Acute disseminated encephalomyelitis: Difference between revisions

Acute disseminated encephalomyelitis
Acute disseminated encephalomyelitis
Other names	Acute demyelinating encephalomyelitis
	Fulminating ADEM showing many lesions. The patient survived, but remained in a persistent vegetative state
Specialty	Neurology

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Acute disseminated encephalomyelitis (ADEM), or acute demyelinating encephalomyelitis, is a rare autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord. As well as causing the brain and spinal cord to become inflamed, ADEM also attacks the nerves of the central nervous system and damages their myelin insulation, which, as a result, destroys the white matter. It is often triggered after the patient has received a viral infection or, perhaps exceedingly rarely specific non-routine vaccinations.^[1]^[2]^[3]^[4]^[5]^[6]

ADEM's symptoms resemble the symptoms of multiple sclerosis (MS), so the disease itself is sorted into the classification of the multiple sclerosis borderline diseases. However, ADEM has several features that distinguish it from MS.^[7] Unlike MS, ADEM occurs usually in children and is marked with rapid fever, although adolescents and adults can get the disease too. ADEM consists of a single flare-up whereas MS is marked with several flare-ups (or relapses), over a long period of time. Relapses following ADEM are reported in up to a quarter of patients, but the majority of these 'multiphasic' presentations following ADEM likely represent MS.^[8] ADEM is also distinguished by a loss of consciousness, coma and death, which is very rare in MS, except in severe cases.

It affects about 8 per 1,000,000 people per year.^[9] Although it occurs in all ages, most reported cases are in children and adolescents, with the average age around 5 to 8 years old.^[10]^[11]^[12] The disease affects males and females almost equally.^[13] The mortality rate may be as high as 5%; however, full recovery is seen in 50 to 75% of cases with increase in survival rates up to 70 to 90% with figures including minor residual disability as well.^[14] The average time to recover from ADEM flare-ups is one to six months.

ADEM produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. Usually these are found in the subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres, cerebellum, brainstem, and spinal cord,^[15] but periventricular white matter and gray matter of the cortex, thalami and basal ganglia may also be involved.

When a person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis^[16] or multiphasic disseminated encephalomyelitis^[17] (MDEM). Also, a fulminant course in adults has been described.^[18]

Signs and symptoms

ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1–3 weeks after infection. Major symptoms include fever, headache, nausea and vomiting, confusion, vision impairment, drowsiness, seizures and coma. Although initially the symptoms are usually mild, they worsen rapidly over the course of hours to days, with the average time to maximum severity being about four and a half days.^[19] Additional symptoms include hemiparesis, paraparesis, and cranial nerve palsies.^[20]

Causes

Since the discovery of the anti-MOG specificity against multiple sclerosis diagnosis^[21] it is considered that ADEM is one of the possible clinical courses of anti-MOG associated encephalomyelitis^[22]

About how the anti-MOG antibodies appear in the patients serum there are several theories:

A preceding antigenic challenge can be identified in approximately two-thirds of people.^[13] Some viral infections thought to induce ADEM include influenza virus, dengue,^[23] enterovirus, measles,^[24] mumps, rubella, varicella zoster, Epstein Barr virus, cytomegalovirus, herpes simplex virus, hepatitis A, and coxsackievirus; while the bacterial infections include Mycoplasma pneumoniae, Borrelia burgdorferi, Leptospira, and beta-hemolytic Streptococci.^[25]
Exposure to vaccines: The only vaccine proven related to ADEM is the Semple form of the rabies vaccine, but hepatitis B, pertussis, diphtheria, measles, mumps, rubella, pneumococcus, varicella, influenza, Japanese encephalitis, and polio vaccines have all been implicated. The majority of the studies that correlate vaccination with ADEM onset use small samples or case studies.^{[citation needed]} Large scale epidemiological studies (e.g., of MMR vaccine or smallpox vaccine) do not show increased risk of ADEM following vaccination.^[9]^[26]^[27]^[28]^[19]^[29]^[30]^[31]^[32]^[33]^[34]
In rare cases, ADEM seems to follow from organ transplantation.^[19] An upper bound for the risk of ADEM from measles vaccination, if it exists, can be estimated to be 10 per million,^[35] which is far lower than the risk of developing ADEM from an actual measles infection, which is about 1 per 1,000 cases. For a rubella infection, the risk is 1 per 5,000 cases.^[29]^[36] Some early vaccines, later shown to have been contaminated with host animal CNS tissue, had ADEM incident rates as high as 1 in 600.^[26]

