Anti-AQP4 disease explained

Synonym:	Neuromyelitis optica spectrum of diseases

Anti-AQP4 diseases, are a group of diseases characterized by auto-antibodies against aquaporin 4.

After the discovery of anti-AQP4 autoantibody in neuromyelitis optica, it was found that it was also present in some patients with other clinically defined diseases, including multiple sclerosis variants like optic-spinal MS.^[1]

The collection of these condition has been named "anti-AQP4 disease" and "neuromyelitis optica spectrum disorders" (NMSD) and they are expected to respond to the same treatments as standard NMO.^[2] Some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases,^[3] while others prefer a more generic term "AQP4-astrocytopathy" that includes also problems in AQP4 with a non-autoimmune origin.^{[4] [1] [5]}

Clinical Spectrum

After finding the anti-AQP4 autoantibody in cases outside the standard Devic's disease course, the spectrum was expanded. The spectrum is now believed to consist of:

• Standard Devic's disease, according to the diagnostic criteria described above
• Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis
• optic-spinal MS (OSMS), previously considered a subtype of MS. This variant can present brain lesions like MS,^[6] but it should not be confused with an AQP4-negative form of inflammatory demyelinating diseases of the central nervous system spectrum, sometimes called optic-spinal MS.
• Longitudinally extensive myelitis
• Optic neuritis associated with systemic autoimmune disease and with higher AQP4 autoantibody levels ^[7]
• Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem^[8]
• Tumefactive demyelination: Tumefactive lesions in NMO are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta.^[9]

Devic's disease is currently considered a syndrome more than a disease, presenting an overlapping with the wide spectrum of multiple sclerosis in the form of Optic-Spinal MS.^[10]

Causes

The reason for the presence of anti-AQP4 autoantibodies is currently unknown. Some researchers have pointed out that it could be paraneoplastic.^[11] It seems also clear that lupus can produce NMO-IgG autoantibodies sometimes, leading to some cases of lupus-derived NMO.^[12]

Diagnosis

Differential diagnosis

AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the oligoclonal bands respect MS can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after the attacks, while in MS they are nearly always present and persistent.^[13]

It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS.^[14]

Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.^{[15] [16]}

Treatment

Currently, there is no cure for Devic's disease, but symptoms can be treated. Some patients recover, but many are left with impairment of vision and limbs, which can be severe.

Attacks

Attacks are treated with short courses of high dosage intravenous corticosteroids such as methylprednisolone IV.

Plasmapheresis can be an effective treatment^[8] when attacks progress or do not respond to corticosteroid treatment. Clinical trials for these treatments contain very small numbers, and most are uncontrolled, though some report high success percentage.^[17]

Secondary prevention

Until recently, no placebo-controlled trials had established the effectiveness of treatments for the prevention of attacks. Most clinicians agree that long term immunosuppression is required to reduce the frequency and severity of attacks. Commonly used immunosuppressant treatments include azathioprine (Imuran) plus prednisone, mycophenolate mofetil plus prednisone, mitoxantrone, intravenous immunoglobulin (IVIG), Rituximab, Soliris and cyclophosphamide.^{[8] [18]}

The disease is known to be auto-antibodies mediated, and (antibody-producing) B-cell depletion has been tried^[19] with monoclonal antibodies showing good results.^[20] Several other disease modifying therapies are being tried. In 2007, Devic's disease was reported to be responsive to glatiramer acetate^[21] and to low-dose corticosteroids.^[22] Use of Mycophenolate mofetil is also currently under research.^[23]

Hematopoietic stem cell transplantation (HSCT) is sometimes used in severe cases of NMO. Early data suggested that then-practiced forms of HSCT were very effective only in the short term.^[24] However, later study data had most patients thriving, with no relapses within 5 years.^[25]

