Editing Acute disseminated encephalomyelitis (section)

==Diagnosis==

The term ADEM has been inconsistently used at different times.<ref name="Cole_2019">{{cite journal | vauthors = Cole J, Evans E, Mwangi M, Mar S | title = Acute Disseminated Encephalomyelitis in Children: An Updated Review Based on Current Diagnostic Criteria | journal = Pediatric Neurology | volume = 100 | issue =  | pages = 26–34 | date = November 2019 | pmid = 31371120 | doi = 10.1016/j.pediatrneurol.2019.06.017 | s2cid = 198267007 }}</ref> Currently, the commonly accepted international standard for the [[clinical case definition]] is the one published by the [[International Pediatric MS Study Group]], revision 2007.<ref>{{cite journal | vauthors = Tenembaum S, Chitnis T, Ness J, Hahn JS | title = Acute disseminated encephalomyelitis | journal = Neurology | volume = 68 | issue = 16 Suppl 2 | pages = S23–36 | date = April 2007 | pmid = 17438235 | doi = 10.1212/01.wnl.0000259404.51352.7f | s2cid = 19893165 }}</ref>

Given that the definition is clinical, it is currently unknown if all the cases of ADEM are positive for anti-MOG autoantibody; in any case, it appears to be strongly related to ADEM diagnosis.<ref name="Weber_2018"/>

===Differential diagnosis===
====Multiple sclerosis====
While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects.<ref name="Koelman_2015" /><ref>{{cite journal | vauthors = Wingerchuk DM, Lucchinetti CF | title = Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis | journal = Current Opinion in Neurology | volume = 20 | issue = 3 | pages = 343–50 | date = June 2007 | pmid = 17495631 | doi = 10.1097/WCO.0b013e3280be58d8 | s2cid = 17386506 }}</ref> Some authors consider MS and its [[Idiopathic inflammatory demyelinating diseases|borderline forms]] to constitute a spectrum, differing only in chronicity, severity, and clinical course,<ref>{{cite book | vauthors = Weinshenker B, Miller D | date = 1999 | chapter =  Multiple sclerosis: one disease or many? | veditors = Siva A, Kesselring J, Thompson A | title = Frontiers in multiple sclerosis | location = London | publisher = Dunitz | pages = 37–46 | isbn = 978-1-85317-506-0 }}</ref><ref>{{cite journal | vauthors = Hartung HP, Grossman RI | title = ADEM: distinct disease or part of the MS spectrum? | journal = Neurology | volume = 56 | issue = 10 | pages = 1257–60 | date = May 2001 | pmid = 11376169 | doi = 10.1212/WNL.56.10.1257 | s2cid = 219199163 }}</ref> while others consider them discretely different diseases.<ref name="Poser_2007" />

Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults,<ref name="Koelman_2016" /><ref name="Schwarz_2001" /> and can also be clinically multiphasic.<ref>{{cite journal | vauthors = Krupp LB, Banwell B, Tenembaum S | collaboration = International Pediatric MS Study Group | title = Consensus definitions proposed for pediatric multiple sclerosis and related disorders | journal = Neurology | volume = 68 | issue = 16 Suppl 2 | pages = S7–12 | date = April 2007 | pmid = 17438241 | doi = 10.1212/01.wnl.0000259422.44235.a8 | s2cid = 26001350 }}</ref>

Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis.<ref name="Lassmann_2010">{{cite journal | vauthors = Lassmann H | title = Acute disseminated encephalomyelitis and multiple sclerosis | journal = Brain | volume = 133 | issue = Pt 2 | pages = 317–19 | date = February 2010 | pmid = 20129937 | doi = 10.1093/brain/awp342 | doi-access = free }}</ref> If MS were defined only by the separation in time and space of the demyelinating lesions as [[McDonald criteria|McDonald]] did,<ref name="pmid11456302">{{cite journal | vauthors = McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS | display-authors = 6 | title = Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis | journal = Annals of Neurology | volume = 50 | issue = 1 | pages = 121–27 | date = July 2001 | pmid = 11456302 | doi = 10.1002/ana.1032 | author2-link = Alastair Compston | s2cid = 13870943 | citeseerx = 10.1.1.466.5368 | author1-link = W. Ian McDonald }}</ref> it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the dividing line as the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination".<ref name="Lassmann_2010" /><ref name="Young_2010">{{cite journal | vauthors = Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, Thomsen KM, Mandrekar JN, Erickson BJ, Lucchinetti CF | display-authors = 6 | title = Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis | journal = Brain | volume = 133 | issue = Pt 2 | pages = 333–48 | date = February 2010 | pmid = 20129932 | pmc = 2822631 | doi = 10.1093/brain/awp321 | doi-access = free }}</ref>
[[File:Acute hemorrhagic Leukoencephalitis in a patient with Multiple sclerosis (MRI).png|thumb|407x407px|Acute hemorrhagic Leukoencephalitis in a patient with Multiple sclerosis.]]
The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenous inflammation with limited "sleeves of demyelination".<ref>{{cite journal | vauthors = Young NP, Weinshenker BG, Lucchinetti CF | title = Acute Disseminated Encephalomyelitis: Current Understanding and Controversies | journal = Seminars in Neurology | volume = 28 | issue = 1 | pages = 84–94 | date = February 2008 | pmid = 18256989 | doi = 10.1055/s-2007-1019130 | doi-access = free }}</ref><ref name="Koelman_2015" /> Nevertheless, MS-like plaques (confluent demyelination) can appear<ref name="auto">{{cite journal | vauthors = Guenther AD, Munoz DG | title = Plaque-like demyelination in acute disseminated encephalomyelitis (ADEM) – an autopsy case report | journal = Clinical Neuropathology | volume = 32 | issue = 6 | pages = 486–91 | year = 2013 | pmid = 23863345 | doi = 10.5414/NP300634 }}</ref>

Plaques in the white matter in MS are sharply delineated, while the [[glial scar]] in ADEM is smooth. Axons are better preserved in ADEM lesions. Inflammation in ADEM is widely disseminated and ill-defined, and finally, lesions are strictly perivenous, while in MS they are disposed around veins, but not so sharply.<ref>{{cite journal | vauthors = Lu Z, Zhang B, Qiu W, Kang Z, Shen L, Long Y, Huang J, Hu X | display-authors = 6 | title = Comparative brain stem lesions on MRI of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e22766 | year = 2011 | pmid = 21853047 | pmc = 3154259 | doi = 10.1371/journal.pone.0022766 | doi-access = free | bibcode = 2011PLoSO...622766L }}</ref>

Nevertheless, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy<ref name="Young_2010" /> or even postmortem<ref name="auto"/> <!-- Treatment of ADEM and [[Neuromyelitis optica]] with long-term immunomodulatory or immunosuppressive drugs --> ADEM in adults can progress to MS<ref name="Schwarz_2001"/>

====Multiphasic disseminated encephalomyelitis====

When the person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis<ref name="Dale_2000" /> (MDEM).

It has been found that anti-[[Myelin oligodendrocyte glycoprotein|MOG]] auto-antibodies are related to this kind of ADEM<ref>{{cite journal | vauthors = Baumann M, Hennes EM, Schanda K, Karenfort M, Bajer-Kornek B, Diepold K, Fiedler B, Marquardt I, Strautmanis J, Vieker S, Reindl M | display-authors = 6 | title = OP65–3006: Clinical characteristics and neuroradiological findings in children with multiphasic demyelinating encephalomyelitis and MOG antibodies. | journal = European Journal of Paediatric Neurology | date = May 2015 | volume = 19 | issue = supplement 1 | pages = S21 | doi = 10.1016/S1090-3798(15)30066-0 | series = Abstracts of the 11th EPNS Congress }}</ref>

Another variant of ADEM in adults has been described, also related to anti-MOG auto-antibodies, has been named fulminant disseminated encephalomyelitis, and it has been reported to be clinically ADEM, but showing MS-like lesions on autopsy.<ref name="DiPauli_2015"/> It has been classified inside the [[anti-MOG associated inflammatory demyelinating diseases]].<ref>{{cite journal | vauthors = Baumann M, Hennes EM, Schanda K, Karenfort M, Kornek B, Seidl R, Diepold K, Lauffer H, Marquardt I, Strautmanis J, Syrbe S, Vieker S, Höftberger R, Reindl M, Rostásy K | display-authors = 6 | title = Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): Extending the spectrum of MOG antibody positive diseases | journal = Multiple Sclerosis | volume = 22 | issue = 14 | pages = 1821–29 | date = December 2016 | pmid = 26869530 | doi = 10.1177/1352458516631038 | s2cid = 30428892 }}</ref>

