Demyelinating and Thrombotic Diseases of the Central

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Demyelinating and thrombotic diseases of the central

nervous system: common pathogenic and triggering

factors

Tatiana Koudriavtseva1*, Rosaria Renna1, Domenico Plantone 1 and Caterina Mainero2,3

1 Neurology Unit, Multiple Sclerosis Center, Regina Elena National Cancer Institute, IFO, Rome, Italy 2 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA

3 Harvard Medical School, Boston, MA, USA *Correspondence: [email protected] Edited by: Hans-Peter Hartung, Heinrich-Heine University Düsseldorf, Germany Reviewed by: Christoph Kleinschnitz, University of Würzburg, Germany

Keywords: multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica, antiphospholipid syndrome, cerebral venous thrombosis, thrombosis

INTRODUCTION SPECIFICITY AND SIMILARITIES OF or may be normal in up to 25% of cases. Demyelinating diseases of the central ner- THROMBOTIC AND DEMYELINATING Gradient-echo and susceptibility-weighted vous system (CNS) affect prevalently DISEASES MR imaging may increase CVT diagnostic young adults and represent the main CEREBRAL VENOUS THROMBOSIS sensitivity, especially in the early throm- cause of neurological disability after Cerebral venous thrombosis of dural sinus botic stages (5). The overall prognosis of trauma in this population (1). Multi- and/or large veins is considered as a rare CVT is better than that of arterial stroke, ple sclerosis (MS), acute disseminated form of cerebrovascular disease (0.5–1% with complete recovery in about two-thirds encephalomyelitis (ADEM), and neu- of all strokes) (5, 10, 11), though a previous of cases (11). romyelitis optica (NMO) are the most pathological study found higher prevalence common inflammatory-demyelinating of CVT (9.3%) in 182 consecutive autop- ACUTE DISSEMINATED ENCEPHALOMYELITIS disorders of the CNS (1, 2). sies (12). Although firstly recognized as an Acute disseminated encephalomyelitis is a Multiple sclerosis shares several features infective disease, CVT is now considered monophasic demyelinating disease of CNS, with antiphospholipid syndrome (APS) as a non-septic condition (11). Infections, which typically ensues to viral or bac- including the clinical presentation, the however, mainly parameningeal, are rec- terial infections and vaccinations occur- relapsing–remitting course,the higher inci- ognized as a common cause of CVT in ring prevalently in children during the dence in females of childbearing age, and children (up to 40% of cases) (5). Other winter and spring (4, 14, 15). The isola- the presence of similar white matter (WM) predisposing factors include both acquired tion of a specific pathogen is uncommon lesions at MRI (3). Likewise, both neu- (APS, pregnancy, puerperium, oral contra- despite the high prevalence of many neurological symptoms and MRI lesions may ceptives, surgery, head trauma, dehydrata- rotropic pathogens in the general popula- overlap in ADEM and in the initial presen- tion,cancer,and parameningeal infections) tion. The clinical symptoms are frequently tation of APS (4). Therefore, MS, ADEM, and genetic (deficiency of antithrombin- non-specific such as headaches, fever, and and APS are part of the reciprocal differ- III, protein C and S, factor V Leiden pos- lethargy, while MRI detects widespread, ential diagnosis (2). APS represents also itivity) conditions (5). CVT can occur at multifocal, and extensive white and deep one of the main risk factors for cere- any age but it is more common in young gray matter lesions with poorly defined bral venous thrombosis (CVT) (5), which people: in the largest cohort study, it has margins, and sometimes large, swollen, is not usually included in the differen- been reported that 78% of cases occur in thoracic cord lesions, completely resolv- tial diagnosis of demyelinating diseases. patients younger than 50 years (13). The ing in up to half of the cases. There is However, several reports in literature have diagnosis of CVT is challenging in rou- a report of even normal MRI in ADEM described an association between CVT and tine practice because the clinical manifes- (16). Furthermore, in acute hemorrhagic MS (6–9). tations may mimic several other diseases leukoencephalitis, a severe and rare variant Although an accurate differential diag- and may be restricted to isolated headache of ADEM, large WM lesions with edema, nosis is desirable for ensuring a more in up to 25% of patients (5). No labora- mass effect and even obvious hemor- targeted therapy, the examination of the tory parameters are diagnostic of CVT or rhages are detected on MRI (1). Although shared features between thrombotic and can rule out it, as, for instance, a normal the MRI features of ADEM have not demyelinating diseases of the CNS would d-dimer level. Brain MRI frequently shows been clearly established, a recent study help to understand their common patho- non-specific lesions, such as hemorrhages, demonstrated a prevalently vasogenic genic mechanisms. infarcts, edema, and diffuse brain swelling edema (17).

