Neuromyelitis optica spectrum disorder: Difference between revisions

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Currently at least two different causes are proposed based on the presence of autoantibodies against [[Aquaporin 4|AQP4]]. AQP4+ NMO is currently considered an [[autoimmune disease]] (autoimmune [[astrocytopathy]],<ref>{{cite journal|last1=Lucchinetti|first1=Claudia F.|last2=Guo|first2=Yong|last3=Popescu|first3=Bogdan F. Gh.|last4=Fujihara|first4=Kazuo|last5=Itoyama|first5=Yasuto|last6=Misu|first6=Tatsuro|title=The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica|journal=Brain Pathology|date=January 2014|volume=24|issue=1|pages=83–97|doi=10.1111/bpa.12099|pmid=24345222|pmc=3905574}}</ref> or autoimmune astrocytic [[channelopathy]]) in which a person's own [[immune system]] attacks the [[astrocyte]]s of the [[optic nerve]]s and [[spinal cord]]. The cause of the AQP4− variants is unknown.
Currently at least two different causes are proposed based on the presence of autoantibodies against [[Aquaporin 4|AQP4]]. AQP4+ NMO is currently considered an [[autoimmune disease]] (autoimmune [[astrocytopathy]],<ref>{{cite journal|last1=Lucchinetti|first1=Claudia F.|last2=Guo|first2=Yong|last3=Popescu|first3=Bogdan F. Gh.|last4=Fujihara|first4=Kazuo|last5=Itoyama|first5=Yasuto|last6=Misu|first6=Tatsuro|title=The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica|journal=Brain Pathology|date=January 2014|volume=24|issue=1|pages=83–97|doi=10.1111/bpa.12099|pmid=24345222|pmc=3905574}}</ref> or autoimmune astrocytic [[channelopathy]]) in which a person's own [[immune system]] attacks the [[astrocyte]]s of the [[optic nerve]]s and [[spinal cord]]. The cause of the AQP4− variants is unknown.


Although inflammation may also affect the brain, the lesions are different from those observed in the related condition, [[multiple sclerosis]].<ref name=Pittock>{{cite journal |vauthors=Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA |title=Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression |journal=Arch. Neurol. |volume=63 |issue=7 |pages=964–968 |year=2006 |pmid=16831965 |doi=10.1001/archneur.63.7.964|url=http://archneur.ama-assn.org/cgi/content/full/63/7/964}}</ref> Spinal cord lesions lead to varying degrees of [[Muscle weakness|weakness]] or [[paralysis]] in the legs or arms, loss of sensation (including [[blindness]]),<ref>{{DorlandsDict|nine/000955053|neuromyelitis optica}}</ref> and/or [[urinary bladder|bladder]] and [[bowel]] dysfunction.<ref name=Wingerchuk>{{cite journal| last =Wingerchuk| first =DM | title =Neuromyelitis optica| journal =The International MS Journal| volume =13| issue =2| pages =42–50| publisher =| year =2006| pmid = 16635421 }}</ref>
Although inflammation may also affect the brain, the lesions are different from those observed in the related condition, [[multiple sclerosis]].<ref name=Pittock>{{cite journal |vauthors=Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA |title=Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression |journal=Arch. Neurol. |volume=63 |issue=7 |pages=964–968 |year=2006 |pmid=16831965 |doi=10.1001/archneur.63.7.964 }}</ref> Spinal cord lesions lead to varying degrees of [[Muscle weakness|weakness]] or [[paralysis]] in the legs or arms, loss of sensation (including [[blindness]]),<ref>{{DorlandsDict|nine/000955053|neuromyelitis optica}}</ref> and/or [[urinary bladder|bladder]] and [[bowel]] dysfunction.<ref name=Wingerchuk>{{cite journal| last =Wingerchuk| first =DM | title =Neuromyelitis optica| journal =The International MS Journal| volume =13| issue =2| pages =42–50| publisher =| year =2006| pmid = 16635421 }}</ref>


Devic's disease is now studied along a collection of similar diseases called "Neuromyelitis optica spectrum diseases".<ref name="international_consensus">{{cite journal|last1=Wingerchuk|first1=D. M.|last2=Banwell|first2=B.|last3=Bennett|first3=J. L.|last4=Cabre|first4=P.|last5=Carroll|first5=W.|last6=Chitnis|first6=T.|last7=de Seze|first7=J.|last8=Fujihara|first8=K.|last9=Greenberg|first9=B.|last10=Jacob|first10=A.|last11=Jarius|first11=S.|last12=Lana-Peixoto|first12=M.|last13=Levy|first13=M.|last14=Simon|first14=J. H.|last15=Tenembaum|first15=S.|last16=Traboulsee|first16=A. L.|last17=Waters|first17=P.|last18=Wellik|first18=K. E.|last19=Weinshenker|first19=B. G.|title=International consensus diagnostic criteria for neuromyelitis optica spectrum disorders|journal=Neurology|date=19 June 2015|volume=85|issue=2|pages=177–189|doi=10.1212/WNL.0000000000001729|pmid=26092914|url=http://www.neurology.org/content/85/2/177.full|pmc=4515040}}</ref> Some cases of this spectrum resemble [[multiple sclerosis]] (MS) in several ways, but require a different course of treatment for optimal results.<ref name=Wingerchuk/>
Devic's disease is now studied along a collection of similar diseases called "Neuromyelitis optica spectrum diseases".<ref name=pmid26587556>{{cite journal |doi=10.1212/WNL.0000000000001729 }}</ref> Some cases of this spectrum resemble [[multiple sclerosis]] (MS) in several ways, but require a different course of treatment for optimal results.<ref name=Wingerchuk/>


In 2004, NMO-IgG (currently known as Anti-AQP IgG) was first described<ref name=Lancet2004>{{cite journal |vauthors=Lennon VA, Wingerchuk DM, Kryzer TJ, etal |title=A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis |journal=Lancet |volume=364 |issue=9451 |pages=2106–2112 |year=2004 |pmid=15589308 |doi=10.1016/S0140-6736(04)17551-X}}</ref> leading to the distinction between positive and negative cases.
In 2004, NMO-IgG (currently known as Anti-AQP IgG) was first described<ref name=Lancet2004>{{cite journal |vauthors=Lennon VA, Wingerchuk DM, Kryzer TJ, etal |title=A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis |journal=Lancet |volume=364 |issue=9451 |pages=2106–2112 |year=2004 |pmid=15589308 |doi=10.1016/S0140-6736(04)17551-X}}</ref> leading to the distinction between positive and negative cases.


In Anti-AQP positive variants, CNS astrocytes, which are the basis for the [[glymphatic system]]<ref name=JExpMed2005>{{cite journal |vauthors=Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR |title=IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel |journal=J. Exp. Med. |volume=202 |issue=4 |pages=473–477 |year=2005 |pmid=16087714 |doi=10.1084/jem.20050304|url=http://www.jem.org/cgi/content/full/202/4/473 |pmc=2212860}}</ref> are the target of the autoimmune attack. NMO-IgG-negative cases are less understood. It seems currently that astrocytes are spared in these IgG negative cases.<ref>{{cite journal|last1=Ikeda|first1=K|last2=Kiyota|first2=N|last3=Kuroda|first3=H|last4=Sato|first4=DK|last5=Nishiyama|first5=S|last6=Takahashi|first6=T|last7=Misu|first7=T|last8=Nakashima|first8=I|last9=Fujihara|first9=K|last10=Aoki|first10=M|title=Severe demyelination but no astrocytopathy in clinically definite neuromyelitis optica with anti-myelin-oligodendrocyte glycoprotein antibody.|journal=Multiple sclerosis (Houndmills, Basingstoke, England)|date=April 2015|volume=21|issue=5|pages=656–9|doi=10.1177/1352458514551455|pmid=25257613}}</ref>
In Anti-AQP positive variants, CNS astrocytes, which are the basis for the [[glymphatic system]]<ref name=pmid16087714>{{cite journal |doi=10.1084/jem.20050304 }}</ref> are the target of the autoimmune attack. NMO-IgG-negative cases are less understood. It seems currently that astrocytes are spared in these IgG negative cases.<ref>{{cite journal|last1=Ikeda|first1=K|last2=Kiyota|first2=N|last3=Kuroda|first3=H|last4=Sato|first4=DK|last5=Nishiyama|first5=S|last6=Takahashi|first6=T|last7=Misu|first7=T|last8=Nakashima|first8=I|last9=Fujihara|first9=K|last10=Aoki|first10=M|title=Severe demyelination but no astrocytopathy in clinically definite neuromyelitis optica with anti-myelin-oligodendrocyte glycoprotein antibody.|journal=Multiple sclerosis (Houndmills, Basingstoke, England)|date=April 2015|volume=21|issue=5|pages=656–9|doi=10.1177/1352458514551455|pmid=25257613}}</ref>