Diagnosis

Currently, the commonly accepted international standard for the clinical case definition is the one published by the International Pediatric MS Study Group, revision 2007.^[37]

Given that the definition is clinical, it is currently unknown if all the cases with ADEM are positive for anti-MOG autoantibody, but in any case it seems strongly related to ADEM diagnosis.^[22]

Differential diagnosis

Multiple sclerosis

While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects.^[13]^[38] Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course,^[39]^[40] while others consider them discretely different diseases.^[6]

Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults,^[8]^[12] and can also be clinically multiphasic.^[41]

Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis.^[42] If MS were defined just by the separation in time and space of the demyelinating lesions as McDonald did,^[43] it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the separation line in the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination".^[42]^[44]

The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenular inflammation with limited "sleeves of demyelination".^[45]^[13] Nevertheless, MS-like plaques (confluent demyelination) can appear^[46]

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.^[47]

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^[44] or even postmortem^[48] ADEM in adults can progress to MS^[49]

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^[17] (MDEM).

It has been found that anti-MOG auto-antibodies are related to this kind of ADEM^[50]

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.^[18] It has been classified inside the anti-MOG associated inflammatory demyelinating diseases.^[51]

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^[update]),^[52] it is seen in about 2% of ADEM cases,^[19] and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema.^[53] Death is common in the first week^[54] and overall mortality is about 70%,^[52] but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange.^[25] About 70% of survivors show residual neurological deficits,^[53] but some survivors have shown surprisingly little deficit considering the magnitude of the white matter affected.^[54]

This disease has been occasionally associated with ulcerative colitis and Crohn's disease, malaria,^[55] septicemia associated with immune complex deposition, methanol poisoning, and other underlying conditions. Also anecdotal association with MS has been reported^[56]

Treatment

No controlled clinical trials have been conducted on ADEM treatment, but aggressive treatment aimed at rapidly reducing inflammation of the CNS is standard. The widely accepted first-line treatment is high doses of intravenous corticosteroids,^[57] such as methylprednisolone or dexamethasone, followed by 3–6 weeks of gradually lower oral doses of prednisolone. Patients treated with methylprednisolone have shown better outcomes than those treated with dexamethasone.^[19] Oral tapers of less than three weeks duration show a higher chance of relapsing,^[11]^[17] and tend to show poorer outcomes.^{[citation needed]} Other anti-inflammatory and immunosuppressive therapies have been reported to show beneficial effect, such as plasmapheresis, high doses of intravenous immunoglobulin (IVIg),^[57]^[58] mitoxantrone and cyclophosphamide. These are considered alternative therapies, used when corticosteroids cannot be used or fail to show an effect.

There is some evidence to suggest that patients may respond to a combination of methylprednisolone and immunoglobulins if they fail to respond to either separately^[59] In a study of 16 children with ADEM, 10 recovered completely after high-dose methylprednisolone, one severe case that failed to respond to steroids recovered completely after IV Ig; the five most severe cases -with ADAM and severe peripheral neuropathy- were treated with combined high-dose methylprednisolone and immunoglobulin, two remained paraplegic, one had motor and cognitive handicaps, and two recovered.^[57] A recent review of IVIg treatment of ADEM (of which the previous study formed the bulk of the cases) found that 70% of children showed complete recovery after treatment with IVIg, or IVIg plus corticosteroids.^[60] A study of IVIg treatment in adults with ADEM showed that IVIg seems more effective in treating sensory and motor disturbances, while steroids seem more effective in treating impairments of cognition, consciousness and rigor.^[58] This same study found one subject, a 71-year-old man who had not responded to steroids, that responded to an IVIg treatment 58 days after disease onset.

Prognosis

Full recovery is seen in 50 to 70% of cases, ranging to 70 to 90% recovery with some minor residual disability (typically assessed using measures such as mRS or EDSS), average time to recover is one to six months.^[14] The mortality rate may be as high as 5%-10%.^[61]^[62] Poorer outcomes are associated with unresponsiveness to steroid therapy, unusually severe neurological symptoms, or sudden onset. Children tend to have more favorable outcomes than adults, and cases presenting without fevers tend to have poorer outcomes.^[63] The latter effect may be due to either protective effects of fever, or that diagnosis and treatment is sought more rapidly when fever is present.