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Despite CVT and ADEM are not usually with relapses, commonly followed by a sec- of CVT and ADEM, it can be hypothe- part of the reciprocal differential diagnosis, ondary progressive phase characterized by sized that inflammatory-thrombotic events the MRI characteristics of ADEM as well steady accumulation of disability. As men- take part in the pathophysiology of ADEM, as its clinical presentation and evolution tioned before, aPL can be detectable in MS, even if to a lesser extent. In the same appear more similar to CVT rather than to and their reactivity appears to be related to way, the characteristics of spinal cord MS. It should be also highlighted that large the severity of the MS stage: aPL reactivity lesions as well as a high frequency of thoracic lesions reported in ADEM are a is higher in secondary progressive MS than aPL associated with increased coagulation hallmark of APS in differential diagnosis in relapsing–remitting MS, and particu- indicators may suggest the presence of with MS (3). larly during the relapses (up to 80%) (22– inflammatory-thrombotic phenomena in 25). Interestingly, aPL reactivity decreases NMO. Indeed, further MR-based studies ANTIPHOSPHOLIPID SYNDROME over few months after relapse. Further- assessing brain and spinal cord venous The diagnostic criteria of APS include arte- more, aPL positive relapsing–remitting MS blood dynamics are needed to confirm such rial/venous thrombosis and/or fetal loss, patients develop more severe clinical and hypothesis. and the persistence of specific antiphos- MRI disease progression over a 3-year Similarly, the association of MS with pholipid antibodies (aPL) at medium or follow-up compared to aPL negative MS an increased risk of venous thromboem- high titer for at least 12 weeks (18). cases (34). bolism reported in epidemiological stud- APS might be associated with infec- Multiple sclerosis is associated with ies, as well as the correlation between MS tions (19, 20). an increased risk of venous thromboem- exacerbations and pro-thrombotic factors Antiphospholipid antibodies are not bolism (35). CVT has been also reported in including aPL positivity, would suggest exclusive of APS and may be found less MS, being generally attributed to lumbar that MS pathogenic mechanisms may, at steadily and/or in low titers in infections puncture and/or to the effects of methyl- least in part, involve thrombotic processes (21), in CVT (5), and in several autoim- prednisolone therapy, but in some cases, (40). Moreover, in experimental allergic mune diseases including MS (22–25) and it was not associated with any predispos- encephalomyelitis (EAE), fibrin deposition NMO spectrum disorders (NMOSD) (26). ing state (6–9). Furthermore, some condi- precedes and regulates the inflammatory Reactivity for aPL and other autoantibod- tions that favor thrombosis such as cranial demyelination, while its genetic or phar- ies has been reported more frequently in radiation, CNS trauma, and puerperium macologic depletion ameliorates both clin- NMOSD compared to MS (26, 27), con- may promote MS reactivation (36). Also ical symptoms and inflammatory response firming the already known higher occur- stress, producing significant hemoconcen- (41). Early perivascular microglial clus- rence of aPL in “neuromyelitic” type of tration and pro-thrombotic blood changes tering is blocked by anticoagulant treat- MS (28). (37), might foster MS relapse. However, the ment or by genetic depletion of fibrino- main risk factors for MS re-exacerbations gen in EAE (42). Thrombin, which has NEUROMYELITIS OPTICA are represented by infections, mostly viral numerous hormone-like functions affect- Neuromyelitis optica is a more severe (36). Viruses are considered to be the prin- ing microglia and astrocytes, was pro- demyelinating disorder compared to MS. cipal environmental factors associated with posed as a therapeutic target in MS It is characterized by optic neuritis, longi- MS as suggested by epidemiological and (43). On the other hand, the concept of tudinally extensive myelitis (three or more genetic studies (38), as well as by the life- thrombo-inflammation was recently intro- spinal segments on MRI), and autoanti- long presence of oligoclonal IgG in the duced since ischemic stroke has been body positivity against the water chan- cerebrospinal fluid in the majority of MS defined as a thrombo-inflammatory dis- nel aquaporin-4 (2, 29). Large spinal cord patients (39). ease (44). Indeed, both innate and adaptive lesions, similar to those of APS and ADEM, immunity are involved during all stages represent one of the diagnostic criteria for DISCUSSION of stroke (45). The inhibition of plasma NMO. Recently, anti-cardiolipin antibod- The close clinical and radiological similar- kallikrein, a key constituent of the proin- ies in NMO patients have been associated ities between inflammatory-demyelinating flammatory contact-kinin system, is effec- with greater antithrombin-III activity and and thrombotic diseases of the CNS sug- tive in wild-type mice up to 3 h post d-dimer levels, a product of fibrin degrada- gest the presence of common underlying stroke (46). In fact, the contact-kinin sys- tion, suggesting the involvement of throm- events. There is a striking incongruence tem, representing an interface between botic pathogenic mechanisms in this dis- regarding the prevalence of CVT, com- inflammatory and thrombotic systems,was order (26, 30). Moreover, several studies monly acknowledged to represent 0.5–1% found activated in different neurologi- supported the association between NMO of all strokes, but found in the 9.3% of con- cal diseases, such as in traumatic brain and various infections (31–33). secutive autopsies. This apparent incon- injury showing a microvascular thrombo- gruence can be partially explained not only sis along with edema and immune cell MULTIPLE SCLEROSIS by the difficulty of CVT clinical diagno- infiltration (47). The data reported in this Multiple sclerosis is a chronic disorder sis but also by the lower occurrence of work would suggest that the concept of of the CNS pathologically characterized CVT of dural sinus or large veins compared thrombo-inflammation is also appropriate by inflammation, demyelination, and neu- to the thrombosis of smaller veins occur- for the inflammatory-demyelinating dis- rodegeneration. MS usually begins with ring, for example, in APS. Thus, on the eases, albeit with quantitatively varying a relapsing–remitting course manifesting basis of similar clinical and MRI features expression.