==Signs and symptoms==
==Signs and symptoms==
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Devic's disease is similar to MS in that the body's [[immune system]] attacks the [[myelin]] surrounding nerve cells. Unlike standard MS, the attacks are not believed to be mediated by the immune system's [[T cell]]s, but rather by [[antibody|antibodies]] called NMO-[[Immunoglobulin G|IgG]], or simply NMO antibodies. These antibodies target the [[protein]] [[aquaporin 4]] in the [[cell membrane]]s of [[astrocyte]]s which acts as a channel for the transport of water across the cell membrane.<ref name=Wingerchuk/>
Devic's disease is similar to MS in that the body's [[immune system]] attacks the [[myelin]] surrounding nerve cells. Unlike standard MS, the attacks are not believed to be mediated by the immune system's [[T cell]]s, but rather by [[antibody|antibodies]] called NMO-[[Immunoglobulin G|IgG]], or simply NMO antibodies. These antibodies target the [[protein]] [[aquaporin 4]] in the [[cell membrane]]s of [[astrocyte]]s which acts as a channel for the transport of water across the cell membrane.<ref name=Wingerchuk/>


Aquaporin&nbsp;4 is found in the astrocytes that surround the [[blood–brain barrier]] (BBB), a system responsible for preventing substances in the blood from crossing into the brain. The blood–brain barrier is weakened in Devic's disease, but it is currently unknown how the auto-antibodies cross the BBB. Some reports point to the [[metalloproteinase]]-2 and [[interleukin]]-6 as culprits for the BBB failure.<ref>Tomohiko Uchida et al. Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption, September 28, 2016, {{doi|10.1177/1352458516672015}}, Mult Scler September 28, 2016</ref> There is broad consensus that AQP4/NMO-IgG initially enters the brain via BBB-deficient sites such as area postrema, where access to CSF occurs<ref>Marlene Thorsen Mørch, Sofie Forsberg Sørensen, Reza Khorooshi, Nasrin Asgari, Trevor Owens, Selective localization of IgG from cerebrospinal fluid to brain parenchyma, Journal of Neuroinflammation, 17 April 2018, https://doi.org/10.1186/s12974-018-1159-8</ref>
Aquaporin&nbsp;4 is found in the astrocytes that surround the [[blood–brain barrier]] (BBB), a system responsible for preventing substances in the blood from crossing into the brain. The blood–brain barrier is weakened in Devic's disease, but it is currently unknown how the auto-antibodies cross the BBB. Some reports point to the [[metalloproteinase]]-2 and [[interleukin]]-6 as culprits for the BBB failure.<ref>Tomohiko Uchida et al. Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption, September 28, 2016, {{doi|10.1177/1352458516672015}}, Mult Scler September 28, 2016</ref> There is broad consensus that AQP4/NMO-IgG initially enters the brain via BBB-deficient sites such as area postrema, where access to CSF occurs.<ref>{{cite journal |doi=10.1186/s12974-018-1159-8 }}</ref>


There are "normal appearing areas" in NMO but compared to patients with MS, NAWM damage is less extensive<ref>Diffusion tensor imaging of normal‐appearing white matter in patients with neuromyelitis optica spectrum disorder and multiple sclerosis, Kim et al, European Journal of Neurology, doi: https://doi.org/10.1111/ene.13321, url: https://onlinelibrary.wiley.com/doi/full/10.1111/ene.13321</ref>
There are "normal appearing areas" in NMO but compared to patients with MS, NAWM damage is less extensive.<ref>{{cite journal |doi=10.1111/ene.13321 }}</ref>


Most research into the pathology of Devic's disease has focused on the spinal cord. The damage can range from [[inflammation|inflammatory]] demyelination to [[necrosis|necrotic]] damage of the [[white matter|white]] and [[grey matter]]s. The inflammatory lesions in Devic's disease have been [[Lesion patterns in multiple sclerosis#Demyelination patterns|classified as type II lesions]] ([[complement system|complement]]-mediated demyelinization), but they differ from MS pattern II lesions in their prominent perivascular distribution. Therefore, the pattern of inflammation is often quite distinct from that seen in MS.<ref name=Wingerchuk/><ref name="pmid12076996"/>
Most research into the pathology of Devic's disease has focused on the spinal cord. The damage can range from [[inflammation|inflammatory]] demyelination to [[necrosis|necrotic]] damage of the [[white matter|white]] and [[grey matter]]s. The inflammatory lesions in Devic's disease have been [[Lesion patterns in multiple sclerosis#Demyelination patterns|classified as type II lesions]] ([[complement system|complement]]-mediated demyelinization), but they differ from MS pattern II lesions in their prominent perivascular distribution. Therefore, the pattern of inflammation is often quite distinct from that seen in MS.<ref name=Wingerchuk/><ref name="pmid12076996"/>


==Diagnosis==
==Diagnosis==
The [[Mayo Clinic]] proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria.<ref>{{cite journal |vauthors=Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG |title=Revised diagnostic criteria for neuromyelitis optica |journal=Neurology |volume=66 |issue=10 |pages=1485–1489 |year=2006 |pmid=16717206 |doi=10.1212/01.wnl.0000216139.44259.74}}</ref> In 2015 a new review was published by an international panel<ref name="international_consensus"/> refining the previous [[clinical case definition]] but leaving the main criteria unmodified:
The [[Mayo Clinic]] proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria.<ref>{{cite journal |vauthors=Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG |title=Revised diagnostic criteria for neuromyelitis optica |journal=Neurology |volume=66 |issue=10 |pages=1485–1489 |year=2006 |pmid=16717206 |doi=10.1212/01.wnl.0000216139.44259.74}}</ref> In 2015 a new review was published by an international panel<ref name=pmid26587556/> refining the previous [[clinical case definition]] but leaving the main criteria unmodified:


Absolute criteria:
Absolute criteria:
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* Longitudinally extensive [[myelitis]] or optic neuritis associated with systemic [[autoimmune]] disease
* Longitudinally extensive [[myelitis]] or optic neuritis associated with systemic [[autoimmune]] disease
* Optic neuritis or myelitis associated with [[lesion]]s in specific brain areas such as the [[hypothalamus]], [[periventricular nucleus]], and [[brainstem]]<ref name=Symposium>{{cite conference | first =Dean | last =Wingerchuk | title =Neuromyelitis Optica (Devic's Syndrome) | booktitle =2006 Rare Neuroimmunologic Disorders Symposium | year =2006 | url =http://www.myelitis.org/rnds2006/Wingerchuk_NMO_Rare%20Neuroimm_062406_final.pdf | format =PDF | accessdate =2007-01-05 | deadurl =yes | archiveurl =https://web.archive.org/web/20060925095337/http://www.myelitis.org/rnds2006/Wingerchuk_NMO_Rare%20Neuroimm_062406_final.pdf | archivedate =2006-09-25 | df = }}</ref>
* Optic neuritis or myelitis associated with [[lesion]]s in specific brain areas such as the [[hypothalamus]], [[periventricular nucleus]], and [[brainstem]]<ref name=Symposium>{{cite conference | first =Dean | last =Wingerchuk | title =Neuromyelitis Optica (Devic's Syndrome) | booktitle =2006 Rare Neuroimmunologic Disorders Symposium | year =2006 | url =http://www.myelitis.org/rnds2006/Wingerchuk_NMO_Rare%20Neuroimm_062406_final.pdf | format =PDF | accessdate =2007-01-05 | deadurl =yes | archiveurl =https://web.archive.org/web/20060925095337/http://www.myelitis.org/rnds2006/Wingerchuk_NMO_Rare%20Neuroimm_062406_final.pdf | archivedate =2006-09-25 | df = }}</ref>
* NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge.<ref>{{cite journal|last1=Fujihara|first1=K|last2=Leite|first2=MI|title=Seronegative NMO: a sensitive AQP4 antibody test clarifies clinical features and next challenges.|journal=Neurology|date=11 June 2013|volume=80|issue=24|pages=2176–7|doi=10.1212/WNL.0b013e318296ea22|pmid=23658387}}</ref><ref>{{cite journal|last1=Marignier|first1=R|last2=Bernard-Valnet|first2=R|last3=Giraudon|first3=P|last4=Collongues|first4=N|last5=Papeix|first5=C|last6=Zéphir|first6=H|last7=Cavillon|first7=G|last8=Rogemond|first8=V|last9=Casey|first9=R|last10=Frangoulis|first10=B|last11=De Sèze|first11=J|last12=Vukusic|first12=S|last13=Honnorat|first13=J|last14=Confavreux|first14=C|last15=NOMADMUS Study|first15=Group|title=Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity.|journal=Neurology|date=11 June 2013|volume=80|issue=24|pages=2194–200|pmid=23658379|doi=10.1212/WNL.0b013e318296e917}}</ref> Some cases could be related to anti-[[myelin oligodendrocyte glycoprotein]] (MOG) autoantibodies.<ref name=Probstel>{{cite journal|last1=Pröbstel|first1=AK|last2=Rudolf|first2=G|last3=Dornmair|first3=K|last4=Collongues|first4=N|last5=Chanson|first5=JB|last6=Sanderson|first6=NS|last7=Lindberg|first7=RL|last8=Kappos|first8=L|last9=de Seze|first9=J|last10=Derfuss|first10=T|title=Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype.|journal=Journal of Neuroinflammation|date=8 March 2015|volume=12|issue=1|pages=46|doi=10.1186/s12974-015-0256-1|pmid=25889963|url=http://www.jneuroinflammation.com/content/12/1/46|pmc=4359547}}</ref>
* NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge.<ref>{{cite journal|last1=Fujihara|first1=K|last2=Leite|first2=MI|title=Seronegative NMO: a sensitive AQP4 antibody test clarifies clinical features and next challenges.|journal=Neurology|date=11 June 2013|volume=80|issue=24|pages=2176–7|doi=10.1212/WNL.0b013e318296ea22|pmid=23658387}}</ref><ref>{{cite journal|last1=Marignier|first1=R|last2=Bernard-Valnet|first2=R|last3=Giraudon|first3=P|last4=Collongues|first4=N|last5=Papeix|first5=C|last6=Zéphir|first6=H|last7=Cavillon|first7=G|last8=Rogemond|first8=V|last9=Casey|first9=R|last10=Frangoulis|first10=B|last11=De Sèze|first11=J|last12=Vukusic|first12=S|last13=Honnorat|first13=J|last14=Confavreux|first14=C|last15=NOMADMUS Study|first15=Group|title=Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity.|journal=Neurology|date=11 June 2013|volume=80|issue=24|pages=2194–200|pmid=23658379|doi=10.1212/WNL.0b013e318296e917}}</ref> Some cases could be related to anti-[[myelin oligodendrocyte glycoprotein]] (MOG) autoantibodies.<ref name=pmid25889963>{{cite journal |doi=10.1186/s12974-015-0256-1 }}</ref>


Whether Devic's disease is a distinct disease or part of the wide [[borderline forms of multiple sclerosis|spectrum of multiple sclerosis]] is debated.<ref name=Saida>{{cite journal |author=Saida T |title=Overview of MS: proposal of new MS definition/classification and review of the results of recent clinical trials |journal=Nippon Rinsho | year=2008 |pmid=18540351 |type=abstract |volume=66 |issue=6 |pages=1081–6}}</ref> Devic's disease differs in that it usually has more severe [[sequelae]] after an acute episode than standard MS, MS infrequently presents as [[transverse myelitis]], and oligoclonal bands in the [[Cerebrospinal fluid|CSF]], as well as [[white matter]] lesions on brain MRI, are uncommon in Devic's disease, but occur in over 90% of MS patients.<ref name=Pearce>{{cite journal |author=Pearce JM |title=Neuromyelitis optica |journal=Spinal Cord |volume=43 |issue=11 |pages=631–634 |year=2005 |pmid=15968305 |doi=10.1038/sj.sc.3101758|url=http://www.nature.com/sc/journal/v43/n11/abs/3101758a.html |type=abstract}}</ref>
Whether Devic's disease is a distinct disease or part of the wide [[borderline forms of multiple sclerosis|spectrum of multiple sclerosis]] is debated.<ref name=Saida>{{cite journal |author=Saida T |title=Overview of MS: proposal of new MS definition/classification and review of the results of recent clinical trials |journal=Nippon Rinsho | year=2008 |pmid=18540351 |type=abstract |volume=66 |issue=6 |pages=1081–6}}</ref> Devic's disease differs in that it usually has more severe [[sequelae]] after an acute episode than standard MS, MS infrequently presents as [[transverse myelitis]], and oligoclonal bands in the [[Cerebrospinal fluid|CSF]], as well as [[white matter]] lesions on brain MRI, are uncommon in Devic's disease, but occur in over 90% of MS patients.<ref name=pmid15968305>{{cite journal |doi=10.1038/sj.sc.3101758 }}</ref>


