent Optic Neuritis (rON) is characterised by Anti-MOG Antibodies: A follow-up study". Neurology. 84 (14 Suppl P5): 274. 
  46. ^ Silvia Tenembaum et al. Spectrum of MOG Autoantibody-Associated Inflammatory Diseases in Pediatric Patients, Neurology 2015; vol. 84 no. 14 Supplement I4-3A
  47. ^ Hain HS, Hakonarson H. The Added Value of Family Material in the Discovery of Multiple Sclerosis Genes. Neuron. 2016 Jun 1;90(5):905-6. doi: http://doi.org/10.1016/j.neuron.2016.05.027
  48. ^ Yvette Morcos et al. A role for hypertrophic astrocytes and astrocyte precursors in a case of rapidly progressive multiple sclerosis, Mult Scler August 2003 vol. 9 no. 4 332-341, doi:10.1191/1352458503ms931oa
  49. ^ Masaki K, Suzuki SO, Matsushita T, Matsuoka T, Imamura S, Yamasaki R, et al. (2013). "Connexin 43 Astrocytopathy Linked to Rapidly Progressive Multiple Sclerosis and Neuromyelitis Optica". PLoS ONE. 8 (8): e72919. Bibcode:2013PLoSO...872919M. doi:10.1371/journal.pone.0072919. PMC 3749992Freely accessible. PMID 23991165. 
  50. ^ Seidi, Osheik, The Role of Therapeutic Plasma Exchange in Clinical Neurology, university of Khartoum, http://khartoumspace.uofk.edu/handle/123456789/19625
  51. ^ Simon A Broadley et al., A new era in the treatment of multiple sclerosis, Med J Aust 2015; 203 (3): 139-141. doi:10.5694/mja14.01218
  52. ^ Yaping Ya et al. Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD, Science China Life Sciences, 26 November 2015, doi:10.1007/s11427-015-4997-y
  53. ^ Vukusic S, Confavreux C (2003). "Primary and secondary progressive multiple sclerosis". J. Neurol. Sci. 206 (2): 153–5. doi:10.1016/S0022-510X(02)00427-6. PMID 12559503. 
  54. ^ Dressel A, Kolb AK, Elitok E, Bitsch A, Bogumil T, Kitze B, Tumani H, Weber F (2006). "Interferon-beta1b treatment modulates cytokines in patients with primary progressive multiple sclerosis". Acta Neurol. Scand. 114 (6): 368–73. doi:10.1111/j.1600-0404.2006.00700.x. PMID 17083335. 
  55. ^ Villar LM; et al. (Aug 2014). "Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis". Ann Neurol. 76 (2): 231–40. doi:10.1002/ana.24190. PMID 24909126. 
  56. ^ María Curbelo, Alejandra Martinez, Judith Steinberg and Adriana Carra, LOMS vs. Other Diseases: The Consequence of "To Be or Not To Be" (P3.081), Neurology April 5, 2016 vol. 86 no. 16 Supplement P3.081
  57. ^ Zwemmer JN, Bot JC, Jelles B, Barkhof F, Polman CH (April 2008). "At the heart of primary progressive multiple sclerosis: three cases with diffuse MRI abnormalities only". Mult. Scler. 14 (3): 428–30. doi:10.1177/1352458507084591. PMID 18208890. 
  58. ^ Rahimian N, Saligheh Rad H, Firouznia K, Ebrahimzadeh SA, Meysamie A, Vafaiean H, Harirchian MH (September 2013). "Magnetic resonance spectroscopic findings of chronic lesions in two subtypes of multiple sclerosis: primary progressive versus relapsing remitting". Iran J Radiol. 10 (3): 128–32. doi:10.5812/iranjradiol.11336. PMC 3857974Freely accessible. PMID 24348597. 
  59. ^ Reinke SN, Broadhurst DL, Sykes BD, Baker GB, Catz I, Warren KG, Power C (2014). "Metabolomic profiling in multiple sclerosis: insights into biomarkers and pathogenesis". Mult. Scler. 20 (10): 1396–400. doi:10.1177/1352458513516528. PMID 24468817. 
  60. ^ Balk L, Tewarie P, Killestein J, Polman C, Uitdehaag B, Petzold A (2014). "Disease course heterogeneity and OCT in multiple sclerosis". Mult. Scler. 20 (9): 1198–1206. doi:10.1177/1352458513518626. PMID 24402036. 
  61. ^ Poser CM, Brinar VV (2004). "The nature of multiple sclerosis". Clin Neurol Neurosurg. 106 (3): 159–71. doi:10.1016/j.clineuro.2004.02.005. PMID 15177764. 
  62. ^ Liguori M, Qualtieri A, Tortorella C, Direnzo V, Bagalà A, et al. (2014). "Proteomic Profiling in Multiple Sclerosis Clinical Courses Reveals Potential Biomarkers of Neurodegeneration". PLoS ONE. 9 (8): e103984. doi:10.1371/journal.pone.0103984. PMC 4123901Freely accessible. PMID 25098164. 
  63. ^ Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP (2008). "'Subclinical MS': follow-up of four cases". Eur. J. Neurol. 15 (8): 858–61. doi:10.1111/j.1468-1331.2008.02155.x. PMID 18507677. 
  64. ^ Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, Clavelou P, Brassat D, Labauge P, Roullet E (2008). "Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile". J. Neurol. Neurosurg. Psychiatr. 79 (2): 195–8. doi:10.1136/jnnp.2006.108274. PMID 18202208. 
  65. ^ Frisullo G, Nociti V, Iorio R, Patanella AK, Marti A, Mirabella M, Tonali PA, Batocchi AP (December 2008). "The persistency of high levels of pSTAT3 expression in circulating CD4+ T cells from CIS patients favors the early conversion to clinically defined multiple sclerosis". J. Neuroimmunol. 205 (1–2): 126–34. doi:10.1016/j.jneuroim.2008.09.003. PMID 18926576. 