ADEM can progress to MS. It will be considered MS if some lesions appear in different times and brain areas^[64]

Motor deficits

Residual motor deficits are estimated to remain in about 8 to 30% of cases, the range in severity from mild clumsiness to ataxia and hemiparesis.^[25]

Neurocognitive

Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability.^[65] Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery.^[66] All six children performed in the normal range on most tests, including verbal IQ and performance IQ, but performed at least one standard deviation below age norms in at least one cognitive domain, such as complex attention (one child), short-term memory (one child) and internalizing behaviour/affect (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS.^[67]

Another study compared nineteen children with a history of ADEM, of which 10 were five years of age or younger at the time (average age 3.8 years old, tested an average of 3.9 years later) and nine were older (mean age 7.7y at time of ADEM, tested an average of 2.2 years later) to nineteen matched controls.^[68] Scores on IQ tests and educational achievement were lower for the young onset ADEM group (average IQ 90) compared to the late onset (average IQ 100) and control groups (average IQ 106), while the late onset ADEM children scored lower on verbal processing speed. Again, all groups means were within one standard deviation of the controls, meaning that while effects were statistically reliable, the children were as a whole, still within the normal range. There were also more behavioural problems in the early onset group, although there is some suggestion that this may be due, at least in part, to the stress of hospitalization at a young age.^[69]^[70]

Research

The relationship between ADEM and anti-MOG associated encephalomyelitis is currently under research.

About animal models, the main animal model for MS, experimental autoimmune encephalomyelitis (EAE) is also an animal model for ADEM.^[71] Being an acute monophasic illness, EAE is far more similar to ADEM than MS.^[72]

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^ ^a ^b ^c Shahar E, Andraus J, Savitzki D, Pilar G, Zelnik N (November 2002). "Outcome of severe encephalomyelitis in children: effect of high-dose methylprednisolone and immunoglobulins". J. Child Neurol. 17 (11): 810–4. doi:10.1177/08830738020170111001. PMID 12585719.
^ ^a ^b Ravaglia S, Piccolo G, Ceroni M, et al. (November 2007). "Severe steroid-resistant post-infectious encephalomyelitis: general features and effects of IVIg". J. Neurol. 254 (11): 1518–23. doi:10.1007/s00415-007-0561-4. PMID 17965959.
^ Straussberg R, Schonfeld T, Weitz R, Karmazyn B, Harel L (February 2001). "Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immunoglobulins". Pediatr. Neurol. 24 (2): 139–43. doi:10.1016/S0887-8994(00)00229-0. PMID 11275464.
^ Feasby T, Banwell B, Benstead T, et al. (April 2007). "Guidelines on the use of intravenous immune globulin for neurologic conditions". Transfus Med Rev. 21 (2 Suppl 1): S57–107. doi:10.1016/j.tmrv.2007.01.002. PMID 17397768.
^ "Menge et al. 2007"
^ Kamel MG, Nam NT, Han NHB, El-Shabouny AE, Makram AM, Abd-Elhay FA, Dang TN, Hieu NLT, Huong VTQ, Tung TH, Hirayama K, Huy NT. (2017 Jun) Post-dengue acute disseminated encephalomyelitis: A case report and meta-analysis. PLoS Negl Trop Dis. 11(6):e0005715, PMC5509372, 10.1371/journal.pntd.0005715
^ Lin CH, Jeng JS, Hsieh ST, Yip PK, Wu RM (February 2007). "Acute disseminated encephalomyelitis: a follow-up study in Taiwan". J. Neurol. Neurosurg. Psychiatry. 78 (2): 162–7. doi:10.1136/jnnp.2005.084194. PMC 2077670. PMID 17028121.
^ Malo-Pion C, Lambert R, Décarie JC, Turpin S. Imaging of Acquired Demyelinating Syndrome With 18F-FDG PET/CT. Clin Nucl Med. 2017 Dec 5. doi: 10.1097/RLU.0000000000001916.
^ Foong J, Rozewicz L, Quaghebeur G, et al. (January 1997). "Executive function in multiple sclerosis. The role of frontal lobe pathology". Brain. 120 (1): 15–26. doi:10.1093/brain/120.1.15. PMID 9055794.
^ Hahn CD, Miles BS, MacGregor DL, Blaser SI, Banwell BL, Hetherington CR (August 2003). "Neurocognitive outcome after acute disseminated encephalomyelitis". Pediatr. Neurol. 29 (2): 117–23. doi:10.1016/S0887-8994(03)00143-7. PMID 14580654.
^ Banwell BL, Anderson PE (March 2005). "The cognitive burden of multiple sclerosis in children". Neurology. 64 (5): 891–4. doi:10.1212/01.WNL.0000152896.35341.51. PMID 15753431.
^ Jacobs RK, Anderson VA, Neale JL, Shield LK, Kornberg AJ (September 2004). "Neuropsychological outcome after acute disseminated encephalomyelitis: impact of age at illness onset". Pediatr. Neurol. 31 (3): 191–7. doi:10.1016/j.pediatrneurol.2004.03.008. PMID 15351018.
^ Douglas JW (August 1975). "Early hospital admissions and later disturbances of behaviour and learning". Dev Med Child Neurol. 17 (4): 456–80. doi:10.1111/j.1469-8749.1975.tb03497.x. PMID 1158052.
^ Daviss WB, Racusin R, Fleischer A, Mooney D, Ford JD, McHugo GJ (May 2000). "Acute stress disorder symptomatology during hospitalization for pediatric injury". J Am Acad Child Adolesc Psychiatry. 39 (5): 569–75. doi:10.1097/00004583-200005000-00010. PMID 10802974.
^ Rivers TM, Schwentker FF (1935). "Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys". J. Exp. Med. 61 (5): 689–701. doi:10.1084/jem.61.5.689. PMC 2133246. PMID 19870385.
^ Sriram S, Steiner I (December 2005). "Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis". Ann. Neurol. 58 (6): 939–45. doi:10.1002/ana.20743. PMID 16315280.