Recently, AQP4 has been found to distinguish standard multiple sclerosis from neuromyelitis optica, but as MS is a [[heterogeneous condition]],<ref>{{cite journal | pmid=11286782 | year=2001 | last1=Lassmann | first1=H | last2=Brück | first2=W | last3=Lucchinetti | first3=C | title=Heterogeneity of multiple sclerosis pathogenesis: Implications for diagnosis and therapy | volume=7 | issue=3 | pages=115–21 | journal=Trends in Molecular Medicine | doi=10.1016/s1471-4914(00)01909-2}}</ref> and some MS cases are reported to be [[KCNJ10|Kir4.1]] channelopathies<ref>{{cite journal | pmid=24032025|pmc=3759297 | year=2013 | last1=Schneider | first1=R | title=Autoantibodies to Potassium Channel KIR4.1 in Multiple Sclerosis | volume=4 | pages=125 | doi=10.3389/fneur.2013.00125 | journal=Frontiers in Neurology}}</ref> (autoimmunity against the potassium channels) it is still possible to consider NMO as part of the MS spectrum. Besides, some NMO-AQP(−) variants are not astrocytopathic, but demyelinating.<ref>{{cite journal|last1=Kurosawa|first1=K|last2=Fujihara|first2=K|title=[Clinical concept, etiology and pathology of neuromyelitis optica].|journal=Nihon rinsho. Japanese journal of clinical medicine|date=November 2014|volume=72|issue=11|pages=1897–902|pmid=25518368}}</ref>
Recently, AQP4 has been found to distinguish standard multiple sclerosis from neuromyelitis optica, but as MS is a [[heterogeneous condition]],<ref>{{cite journal | pmid=11286782 | year=2001 | last1=Lassmann | first1=H | last2=Brück | first2=W | last3=Lucchinetti | first3=C | title=Heterogeneity of multiple sclerosis pathogenesis: Implications for diagnosis and therapy | volume=7 | issue=3 | pages=115–21 | journal=Trends in Molecular Medicine | doi=10.1016/s1471-4914(00)01909-2}}</ref> and some MS cases are reported to be [[KCNJ10|Kir4.1]] channelopathies<ref>{{cite journal | pmid=24032025|pmc=3759297 | year=2013 | last1=Schneider | first1=R | title=Autoantibodies to Potassium Channel KIR4.1 in Multiple Sclerosis | volume=4 | pages=125 | doi=10.3389/fneur.2013.00125 | journal=Frontiers in Neurology}}</ref> (autoimmunity against the potassium channels) it is still possible to consider NMO as part of the MS spectrum. Besides, some NMO-AQP(−) variants are not astrocytopathic, but demyelinating.<ref>{{cite journal|last1=Kurosawa|first1=K|last2=Fujihara|first2=K|title=[Clinical concept, etiology and pathology of neuromyelitis optica].|journal=Nihon rinsho. Japanese journal of clinical medicine|date=November 2014|volume=72|issue=11|pages=1897–902|pmid=25518368}}</ref>
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AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the [[oligoclonal bands]] respect MS{{Clarify|reason=vague|date=May 2015}} 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.<ref>{{cite journal|last1=Bergamaschi|first1=R|last2=Tonietti|first2=S|last3=Franciotta|first3=D|last4=Candeloro|first4=E|last5=Tavazzi|first5=E|last6=Piccolo|first6=G|last7=Romani|first7=A|last8=Cosi|first8=V|title=Oligoclonal bands in Devic's neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations|journal=Multiple Sclerosis|date=1 February 2004|volume=10|issue=1|pages=2–4|doi=10.1191/1352458504ms988oa|pmid=14760945}}</ref>
AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the [[oligoclonal bands]] respect MS{{Clarify|reason=vague|date=May 2015}} 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.<ref>{{cite journal|last1=Bergamaschi|first1=R|last2=Tonietti|first2=S|last3=Franciotta|first3=D|last4=Candeloro|first4=E|last5=Tavazzi|first5=E|last6=Piccolo|first6=G|last7=Romani|first7=A|last8=Cosi|first8=V|title=Oligoclonal bands in Devic's neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations|journal=Multiple Sclerosis|date=1 February 2004|volume=10|issue=1|pages=2–4|doi=10.1191/1352458504ms988oa|pmid=14760945}}</ref>


It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS<ref>Komatsu et al. Long spinal cord lesions in a patient with pathologically proven multiple sclerosis. J Clin Neurosci. 2017 Apr 29. pii: S0967-5868(16)31496-5. {{doi|10.1016/j.jocn.2017.03.022}}, {{PMID|28465080}}</ref>
It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS.<ref name=pmid28465080>{{cite journal |doi=10.1016/j.jocn.2017.03.022 }}</ref>


Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.<ref name="pmid29204291">{{cite journal |vauthors=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, Pietro Sechi G |title=Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder |journal=Mult Scler J Exp Transl Clin |volume=3 |issue=4 |pages=2055217317742425 |year=2017 |pmid=29204291 |pmc=5703109 |doi=10.1177/2055217317742425 }}</ref><ref name="pmid29208041">{{cite journal |vauthors = Jurynczyk M, Probert F, Yeo T, Tackley G, ((Claridge TDW)), 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 |title=Metabolomics reveals distinct, antibody-independent, molecular signatures of MS, AQP4-antibody and MOG-antibody disease |journal=Acta Neuropathol Commun |volume=5 |issue=1 |pages=95 |year=2017 |pmid=29208041 |pmc=5718082 |doi=10.1186/s40478-017-0495-8 }}</ref>
Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.<ref name="pmid29204291">{{cite journal |vauthors=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, Pietro Sechi G |title=Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder |journal=Mult Scler J Exp Transl Clin |volume=3 |issue=4 |pages=2055217317742425 |year=2017 |pmid=29204291 |pmc=5703109 |doi=10.1177/2055217317742425 }}</ref><ref name="pmid29208041">{{cite journal |vauthors = Jurynczyk M, Probert F, Yeo T, Tackley G, ((Claridge TDW)), 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 |title=Metabolomics reveals distinct, antibody-independent, molecular signatures of MS, AQP4-antibody and MOG-antibody disease |journal=Acta Neuropathol Commun |volume=5 |issue=1 |pages=95 |year=2017 |pmid=29208041 |pmc=5718082 |doi=10.1186/s40478-017-0495-8 }}</ref>
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===Secondary prevention===
===Secondary prevention===
No controlled trials have established the effectiveness of treatments for the prevention of attacks. Many clinicians agree that long term [[immunosuppression]] is required to reduce the frequency and severity of attacks, while others argue the exact opposite.<ref name="Poser and Brinar 2007">{{cite journal |vauthors=Poser CM, Brinar VV |title=Disseminated encephalomyelitis and multiple sclerosis: two different diseases – a critical review |journal=Acta Neurol. Scand. |volume=116 |issue=4 |pages=201–206 |year=2007 |pmid=17824894 |doi=10.1111/j.1600-0404.2007.00902.x}}</ref> Commonly used immunosuppressant treatments include [[azathioprine]] (Imuran) plus [[prednisone]], [[mycophenolate mofetil]] plus prednisone, [[mitoxantrone]], [[intravenous immunoglobulin]] (IVIG), and [[cyclophosphamide]].<ref name=Symposium/><ref>{{cite journal |vauthors=Weinstock-Guttman B, Ramanathan M, Lincoff N, etal |title=Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease) |journal=Arch. Neurol. |volume=63 |issue=7 |pages=957–963 |year=2006 |pmid=16831964 |doi=10.1001/archneur.63.7.957|url=http://archneur.ama-assn.org/cgi/content/full/63/7/957}}</ref>
No controlled trials have established the effectiveness of treatments for the prevention of attacks. Many clinicians agree that long term [[immunosuppression]] is required to reduce the frequency and severity of attacks, while others argue the exact opposite.<ref name="Poser and Brinar 2007">{{cite journal |vauthors=Poser CM, Brinar VV |title=Disseminated encephalomyelitis and multiple sclerosis: two different diseases – a critical review |journal=Acta Neurol. Scand. |volume=116 |issue=4 |pages=201–206 |year=2007 |pmid=17824894 |doi=10.1111/j.1600-0404.2007.00902.x}}</ref> Commonly used immunosuppressant treatments include [[azathioprine]] (Imuran) plus [[prednisone]], [[mycophenolate mofetil]] plus prednisone, [[mitoxantrone]], [[intravenous immunoglobulin]] (IVIG), and [[cyclophosphamide]].<ref name=Symposium/><ref>{{cite journal |vauthors=Weinstock-Guttman B, Ramanathan M, Lincoff N, etal |title=Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease) |journal=Arch. Neurol. |volume=63 |issue=7 |pages=957–963 |year=2006 |pmid=16831964 |doi=10.1001/archneur.63.7.957 }}</ref>


Though the disease is known to be auto-antibodies mediated, [[B-cell]] depletion has been tried<ref>{{cite journal |vauthors=Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG |title=Neuromyelitis optica |journal=Current Opinion in Neurology |volume=20 |issue=3 |pages=255–260 |year=2007 |pmid=17495617 |doi=10.1097/WCO.0b013e32814f1c6b}}</ref> with the [[monoclonal antibody]] [[rituximab]], showing good results.<ref>Evangelopoulos M. et al. 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. J Neurol Sci. 2017 Jan 15;372:92–96. {{doi|10.1016/j.jns.2016.11.016}}. {{PMID|28017256}}</ref>
Though the disease is known to be auto-antibodies mediated, [[B-cell]] depletion has been tried<ref>{{cite journal |vauthors=Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG |title=Neuromyelitis optica |journal=Current Opinion in Neurology |volume=20 |issue=3 |pages=255–260 |year=2007 |pmid=17495617 |doi=10.1097/WCO.0b013e32814f1c6b}}</ref> with the [[monoclonal antibody]] [[rituximab]], showing good results.<ref name=pmid28017256>{{cite journal |doi=10.1016/j.jns.2016.11.016 }}</ref>