Notes and References

1. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders . Neurology . 85 . 2 . 177–89 . July 2015 . 26092914 . 4515040 . 10.1212/WNL.0000000000001729 .
2. Fujihara K, Sato DK . AQP4 antibody serostatus: Is its luster being lost in the management and pathogenesis of NMO? . Neurology . 81 . 14 . 1186–8 . October 2013 . 23997154 . 10.1212/WNL.0b013e3182a6cc23 . 35351168 .
3. Pittock SJ, Lucchinetti CF . Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later . Annals of the New York Academy of Sciences . 1366 . 1 . 20–39 . February 2016 . 26096370 . 4675706 . 10.1111/nyas.12794 . 2016NYASA1366...20P .
4. Masaki K . Early disruption of glial communication via connexin gap junction in multiple sclerosis, Baló's disease and neuromyelitis optica . Neuropathology . 35 . 5 . 469–80 . October 2015 . 26016402 . 10.1111/neup.12211 . 6371457 . free .
5. Masaki K, Suzuki SO, Matsushita T, Matsuoka T, Imamura S, Yamasaki R, Suzuki M, Suenaga T, Iwaki T, Kira J . Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica . PLOS ONE . 8 . 8 . e72919 . 2013 . 23991165 . 3749992 . 10.1371/journal.pone.0072919 . 2013PLoSO...872919M . free .
6. Li Y, Xie P, Lv F, Mu J, Li Q, Yang Q, Hu M, Tang H, Yi J . Brain magnetic resonance imaging abnormalities in neuromyelitis optica . Acta Neurologica Scandinavica . 118 . 4 . 218–25 . October 2008 . 18384459 . 10.1111/j.1600-0404.2008.01012.x . 22270592 .
7. Isobe . Noriko . Yonekawa . Tomomi . Matsushita . Takuya . Masaki . Katsuhisa . Yoshimura . Satoshi . Fichna . Jakub . Chen . Shu . Furmaniak . Jadwiga . Smith . Bernard Rees . Kira . Jun-ichi . 2013-05-01 . Clinical Relevance of Serum Aquaporin-4 Antibody Levels in Neuromyelitis Optica . Neurochemical Research . en . 38 . 5 . 997–1001 . 10.1007/s11064-013-1009-0 . 23456674 . 18623455 . 1573-6903.
8. Dean . Wingerchuk . Neuromyelitis Optica (Devic's Syndrome) . 2006 Rare Neuroimmunologic Disorders Symposium . 2006 . 2007-01-05 . dead . https://web.archive.org/web/20060925095337/http://www.myelitis.org/rnds2006/Wingerchuk_NMO_Rare%20Neuroimm_062406_final.pdf . 2006-09-25 .
9. Harmel J, Ringelstein M, Ingwersen J, Mathys C, Goebels N, Hartung HP, Jarius S, Aktas O . Interferon-β-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab . BMC Neurology . 14 . 247 . December 2014 . 25516429 . 4301061 . 10.1186/s12883-014-0247-3 . free .
10. Lassmann H, Brück W, Lucchinetti C . Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy . Trends in Molecular Medicine . 7 . 3 . 115–21 . March 2001 . 11286782 . 10.1016/s1471-4914(00)01909-2 .
11. Iorio R, Rindi G, Erra C, Damato V, Ferilli M, Sabatelli M . Neuromyelitis optica spectrum disorder as a paraneoplastic manifestation of lung adenocarcinoma expressing aquaporin-4 . Multiple Sclerosis . 21 . 6 . 791–4 . May 2015 . 25716881 . 10.1177/1352458515572241 . 22763815 .
12. Kovacs KT, Kalluri SR, Boza-Serrano A, Deierborg T, Csepany T, Simo M, Rokusz L, Miseta A, Alcaraz N, Czirjak L, Berki T, Molnar T, Hemmer B, Illes Z . Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus: A preliminary study . Multiple Sclerosis . 22 . 9 . 1192–201 . August 2016 . 26514978 . 10.1177/1352458515613165 . 3808843 .
13. Bergamaschi R, Tonietti S, Franciotta D, Candeloro E, Tavazzi E, Piccolo G, Romani A, Cosi V . Oligoclonal bands in Devic's neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations . Multiple Sclerosis . 10 . 1 . 2–4 . February 2004 . 14760945 . 10.1191/1352458504ms988oa . 11730134 .