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Inflammation and coagulation repre- Schering outside the submitted work. CM of cerebral vein and dural sinus thrombosis: sent the main components of innate reports consulting fees from Biogen Idec results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). immunity, an universal immediate defense outside the submitted work. Other authors Stroke (2004) 35:664–70. doi:10.1161/01.STR. against infections, which stimulates and have nothing to declare. 0000117571.76197.26 modulates the adaptive one. Thrombotic 14. Dale RC, Branson JA. Acute disseminated events occur when coagulation processes REFERENCES encephalomyelitis or multiple sclerosis: can the 1. Karussis D. The diagnosis of multiple sclero- prevail over the natural anticoagulant sys- initial presentation help in establishing a cor- sis and the various related demyelinating syn- rect diagnosis? Arch Dis Child (2005) 90(6):636–9. tem (48). Therefore,the presence of throm- dromes: a critical review. J Autoimmun (2014) 4(8– doi:10.1136/adc.2004.062935 bosis should indicate the occurrence of 49):134–42. doi:10.1016/j.jaut.2014.01.022 15. Absoud M, Lim MJ, Chong WK, De Goede intense and/or prolonged inflammatory- 2. Miller DH, Weinshenker BG, Filippi M, Banwell CG, Foster K, Gunny R, et al. Paediatric thrombotic processes. This could take BL, Cohen JA, Freedman MS, et al. Differential acquired demyelinating syndromes: incidence, diagnosis of suspected multiple sclerosis: a con- clinical and magnetic resonance imaging fea- place in the course of subclinical chronic sensus approach. Mult Scler (2008) 14(9):1157–74. tures. Mult Scler (2013) 19(1):76–86. doi:10.1177/ infections prevalently in individuals with doi:10.1177/1352458508096878 1352458512445944 a reduced anticoagulant and/or anti- 3. Ferreira S, D’Cruz DP, Hughes GR. Multiple scle- 16. Höllinger P, Sturzenegger M, Mathis J, Schroth G, oxidative capacity, resulting in their indi- rosis, neuropsychiatric lupus and antiphospho- Hess CW. Acute disseminated encephalomyelitis lipid syndrome: where do we stand? Rheumatol- vidual susceptibility to these diseases. All in adults: a reappraisal of clinical, CSF, EEG, ogy (Oxford) (2005) 44(4):434–42. doi:10.1093/ and MRI findings. J Neurol (2002) 249(3):320–9. disorders described above occur preva- rheumatology/keh532 doi:10.1007/s004150200012 lently in the young age, characterized by 4. Menge T, Hemmer B, Nessler S, Wiendl H, 17. Zuccoli G, Panigrahy A, Sreedher G, Bailey a first contact with external pathogens, Neuhaus O, Hartung HP,et al. Acute disseminated A, Laney EJ IV, La Colla L, et al. Vasogenic and are closely linked with concomitant or encephalomyelitis: an update. Arch Neurol (2005) edema characterizes pediatric acute dissemi- 62(11):1673–80. doi:10.1001/archneur.62.11.1673 immediately preceding clinical infections. nated encephalomyelitis. Neuroradiology (2014) 5. Saposnik G, Barinagarrementeria F, Brown 56(8):679–84. doi:10.1007/s00234-014-1379-2 It is more realistic to assume that a massive RD Jr, Bushnell CD, Cucchiara B, Cush- 18. Miyakis S, Lockshin MD, Atsumi T, Branch DW, and steady response of innate immunity is man M, et al. Diagnosis and management of Brey RL, Cervera R, et al. International consen- triggered directly by the pathogen rather cerebral venous thrombosis: a statement for sus statement on an update of the classification than by an indirect autoimmune reaction. healthcare professionals from the American criteria for definite antiphospholipid syndrome Heart Association/American Stroke Association. (APS). J Thromb Haemost (2006) 4(2):295–306. Even autoantibodies including aPL may be Stroke (2011) 42(4):1158–92. doi:10.1161/STR. doi:10.1111/j.1538-7836.2006.01753.x an expression of a reaction against the self- 0b013e31820a8364 19. Harel M, Aron-Maor A, Sherer Y, Blank M, components damaged during infections or 6. Vandenberghe N, Debouverie M, Anxionnat