Several other disease modifying therapies are being tried. In 2007, Devic's disease was reported to be responsive to [[glatiramer acetate]]<ref>{{cite journal |vauthors=Gartzen K, Limmroth V, Putzki N |title=Relapsing neuromyelitis optica responsive to glatiramer acetate treatment |journal=Eur. J. Neurol. |volume=14 |issue=6 |pages=e12–3 |year=2007 |pmid=17539924 |doi=10.1111/j.1468-1331.2007.01807.x}}</ref> and to low-dose corticosteroids.<ref>{{cite journal |vauthors=Watanabe S, Misu T, Miyazawa I, etal |title=Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis |journal= Multiple Sclerosis|volume= 13|issue= 8|pages= 968–74|year=2007 |pmid=17623727 |doi=10.1177/1352458507077189}}</ref> Use of [[Mycophenolate mofetil]] is also currently under research.
Several other disease modifying therapies are being tried. In 2007, Devic's disease was reported to be responsive to [[glatiramer acetate]]<ref>{{cite journal |vauthors=Gartzen K, Limmroth V, Putzki N |title=Relapsing neuromyelitis optica responsive to glatiramer acetate treatment |journal=Eur. J. Neurol. |volume=14 |issue=6 |pages=e12–3 |year=2007 |pmid=17539924 |doi=10.1111/j.1468-1331.2007.01807.x}}</ref> and to low-dose corticosteroids.<ref>{{cite journal |vauthors=Watanabe S, Misu T, Miyazawa I, etal |title=Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis |journal= Multiple Sclerosis|volume= 13|issue= 8|pages= 968–74|year=2007 |pmid=17623727 |doi=10.1177/1352458507077189}}</ref> Use of [[Mycophenolate mofetil]] is also currently under research.
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</ref>
</ref>


[[Hematopoietic stem cell transplantation]] (HSCT) is sometimes used in severe cases of NMO. Currently available data suggest that this procedure can reduce inflammatory activity in the short term, but a clear majority of the patients will relapse within 5 years.<ref>{{Cite journal|last=Burman|first=Joachim|last2=Tolf|first2=Andreas|last3=Hägglund|first3=Hans|last4=Askmark|first4=Håkan|date=2018-02-01|title=Autologous haematopoietic stem cell transplantation for neurological diseases|url=http://jnnp.bmj.com/content/89/2/147|journal=J Neurol Neurosurg Psychiatry|language=en|volume=89|issue=2|pages=147–155|doi=10.1136/jnnp-2017-316271|issn=0022-3050|pmid=28866625}}</ref>
[[Hematopoietic stem cell transplantation]] (HSCT) is sometimes used in severe cases of NMO. Currently available data suggest that this procedure can reduce inflammatory activity in the short term, but a clear majority of the patients will relapse within 5 years.<ref name=pmid28866625>{{cite journal |doi=10.1136/jnnp-2017-316271 }}</ref>


==Prognosis==
==Prognosis==
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Since the discovery of AQP4 autoantibody, it has been found that it appears also in patients with NMO-like symptoms that do not fulfill the clinical requirements to be diagnosed NMO (Recurrent and simultaneous optic nerve and spinal cord inflammation).<ref name=Masaki2013>{{cite journal|last1=Masaki|first1=K|last2=Suzuki|first2=SO|last3=Matsushita|first3=T|last4=Matsuoka|first4=T|last5=Imamura|first5=S|last6=Yamasaki|first6=R|last7=Suzuki|first7=M|last8=Suenaga|first8=T|last9=Iwaki|first9=T|last10=Kira|first10=J|title=Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica.|journal=PLOS ONE|date=2013|volume=8|issue=8|pages=e72919|doi=10.1371/journal.pone.0072919|pmid=23991165|pmc=3749992}}</ref>
Since the discovery of AQP4 autoantibody, it has been found that it appears also in patients with NMO-like symptoms that do not fulfill the clinical requirements to be diagnosed NMO (Recurrent and simultaneous optic nerve and spinal cord inflammation).<ref name=Masaki2013>{{cite journal|last1=Masaki|first1=K|last2=Suzuki|first2=SO|last3=Matsushita|first3=T|last4=Matsuoka|first4=T|last5=Imamura|first5=S|last6=Yamasaki|first6=R|last7=Suzuki|first7=M|last8=Suenaga|first8=T|last9=Iwaki|first9=T|last10=Kira|first10=J|title=Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica.|journal=PLOS ONE|date=2013|volume=8|issue=8|pages=e72919|doi=10.1371/journal.pone.0072919|pmid=23991165|pmc=3749992}}</ref>


The term NMOSD (NMO Spectrum Disorders) has been designed to allow incorporation of cases associated a non-AQP4 biomarkers.<ref name="international_consensus"/> Therefore, it includes all the clinical variants due to anti-AQP4 plus other non-related but clinically similar syndromes like [[antiMOG associated encephalomyelitis]]. Some cases with MOG+ and AQP4+ antibodies have been found<ref>{{cite journal | author = Di Pauli Franziska | year = 2015 | title = Fulminant demyelinating encephalomyelitis. Insights from antibody studies and neuropathology | journal = Neurol Neuroimmunol Neuroinflamm | volume = 2 | issue = 6| page = e175 | doi = 10.1212/NXI.0000000000000175 | pmid=26587556 | pmc=4635550}}</ref>
The term NMOSD (NMO Spectrum Disorders) has been designed to allow incorporation of cases associated a non-AQP4 biomarkers.<ref name=pmid26587556/> Therefore, it includes all the clinical variants due to anti-AQP4 plus other non-related but clinically similar syndromes like [[antiMOG associated encephalomyelitis]]. Some cases with MOG+ and AQP4+ antibodies have been found<ref>{{cite journal | author = Di Pauli Franziska | year = 2015 | title = Fulminant demyelinating encephalomyelitis. Insights from antibody studies and neuropathology | journal = Neurol Neuroimmunol Neuroinflamm | volume = 2 | issue = 6| page = e175 | doi = 10.1212/NXI.0000000000000175 | pmid=26587556 | pmc=4635550}}</ref>


The collection of these condition has been named "neuromyelitis optica spectrum disorders" (NMSD) and they are expected to respond to the same treatments as standard NMO.<ref>{{cite journal|last1=Fujihara|first1=K.|last2=Sato|first2=D. K.|title=AQP4 antibody serostatus: Is its luster being lost in the management and pathogenesis of NMO?|journal=Neurology|date=30 August 2013|volume=81|issue=14|pages=1186–1188|doi=10.1212/WNL.0b013e3182a6cc23|pmid=23997154}}</ref> Some authors propose to use the name "autoimmune aquaporin-4 [[channelopathy]]" for these diseases,<ref name=Pittock2015/> while others prefer a more generic term "AQP4-astrocytopathy" that includes also problems in AQP4 with a non-autoimmune origin.<ref name="ReferenceA">{{cite journal|last1=Masaki|first1=Katsuhisa|title=Early disruption of glial communication via connexin gap junction in multiple sclerosis, Baló's disease and neuromyelitis optica|journal=Neuropathology|date=October 2015|volume=35|issue=5|pages=469–480|doi=10.1111/neup.12211|pmid=26016402}}</ref>
The collection of these condition has been named "neuromyelitis optica spectrum disorders" (NMSD) and they are expected to respond to the same treatments as standard NMO.<ref>{{cite journal|last1=Fujihara|first1=K.|last2=Sato|first2=D. K.|title=AQP4 antibody serostatus: Is its luster being lost in the management and pathogenesis of NMO?|journal=Neurology|date=30 August 2013|volume=81|issue=14|pages=1186–1188|doi=10.1212/WNL.0b013e3182a6cc23|pmid=23997154}}</ref> Some authors propose to use the name "autoimmune aquaporin-4 [[channelopathy]]" for these diseases,<ref name=Pittock2015/> while others prefer a more generic term "AQP4-astrocytopathy" that includes also problems in AQP4 with a non-autoimmune origin.<ref name="ReferenceA">{{cite journal|last1=Masaki|first1=Katsuhisa|title=Early disruption of glial communication via connexin gap junction in multiple sclerosis, Baló's disease and neuromyelitis optica|journal=Neuropathology|date=October 2015|volume=35|issue=5|pages=469–480|doi=10.1111/neup.12211|pmid=26016402}}</ref>
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Similar instances of [[optic neuritis]] and myelitis were reported, and many believed it constituted a distinct clinical entity. However, some patients had [[pathology]] in other parts of the [[brain]], a feature which was more suggestive of [[acute disseminated encephalomyelitis]] or MS.{{citation needed|date=February 2016}}
Similar instances of [[optic neuritis]] and myelitis were reported, and many believed it constituted a distinct clinical entity. However, some patients had [[pathology]] in other parts of the [[brain]], a feature which was more suggestive of [[acute disseminated encephalomyelitis]] or MS.{{citation needed|date=February 2016}}