14. Komatsu J, Sakai K, Nakada M, Iwasa K, Yamada M . Long spinal cord lesions in a patient with pathologically proven multiple sclerosis . Journal of Clinical Neuroscience . 42 . 106–108 . August 2017 . 28465080 . 10.1016/j.jocn.2017.03.022 . 3443914 .
15. Arru G, Sechi E, Mariotto S, Farinazzo A, Mancinelli C, Alberti D, Ferrari S, Gajofatto A, Capra R, Monaco S, Deiana GA, Caggiu E, Mameli G, Sechi LA, Sechi GP . Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder . Multiple Sclerosis Journal: Experimental, Translational and Clinical . 3 . 4 . 2055217317742425 . 2017 . 29204291 . 5703109 . 10.1177/2055217317742425 .
16. Jurynczyk M, Probert F, Yeo T, Tackley G, Claridge TD, Cavey A, Woodhall MR, Arora S, Winkler T, Schiffer E, Vincent A, DeLuca G, Sibson NR, Isabel Leite M, Waters P, Anthony DC, Palace J . Metabolomics reveals distinct, antibody-independent, molecular signatures of MS, AQP4-antibody and MOG-antibody disease . Acta Neuropathologica Communications . 5 . 1 . 95 . December 2017 . 29208041 . 5718082 . 10.1186/s40478-017-0495-8 . free .
17. Morgan SM, Zantek ND, Carpenter AF . Therapeutic plasma exchange in neuromyelitis optica: a case series . Journal of Clinical Apheresis . 29 . 3 . 171–7 . June 2014 . 24136389 . 10.1002/jca.21304 . 24287933 . free .
18. Weinstock-Guttman B, Ramanathan M, Lincoff N, Napoli SQ, Sharma J, Feichter J, Bakshi R . Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease) . Archives of Neurology . 63 . 7 . 957–63 . July 2006 . 16831964 . 10.1001/archneur.63.7.957 .
19. Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG . Neuromyelitis optica . Current Opinion in Neurology . 20 . 3 . 255–60 . June 2007 . 17495617 . 10.1097/WCO.0b013e32814f1c6b . 21483082 .
20. Evangelopoulos ME, Andreadou E, Koutsis G, Koutoulidis V, Anagnostouli M, Katsika P, Evangelopoulos DS, Evdokimidis I, Kilidireas C . Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up . Journal of the Neurological Sciences . 372 . 92–96 . January 2017 . 28017256 . 10.1016/j.jns.2016.11.016 . 206291987 .
21. Gartzen K, Limmroth V, Putzki N . Relapsing neuromyelitis optica responsive to glatiramer acetate treatment . European Journal of Neurology . 14 . 6 . e12–3 . June 2007 . 17539924 . 10.1111/j.1468-1331.2007.01807.x . 24668975 .
22. Watanabe S, Misu T, Miyazawa I, Nakashima I, Shiga Y, Fujihara K, Itoyama Y . Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis . Multiple Sclerosis . 13 . 8 . 968–74 . September 2007 . 17623727 . 10.1177/1352458507077189 . 6308153 .
23. Montcuquet A, Collongues N, Papeix C, Zephir H, Audoin B, Laplaud D, Bourre B, Brochet B, Camdessanche JP, Labauge P, Moreau T, Brassat D, Stankoff B, de Seze J, Vukusic S, Marignier R . Effectiveness of mycophenolate mofetil as first-line therapy in AQP4-IgG, MOG-IgG, and seronegative neuromyelitis optica spectrum disorders . Multiple Sclerosis . 23 . 10 . 1377–1384 . September 2017 . 27885065 . 10.1177/1352458516678474 . 21685585 .
24. Burman J, Tolf A, Hägglund H, Askmark H . Autologous haematopoietic stem cell transplantation for neurological diseases . Journal of Neurology, Neurosurgery, and Psychiatry . 89 . 2 . 147–155 . February 2018 . 28866625 . 5800332 . 10.1136/jnnp-2017-316271 .
25. 10.1212/WNL.0000000000008394. 2019. Burt. Richard K.. Balabanov. Roumen. Han. Xiaoqiang. Burns. Carol. Gastala. Joseph. Jovanovic. Borko. Helenowski. Irene. Jitprapaikulsan. Jiraporn. Fryer. James P.. Pittock. Sean J.. Neurology. 93. 18. e1732–e1741. 31578302. 6946475.