  66. ^ Mackay Roland P.; Hirano Asao (1967). "Report of two clinically silent cases discovered at autopsy". Arch Neurol. 17 (6): 588–600. doi:10.1001/archneur.1967.00470300030007. PMID 6054893. 
  67. ^ Engell T (May 1989). "A clinical patho-anatomical study of clinically silent multiple sclerosis". Acta Neurol Scand. 79 (5): 428–30. doi:10.1111/j.1600-0404.1989.tb03811.x. PMID 2741673. 
  68. ^ Gabelic T, Ramasamy DP, Weinstock-Guttman B, Hagemeier J, Kennedy C, Melia R, Hojnacki D, Ramanathan M, Zivadinov R (2014). "Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of patients with multiple sclerosis". AJNR Am J Neuroradiol. 35 (1): 106–12. doi:10.3174/ajnr.A3653. PMID 23886745. Lay summarymsdiscovery.org. 
  69. ^ Gabelic T, Weinstock-Guttman B, Melia R, Lincoff N, Masud MW, Kennedy C, Brinar V, Ramasamy DP, Carl E, Bergsland N, Ramanathan M, Zivadinov R (2013). "Retinal nerve fiber thickness and MRI white matter abnormalities in healthy relatives of multiple sclerosis patients". Clin Neurol Neurosurg. 115 Suppl 1: S49–54. doi:10.1016/j.clineuro.2013.09.021. PMID 24321155. 
  70. ^ Rossi S; et al. (2015). "Subclinical central inflammation is risk for RIS and CIS conversion to MS". Mult Scler. 21 (11): 1443–52. doi:10.1177/1352458514564482. PMID 25583841. 
  71. ^ Cramer; et al. (2015). "Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis". Brain. 138 (Pt 9): 2571–83. doi:10.1093/brain/awv203. PMC 4547053Freely accessible. PMID 26187333. 
  72. ^ Sazonov DV, Malkova NA, Bulatova EV, Riabukhina OV (2009). "[Combined therapy of aggressive remitted multiple sclerosis with mitoxantrone in combination with copaxone]". Zh Nevrol Psikhiatr Im S S Korsakova. 109 (12): 76–9. PMID 20037526. 
  73. ^ Rush, MacLean, Freedman. Aggressive multiple sclerosis: proposed definition and treatment algorithm. Nat Rev Neurol. 2015 Jun 2. doi: 10.1038/nrneurol.2015.85. PMID 26032396
  74. ^ Chabas D, Castillo-Trivino T, Mowry EM, Strober JB, Glenn OA, Waubant E (September 2008). "Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype?". Neurology. 71 (14): 1090–3. doi:10.1212/01.wnl.0000326896.66714.ae. PMID 18824673. 
  75. ^ Link H, Huang YM (2006). "Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness". Neuroimmunology. 180 (1–2): 17–28. doi:10.1016/j.jneuroim.2006.07.006. PMID 16945427. 
  76. ^ Imrell K, Landtblom AM, Hillert J, Masterman T (2006). "Multiple sclerosis with and without CSF bands: Clinically indistinguishable but immunogenetically distinct". Neurology. 67 (6): 1062–1064. doi:10.1212/01.wnl.0000237343.93389.35. PMID 17000979. 
  77. ^ Zeman AZ, Kidd D, McLean BN, Kelly MA, Francis DA, Miller DH, Kendall BE, Rudge P, Thompson EJ, McDonald WI (1996). "A study of oligoclonal band negative multiple sclerosis". J Neurol Neurosurg Psychiatry. 60 (1): 27–30. doi:10.1136/jnnp.60.1.27. PMC 486185Freely accessible. PMID 8558146. 
  78. ^ Alex Rovira et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—clinical implementation in the diagnostic process, Nature Reviews Neurology 11, 471–482 (2015), 07 July 2015, doi:http://doi.org/10.1038/nrneurol.2015.106
  79. ^ Niraj Mistry et al. Central Veins in Brain Lesions Visualized With High-Field Magnetic Resonance Imaging. A Pathologically Specific Diagnostic Biomarker for Inflammatory Demyelination in the Brain, JAMA neurology, May 2013, Vol 70, No. 5
  80. ^ a b David G Haegert (2015) The Definition of Multiple Sclerosis: Implications for Research. J Mult Scler (Foster City) 2: 1000e105. doi: http://doi.org/10.4172/2376-0389.1000e105
  81. ^ Susman, Ed, News from the ECTRIMS Congress: MS Discordant Twins Often Have Silent Lesions on Imaging, Neurology Today, 3 November 2016 - Volume 16 - Issue 21 - p 18–19, doi:10.1097/01.NT.0000508402.13786.97
  82. ^ a b McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis" (PDF). Ann. Neurol. 50 (1): 121–7. doi:10.1002/ana.1032. PMID 11456302. 
  83. ^ Lassmann H (2010). "Acute disseminated encephalomyelitis and multiple sclerosis". Brain. 133 (Pt 2): 317–9. doi:10.1093/brain/awp342. PMID 20129937. 
  84. ^ Dutta R, Trapp BD (2006). "[Pathology and definition of multiple sclerosis]". Rev Prat (in French). 56 (12): 1293–8. PMID 16948216. 
  85. ^ Quintana FJ et al. Epitope spreading as an early pathogenic event in pediatric multiple sclerosis. Neurology. 2014 Dec 9;83(24):2219-26. doi: 10.1212/WNL.0000000000001066. Epub 2014 Nov 7.