In 2002, [[Mayo Clinic]] researchers identified an [[humoral]] mechanism, targeting a perivascular protein, as the culprit for NMO <ref name="pmid12076996">{{cite journal |vauthors = Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H |title=A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica |journal=Brain |volume=125 |issue=Pt 7 |pages=1450–61 |year=2002 |pmid=12076996 |pmc=5444467 |doi=10.1093/brain/awf151}}</ref> and in 2004 an unknown specific autoantibody was found.<ref name=Lancet2004/> In 2005 they identified the [[aquaporin 4]] protein as the target of the disease, and developed a test to aid in the diagnosis of Devic's disease by detection of an antibody, NMO-[[Immunoglobulin G|IgG]], in the blood.<ref name=JExpMed2005/> Some patients with NMO may be [[serostatus|seronegative]] for NMO-IgG, whilst some patients with NMO-IgG may still not fulfill clinical criteria for NMO thus serological testing is now an important part of the diagnostic procedure and seropositive and seronegative cases are described in a manner similar to [[myasthenia gravis]]. According to the Mayo Clinic report, this was the first time a molecular target had been identified for a type of demyelinating inflammatory disease.<ref>{{cite web |url=http://www.mayoclinic.org/devics-disease/research.html |title=Devic's Disease Research – Mayo Clinic |archiveurl=https://web.archive.org/web/20090216045621/http://www.mayoclinic.org/devics-disease/research.html|archivedate=2009-02-16}}</ref>
In 2002, [[Mayo Clinic]] researchers identified an [[humoral]] mechanism, targeting a perivascular protein, as the culprit for NMO <ref name="pmid12076996">{{cite journal |vauthors = Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H |title=A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica |journal=Brain |volume=125 |issue=Pt 7 |pages=1450–61 |year=2002 |pmid=12076996 |pmc=5444467 |doi=10.1093/brain/awf151}}</ref> and in 2004 an unknown specific autoantibody was found.<ref name=Lancet2004/> In 2005 they identified the [[aquaporin 4]] protein as the target of the disease, and developed a test to aid in the diagnosis of Devic's disease by detection of an antibody, NMO-[[Immunoglobulin G|IgG]], in the blood.<ref name=pmid16087714/> Some patients with NMO may be [[serostatus|seronegative]] for NMO-IgG, whilst some patients with NMO-IgG may still not fulfill clinical criteria for NMO thus serological testing is now an important part of the diagnostic procedure and seropositive and seronegative cases are described in a manner similar to [[myasthenia gravis]]. According to the Mayo Clinic report, this was the first time a molecular target had been identified for a type of demyelinating inflammatory disease.<ref>{{cite web |url=http://www.mayoclinic.org/devics-disease/research.html |title=Devic's Disease Research – Mayo Clinic |archiveurl=https://web.archive.org/web/20090216045621/http://www.mayoclinic.org/devics-disease/research.html|archivedate=2009-02-16}}</ref>


==Research directions==
==Research directions==
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Currently, the most promising non-aquaporin biomarker is the presence of the [[myelin oligodendrocyte glycoprotein|anti-MOG]] autoantibody, which together with the anti-AQP4 can classify the NMO cases in four classes, according to the presence or absence of any of the two antibodies.<ref name="kezuka">{{cite journal|last1=Kezuka|first1=Takeshi|last2=Usui|first2=Yoshihiko|last3=Yamakawa|first3=Naoyuki|last4=Matsunaga|first4=Yoshimichi|last5=Matsuda|first5=Ryusaku|last6=Masuda|first6=Masayuki|last7=Utsumi|first7=Hiroya|last8=Tanaka|first8=Keiko|last9=Goto|first9=Hiroshi|title=Relationship Between NMO-Antibody and Anti–MOG Antibody in Optic Neuritis|journal=Journal of Neuro-Ophthalmology|date=June 2012|volume=32|issue=2|pages=107–110|doi=10.1097/WNO.0b013e31823c9b6c|pmid=22157536}}</ref>
Currently, the most promising non-aquaporin biomarker is the presence of the [[myelin oligodendrocyte glycoprotein|anti-MOG]] autoantibody, which together with the anti-AQP4 can classify the NMO cases in four classes, according to the presence or absence of any of the two antibodies.<ref name="kezuka">{{cite journal|last1=Kezuka|first1=Takeshi|last2=Usui|first2=Yoshihiko|last3=Yamakawa|first3=Naoyuki|last4=Matsunaga|first4=Yoshimichi|last5=Matsuda|first5=Ryusaku|last6=Masuda|first6=Masayuki|last7=Utsumi|first7=Hiroya|last8=Tanaka|first8=Keiko|last9=Goto|first9=Hiroshi|title=Relationship Between NMO-Antibody and Anti–MOG Antibody in Optic Neuritis|journal=Journal of Neuro-Ophthalmology|date=June 2012|volume=32|issue=2|pages=107–110|doi=10.1097/WNO.0b013e31823c9b6c|pmid=22157536}}</ref>


MOG antibodies are currently considered mostly absent in multiple sclerosis.<ref>{{cite journal|last1=Ketelslegers|first1=I. A.|last2=Van Pelt|first2=D. E.|last3=Bryde|first3=S.|last4=Neuteboom|first4=R. F.|last5=Catsman-Berrevoets|first5=C. E.|last6=Hamann|first6=D.|last7=Hintzen|first7=R. Q.|title=Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort|journal=Multiple Sclerosis Journal|date=6 February 2015|volume=21|issue=12|pages=1513–1520|doi=10.1177/1352458514566666|pmid=25662345}}</ref> Therefore, it can be said that anti-MOG is a group contained inside AQP-Negative NMO.<ref name=Probstel/>
MOG antibodies are currently considered mostly absent in multiple sclerosis.<ref>{{cite journal|last1=Ketelslegers|first1=I. A.|last2=Van Pelt|first2=D. E.|last3=Bryde|first3=S.|last4=Neuteboom|first4=R. F.|last5=Catsman-Berrevoets|first5=C. E.|last6=Hamann|first6=D.|last7=Hintzen|first7=R. Q.|title=Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort|journal=Multiple Sclerosis Journal|date=6 February 2015|volume=21|issue=12|pages=1513–1520|doi=10.1177/1352458514566666|pmid=25662345}}</ref> Therefore, it can be said that anti-MOG is a group contained inside AQP-Negative NMO.<ref name=pmid25889963/>