R, Shoenfeld Y. The infectious etiology of the injury similarly to physiological process of Clavelou P, Bouly S, Weber M. Cerebral venous antiphospholipid syndrome: links between infec- elimination of aged cells and proteins. thrombosis in four patients with multiple sclero- tion and autoimmunity. Immunobiology (2005) sis. Eur J Neurol (2003) 10(1):63–6. doi:10.1046/j. 210(10):743–7. doi:10.1016/j.imbio.2005.10.004 In conclusion, we speculate that 1468-1331.2003.00513.x 20. Justo D, Finn T, Atzmony L, Guy N, demyelinating and thrombotic diseases 7. Maurelli M, Bergamaschi R, Candeloro E, Tode- Steinvil A. Thrombosis associated with of the CNS share widespread occurrence schini A, Micieli G. Cerebral venous thrombo- acute cytomegalovirus infection: a meta- of inflammatory-thrombotic processes. sis and demyelinating diseases: report of a case analysis. Eur J Intern Med (2011) 22(2):195–9. in a clinically isolated syndrome suggestive of The triggering factors underlying these doi:10.1016/j.ejim.2010.11.006 multiple sclerosis onset and review of the litera- 21. Horstman LL, Jy W, Bidot CJ, Ahn YS, Kelley processes are still unknown. Inflammatory ture. Mult Scler (2005) 11(2):242–4. doi:10.1191/ RE, Zivadinov R, et al. Antiphospholipid antibod- and coagulant pathways are closely linked 1352458505ms1125cr ies: paradigm in transition. J Neuroinflammation during activation of the innate immune 8. Kalanie H, Harandi AA, Alidaei S, Heidari D, (2009) 20(6):3. doi:10.1186/1742-2094-6-3 system. Hence, it is possible that common Shahbeigi S, Ghorbani M. Venous thrombosis in 22. Spadaro M, Amendolea MA, Mazzucconi MG, multiple sclerosis patients after high-dose intra- Fantozzi R, Di Lello R, Zangari P,et al. Autoimmu- pathogenic factors, including subclinical venous methylprednisolone: the preventive effect nity in multiple sclerosis: study of a wide spectrum chronic infections, exert their role at the of enoxaparin. Thrombosis (2011) 2011:785459. of autoantibodies. Mult Scler (1999) 5(2):121–5. level of the innate immune system in genet- doi:10.1155/2011/785459 doi:10.1191/135245899678847211 ically or environmentally induced sus- 9. Presicci A, Garofoli V, Simone M, Campa MG, 23. Bidot CJ, Horstman LL, Jy W, Jimenez JJ, Bidot C ceptible individuals. This viewpoint does Lamanna AL, Margari L. Cerebral venous throm- Jr, Ahn YS, et al. Clinical and neuroimaging cor- bosis after lumbar puncture and intravenous high relates of antiphospholipid antibodies in multiple not aim to belittle the importance of dose corticosteroids: a case report of a childhood sclerosis: a preliminary study. BMC Neurol (2007) specific characteristics of these diseases, multiple sclerosis. Brain Dev (2013) 35(6):602–5. 7:36. doi:10.1186/1471-2377-7-36 which could be related to different causal doi:10.1016/j.braindev.2012.09.001 24. Garg N, Zivadinov R, Ramanathan M, Vasiliu I, pathogens together with concomitant and 10. Stam J. Thrombosis of the cerebral veins and Locke J, Watts K, et al. Clinical and MRI corre- genetic factors, but it is aimed to find their sinuses. N Engl J Med (2005) 352(17):1791–8. lates of autoreactive antibodies in multiple scle- doi:10.1056/NEJMra042354 rosis patients. J Neuroimmunol (2007) 187(1– reciprocal factual connections in order to 11. Bousser MG, Ferro JM. Cerebral venous throm- 2):159–65. doi:10.1016/j.jneuroim.2007.04.008 better control them and develop more bosis: an update. Lancet Neurol (2007) 6:162–70. 25. Koudriavtseva T, D’Agosto G, Mandoj C, Sperduti appropriate therapeutic strategies. doi:10.1016/S1474-4422(07)70029-7 I, Cordiali-Fei P. High frequency of antiphospho- 12. Towbin A. The syndrome of latent cerebral venous lipid antibodies in relapse of multiple sclerosis: thrombosis: its frequency and relation to age and a possible indicator of inflammatory-thrombotic ACKNOWLEDGMENTS congestive heart failure. Stroke (1973) 4(3):419–30. processes. Neurol Sci (2014) 35(11):1737–41. doi:

TK reports consulting fees from Bayer doi:10.1161/01.STR.4.3.419 10.1007/s10072-014-1823-4 Schering, and Institutional grant from 13. Ferro JM, Canhao P, Stam J, Bousser MG, Bari- 26. Iong Y, He Y, Zheng Y, Chen M, Zhang B, Gao C. Merck Serono, Biogen Idec, Novartis, Bayer nagarrementeria F. ISCVT Investigators. Prognosis Serum anticardiolipin antibodies in patients with

www.frontiersin.org March 2015 | Volume 6 | Article 63| 3 Koudriavtseva et al. Demyelinating and thrombotic brain diseases

neuromyelitis optica spectrum disorder. J Neurol results from a 3-year longitudinal study. Neurol Res 44. Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic (2013) 260(12):3150–7. doi:10.1007/s00415-013- (2012) 34(8):761–9. doi:10.1179/1743132812Y. stroke: a thrombo-inﬂammatory disease? J Phys- 7128-3 0000000076 iol (2011) 1(589):4115–23. doi:10.1113/jphysiol.

27. Wu L, Huang D, Yang Y, Wu W. Combined screen- 35. Christensen S, Farkas DK, Pedersen L, Miret 2011.212886 ing for serum anti-nuclear and anti-aquaporin- M, Christiansen CF, Sørensen HT. Multiple scle- 45. Magnus T, Wiendl H, Kleinschnitz C. 4 antibodies improves diagnostic accuracy for rosis and risk of venous thromboembolism: a Immune mechanisms of stroke. Curr distinguishing neuromyelitis optica from multi- population-based cohort study. Neuroepidemiol- Opin Neurol (2012) 25(3):334–40. ple sclerosis. Eur Neurol (2014) 72(1–2):103–8. ogy (2012) 38(2):76–83. doi:10.1159/000335496 doi:10.1097/WCO.0b013e328352ede6 doi:10.1159/000358218 36. Vollmer T. The natural history of relapses in 46. Göb E,Reymann S,Langhauser F,Schuhmann MK,

28. Karussis D, Leker RR, Ashkenazi A, Abramsky O. A multiple sclerosis. J Neurol Sci (2007) 256(Suppl Kraft P, Thielmann I, et al. Blocking of plasma subgroup of multiple sclerosis patients with anti- 1):S5–13. doi:10.1016/j.jns.2007.01.065 kallikrein ameliorates stroke by reducing throm- cardiolipin antibodies and unusual clinical man- 37. Austin AW, Patterson SM, von Känel R. Hemo- boinﬂammation. Ann Neurol (2015). doi:10.1002/ ifestations: do they represent a new nosological concentration and hemostasis during acute stress: ana.24380 entity? Ann Neurol (1998) 44(4):629–34. doi:10. interacting and independent effects. Ann Behav 47. Albert-Weissenberger C, Mencl S, Hopp S, Klein- 1002/ana.410440408 Med (2011) 42(2):153–73. doi:10.1007/s12160- schnitz C, Sirén AL. Role of the kallikrein-kinin

