pathophysiology of multiple sclerosis#Demyelination patterns

{{main |Pathology of multiple sclerosis}}

File:Myelin sheath damage in multiple sclerosis.svg

Multiple sclerosis can be pathologically defined as the presence of distributed glial scars (or sclerosis) in the central nervous system disseminated in time (DIT) and space (DIS).{{cite journal |vauthors=Dutta R, Trapp BD | date = Jun 2006 | title = Pathology and definition of multiple sclerosis | journal = Rev Prat | volume = 56 | issue = 12 | pages = 1293–8 | pmid = 16948216 }} The gold standard for MS diagnosis is pathological correlation, though given its limited availability, other diagnosis methods are normally used.{{cite journal |vauthors=Fakhredin RB, Saade C, Kerek R, El-Jamal L, Khoury SJ, El-Merhi F | date = 27 July 2016 | title = Imaging in multiple sclerosis: A new spin on lesions | journal = J. Med. Imaging Radiat. Oncol. | doi = 10.1111/1754-9485.12498 | pmid = 27464473 | volume=60 | issue = 5 | pages=577–586| s2cid = 5005413 | doi-access = free }} The scleroses that define the disease are the remainders of previous demyelinating lesions in the CNS white matter of a patient (encephalomyelitis) showing special characteristics, such as confluent instead of perivenous demyelination.{{cite journal |vauthors=Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, Thomsen KM, Mandrekar JN, Erickson BJ, Lucchinetti CF | year = 2010 | title = Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis | journal = Brain | volume = 133 | issue = 2 | pages = 333–348 | doi = 10.1093/brain/awp321 | pmid=20129932 | pmc=2822631}}

There are three phases for how an unknown underlying condition may cause damage in MS:

1. An unknown soluble factor (produced by CD8+ T-cells or CD20+ B-cells), creates a toxic environment that activates microglia.{{cite journal | author = Lassman H | date = Mar 2019 | title = The changing concepts in the neuropathology of acquired demyelinating central nervous system disorders | journal = Curr Opin Neurol | volume = 32| issue = 3| pages = 313–319 | doi = 10.1097/WCO.0000000000000685|pmid=30893100| s2cid = 84841404 }}{{cite journal | author = Lassman H | year = 2019 | title = Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis | journal = Front Immunol | volume = 9 | page = 3116 | doi = 10.3389/fimmu.2018.03116 | pmid=30687321 | pmc=6335289| doi-access = free }}
2. MRI-abnormal areas with hidden damage appear in the brain and spine (NAWM, NAGM, DAWM). Some clusters of activated microglia, axonal transection and myelin degeneration are present.{{cite journal|vauthors=van der Valk P, Amor S | title=Preactive lesions in multiple sclerosis. | journal=Curr Opin Neurol | year= 2009 | volume= 22 | issue= 3 | pages= 207–13 | pmid=19417567 | doi=10.1097/WCO.0b013e32832b4c76 | s2cid=46351467 }}{{cite journal |vauthors=Bsibsi M, Holtman IR, Gerritsen WH, Eggen BJ, Boddeke E, van der Valk P, van Noort JM, Amor S | year = 2013 | title = Alpha-B-Crystallin Induces an Immune-Regulatory and Antiviral Microglial Response in Preactive Multiple Sclerosis Lesions | journal = J Neuropathol Exp Neurol | volume = 72 | issue = 10 | pages = 970–9 | doi = 10.1097/NEN.0b013e3182a776bf | pmid = 24042199 | doi-access = free }}{{cite journal | author = Ontaneda | date = Nov 2014 | title = Identifying the Start of Multiple Sclerosis Injury: A Serial DTI Study | journal = J Neuroimaging | volume = 24 | issue = 6 | pages = 569–76 | doi = 10.1111/jon.12082 | pmid = 25370339 | pmc = 4221810 |display-authors=etal}}
3. Leaks in the blood–brain barrier appear and immune cells infiltrate, causing demyelination.{{cite journal |vauthors=Goodkin DE, Rooney WD, Sloan R, etal |title=A serial study of new MS lesions and the white matter from which they arise |journal=Neurology |volume=51 |issue=6 |pages=1689–97 |date=December 1998 |pmid=9855524 |url=http://www.neurology.org/cgi/content/abstract/51/6/1689 |doi=10.1212/wnl.51.6.1689 |s2cid=21375563 |access-date=2008-09-28 |archive-date=2008-05-22 |archive-url=https://web.archive.org/web/20080522131435/http://www.neurology.org/cgi/content/abstract/51/6/1689 |url-status=dead }} and axon destruction.{{cite journal |vauthors=Tallantyre EC, Bø L, Al-Rawashdeh O, Owens T, Polman CH, Lowe JS, Evangelou N |title=Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis |journal=Mult Scler |date=April 2010 |volume=16 | issue=4 | pages=406–411 | doi= 10.1177/1352458510364992 |pmid=20215480|s2cid=8176814 }}

Multiple sclerosis differs from other idiopathic inflammatory demyelinating diseases in its confluent subpial cortical lesions. These types of lesions are the most specific finding for MS, being exclusively present in MS patients, though currently they can only be detected at autopsy.{{cite journal | author = Lassmann Hans | year = 2014 | title = Multiple sclerosis: Lessons from molecular neuropathology | journal = Experimental Neurology | volume = 262 | pages = 2–7 | doi = 10.1016/j.expneurol.2013.12.003 | pmid = 24342027 | s2cid = 25337149 }}

Most MS findings take place inside the white matter, and lesions appear mainly in a periventricular distribution (clustered around the ventricles of the brain). Apart from white matter demyelination, the cortex and deep gray matter (GM) nuclei can be affected, together with diffuse injury of the NAWM.{{cite journal |vauthors=Lassmann H, Brück W, Lucchinetti CF |title=The immunopathology of multiple sclerosis: an overview |journal=Brain Pathol. |volume=17 |issue=2 |pages=210–8 |date=April 2007 |pmid=17388952 |doi=10.1111/j.1750-3639.2007.00064.x|pmc=8095582 |s2cid=20047423 |doi-access=free }} GM atrophy is independent of classical MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS{{cite journal |vauthors=Pirko I, Lucchinetti CF, Sriram S, Bakshi R |title=Gray matter involvement in multiple sclerosis |journal=Neurology |volume=68 |issue=9 |pages=634–42 |date=February 2007 |pmid=17325269 |doi=10.1212/01.wnl.0000250267.85698.7a|s2cid=40321377 }}

At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, intrathecal Ig production with oligoclonal bands, an environment fostering immune cell persistence, and a disruption of the blood–brain barrier outside of active lesions.{{cite journal |vauthors=Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R |title=Compartmentalization of inflammation in the CNS: A major mechanism driving progressive multiple sclerosis |journal=J Neurol Sci |volume=274 |issue=1–2 |pages=42–4 |date=November 2008 |pmid=18715571 |doi=10.1016/j.jns.2008.06.032|s2cid=34995402 }} The scars that give the name to the condition are produced by astrocytes healing old lesions.{{cite journal |vauthors=Brosnan CF, Raine CS | year = 2013 | title = The astrocyte in multiple sclerosis revisited | journal = Glia | volume = 61 | issue = 4 | pages = 453–465 | doi = 10.1002/glia.22443 | pmid = 23322421 | s2cid = 43783397 }} MS is active even during remission periods.{{cite journal |vauthors=Kirov I, Patil V, Babb J, Rusinek H, Herbert J, Gonen O |title=MR Spectroscopy Indicates Diffuse Multiple Sclerosis Activity During Remission |journal=J. Neurol. Neurosurg. Psychiatry |volume= 80 |issue= 12 |pages= 1330–6 |date=June 2009 |pmid=19546105 |doi=10.1136/jnnp.2009.176263 |pmc=2900785}}

Follicle-like aggregates in the meninges are formed only in secondary progressive MS.{{cite journal |author=Shinji Oki |title=Novel mechanisms of chronic inflammation in secondary progressive multiple sclerosis |journal=Neuroimmunology |volume=9 |issue=S1 |pages=13–19|date=March 2018 | doi=10.1111/cen3.12437 |doi-access=free }} and correlate with the degree of subpial cortical demyelination and brain atrophy, suggesting that they might contribute to cortical pathology in SPMS

These ectopic lymphoid follicles are composed mainly of EBV infected B-cells.{{cite journal |vauthors=Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F | title=Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain |journal=Journal of Experimental Medicine| volume=204 | issue=12 | pages=2899–2912 |date=Nov 2007 | doi=10.1084/jem.20071030 | pmid=17984305 |pmc=2118531}}