====Acute hemorrhagic leukoencephalitis====

Acute hemorrhagic leukoencephalitis (AHL, or AHLE), acute hemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare (less than 100 cases have been reported in the medical literature {{as of|2006|lc=y}}),<ref name="Davies_2006">{{cite journal | vauthors = Davies NW, Sharief MK, Howard RS | title = Infection-associated encephalopathies: their investigation, diagnosis, and treatment | journal = Journal of Neurology | volume = 253 | issue = 7 | pages = 833–45 | date = July 2006 | pmid = 16715200 | doi = 10.1007/s00415-006-0092-4 | s2cid = 26350300 | doi-access = free }}</ref> it is seen in about 2% of ADEM cases,<ref name="Tenembaum_2002" /> and is characterized by [[necrosis|necrotizing vasculitis]] of [[venules]] and hemorrhage, and edema.<ref name="Stone_2007">{{cite journal | vauthors = Stone MJ, Hawkins CP | title = A medical overview of encephalitis | journal = Neuropsychological Rehabilitation | volume = 17 | issue = 4–5 | pages = 429–49 | year = 2007 | pmid = 17676529 | doi = 10.1080/09602010601069430 | s2cid = 24249705 }}</ref> Death is common in the first week<ref name="Archer_2003">{{cite journal | vauthors = Archer H, Wall R | title = Acute haemorrhagic leukoencephalopathy: two case reports and review of the literature | journal = The Journal of Infection | volume = 46 | issue = 2 | pages = 133–37 | date = February 2003 | pmid = 12634076 | doi = 10.1053/jinf.2002.1096 }}</ref> and overall mortality is about 70%,<ref name="Davies_2006" /> but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange.<ref name="Tenembaum_2007" /> About 70% of survivors show residual neurological deficits,<ref name="Stone_2007" /> but some survivors have shown surprisingly little deficit considering the extent of the white matter affected.<ref name="Archer_2003" />

This disease has been occasionally associated with [[ulcerative colitis]] and [[Crohn's disease]], [[malaria]],<ref name="Venugopal_2013">{{cite journal | vauthors = Venugopal V, Haider M | title = First case report of acute hemorrhagic leukoencephalitis following Plasmodium vivax infection | journal = Indian Journal of Medical Microbiology | volume = 31 | issue = 1 | pages = 79–81 | year = 2013 | pmid = 23508437 | doi = 10.4103/0255-0857.108736 | doi-access = free }}</ref> [[sepsis]] associated with immune complex deposition, [[methanol]] poisoning, and other underlying conditions. Also anecdotal association with MS has been reported<ref>{{cite journal | vauthors = Yildiz Ö, Pul R, Raab P, Hartmann C, Skripuletz T, Stangel M | title = Acute hemorrhagic leukoencephalitis (Weston-Hurst syndrome) in a patient with relapse-remitting multiple sclerosis | journal = Journal of Neuroinflammation | volume = 12 | issue = 1 | pages = 175 | date = September 2015 | pmid = 26376717 | pmc = 4574135 | doi = 10.1186/s12974-015-0398-1 | doi-access = free }}</ref>

Laboratory studies that support diagnosis of AHL are: peripheral leukocytosis, cerebrospinal fluid (CSF) pleocytosis associated with normal glucose and increased protein. On magnetic resonance imaging (MRI), lesions of AHL typically show extensive T2-weighted and fluid-attenuated inversion recovery (FLAIR) white matter hyperintensities with areas of hemorrhages, significant edema, and mass effect.<ref name="Mondia_2019">{{cite journal | vauthors = Mondia MW, Reyes NG, Espiritu AI, Pascual V JL | title = Acute hemorrhagic leukoencephalitis of Weston Hurst secondary to herpes encephalitis presenting as status epilepticus: A case report and review of literature | journal = Journal of Clinical Neuroscience | volume = 67 | issue =  | pages = 265–70 | date = September 2019 | pmid = 31239199 | doi = 10.1016/j.jocn.2019.06.020 | s2cid = 195261409 }}</ref>