29. Wingerchuk DM, Lennon VA, Pittock SJ, 011-9274-0 system in traumatic brain injury. Front Cell Neu- Lucchinetti CF, Weinshenker BG. Revised diag- 38. Mechelli R,AnnibaliV,Ristori G,Vittori D,Coarelli rosci (2014) 8:345. doi:10.3389/fncel.2014.00345 nostic criteria for neuromyelitis optica. Neurol- G, Salvetti M. Multiple sclerosis etiology: beyond 48. Esmon CT, Xu J, Lupu F. Innate immunity and ogy (2006) 66(10):1485–9. doi:10.1212/01.wnl. genes and environment. Expert Rev Clin Immunol coagulation. J Thromb Haemost (2011) 9(Suppl 0000216139.44259.74 (2010) 6(3):481–90. doi:10.1586/eci.10.11 1):182–8. doi:10.1111/j.1538-7836.2011.04323.x 30. Koudriavtseva T, Plantone D, Renna R. Antiphos- 39. Owens GP, Gilden D, Burgoon MP, Yu X,

pholipid antibodies: a possible biomarker of Bennett JL. Viruses and multiple sclerosis. Conflict of Interest Statement: The authors declare disease activity in multiple sclerosis and neu- Neuroscientist (2011) 17(6):659–76. doi:10.1177/ that the research was conducted in the absence of any romyelitis optica spectrum disorders. J Neurol 1073858411386615 commercial or financial relationships that could be (2014) 261(10):2028–9. doi:10.1007/s00415-014- 40. Koudriavtseva T. Thrombotic processes in multi- construed as a potential conflict of interest. 7506-5 ple sclerosis as manifestation of innate immune

31. Koga M, Takahashi T, Kawai M, Fujihara K, Kanda activation. Front Neurol (2014) 5:119. doi:10.3389/ Received: 06 February 2015; accepted: 11 March 2015; T.A serological analysis of viral and bacterial infec- fneur.2014.00119 published online: 24 March 2015. tions associated with neuromyelitis optica. J Neurol 41. Akassoglou K, Adams RA, Bauer J, Mercado P, Citation: Koudriavtseva T, Renna R, Plantone D and Sci (2011) 300(1–2):19–22. doi:10.1016/j.jns.2010. Tseveleki V, Lassmann H, et al. Fibrin depletion Mainero C (2015) Demyelinating and thrombotic dis- 10.013 decreases inﬂammation and delays the onset of eases of the central nervous system: common patho- 32. Long Y, Gao C, Qiu W, Hu X, Shu Y, Peng demyelination in a tumor necrosis factor trans- genic and triggering factors. Front. Neurol. 6:63. doi:

F, et al. Helicobacter pylori infection in neu- genic mouse model for multiple sclerosis. Proc Natl 10.3389/fneur.2015.00063 romyelitis optica and multiple sclerosis. Neu- Acad Sci U S A (2004) 101:6698–703. doi:10.1073/ This article was submitted to Multiple Sclerosis and roimmunomodulation (2013) 20(2):107–12. doi: pnas.0303859101 Neuroimmunology, a section of the journal Frontiers in 10.1159/000345838 42. Davalos D, Ryu JK, Merlini M, Baeten KM, Le Neurology. 33. Masuda S, Mori M, Arai K, Uzawa A, Muto M, Moan N, Petersen MA, et al. Fibrinogen-induced Copyright © 2015 Koudriavtseva, Renna, Plantone and Uchida T, et al. Epstein-Barr virus persistence and perivascular microglial clustering is required for Mainero. This is an open-access article distributed under

reactivation in neuromyelitis optica. J Neurol Neu- the development of axonal damage in neuroin- the terms of the Creative Commons Attribution License rosurg Psychiatry (2014). doi:10.1136/jnnp-2014- ﬂammation. Nat Commun (2012) 3:1227. doi:10. (CC BY). The use, distribution or reproduction in other 308095 1038/ncomms2230 forums is permitted, provided the original author(s) or 34. Zivadinov R, Ramanathan M, Ambrus J, Hus- 43. Chapman J. Coagulation in inﬂammatory dis- licensor are credited and that the original publication in sein S, Ramasamy DP, Dwyer MG, et al. Anti- eases of the central nervous system. Semin Thromb this journal is cited, in accordance with accepted aca- phospholipid antibodies are associated with Hemost (2013) 39(8):876–80. doi:10.1055/s-0033- demic practice. No use, distribution or reproduction is

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