Four different damage patterns have been identified in patient's brain tissues. The original report{{citation needed|date=May 2022}} suggests that there may be several types of MS with different immune causes, and that MS may be a family of several diseases. Though originally a biopsy was required to classify the lesions of a patient, since 2012 it is possible to classify them by a blood testF. Quintana et al., Specific Serum Antibody Patterns Detected with Antigen Arrays Are Associated to the Development of MS in Pediatric Patients, Neurology, 2012. Freely available at [http://www.neurology.org/cgi/content/meeting_abstract/78/1_MeetingAbstracts/S60.006] {{Webarchive|url=https://web.archive.org/web/20220606001706/https://www.neurology.org/lookup/content/meeting_abstract/78/1_MeetingAbstracts/S60.006 |date=2022-06-06 }} looking for antibodies against 7 lipids, three of which are cholesterol derivativesHarnessing the clinical value of biomarkers in MS, International Journal of MS care, June 2012 [http://ijmsc.org/doi/pdf/10.7224/1537-2073-14.S5.1] Cholesterol crystals are believed to both impair myelin repair and aggravate inflammation.{{cite journal | vauthors=Chen Y, Popko B | title=Cholesterol crystals impede nerve repair | journal= Science | volume=359 | issue=6376 | pages=635–636 | year=2018 | doi= 10.1126/science.aar7369 | pmid = 29439228 | bibcode=2018Sci...359..635C | s2cid=3257111 }}{{cite journal | vauthors=Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M, Sen P, Ruhwedel T, Mitkovski M, Trendelenburg G, Lütjohann D, Möbius W, Simons M | title=Defective cholesterol clearance limits remyelination in the aged central nervous system | journal= Science | volume=359 | issue=6376 | pages=684–688 | year=2018 | doi= 10.1126/science.aan4183 | pmid = 29301957 | bibcode=2018Sci...359..684C | hdl=21.11116/0000-0000-2F49-B | doi-access=free }}

It is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. In any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more effective treatment decisions.{{citation needed|date=October 2021}}

According to one of the researchers involved in the original research, "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."

The four identified patterns are:{{cite journal |vauthors= Lucchinetti CF, Brück W, Rodriguez M, Lassmann H | date = Jul 1996 | title = Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis | journal = Brain Pathol | volume = 6 | issue = 3 | pages = 259–74 | pmid = 8864283 | doi=10.1111/j.1750-3639.1996.tb00854.x| pmc = 7161824 }}

; Pattern I : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.{{cite web | url=http://immserv1.path.cam.ac.uk/~immuno/part1/lec10/lec10_97.html | title=Part 1B Pathology: Lecture 11 - The Complement System | access-date=2006-05-10 | first=Nick | last=Holmes | date=15 November 2001 | url-status=dead | archive-url=https://web.archive.org/web/20060109221235/http://immserv1.path.cam.ac.uk/~immuno/part1/lec10/lec10_97.html | archive-date=9 January 2006 }}

; Pattern II : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.{{cite journal | journal=Brain | volume=122 | issue=12 | pages=2279–2295 |date=December 1999 | title=A quantitative analysis of oligodendrocytes in multiple sclerosis lesions - A study of 113 cases |vauthors=Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H | doi=10.1093/brain/122.12.2279 | pmid=10581222| doi-access=free }} This pattern has been considered similar to damage seen in NMO, though AQP4 damage does not appear in pattern II MS lesions{{cite journal | pmid = 19822791 | doi=10.1001/archneurol.2009.199 | volume=66 | issue=10 | title=Humoral pattern II multiple sclerosis pathology not associated with neuromyelitis Optica IgG | pmc=2767176 |date=October 2009 |vauthors=Kale N, Pittock SJ, Lennon VA, etal | journal=Arch Neurol | pages=1298–9 }} Nevertheless, pattern II has been reported to respond to plasmapheresis,{{cite journal |vauthors=Wilner AN, Goodman |title=Some MS patients have "Dramatic" responses to Plasma Exchange |journal=Neurology Reviews |volume=8 |issue=3 |date=March 2000 |url=http://www.neurologyreviews.com/mar00/nr_mar00_MSpatients.html |access-date=2006-05-05 |archive-url=https://web.archive.org/web/20010223022848/http://www.neurologyreviews.com/mar00/nr_mar00_MSpatients.html |archive-date=2001-02-23 |url-status=dead }} which points to something pathogenic into the blood serum.

:The complement system infiltration in these cases convert this pattern into a candidate for research into autoimmune connections like anti-Kir4.1,{{Cite journal |doi=10.1056/NEJMoa1110740 |pmid=22784115 |title=Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis |journal=New England Journal of Medicine |volume=367 |issue=2 |pages=115–23 |year=2012 |last1=Srivastava |first1=Rajneesh |last2=Aslam |first2=Muhammad |last3=Kalluri |first3=Sudhakar Reddy |last4=Schirmer |first4=Lucas |last5=Buck |first5=Dorothea |last6=Tackenberg |first6=Björn |last7=Rothhammer |first7=Veit |last8=Chan |first8=Andrew |last9=Gold |first9=Ralf |last10=Berthele |first10=Achim |last11=Bennett |first11=Jeffrey L. |last12=Korn |first12=Thomas |last13=Hemmer |first13=Bernhard |pmc=5131800}} anti-Anoctamin-2{{Cite journal |doi=10.1073/pnas.1518553113 |title=Anoctamin 2 identified as an autoimmune target in multiple sclerosis |journal=Proceedings of the National Academy of Sciences |volume=113 |issue=8 |pages=2188–2193 |year=2016 |last1=Ayoglu |first1=Burcu |last2=Mitsios |first2=Nicholas |last3=Kockum |first3=Ingrid |last4=Khademi |first4=Mohsen |last5=Zandian |first5=Arash |last6=Sjöberg |first6=Ronald |last7=Forsström |first7=Björn |last8=Bredenberg |first8=Johan |last9=Lima Bomfim |first9=Izaura |last10=Holmgren |first10=Erik |last11=Grönlund |first11=Hans |last12=Guerreiro-Cacais |first12=André Ortlieb |last13=Abdelmagid |first13=Nada |last14=Uhlén |first14=Mathias |last15=Waterboer |first15=Tim |last16=Alfredsson |first16=Lars |last17=Mulder |first17=Jan |last18=Schwenk |first18=Jochen M. |last19=Olsson |first19=Tomas |last20=Nilsson |first20=Peter |pmid=26862169 |pmc=4776531|bibcode=2016PNAS..113.2188A |doi-access=free }} or anti-MOG mediated MS{{cite journal | author = Spadaro Melania | year = 2015 | title = Histopathology and clinical course of MOG-antibody-associated encephalomyelitis | journal = Annals of Clinical and Translational Neurology | volume = 2 | issue = 3 | pages = 295–301 | doi = 10.1002/acn3.164 | pmid = 25815356 | pmc = 4369279 |display-authors=etal}} About the last possibility, research has found antiMOG antibodies in some pattern-II MS patients.{{cite journal |vauthors=Jarius S, Metz I, König FB, Ruprecht K, Reindl M, Paul F, Brück W, Wildemann B | date = 11 Feb 2016 | title = 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. | journal = Mult Scler | volume = 22 | issue = 12 | pages = 1541–1549 | doi = 10.1177/1352458515622986 | pmid = 26869529 | s2cid = 1387384 }}

:Pattern II pathogenic T cells has been shown to be different from others{{cite journal | author = Planas Raquel | year = 2015 | title = Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions | journal = Annals of Clinical and Translational Neurology| volume = 2 | issue = 9 | pages = 875–893 | doi = 10.1002/acn3.218 | pmid = 26401510 | pmc = 4574806 |display-authors=etal}}{{cite journal |vauthors=Antel JP, Ludwin SK, Bar-Or A | year = 2015 | title = Sequencing the immunopathologic heterogeneity in multiple sclerosis | journal = Annals of Clinical and Translational Neurology | volume = 2 | issue = 9 | pages = 873–874 | doi = 10.1002/acn3.230 |pmid=26401509 | pmc=4574805}} The functional characterization shows that T cells releasing Th2 cytokines and helping B cells dominate the T-cell infiltrate in pattern II brain lesions.