The clinical course and the response to therapy is different for these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group.<ref name="kezuka"/> The MOG-related neuromyelitis optica can be radiologically identified by the [[Conus medullaris|conus]] involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging.<ref>{{cite journal|last1=Kitley|first1=Joanna|last2=Waters|first2=Patrick|last3=Woodhall|first3=Mark|last4=Leite|first4=M. Isabel|last5=Murchison|first5=Andrew|last6=George|first6=Jithin|last7=Küker|first7=Wilhelm|last8=Chandratre|first8=Saleel|last9=Vincent|first9=Angela|last10=Palace|first10=Jacqueline|title=Neuromyelitis Optica Spectrum Disorders With Aquaporin-4 and Myelin-Oligodendrocyte Glycoprotein Antibodies|journal=JAMA Neurology|date=1 March 2014|volume=71|issue=3|pages=276–83|doi=10.1001/jamaneurol.2013.5857|pmid=24425068}}</ref>
The clinical course and the response to therapy is different for these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group.<ref name="kezuka"/> The MOG-related neuromyelitis optica can be radiologically identified by the [[Conus medullaris|conus]] involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging.<ref>{{cite journal|last1=Kitley|first1=Joanna|last2=Waters|first2=Patrick|last3=Woodhall|first3=Mark|last4=Leite|first4=M. Isabel|last5=Murchison|first5=Andrew|last6=George|first6=Jithin|last7=Küker|first7=Wilhelm|last8=Chandratre|first8=Saleel|last9=Vincent|first9=Angela|last10=Palace|first10=Jacqueline|title=Neuromyelitis Optica Spectrum Disorders With Aquaporin-4 and Myelin-Oligodendrocyte Glycoprotein Antibodies|journal=JAMA Neurology|date=1 March 2014|volume=71|issue=3|pages=276–83|doi=10.1001/jamaneurol.2013.5857|pmid=24425068}}</ref>

Revision as of 15:28, 28 May 2018

Devic's disease
SpecialtyNeurology Edit this on Wikidata

Neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is a heterogeneous condition consisting of the simultaneous inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). It can be monophasic or recurrent.

Currently at least two different causes are proposed based on the presence of autoantibodies against AQP4. AQP4+ NMO is currently considered an autoimmune disease (autoimmune astrocytopathy,[1] or autoimmune astrocytic channelopathy) in which a person's own immune system attacks the astrocytes of the optic nerves and spinal cord. The cause of the AQP4− variants is unknown.

Although inflammation may also affect the brain, the lesions are different from those observed in the related condition, multiple sclerosis.[2] Spinal cord lesions lead to varying degrees of weakness or paralysis in the legs or arms, loss of sensation (including blindness),[3] and/or bladder and bowel dysfunction.[4]

Devic's disease is now studied along a collection of similar diseases called "Neuromyelitis optica spectrum diseases".[5] Some cases of this spectrum resemble multiple sclerosis (MS) in several ways, but require a different course of treatment for optimal results.[4]

In 2004, NMO-IgG (currently known as Anti-AQP IgG) was first described[6] leading to the distinction between positive and negative cases.

In Anti-AQP positive variants, CNS astrocytes, which are the basis for the glymphatic system[7] are the target of the autoimmune attack. NMO-IgG-negative cases are less understood. It seems currently that astrocytes are spared in these IgG negative cases.[8]

Signs and symptoms

The main symptoms of Devic's disease are loss of vision and spinal cord function. Optic neuritis may manifest as visual impairment with decreased visual acuity, although visual field defects, or loss of color vision may occur in isolation or prior to formal loss of acuity. Spinal cord dysfunction can lead to muscle weakness, reduced sensation, or loss of bladder and bowel control.[9] The typical patient has an acute and severe spastic weakness of the legs (paraparesis) or all four limbs (quadriparesis) with sensory signs, often accompanied by loss of bladder control.[citation needed]

Pathophysiology

Illustration of the four different types of glial cells found in the central nervous system: ependymal cells, astrocytes, microglial cells, and oligodendrocytes

Causes

Devic's disease has been associated with many systemic diseases, based on anecdotal evidence of some Devic's disease patients with a comorbid condition. Such conditions include: collagen vascular diseases, autoantibody syndromes, infections with varicella-zoster virus, Epstein–Barr virus, and HIV, and exposure to clioquinol and antituberculosis drugs.[10]

The discovery of NMO-IgG has opened a new way into the research for the causes. Currently two principal causes are accepted:

  • In NMO-IgG positive patients, the cause of the neuromyelitis optica (understood as the syndrome) is an autoimmune aquaporin-4 channelopathy, due to these specific autoantibodies.[11] In these cases, astrocytes are the victims of the autoimmune attack.
  • In NMO-IgG negative patients, or at least a subset of them, the cause is an antiMOG associated encephalomyelitis,[12]

About the presence of NMO-IgG, some researchers have pointed out that some other cases could be paraneoplastic.[13] It seems also clear that lupus can produce NMO-IgG autoantibodies sometimes, leading to some cases of lupus-derived NMO.[14]

In any case, the IgG generation is produced mainly intrathecally.[15]

Mechanism

Devic's disease is similar to MS in that the body's immune system attacks the myelin surrounding nerve cells. Unlike standard MS, the attacks are not believed to be mediated by the immune system's T cells, but rather by antibodies called NMO-IgG, or simply NMO antibodies. These antibodies target the protein aquaporin 4 in the cell membranes of astrocytes which acts as a channel for the transport of water across the cell membrane.[4]

Aquaporin 4 is found in the astrocytes that surround the blood–brain barrier (BBB), a system responsible for preventing substances in the blood from crossing into the brain. The blood–brain barrier is weakened in Devic's disease, but it is currently unknown how the auto-antibodies cross the BBB. Some reports point to the metalloproteinase-2 and interleukin-6 as culprits for the BBB failure.[16] There is broad consensus that AQP4/NMO-IgG initially enters the brain via BBB-deficient sites such as area postrema, where access to CSF occurs.[17]

There are "normal appearing areas" in NMO but compared to patients with MS, NAWM damage is less extensive.[18]

Most research into the pathology of Devic's disease has focused on the spinal cord. The damage can range from inflammatory demyelination to necrotic damage of the white and grey matters. The inflammatory lesions in Devic's disease have been classified as type II lesions (complement-mediated demyelinization), but they differ from MS pattern II lesions in their prominent perivascular distribution. Therefore, the pattern of inflammation is often quite distinct from that seen in MS.[4][19]

Diagnosis

The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria.[20] In 2015 a new review was published by an international panel[5] refining the previous clinical case definition but leaving the main criteria unmodified:

Absolute criteria:

  1. Optic neuritis
  2. Acute myelitis

Supportive criteria:

  1. Brain MRI not meeting criteria for MS at disease onset
  2. Spinal cord MRI with continuous T2-weighted signal abnormality extending over three or more vertebral segments, indicating a relatively large lesion in the spinal cord
  3. NMO-IgG seropositive status (The NMO-IgG test checks the existence of antibodies against the aquaporin 4 antigen.)

Variants

After the development of the NMO-IgG test, the spectrum of disorders comprising Devic's disease 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
  • Asian optic-spinal MS—this variant can present brain lesions like MS.[21]
  • Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease
  • Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem[22]
  • NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge.[23][24] Some cases could be related to anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies.[25]

Whether Devic's disease is a distinct disease or part of the wide spectrum of multiple sclerosis is debated.[26] Devic's disease differs in that it usually has more severe sequelae after an acute episode than standard MS, MS infrequently presents as transverse myelitis, and oligoclonal bands in the CSF, as well as white matter lesions on brain MRI, are uncommon in Devic's disease, but occur in over 90% of MS patients.[27]

Recently, AQP4 has been found to distinguish standard multiple sclerosis from neuromyelitis optica, but as MS is a heterogeneous condition,[28] and some MS cases are reported to be Kir4.1 channelopathies[29] (autoimmunity against the potassium channels) it is still possible to consider NMO as part of the MS spectrum. Besides, some NMO-AQP(−) variants are not astrocytopathic, but demyelinating.[30]

Tumefactive lesions

Tumefactive demyelinating lesions in NMO are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta.[31]

Differential diagnosis

AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the oligoclonal bands respect MS[clarification needed] 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.[32]

It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS.[33]

Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.[34][35]

Treatment

Chemical structure of methylprednisolone, which is used to treat attacks

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[22] 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.[36]

Secondary prevention

No controlled trials have established the effectiveness of treatments for the prevention of attacks. Many clinicians agree that long term immunosuppression is required to reduce the frequency and severity of attacks, while others argue the exact opposite.[37] Commonly used immunosuppressant treatments include azathioprine (Imuran) plus prednisone, mycophenolate mofetil plus prednisone, mitoxantrone, intravenous immunoglobulin (IVIG), and cyclophosphamide.[22][38]

Though the disease is known to be auto-antibodies mediated, B-cell depletion has been tried[39] with the monoclonal antibody rituximab, showing good results.[40]

Several other disease modifying therapies are being tried. In 2007, Devic's disease was reported to be responsive to glatiramer acetate[41] and to low-dose corticosteroids.[42] Use of Mycophenolate mofetil is also currently under research. [43]

Hematopoietic stem cell transplantation (HSCT) is sometimes used in severe cases of NMO. Currently available data suggest that this procedure can reduce inflammatory activity in the short term, but a clear majority of the patients will relapse within 5 years.[44]

Prognosis

Normally, some measure of improvement appears in a few weeks, but residual signs and disability may persist, sometimes severely.