External links

Acute Disseminated Encephalomyelitis (ADEM) at myelitis.org
Acute disseminated encephalomyelitis at NIH's Office of Rare Diseases
Acute Disseminated Encephalomyelitis Information Page at NINDS
Information for parents about Acute disseminated encephalomyelitis

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[60] Feasby T, Banwell B, Benstead T, et al. (April 2007). "Guidelines on the use of intravenous immune globulin for neurologic conditions". Transfus Med Rev. 21 (2 Suppl 1): S57–107. doi:10.1016/j.tmrv.2007.01.002. PMID 17397768.

[61] "Menge et al. 2007"

[62] Kamel MG, Nam NT, Han NHB, El-Shabouny AE, Makram AM, Abd-Elhay FA, Dang TN, Hieu NLT, Huong VTQ, Tung TH, Hirayama K, Huy NT. (2017 Jun) Post-dengue acute disseminated encephalomyelitis: A case report and meta-analysis. PLoS Negl Trop Dis. 11(6):e0005715, PMC5509372, 10.1371/journal.pntd.0005715

[63] Lin CH, Jeng JS, Hsieh ST, Yip PK, Wu RM (February 2007). "Acute disseminated encephalomyelitis: a follow-up study in Taiwan". J. Neurol. Neurosurg. Psychiatry. 78 (2): 162–7. doi:10.1136/jnnp.2005.084194. PMC 2077670. PMID 17028121.

[64] Malo-Pion C, Lambert R, Décarie JC, Turpin S. Imaging of Acquired Demyelinating Syndrome With 18F-FDG PET/CT. Clin Nucl Med. 2017 Dec 5. doi: 10.1097/RLU.0000000000001916.

[65] Foong J, Rozewicz L, Quaghebeur G, et al. (January 1997). "Executive function in multiple sclerosis. The role of frontal lobe pathology". Brain. 120 (1): 15–26. doi:10.1093/brain/120.1.15. PMID 9055794.

[66] Hahn CD, Miles BS, MacGregor DL, Blaser SI, Banwell BL, Hetherington CR (August 2003). "Neurocognitive outcome after acute disseminated encephalomyelitis". Pediatr. Neurol. 29 (2): 117–23. doi:10.1016/S0887-8994(03)00143-7. PMID 14580654.

[67] Banwell BL, Anderson PE (March 2005). "The cognitive burden of multiple sclerosis in children". Neurology. 64 (5): 891–4. doi:10.1212/01.WNL.0000152896.35341.51. PMID 15753431.

[68] Jacobs RK, Anderson VA, Neale JL, Shield LK, Kornberg AJ (September 2004). "Neuropsychological outcome after acute disseminated encephalomyelitis: impact of age at illness onset". Pediatr. Neurol. 31 (3): 191–7. doi:10.1016/j.pediatrneurol.2004.03.008. PMID 15351018.

[69] Douglas JW (August 1975). "Early hospital admissions and later disturbances of behaviour and learning". Dev Med Child Neurol. 17 (4): 456–80. doi:10.1111/j.1469-8749.1975.tb03497.x. PMID 1158052.

[70] Daviss WB, Racusin R, Fleischer A, Mooney D, Ford JD, McHugo GJ (May 2000). "Acute stress disorder symptomatology during hospitalization for pediatric injury". J Am Acad Child Adolesc Psychiatry. 39 (5): 569–75. doi:10.1097/00004583-200005000-00010. PMID 10802974.