; Pattern III : The scars are diffuse with inflammation, distal oligodendrogliopathy, microglial activation and loss of myelin-associated glycoprotein (MAG). It is considered atypical and an overlap between MS and Balo concentric sclerosis. The scars do not surround the blood vessels, and a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis. At first, some researchers thought it was an early stage of the evolution of the other patterns.{{cite journal |last1=Barnett |first1=MH |last2=Prineas |first2=JW |name-list-style=vanc |title=Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion |url=http://www.direct-ms.org/pdf/ImmunologyMS/Prineas%20new%20lesion.pdf |pmid=15048884 |journal=Annals of Neurology |doi=10.1002/ana.20016 |volume=55 |issue=4 |date=April 2004 |pages=458–68 |s2cid=5659495 |access-date=2009-10-28 |archive-url=https://web.archive.org/web/20131029184151/http://www.direct-ms.org/pdf/ImmunologyMS/Prineas%20new%20lesion.pdf |archive-date=2013-10-29 |url-status=dead }}{{Cite journal |doi=10.1093/brain/awm236 |title=Lesion genesis in a subset of patients with multiple sclerosis: A role for innate immunity? |journal=Brain |volume=130 |issue=11 |pages=2800–2815 |year=2007 |last1=Marik |first1=C. |last2=Felts |first2=P. A. |last3=Bauer |first3=J. |last4=Lassmann |first4=H. |last5=Smith |first5=K. J. |pmid=17956913 |pmc=2981817}} Recently, it is thought that it represents ischaemia-like injury with absence of oligoclonal bands in the CSF, related to the pathogenesis of Balo concentric sclerosis.{{cite journal | author = Hardy TA, Tobin WO, Lucchinetti CF | year = 2016 | title = Exploring the overlap between multiple sclerosis, tumefactive demyelination and Baló's concentric sclerosis | journal = Multiple Sclerosis Journal| volume = 22| issue = 8 | pages = 986–992| doi = 10.1177/1352458516641776 | pmid = 27037180 | s2cid = 3810418 }}

; Pattern IV : The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal-appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

These differences are noticeable only in early lesions{{cite journal |vauthors=Breij EC, Brink BP, Veerhuis R, etal |title=Homogeneity of active demyelinating lesions in established multiple sclerosis |journal=Annals of Neurology |volume=63 |issue=1 |pages=16–25 |year=2008 |pmid=18232012 |doi=10.1002/ana.21311 |s2cid=205340842 }} and the heterogeneity was controversial for some time because some research groups thought that these four patterns could be a consequence of the age of the lesions.{{cite journal |author1=Michael H. Barnett |author2=John W. Prineas |title=Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion |journal=Annals of Neurology |volume=55 |issue=1 |pages=458–468 |year=2004 |pmid=15048884 |doi=10.1002/ana.20016 |s2cid=5659495 |url=http://www.cpnhelp.org/files/Ref1_Annals04.pdf}} Nevertheless, after some debate among research groups, the four patterns model is accepted and the exceptional case found by Prineas has been classified as NMO{{cite journal |vauthors=Brück W, Popescu B, Lucchinetti CF, Markovic-Plese S, Gold R, Thal DR, Metz I | date = Sep 2012 | title = Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate | journal = Ann Neurol | volume = 72 | issue = 3 | pages = 385–94 | doi = 10.1002/ana.23621 | pmid = 23034911 | s2cid = 1662420 }}{{cite journal |vauthors=Arnold P, Mojumder D, Detoledo J, Lucius R, Wilms H | date = Feb 2014 | title = Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways | journal = Clin Pharmacol | volume = 6 | pages = 35–42 | doi = 10.2147/CPAA.S35033 | pmid = 24591852 | pmc = 3938468 | doi-access = free }}

For some investigation teams this means that MS is an immunopathogenetically heterogeneous disease. The latter hypothesis is further corroborated by a recent study that demonstrated significant differences in routine cerebrospinal fluid findings between patients with pattern I lesions and patients with non-pattern I lesions, including a lack of CSF-restricted oligoclonal bands, in most pattern II and III patients.{{cite journal |vauthors=Jarius S, König FB, Metz I, Ruprecht K, Paul F, Brück W, Wildemann B | date = 29 Aug 2017 | title = Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis | journal = J Neuroinflammation | volume = 14 | issue = 1 | pages = 171 | doi = 10.1186/s12974-017-0929-z | pmid = 28851393 | pmc=5576197 | doi-access = free }} Finally, some previously diagnosed with pattern II MS were later found to have in fact MOG-IgG-related encephalomyelitis, suggesting that both the current clinicoradiological diagnostic criteria for MS and the histopathological criteria for MS may be insufficiently specific. This was already indicated by previous studies that found a relatively high rate of false diagnoses of MS among patients with AQP4-IgG-positive neuromyelitis optica spectrum disorders or MOG encephalomyelitis.

Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.{{cite journal |vauthors=Quintana FJ, Farez MF, Viglietta V, etal |title=Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis |journal=Proc Natl Acad Sci USA |volume=105 |issue=48 |pages=18889–94 |date=December 2008 |pmid=19028871 |pmc=2596207 |doi=10.1073/pnas.0806310105 |bibcode=2008PNAS..10518889Q|doi-access=free }}

Another development in this area is the finding that some lesions present mitochondrial defects that could distinguish types of lesions.{{cite journal |vauthors=Mahad D, Ziabreva I, Lassmann H, Turnbull D |title=Mitochondrial defects in acute multiple sclerosis lesions |journal= Brain |volume= 131 |issue= Pt 7 |pages= 1722–35 |year=2008 |pmid=18515320 |doi=10.1093/brain/awn105 |pmc=2442422}}

In multiple sclerosis, inflammation, demyelination, and neurodegeneration are observed together. Some clinical trials have shown that the inflammation produces both the relapses and the demyelination, and that neurodegeneration (axonal transection) is independent from inflammation, produces the accumulative disability, and advances even when inflammation and demyelination are delayed.{{cite journal |vauthors=Coles AJ, Wing MG, Molyneux P, Paolillo A, Davie CM, Hale G, etal | title=Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. | journal=Ann Neurol | year= 1999 | volume= 46 | issue= 3 | pages= 296–304 | pmid=10482259| doi=10.1002/1531-8249(199909)46:3<296::AID-ANA4>3.0.CO;2-# | s2cid=13969069 }} It seems that neurodegeneration is produced by damaged mitochondria, which in turn comes from activated microglia.{{cite journal |vauthors=Witte ME, Mahad DJ, Lassmann H, Horssen J | year = 2014| title = Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis | journal = Trends in Molecular Medicine | volume = 20 | issue = 3| pages = 179–187 | doi = 10.1016/j.molmed.2013.11.007 | pmid = 24369898}}

Currently it is unknown what the primary cause of MS is; if MS is a heterogeneous disease, the lesion development process would not be unique. In particular, some PPMS patients having a special clinical course named rapidly progressive multiple sclerosis could have a special genetic cause{{cite journal | author = Wang Zhe | year = 2016 | title = Nuclear Receptor NR1H3 in Familial Multiple Sclerosis | journal = Neuron | volume = 90 | issue = 5 | pages = 948–954 | doi = 10.1016/j.neuron.2016.04.039 | pmid = 27253448 | pmc=5092154|display-authors=etal}} and a different development process.

Several types of damage appear in the brain: normal appearing white matter (NAWM) and characteristic lesions. Changes in NAWM include axonal injury without demyelination, low-grade inflammation, and microglial and astrocytic activation{{cite journal | vauthors = Abdelhak A, Weber MS, Tumani H | year = 2017 | title = Primary Progressive Multiple Sclerosis: Putting Together the Puzzle | journal = Front. Neurol. | pages = 8–234 | doi = 10.3389/fneur.2017.00234 | pmid = 28620346 | pmc=5449443 | volume=8| doi-access = free }}

File:Glial Cell Types.png

MS lesions develop inside NAWM areas. Their shape is influenced by their activity{{Cite journal|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jon.12633|title=Three-Dimensional Lesion Phenotyping and Physiologic Characterization Inform Remyelination Ability in Multiple Sclerosis|first1=Dinesh K.|last1=Sivakolundu|first2=Madison R.|last2=Hansen|first3=Kathryn L.|last3=West|first4=Yeqi|last4=Wang|first5=Thomas|last5=Stanley|first6=Andrew|last6=Wilson|first7=Morgan|last7=McCreary|first8=Monroe P.|last8=Turner|first9=Marco C.|last9=Pinho|first10=Braeden D.|last10=Newton|first11=Xiaohu|last11=Guo|first12=Bart|last12=Rypma|first13=Darin T.|last13=Okuda|date=January 27, 2019|journal=Journal of Neuroimaging|volume=29|issue=5|pages=605–614|via=Wiley Online Library|doi=10.1111/jon.12633|pmid=31148298|s2cid=171094100}}

The most accepted sequence of events is first NAWM appearance, then the so-called pre-active lesions, with activated microglia, and finally the BBB (blood-brain barrier) breakdown, which enables the entry of T-cells to the CNS. This marks the beginning of an autoimmune attack which destroys myelin in active lesions.{{cite journal |vauthors=Allen IV, McQuaid S, Mirakhur M, Nevin G | year = 2001 | title = Pathological abnormalities in the normal-appearing white matter in multiple sclerosis | journal = Neurological Sciences | volume = 22 | issue = 2| pages = 141–144 | doi=10.1007/s100720170012 | pmid=11603615| s2cid = 26091720 }} When the attack is resolved, a characteristic glial scar is formed by astrocytes.