The disease can be monophasic, i.e. a single episode with permanent remission. However, at least 85% of patients have a relapsing form of the disease with repeated attacks of transverse myelitis and/or optic neuritis. In patients with the monophasic form, the transverse myelitis and optic neuritis occur simultaneously or within days of each other. On the other hand, patients with the relapsing form are more likely to have weeks or months between the initial attacks, and to have better motor recovery after the initial transverse myelitis event. Relapses usually occur early, with about 55% of patients having a relapse in the first year and 90% in the first five years.[4]

It is possible that the relapsing form is related to the antiAQP4+ seropositive status and the monophasic form related to its absence[45] Unlike multiple sclerosis, Devic's disease rarely has a secondary progressive phase in which patients have increasing neurologic decline between attacks without remission. Instead, disabilities arise from the acute attacks.[4]

Approximately 20% of patients with monophasic Devic's disease have permanent visual loss, and 30% have permanent paralysis in one or both legs. Among patients with relapsing Devic's disease, 50% have paralysis or blindness within five years. In some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure and subsequent death. However, the spectrum of Devic's disease has widened due to improved diagnostic criteria, and the options for treatment have improved; as a result, researchers believe these estimates will be lowered.[4]

Epidemiology

The prevalence and incidence of Devic's disease has not been established, partly because the disease is underrecognized and often confused with MS.[4] Devic's disease is more common in women than men, with women comprising over two-thirds of patients and more than 80% of those with the relapsing form of the disease.[4]

A retrospective study found that prevalence of NMOsd was 1.5% inside a random sample of neurological patients, with a MS:NMOsd ratio of 42.7. Among 13 NMOsd patients, 77% had long spinal cord lesions, 38% had severe optic neuritis and 23% had brain or brainstem lesions. Only 56% had clinically definite NMO at follow-up.[46]

According to the Walton Centre in England, "NMO seems to be present across the world unlike MS, which has a higher incidence in temperate climates and white races. Africans and Asians especially in Far East may have a higher risk of NMO, although the exact incidence of this disease is unknown, making specific conclusions difficult". Although many people who have Devic's disease were initially misdiagnosed with MS, 35% of African Americans are often misdiagnosed with MS when they really have NMO.[citation needed]

Devic's disease is more common in Asians than Caucasians. In fact, Asian optic-spinal MS (which constitutes 30% of the cases of MS in Japan) has been suggested to be identical to Devic's disease (differences between optic-spinal and classic MS in Japanese patients). In the indigenous populations of tropical and subtropical regions, MS is rare, but when it appears, it often takes the form of optic-spinal MS.[47]

The majority of Devic's disease patients have no affected relatives, and it is generally regarded as a nonfamilial condition.[4]

Neuromyelitis optica spectrum disorders

Since the discovery of AQP4 autoantibody, it has been found that it appears also in patients with NMO-like symptoms that do not fulfill the clinical requirements to be diagnosed NMO (Recurrent and simultaneous optic nerve and spinal cord inflammation).[48]

The term NMOSD (NMO Spectrum Disorders) has been designed to allow incorporation of cases associated a non-AQP4 biomarkers.[5] Therefore, it includes all the clinical variants due to anti-AQP4 plus other non-related but clinically similar syndromes like antiMOG associated encephalomyelitis. Some cases with MOG+ and AQP4+ antibodies have been found[49]

The collection of these condition has been named "neuromyelitis optica spectrum disorders" (NMSD) and they are expected to respond to the same treatments as standard NMO.[50] Some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases,[11] while others prefer a more generic term "AQP4-astrocytopathy" that includes also problems in AQP4 with a non-autoimmune origin.[51]

History

Sir Thomas Clifford Allbutt

First reports on an association of spinal cord and optic nerve disorders appeared in the early 19th century.[52] However, only an 1870 report by Sir Thomas Clifford Allbutt created sustained interest of neurologists and ophthalmologists in this rare syndrome.[53] In 1894, Eugène Devic and his PhD student Fernand Gault described 16 patients who had lost vision in one or both eyes and within weeks developed severe spastic weakness of the limbs, loss of sensation and often bladder control. They recognized these symptoms were the result of inflammation of the optic nerve and spinal cord, respectively.[52][54][55]

Similar instances of optic neuritis and myelitis were reported, and many believed it constituted a distinct clinical entity. However, some patients had pathology in other parts of the brain, a feature which was more suggestive of acute disseminated encephalomyelitis or MS.[citation needed]

In 2002, Mayo Clinic researchers identified an humoral mechanism, targeting a perivascular protein, as the culprit for NMO [19] and in 2004 an unknown specific autoantibody was found.[6] In 2005 they identified the aquaporin 4 protein as the target of the disease, and developed a test to aid in the diagnosis of Devic's disease by detection of an antibody, NMO-IgG, in the blood.[7] Some patients with NMO may be seronegative for NMO-IgG, whilst some patients with NMO-IgG may still not fulfill clinical criteria for NMO thus serological testing is now an important part of the diagnostic procedure and seropositive and seronegative cases are described in a manner similar to myasthenia gravis. According to the Mayo Clinic report, this was the first time a molecular target had been identified for a type of demyelinating inflammatory disease.[56]

Research directions

Since the discovery of AQP-4 involvement, some research studies have focused on targeted treatment aimed at anti-aquaporin 4 antibodies. The most established method for antibody removal is plasmapheresis. A number of drugs are being studied: aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor).[57]

There is little research into the primary causes of the Anti-AQP4 auto-antibodies. It has been noticed that some cases could be paraneoplastic.[13]

In addition, several NMO variants have been discovered with antibodies other than those for AQP4. Six different patterns of damage have been reported in NMO, raising the possibility of five different types of AQP4-negative variants.[58]

MOG-associated NMO

Main article: antiMOG associated encephalomyelitis

Currently, the most promising non-aquaporin biomarker is the presence of the anti-MOG autoantibody, which together with the anti-AQP4 can classify the NMO cases in four classes, according to the presence or absence of any of the two antibodies.[59]

MOG antibodies are currently considered mostly absent in multiple sclerosis.[60] Therefore, it can be said that anti-MOG is a group contained inside AQP-Negative NMO.[25]

The clinical course and the response to therapy is different for these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group.[59] The MOG-related neuromyelitis optica can be radiologically identified by the conus involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging.[61]

Other AQP4-negative variants

Other auto-antibody under research is flotillin. It has been found in seronegative NMO and some MS patients[62]

Finally, other proteins under study are Connexin 43 and anti-AQP1 though, as of 2015, there are only initial reports about the involvement of these proteins[48][51]

The group AQP+/MOG+ is very small and it can be considered a coincidence of two independent problems in the same person. Assuming these cases could be verified, currently five different kinds of NMO are being considered:

  • NMO derived from an autoimmune channelopathy (AQP4-Ab+), around 80% of the cases
  • NMO derived from an antiMOG associated encephalomyelitis,[12] around 10% of the cases
  • Connexin-43 NMO
  • Aquaporin-1 associated NMO
  • Idiopatic NMO, defined by the absence of all previous antibodies

Notable patients

See also

References

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