Current models can be divided into two categories: inside-out and outside-in. In the former, it is hypothesized that a problem in CNS cells produces an immune response that destroys myelin and subsequently breaks the BBB. In latter, an external factor produces BBB leaks, enters the CNS, and destroys myelin and axons.{{cite journal |vauthors=Tsunoda I, Fujinami RS| title=Inside-Out versus Outside-In models for virus induced demyelination: axonal damage triggering demyelination. | journal=Springer Semin Immunopathol | year= 2002 | volume= 24 | issue= 2 | pages= 105–25 | pmid=12503060 | doi=10.1007/s00281-002-0105-z| pmc=7079941 }} Whatever the underlying condition for MS is, it appears that damage is triggered by an unknown soluble factor in the CSF, potentially produced in meningeal areas; this factor can diffuse into the cortical parenchyma and destroy myelin either directly or indirectly through microglia activation.

The evolution of a preactive lesion is related to microglia reactivity. Increased expression of pro-inflammatory cell surface markers have been observed in NAWM and "initial" lesions, corresponding to a so-called loss of homeostatic microglial equilibrium.{{cite journal |vauthors=Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H | year = 2017| title = Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis | journal = Brain | volume = 140 | issue = 7| pages = 1900–1913 | doi = 10.1093/brain/awx113 | pmid = 28541408| pmc = 6057548}}

Some authors report active lesion formation before BBB breakdown;{{cite journal |vauthors=Werring DJ, Brassat D, Droogan AG, etal |title=The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study |journal=Brain |volume=123 |pages=1667–76 |date=August 2000 |pmid=10908196 |doi= 10.1093/brain/123.8.1667 |issue=8|doi-access= }} others point to adipsin as a factor of the breakdown.{{Cite journal |doi=10.1111/cen.12856 |title=Quantification and regulation of adipsin in human cerebrospinal fluid (CSF) |journal=Clinical Endocrinology |volume=84 |issue=2 |pages=194–202 |year=2016 |last1=Schmid |first1=Andreas |last2=Hochberg |first2=Alexandra |last3=Berghoff |first3=Martin |last4=Schlegel |first4=Jutta |last5=Karrasch |first5=Thomas |last6=Kaps |first6=Manfred |last7=Schäffler |first7=Andreas |pmid=26186410|s2cid=20283115 }}

MS lesions are driven mainly by T-cells. It has been found recently that B-cells are also involved.{{Cite journal |doi= 10.1016/j.jneuroim.2015.11.022 |pmid= 26857494 |title= B cells from relapsing remitting multiple sclerosis patients support neuro-antigen-specific Th17 responses |journal= Journal of Neuroimmunology |volume= 291 |pages= 46–53 |year= 2016 |last1= Ireland |first1= Sara J. |last2= Guzman |first2= Alyssa A. |last3= Frohman |first3= Elliot M. |last4= Monson |first4= Nancy L.|s2cid= 35092041 }}

The blood–brain barrier (BBB) is a protective barrier that denies the entrance of foreign material into the nervous system. BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions.Alireza Minagar and J Steven Alexander, Blood–brain barrier disruption in multiple sclerosis [http://www.direct-ms.org/sites/default/files/Minagar%20BBB%20disruption%2003.pdf] {{Webarchive|url=https://web.archive.org/web/20111001201606/http://www.direct-ms.org/sites/default/files/Minagar%20BBB%20disruption%2003.pdf |date=2011-10-01 }}

The BBB is composed of endothelial cells which line the blood vessel walls of the central nervous system. Compared to normal endothelial cells, the cells lining the BBB are connected by occludin and claudin which form tight junctions in order to create a barrier to keep out larger molecules such as proteins. In order to pass through, molecules must be taken in by transport proteins or an alteration in the BBB permeability must occur, such as interactions with associated adaptor proteins like ZO-1, ZO-2 and ZO-3.{{cite journal |last=Correale |first=Jorge |author2=Andrés Villa |title=The blood–brain-barrier in multiple sclerosis: Functional roles and therapeutic targeting |journal=Autoimmunity |date=24 July 2006 |volume=40 |issue=2 |pages=148–160 |doi=10.1080/08916930601183522 |pmid=17453713|s2cid=20027248 }}

The BBB is compromised due to active recruitment of lymphocytes and monocytes and their migration across the barrier. Release of chemokines allow for the activation of adhesion molecules on the lymphocytes and monocytes, resulting in an interaction with the endothelial cells of the BBB which then activate the expression of matrix metalloproteinases to degrade the barrier. This results in disruption of the BBB, causing an increase in barrier permeability due to the degradation of tight junctions which maintain barrier integrity. Inducing the formation of tight junctions can restore BBB integrity and reduces its permeability, which can be used to reduce the damage caused by lymphocyte and monocyte migration across the barrier as restored integrity would restrict their movement.{{cite journal |vauthors=Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, Couraud PO, Lopez-Tremoleda J, Christian HC, Weksler BB, Malaspina A, Solito E |title=Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications |journal=Proceedings of the National Academy of Sciences of the United States of America |date=15 January 2013 |volume=110 |issue=3 |pages=832–841 |doi=10.1073/pnas.1209362110 |pmid=23277546 |bibcode=2013PNAS..110..832C |pmc=3549094|doi-access=free }}

After barrier breakdown symptoms may appear, such as swelling. Activation of macrophages and lymphocytes and their migration across the barrier may result in direct attacks on myelin sheaths within the central nervous system, leading to the characteristic demyelination event observed in MS.{{cite journal |last=Prat |first=Elisabetta |author2=Roland Martin |title=The immunopathogenesis of multiple sclerosis |journal=Journal of Rehabilitation Research and Development |date=March–April 2002 |volume=39 |issue=2 |pages=187–99 |pmid=12051463 }} After demyelination has occurred, the degraded myelin sheath components, such as myelin basic proteins and Myelin oligodendrocyte glycoproteins, are then used as identifying factors to facilitate further immune activity upon myelin sheaths. Further activation of cytokines is also induced by macrophage and lymphocyte activity, promoting inflammatory activity as well continued activation of proteins such as matrix metalloproteinases, which have detrimental effect on BBB integrity.{{cite journal |vauthors=Gray E, Thomas TL, Betmouni S, Scolding N, Love S |title=Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques |journal=J Neuropathol Exp Neurol |volume=67 |issue=9 |pages=888–99 |date=September 2008 |pmid=18716555 |doi=10.1097/NEN.0b013e318183d003|doi-access=free }}

Recently it has been found that BBB damage happens even in non-enhancing lesions.{{cite journal |vauthors=Soon D, Tozer DJ, Altmann DR, Tofts PS, Miller DH |title=Quantification of subtle blood–brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes |journal= Multiple Sclerosis |volume= 13 |issue= 7 |pages= 884–94 |year=2007 |pmid=17468443 |doi=10.1177/1352458507076970|s2cid=25246162 }} MS has an important vascular component.{{cite journal |vauthors=Minagar A, Jy W, Jimenez JJ, Alexander JS |title=Multiple sclerosis as a vascular disease |journal=Neurol. Res. |volume=28 |issue=3 |pages=230–5 |year=2006 |pmid=16687046 |doi=10.1179/016164106X98080|s2cid=16896871 }}

Postmortem studies of the BBB, especially the vascular endothelium, show immunological abnormalities. Microvessels in periplaque areas coexpressed HLA-DR and VCAM-1, some others HLA-DR and urokinase plasminogen activator receptor, and others HLA-DR and ICAM-1.{{cite journal |vauthors= Washington R, Burton J, Todd RF 3rd, Newman W, Dragovic L, Dore-Duffy P | date = Jan 1994 | title = Expression of immunologically relevant endothelial cell activation antigens on isolated central nervous system microvessels from patients with multiple sclerosis | journal = Ann. Neurol. | volume = 35 | issue = 1 | pages = 89–97 | doi = 10.1002/ana.410350114 | pmid = 7506877 | s2cid = 24330062 }}

The damaged white matter is known as "Normal-appearing white matter" (NAWM) and is where lesions appear. These lesions form in NAWM before blood–brain barrier breakdown.{{cite journal |title=Pathological abnormalities in the normal-appearing white matter in multiple sclerosis |year=2001 |journal=Neurol Sci |pmid=11603615 |volume=22 |issue=2 |pages=141–4 |doi=10.1007/s100720170012 |last2=McQuaid |first2=S |last3=Mirakhur |first3=M |last4=Nevin |first4=G |author=Allen |s2cid=26091720 |display-authors=1 }}

BBB can be broken centripetally (the most normal) or centrifugally.{{cite journal | pmid = 21635955 | doi=10.1016/j.neuroimage.2011.05.038 | title=Population-Wide Principal Component-Based Quantification of Blood-Brain-Barrier Dynamics in Multiple Sclerosis |date=May 2011 |vauthors=Shinohara RT, Crainiceanu CM, Caffo BS, Gaitán MI, Reich DS | journal = NeuroImage | volume = 57 | issue = 4 | pages = 1430–46 | pmc = 3138825}} Several possible biochemical disrupters were proposed. Some hypotheses about how the BBB is compromised revolve around the presence of compounds in the blood that could interact with vessels only in the NAWM areas. The permeability of two cytokines, Interleukin 15 and LPS, may be involved in BBB breakdown.{{cite journal |vauthors=Pan W, Hsuchou H, Yu C, Kastin AJ |title=Permeation of blood-borne IL15 across the blood–brain barrier and the effect of LPS |journal=J. Neurochem. |volume= 106 |issue= 1 |pages= 313–9 |year=2008 |pmid=18384647 |pmc=3939609 |doi=10.1111/j.1471-4159.2008.05390.x}} Breakdown is responsible for monocyte infiltration and inflammation in the brain.{{cite journal |vauthors=Reijerkerk A, Kooij G, van der Pol SM, Leyen T, van Het Hof B, Couraud PO, Vivien D, Dijkstra CD, de Vries HE |title=Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier |journal= Journal of Immunology |volume= 181 |issue= 5 |pages= 3567–74 |year= 2008 |pmid=18714030 |doi=10.4049/jimmunol.181.5.3567|doi-access= free }} Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase.{{cite journal |vauthors=Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A |title=Monocyte migration and LFA-1 mediated attachment to brain microvascular endothelia is regulated by SDF-1α through Lyn kinase |journal= Journal of Immunology |volume=181 |issue=7 |pages=4632–7 |date=October 2008 |pmid=18802065 |pmc=2721474 |doi=10.4049/jimmunol.181.7.4632}}

Using iron nanoparticles, involvement of macrophages in BBB breakdown can be detected.{{cite journal |vauthors=Petry KG, Boiziau C, Dousset V, Brochet B |title=Magnetic resonance imaging of human brain macrophage infiltration |journal=Neurotherapeutics |volume=4 |issue=3 |pages=434–42 |year=2007 |pmid=17599709 |doi=10.1016/j.nurt.2007.05.005|pmc=7479730 |doi-access=free }} A special role is played by Matrix metalloproteinases. These increase BBB T-cell permeability, specially in the case of MMP-9 and are supposedly related to the mechanism of action of interferons.{{cite journal |vauthors=Boz C, Ozmenoglu M, Velioglu S, etal |title=Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta |journal=Clin Neurol Neurosurg |volume=108 |issue=2 |pages=124–8 |date=February 2006 |pmid=16412833 |doi=10.1016/j.clineuro.2005.01.005 |s2cid=22541507 }}

Whether BBB dysfunction is the cause or the consequence of MS{{cite journal |vauthors=Waubant E |title=Biomarkers indicative of blood–brain barrier disruption in multiple sclerosis |journal=Dis. Markers |volume=22 |issue=4 |pages=235–44 |year=2006 |pmid=17124345 |pmc=3850823 |doi=10.1155/2006/709869|doi-access=free }} is disputed, because activated T-Cells can cross a healthy BBB when they express adhesion proteins.{{EMedicine |neuro |228 |Multiple Sclerosis}} Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins. (Adhesion molecules could also play a role in inflammation{{cite journal |vauthors=Elovaara I, Ukkonen M, Leppäkynnäs M, etal |title=Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy |journal=Arch. Neurol. |volume=57 |issue=4 |pages=546–51 |date=April 2000 |pmid=10768630 |url=http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=10768630 |doi=10.1001/archneur.57.4.546|doi-access=free }}) In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule, also called CD166), and is under study as therapeutic target.Alexandre Prat, Nicole Beaulieu, Sylvain-Jacques Desjardins, [http://www.medicalnewstoday.com/articles/94734.php New Therapeutic Target For Treatment Of Multiple Sclerosis, Jan. 2008] {{Webarchive|url=https://web.archive.org/web/20110516070039/http://www.medicalnewstoday.com/articles/94734.php |date=2011-05-16 }} Another protein involved is CXCL12,{{cite journal |vauthors=McCandless EE, Piccio L, Woerner BM, etal |title=Pathological Expression of CXCL12 at the Blood-Brain Barrier Correlates with Severity of Multiple Sclerosis |journal=Am J Pathol |volume=172 |issue=3 |pages=799–808 |date=March 2008 |pmid=18276777 |pmc=2258272 |doi=10.2353/ajpath.2008.070918 }} which is found also in brain biopsies of inflammatory elements,{{cite journal |vauthors=Moll NM, Cossoy MB, Fisher E, etal |title=Imaging correlates of leukocyte accumulation and CXCR4/CXCR12 in multiple sclerosis |journal=Arch. Neurol. |volume=66 |issue=1 |pages=44–53 |date=January 2009 |pmid=19139298 |doi=10.1001/archneurol.2008.512 |url=http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=19139298 |pmc=2792736}} and which could be related to the behavior of CXCL13 under methylprednisolone therapy.{{cite journal |vauthors=Michałowska-Wender G, Losy J, Biernacka-Łukanty J, Wender M |title=Impact of methylprednisolone treatment on the expression of macrophage inflammatory protein 3alpha and B lymphocyte chemoattractant in serum of multiple sclerosis patients |journal=Pharmacol Rep |volume=60 |issue=4 |pages=549–54 |year=2008 |pmid=18799824 |url=http://www.if-pan.krakow.pl/pjp/pdf/2008/4_549.pdf }} Some molecular biochemical models for relapses have been proposed.{{cite journal |vauthors=Steinman L |title=A molecular trio in relapse and remission in multiple sclerosis |journal=Nature Reviews Immunology |volume= 9 |issue= 6 |pages= 440–7 |date=May 2009 |pmid=19444308 |doi=10.1038/nri2548|s2cid=36182621 }}

Normally, gadolinium enhancement is used to show BBB disruption on MRIs.{{cite journal |vauthors=Waubant E |title=Biomarkers indicative of blood–brain barrier disruption in multiple sclerosis |journal=Disease Markers |volume=22 |issue=4 |pages=235–44 |year=2006 |pmid=17124345 |pmc=3850823 |url=http://iospress.metapress.com/openurl.asp?genre=article&issn=0278-0240&volume=22&issue=4&spage=235 |doi=10.1155/2006/709869|doi-access=free }} Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions and in gray matter in SPMS. They persist in inactive lesions, particularly in PPMS.{{cite journal |vauthors=Leech S, Kirk J, Plumb J, McQuaid S |title=Persistent endothelial abnormalities and blood–brain barrier leak in primary and secondary progressive multiple sclerosis |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=1 |pages=86–98 |year=2007 |pmid=17239011 |doi=10.1111/j.1365-2990.2006.00781.x|s2cid=23431213 |doi-access=free }}

A uric acid deficiency was implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing BBB breakdown through inactivation of peroxynitrite.{{cite journal |vauthors=Kean R, Spitsin S, Mikheeva T, Scott G, Hooper D |title=The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity |journal=Journal of Immunology |volume=165 |issue=11 |pages=6511–8 |year=2000 |pmid=11086092 |doi=10.4049/jimmunol.165.11.6511|doi-access=free }} The low level of uric acid found in people with MS is manifestedly causative rather than a tissue damage consequence in the white matter lesions,{{cite journal |vauthors=Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D |title=Serum uric acid and multiple sclerosis |journal=Clinical Neurology and Neurosurgery |volume=108 |issue=6 |pages=527–31 |year=2006 |pmid=16202511 |doi=10.1016/j.clineuro.2005.08.004|s2cid=43593334 }} but not in the grey matter lesions.{{cite journal |vauthors=van Horssen J, Brink BP, de Vries HE, van der Valk P, Bø L |title=The blood–brain barrier in cortical multiple sclerosis lesions |journal=J Neuropathol Exp Neurol |volume=66 |issue=4 |pages=321–8 |date=April 2007 |pmid=17413323 |doi=10.1097/nen.0b013e318040b2de|doi-access=free }} Uric acid levels are lower during relapses.{{cite journal |vauthors=Guerrero AL, Martín-Polo J, Laherrán E, etal |title=Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment |journal=Eur. J. Neurol. |volume=15 |issue=4 |pages=394–7 |date=April 2008 |pmid=18312403 |doi=10.1111/j.1468-1331.2008.02087.x |s2cid=32529370 }}

It is not known what causes MS. Several problems appear together with the white matter lesions, like cortical lesions and normal-appearing tissues. Several theories have been proposed to explain it.

Some areas that appear normal under normal MRI look abnormal under special MRI, like magnetisation transfer MTR-MRI. These are called Normal Appearing White Matter (NAWM) and Normal Appearing Grey Matter (NAGM). The cause why the normal appearing areas appear in the brain is unknown, but seems clear that they appear mainly in the ventricles and that they predict the course of the disease.J. William Brown et al. An Abnormal Periventricular Gradient in Magnetisation Transfer Ratio Occurs Early in Multiple Sclerosis. Neurology 2016; vol. 86 no. 16 Supplement S41.002

Given that MS lesions begin inside the NAWM areas, these areas are expected to be produced by the same underlying condition that produces the lesions, and therefore the ultimate MS underlying condition, whatever it is. Historically, several theories about how these areas appear have been presented:

The search for an auto-antigen has taken a long time, but at least there is one reported. It is the enzyme GDP-L-fucose synthase.[http://neurosciencenews.com/multiple-sclerosis-gut-flora-10003/ University of Zurich(2018, October 11). Link Between Gut Flora and Multiple Sclerosis Discovered. NeuroscienceNews. Retrieved October 11, 2018]{{cite journal | doi = 10.1126/scitranslmed.aat4301 | pmid=30305453 | volume=10 | issue=462 | title=GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis | year=2018 | journal=Science Translational Medicine | page=eaat4301 | author=Planas R, Santos R, Tomas-Ojer P, Cruciani C, Lutterotti A, Faigle W, Schaeren-Wiemers N, Espejo C, Eixarch H, Pinilla C, Martin R, Sospedra M| s2cid=52959112 | url= https://www.zora.uzh.ch/id/eprint/158835/1/2018_Planas_GDP_L-Fucose_Sci_Transl._Med._in_press.pdf| doi-access=free }}

This theory in part could also explain why some patients report amelioration under dietary treatment.

Human endogenous retroviruses (HERVs) have been reported in MS for several years.

In fact, one of the families, Human Endogenous Retrovirus-W was first discovered while studying MS patients.

Recent research as of 2019 point to one of the HERV-W viruses (pHEV-W), and specifically one of the proteins of the viral capsid that has been found to activate microglia in vitro. Activated microglia in turn produces demyelination.{{cite journal | author = Kremer | display-authors = etal | year = 2019| title = pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis | journal = PNAS | volume = 116| issue = 30 | pages = 15216–15225| doi = 10.1073/pnas.1901283116 | doi-access = free | pmid = 31213545 | pmc = 6660731| bibcode = 2019PNAS..11615216K }} Some interactions between the Epstein-Barr virus and the HERVs could be the trigger of the MS microglia reactions.{{cite journal | author = Lisak RP | year = 2019| title = Human retrovirus pHEV-W envelope protein and the pathogenesis of multiple sclerosis | journal = PNAS | volume = 116| issue = 30| pages = 14791–14793| doi = 10.1073/pnas.1909786116 | doi-access = free | pmid = 31289223 | pmc = 6660775| bibcode = 2019PNAS..11614791L}} Supporting this study, a monoclonal antibody against the viral capside (Temelimab) has shown good results in trials in phase IIb.Hans-Peter Hartung et al, Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial, The Lancet 17 May 2019 [https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3388820]

• Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins.{{cite journal |vauthors=Lassmann H |date=July 2005 |title=Multiple sclerosis pathology: evolution of pathogenetic concepts |journal=Brain Pathology |volume=15 |issue=3 |pages=217–22 |doi=10.1111/j.1750-3639.2005.tb00523.x |pmid=16196388 |s2cid=8342303 |pmc=8095927 }}{{vn |date=September 2010}} Some other authors like Tracy PutnamPutnam, T.J. (1937) Evidence of vascular occlusion in multiple sclerosis pointed to venous obstructions.
• Mechanical flow: Later the focus moved to softer hemodynamic abnormalities, which were showing precede changes in sub-cortical gray matter{{cite journal |vauthors=Varga AW, Johnson G, Babb JS, Herbert J, Grossman RI, Inglese M |title=White Matter Hemodynamic Abnormalities precede Sub-cortical Gray Matter Changes in Multiple Sclerosis |journal=J. Neurol. Sci. |volume=282 |issue=1–2 |pages=28–33 |date=July 2009 |pmid=19181347 |doi=10.1016/j.jns.2008.12.036 |pmc=2737614}} and in substantia nigra.{{cite journal |vauthors=Walter U, Wagner S, Horowski S, Benecke R, Zettl UK |title=Transcranial brain sonography findings predict disease progression in multiple sclerosis |journal=Neurology |volume=73 |issue=13 |pages=1010–7 |date=September 2009 |pmid=19657105 |doi=10.1212/WNL.0b013e3181b8a9f8 |s2cid=42295275 }} However, such reports of a "hemodynamic cause of MS" are not universal, and possibly not even common. At this time the evidence is largely anecdotal and some MS patients have no blood flow issues. Possibly vascular problems may be an aggravating factor, like many others in MS. Indeed, the research, by demonstrating patients with no hemodynamic problems actually prove that this is not the only cause of MS.
• Endothelium: Other theories point to a possible primary endothelial dysfunction.{{cite journal | pmid = 17239011 | doi=10.1111/j.1365-2990.2006.00781.x | volume=33 | issue=1 | title=Persistent endothelial abnormalities and blood–brain barrier leak in primary and secondary progressive multiple sclerosis |date=February 2007 |vauthors=Leech S, Kirk J, Plumb J, McQuaid S | journal=Neuropathol. Appl. Neurobiol. | pages=86–98| s2cid=23431213 | doi-access=free }} The importance of vascular misbehaviour in MS pathogenesis has also been independently confirmed by seven-tesla MRI.{{cite journal |vauthors=Ge Y, Zohrabian VM, Grossman RI |title=7T MRI: New Vision of Microvascular Abnormalities in Multiple Sclerosis |journal= Archives of Neurology |volume= 65 |issue= 6 |pages= 812–6 |year=2008 |pmid=18541803 |doi=10.1001/archneur.65.6.812 |pmc=2579786}} It is reported that a number of studies have provided evidence of vascular occlusion in MS, which suggest the possibility of a primary vascular injury in MS lesions or at least that they are occasionally correlated.{{cite journal |title=Normal-appearing White and Grey Matter Damage in Multiple Sclerosis. Book review |journal=AJNR |volume= 27 |issue= 4 |pages=945–946 |year=2004 |url=http://www.ajnr.org/cgi/content/full/27/4/945 |vauthors=Filippi M, Comi G}}
• Venous insufficiency: Some morphologically special medullar lesions (wedge-shaped) have also been linked to venous insufficiency.{{cite journal | pmid = 20056253 |name-list-style=vanc | last1 = Qiu | first1 = W | doi=10.1016/j.jns.2009.12.017 | last2 = Raven | first2 = S | last3 = Wu | first3 = JS | last4 = Carroll | first4 = WM | last5 = Mastaglia | first5 = FL | last6 = Kermode | first6 = AG | title = Wedge-shaped medullary lesions in multiple sclerosis | journal = Journal of the Neurological Sciences | volume=290 | issue=1–2 |date=March 2010 | pages=190–3|s2cid=37956361 }}
• BBB infection: It has also been pointed out that some infectious agents with positive correlation to MS, specially Chlamydia pneumoniae, can cause problems in veins and arteries walls{{cite journal |vauthors=Gutiérrez J, Linares-Palomino J, Lopez-Espada C, Rodríguez M, Ros E, Piédrola G, del C, Maroto M | year = 2001 | title = Chlamydia pneumoniae DNA in the Arterial Wall of Patients with Peripheral Vascular Disease | journal = Infection | volume = 29 | issue = 4 | pages = 196–200 | doi = 10.1007/s15010-001-1180-0 | pmid = 11545479 | s2cid = 11195241 | hdl = 10481/88081 | hdl-access = free }}
• CCSVI: The term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. Instead of intracranial venous problems he described extracranial blockages, and he stated that the location of those obstructions seemed to influence the clinical course of the disease.{{Cite journal |vauthors=Zamboni P, Galeotti R, Menegatti E, etal |title=Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis |journal=J. Neurol. Neurosurg. Psychiatry |volume=80 |issue=4 |pages=392–9 |date=April 2009 |pmid=19060024 |pmc=2647682 |doi=10.1136/jnnp.2008.157164 |url=}} According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis.{{Cite journal |vauthors=Khan O, Filippi M, Freedman MS, etal |title=Chronic cerebrospinal venous insufficiency and multiple sclerosis |journal=Annals of Neurology |volume=67 |issue=3 |pages=286–90 |date=March 2010 |pmid=20373339 |doi=10.1002/ana.22001 |url=http://www3.interscience.wiley.com/journal/123283159/abstract|archive-url=https://archive.today/20101123071249/http://www3.interscience.wiley.com/journal/123283159/abstract|url-status=dead|archive-date=2010-11-23|citeseerx=10.1.1.606.8269 |s2cid=16580847 }} Zamboni's results were criticized as some of his studies were not blinded and they need to be verified by further studies. {{As of |2010}} the theory is considered at least defensible{{cite journal |author=Bryce Weir |year=2010 |title=MS, A vascular ethiology? |journal=Can. J. Neurol. Sci. |volume=37 |issue=6 |pages=745–757 |pmid=21059535 |doi=10.1017/s0317167100051404 |s2cid=1447729 |doi-access=free }}
• A more detailed evidence of a correlation between the place and type of venous malformations imaged and the reported symptoms of multiple sclerosis in the same patients was published in 2010.{{Cite journal |vauthors=Bartolomei I, etal. |title=Haemodynamic patterns in chronic cereblrospinal venous insufficiency in multiple sclerosis. Correlation of symptoms at onset and clinical course |journal=Int Angiol |volume=29 |issue=2 |pages=183–8 |date=April 2010 |pmid=20351667}}
• Haemodynamic problems have been found in the blood flow of MS patients using Doppler,{{cite journal |vauthors=Zamboni P, Menegatti E, Bartolomei I, etal |title=Intracranial venous haemodynamics in multiple sclerosis |journal=Curr Neurovasc Res |volume=4 |issue=4 |pages=252–8 |date=November 2007 |pmid=18045150 |doi=10.2174/156720207782446298 |url=http://www.bentham-direct.org/pages/content.php?CNR/2007/00000004/00000004/004AG.SGM|archive-url=https://archive.today/20120720030229/http://www.bentham-direct.org/pages/content.php?CNR/2007/00000004/00000004/004AG.SGM|url-status=usurped|archive-date=July 20, 2012}} initially using transcranial color-coded duplex sonography (TCCS), pointing to a relationship with a vascular disease called chronic cerebro-spinal venous insufficiency (CCSVI).{{cite journal |vauthors=Zamboni P, Galeotti R, Menegatti E, etal |title=Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis |journal=J. Neurol. Neurosurg. Psychiatry |volume=80 |issue=4 |pages=392–9 |date=April 2009 |pmid=19060024 |pmc=2647682 |doi=10.1136/jnnp.2008.157164 }}{{Cite journal |vauthors=Lee AB, Laredo J, Neville R |title=Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency |journal=Int Angiol |volume=29 |issue=2 |pages=95–108 |date=April 2010 |pmid=20351665 |url=http://www.fondazionehilarescere.org/pdf/03-2518-ANGY.pdf |url-status=dead |archive-url=https://web.archive.org/web/20100704204425/http://www.fondazionehilarescere.org/pdf/03-2518-ANGY.pdf |archive-date=2010-07-04 }} In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.{{cite journal |vauthors=Al-Omari MH, Rousan LA |title=Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis |journal=Int Angiol |volume=29 |issue=2 |pages=115–20 |date=April 2010 |pmid=20351667}}{{Cite journal |vauthors=Krogias C, Schröder A, Wiendl H, Hohlfeld R, Gold R |title=["Chronic cerebrospinal venous insufficiency" and multiple sclerosis : Critical analysis and first observation in an unselected cohort of MS patients.] |journal=Nervenarzt |volume= 81 |issue= 6 |pages= 740–6 |date=April 2010 |pmid=20386873 |doi=10.1007/s00115-010-2972-1|s2cid=115894763 }}{{cite journal |vauthors=Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ |title=No cerebrocervical venous congestion in patients with multiple sclerosis |journal=Annals of Neurology |volume=68 |issue=2 |pages=173–83 |date=August 2010 |pmid=20695010 |doi=10.1002/ana.22085|s2cid=17142252 |doi-access=free }}{{cite journal | doi = 10.1002/ana.22132 |vauthors=Sundström P, Wåhlin A, Ambarki K, Birgander R, Eklund A, Malm J | title = Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study | journal = Annals of Neurology | year = 2010 | volume = 68 | issue = 2 | pages = 255–259 | pmid = 20695018 |s2cid=8032779 }} but is important to note that positives have appeared among the blinded studies.
• CSF flow: Other theories focus in the possible role of cerebrospinal fluid flow impairment.Damadian RV, Chu D. The possible role of cranio-cervical trauma and abnormal CSF hydrodynamics in the genesis of multiple sclerosis, 2011, [http://www.noninvasiveicp.com/sites/default/files/straipsniams/node_144/sclerosis.pdf] This theory could be partially consistent with the previous one.{{cite journal | author = Zamboni | year = 2010 | title = CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies | journal = Int Angiol | volume = 29 | issue = 2 | pages = 140–8 | pmid = 20351670 |display-authors=etal}} Currently a small trial with 8 participants has been performedRaymond V. Damadian and David Chu, The Possible Role of Cranio-Cervical Trauma and Abnormal CSF Hydrodynamics in the Genesis of Multiple Sclerosis [http://www.fonar.com/news/pdf/PCP41_damadian.pdf] [http://www.fonar.com/news/110211.htm] [http://www.fonar.com/news/100511.htm]

Whatever the underlying primary condition is, it is expected to be a soluble factor in the CSF, maybe an unknown cytokine or ceramide, or a combination of them. Also B-cells and microglia could be involved.{{cite journal |vauthors=Robert P, etal | year = 2012 | title = Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro | journal = Journal of Neuroimmunology | volume = 246 | issue = 1–2 | pages = 85–95 | doi = 10.1016/j.jneuroim.2012.02.015 | pmid = 22458983| s2cid = 36221841 }}Ilana Katz Sand et al. CSF from MS Patients Induces Mitochondrial Dysfunction in Unmyelinated Neuronal Cultures, Neurology February 12, 2013; 80(Meeting Abstracts 1): P05.179 In particular, it is known that B-cells of MS patients secrete an unknown toxin against oligodendrocytes{{cite journal | pmid = 30687321 | doi=10.3389/fimmu.2018.03116 | volume=9 | title=Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis | pmc=6335289 | year=2019 | author=Lassmann H | journal=Front Immunol | page=3116| doi-access=free }}

It has been reported several times that CSF of some MS patients can damage myelin in culture{{cite journal |vauthors= Alcázar A, Regidor I, Masjuan J, Salinas M, Alvarez-Cermeño JC | date = Apr 2000 | title = Axonal damage induced by cerebrospinal fluid from patients with relapsing-remitting multiple sclerosis | journal = J Neuroimmunol | volume = 104 | issue = 1 | pages = 58–67 | doi=10.1016/s0165-5728(99)00225-8 | pmid = 10683515 | s2cid = 39308295 }}{{cite journal |vauthors=Alvarez-Cermeño JC, Cid C, Regidor I, Masjuan J, Salinas-Aracil M, Alcázar-González A | year = 2002 | title = The effect of cerebrospinal fluid on neurone culture: implications in the pathogenesis of multiple sclerosis | journal = Rev Neurol | volume = 35 | issue = 10 | pages = 994–7 | pmid = 12436405 }}{{cite journal |vauthors=Cid C, Alvarez-Cermeño JC, Camafeita E, Salinas M, Alcázar A | date = Feb 2004 | title = Antibodies reactive to heat shock protein 90 induce oligodendrocyte precursor cell death in culture. Implications for demyelination in multiple sclerosis | journal = FASEB J. | volume = 18 | issue = 2 | pages = 409–11 | doi=10.1096/fj.03-0606fje | doi-access = free | pmid = 14688203 | s2cid = 25028369 }}{{cite journal | author = Tiwari-Woodruff SK, Myers LW, Bronstein JM | date = Aug 2004 | title = Cerebrospinal fluid immunoglobulin G promotes oligodendrocyte progenitor cell migration | journal = J. Neurosci. Res. | volume = 77 | issue = 3| pages = 363–6 | doi=10.1002/jnr.20178| pmid = 15248292 | s2cid = 24586153 }}{{cite journal |vauthors=Cristofanilli M, Cymring B, Lu A, Rosenthal H, Sadiq SA | date = Oct 2013 | title = Cerebrospinal fluid derived from progressive multiple sclerosis patients promotes neuronal and oligodendroglial differentiation of human neural precursor cells in vitro | journal = Neuroscience | volume = 250 | pages = 614–21 | doi = 10.1016/j.neuroscience.2013.07.022 | pmid = 23876320 | s2cid = 23241423 }} and mice{{Cite journal |doi=10.1016/j.expneurol.2014.07.020 |pmid=25111532 |title=Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice |journal=Experimental Neurology |volume=261 |pages=620–32 |year=2014 |last1=Cristofanilli |first1=Massimiliano |last2=Rosenthal |first2=Hannah |last3=Cymring |first3=Barbara |last4=Gratch |first4=Daniel |last5=Pagano |first5=Benjamin |last6=Xie |first6=Boxun |last7=Sadiq |first7=Saud A.|s2cid=21263405 }}{{cite journal |vauthors=Saeki Y, Mima T, Sakoda S, Fujimura H, Arita N, Nomura T, Kishimoto T | year = 1992 | title = Transfer of multiple sclerosis into severe combined immunodeficiency mice by mononuclear cells from cerebrospinal fluid of the patients | journal = PNAS | volume = 89 | issue = 13 | pages = 6157–6161 | doi=10.1073/pnas.89.13.6157| pmid = 1631103 | pmc = 402141 | bibcode = 1992PNAS...89.6157S | doi-access = free }} and ceramides have been recently brought into the stage.{{cite journal |vauthors=Vidaurre OG, etal | date = Aug 2014 | title = Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics | journal = Brain | volume = 137 | issue = 8 | pages = 2271–86 | doi = 10.1093/brain/awu139 | pmid=24893707 | pmc=4164163}} Whatever the problem is, it produces apoptosis of neurons respecting astrocytes{{cite journal | author = Burgal, Mathur | date = Jul 2014 | title = Molecular Shots | journal = Ann Neurosci | volume = 21 | issue = 3 | page = 123 | doi = 10.5214/ans.0972.7531.210311 | pmid = 25206080 | pmc = 4158786 }}

In 2012 it was reported that a subset of MS patients have a seropositive anti-Kir4.1 status,{{cite journal |vauthors=Srivastava R, etal | date = Jul 2012 | title = Potassium channel KIR4.1 as an immune target in multiple sclerosis | journal = N Engl J Med | volume = 367 | issue = 2 | pages = 115–23 | doi = 10.1056/NEJMoa1110740 | pmid = 22784115 | pmc=5131800}} which can represent up to a 47% of the MS cases, and the study has been reproduced by at least two other groups.{{Cite journal |doi=10.3389/fneur.2013.00125 |title=Autoantibodies to Potassium Channel KIR4.1 in Multiple Sclerosis |journal=Frontiers in Neurology |volume=4 |year=2013 |last1=Schneider |first1=Raphael |pmid=24032025 |pmc=3759297 |page=125|doi-access=free }}{{Cite journal

|first1=Fabiana |last1=Marnetto |title= Detection of potassium channel KIR4.1 antibodies in Multiple Sclerosis patients

|journal= Journal of Immunological Methods |volume=445 |year=2017 |pages=53–58 |doi= 10.1016/j.jim.2017.03.008|pmid=28300540 }}

In 2016 a similar association was reported for anti-Anoctamin-2{{cite journal | author = Ayoglua Burcu | year = 2016 | title = Anoctamin 2 identified as an autoimmune target in multiple sclerosis | journal = PNAS | volume = 113 | issue = 8 | pages = 2188–2193 | doi = 10.1073/pnas.1518553113 | pmid = 26862169 | pmc = 4776531 |display-authors=etal| bibcode = 2016PNAS..113.2188A | doi-access = free }}

If the existence of any of these subsets of MS is confirmed, the situation would be similar to what happened for Devic Disease and Aquaporin-4{{Citation needed|date=October 2017}}. MS could be considered a heterogeneous condition or a new medical entity will be defined for these cases.

Some authors propose a primary neurodegenerative factor. Maybe the strongest argument supporting this theory comes from the comparison with NMO. Though autoimmune demyelination is strong, axons are preserved, showing that the standard model of a primary demyelination cannot be hold.{{cite journal | author = Matthews Lucy | year = 2015 | title = Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis | journal = PLOS ONE | volume = 10 | issue = 9 | pages = e0137715 | doi = 10.1371/journal.pone.0137715 | pmid = 26381510 | pmc = 4575169 |display-authors=etal| bibcode = 2015PLoSO..1037715M | doi-access = free }} The theory of the trans-synaptic degeneration, is compatible with other models based in the CSF biochemistry.{{cite journal |vauthors= Alcázar A, etal | year = 2000 | title = Axonal damage induced by cerebrospinal fluid from patients with relapsing-remitting multiple sclerosis | journal = Journal of Neuroimmunology | volume = 104 | issue = 1 | pages = 58–67 | doi = 10.1016/S0165-5728(99)00225-8 | pmid = 10683515| s2cid = 39308295 }}

Others propose an oligodendrocyte stress as primary dysfunction, which activates microglia creating the NAWM areasPeferoen, L., D. Vogel, Marjolein Breur, Wouter Gerritsen, C. Dijkstra, and S. Amor. "Do stressed oligodendrocytes trigger microglia activation in pre-active MS lesions?." In GLIA, vol. 61, pp. S164-S164. 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY-BLACKWELL, 2013. and others propose a yet-unknown intrinsic CNS trigger induces the microglial activation and clustering, which they point out could be again axonal injury or oligodendrocyte stress.{{cite journal |vauthors=van Horssen J, etal | title = Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation | doi = 10.1186/1742-2094-9-156 | pmid = 22747960 | pmc = 3411485 | journal = Journal of Neuroinflammation | volume = 9 | page = 156| year = 2012 | doi-access = free }}

Finally, other authors point to a cortical pathology which starts in the brain external layer (pial surface) and progresses extending into the brain inner layers{{cite journal |vauthors=Mainero C, etal | year = 2015 | title = A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging | journal = Brain | volume = 138 | issue = Pt 4 | pages = 932–45 | doi = 10.1093/brain/awv011 | pmid = 25681411 | pmc = 4677339 }}

If as expected MS is an heterogeneous disease and the lesion development process would not be unique. In particular, some PPMS patients have been found to have a special genetic variant named rapidly progressive multiple sclerosis which would behave differently from what here is explained.

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.

:Main:Multiple sclerosis biomarkers

Several biomarkers for diagnosis, disease evolution and response to medication (current or expected) are under research. While most of them are still under research, there are some of them already well stablished:

• oligoclonal bands: They present proteins that are in the CNS or in blood. Those that are in CNS but not in blood suggest a diagnosis of MS.
• MRZ-Reaction: A polyspecific antiviral immune response against the viruses of measles, rubella and zoster found in 1992.{{cite journal | author = Hottenrott T, Dersch R, Berger B, Rauer S, Eckenweiler M, Huzly D, Stich O | year = 2015 | title = The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort | journal = Fluids Barriers CNS | volume = 12 | page = 27 | doi = 10.1186/s12987-015-0024-8 | pmid = 26652013 | pmc = 4677451 | doi-access = free }} In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (69% vs. 92%) for MS.
• free light chains (FLC). Several authors have reported that they are comparable or even better than oligoclonal bands.{{cite journal |author1=Fabio Duranti |author2=Massimo Pieri |author3=Rossella Zenobi |author4=Diego Centonze |author5=Fabio Buttari |author6=Sergio Bernardini |author7=Mariarita Dessi |title=kFLC Index: a novel approach in early diagnosis of Multiple Sclerosis |url=http://worldwidejournals.in/ojs/index.php/ijsr/article/download/6571/6613 |journal=International Journal of Scientific Research |volume=4 |issue=8 |access-date=2018-08-27 |archive-url=https://web.archive.org/web/20160828121810/http://worldwidejournals.in/ojs/index.php/ijsr/article/download/6571/6613 |archive-date=2016-08-28 |url-status=dead }}

• Multiple sclerosis borderline

{{Reflist |30em}}

• [http://www.nationalmssociety.org/Research-TargetedLesion.asp The lesion project page] {{Webarchive|url=https://web.archive.org/web/20070227190055/http://www.nationalmssociety.org/Research-TargetedLesion.asp |date=2007-02-27 }}
• [http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=multiple%2Bsclerosis&srch_type=all#top MRI and CT of Multiple Sclerosis]{{Dead link|date=August 2023 |bot=InternetArchiveBot |fix-attempted=yes }} MedPix Image Database

{{Multiple sclerosis}}

{{DEFAULTSORT:Pathophysiology Of Multiple Sclerosis}}

Category:Neurology

Category:Multiple sclerosis

Lesion Project

Multiple sclerosis