[71] Rivers TM, Schwentker FF (1935). "Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys". J. Exp. Med. 61 (5): 689–701. doi:10.1084/jem.61.5.689. PMC 2133246. PMID 19870385.

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 '''Acute disseminated encephalomyelitis''' ('''ADEM'''), or '''acute [[Demyelinating disease|demyelinating]] encephalomyelitis''', is a rare [[autoimmune]] disease marked by a sudden, widespread attack of inflammation in the [[brain]] and [[spinal cord]]. As well as causing the brain and spinal cord to become inflamed, ADEM also attacks the nerves of the central nervous system and damages their myelin insulation, which, as a result, destroys the [[white matter]]. It is often triggered after the patient has received a [[virus (biology)|viral]] [[infection]] or, perhaps exceedingly rarely specific non-routine [[vaccinations]].<ref>{{cite journal |author =Dale RC |title=Acute disseminated encephalomyelitis |journal=Semin Pediatr Infect Dis |volume=14 |issue=2 |pages=90–5 |date=April 2003 |pmid=12881796 |doi=10.1053/spid.2003.127225 |url=}}</ref><ref>{{cite journal |author =Garg RK |title=Acute disseminated encephalomyelitis |journal=Postgrad Med J |volume=79 |issue=927 |pages=11–7 |date=January 2003 |pmid=12566545 |doi= 10.1136/pmj.79.927.11|url=http://pmj.bmj.com/cgi/pmidlookup?view=long&pmid=12566545 |pmc=1742586}}</ref><ref>{{cite journal |author =Jones CT |title=Childhood autoimmune neurologic diseases of the central nervous system |journal=Neurol Clin |volume=21 |issue=4 |pages=745–64 |date=November 2003 |pmid=14743647 |doi= 10.1016/S0733-8619(03)00007-0|url=}}</ref><ref>{{cite journal |vauthors =Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C |title=Post-vaccination encephalomyelitis: literature review and illustrative case |journal=J Clin Neurosci |volume=15 |issue=12 |pages=:1315–1322 |date=Dec 2008 |pmid=18976924 |doi=10.1016/j.jocn.2008.05.002 |url= }}</ref><ref>{{cite journal |author =Rust RS |title=Multiple sclerosis, acute disseminated encephalomyelitis, and related conditions |journal=Semin Pediatr Neurol |volume=7 |issue=2 |pages=66–90 |date=June 2000 |pmid=10914409 |doi= 10.1053/pb.2000.6693|url=}}</ref><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=201–6 |date=October 2007 |pmid=17824894 |doi=10.1111/j.1600-0404.2007.00902.x |url=}}</ref>
-ADEM's symptoms resemble the symptoms of [[multiple sclerosis]] (MS), so the disease itself is sorted into the classification of the [[multiple sclerosis borderline]] diseases. However, ADEM has several features that distinguish it from MS.<ref>Lauren B. Krupp et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders, 2007 by AAN Enterprises, Inc. [http://www.mc.vanderbilt.edu/documents/neurology/files/Consensus%20definitions%20proposed%20for%20pediatric%20multiple%20sclerosis%20and%20related%20disorders%20(International%20Pediatric%20MS%20Study%20Group,%20Neurology,%202007)(1).pdf]</ref> Unlike MS, ADEM occurs usually in children and is marked with rapid fever, although adolescents and adults can get the disease too. ADEM consists of a single flare-up whereas MS is marked with several flare-ups (or relapses), over a long period of time. Relapses following ADEM are reported in up to a quarter of patients, but the majority of these 'multiphasic' presentations following ADEM likely represent MS.<ref name=":0">{{Cite journal|last=Koelman|first=Diederik L. H.|last2=Chahin|first2=Salim|last3=Mar|first3=Soe S.|last4=Venkatesan|first4=Arun|last5=Hoganson|first5=George M.|last6=Yeshokumar|first6=Anusha K.|last7=Barreras|first7=Paula|last8=Majmudar|first8=Bittu|last9=Klein|first9=Joshua P.|date=2016-05-31|title=Acute disseminated encephalomyelitis in 228 patients A retrospective, multicenter US study|url=http://www.neurology.org/content/86/22/2085|journal=Neurology|language=en|volume=86|issue=22|pages=2085–2093|doi=10.1212/WNL.0000000000002723|issn=0028-3878|pmid=27164698}}</ref> ADEM is also distinguished by a loss of consciousness, coma and death, which is very rare in MS, except in severe cases.
+ADEM's symptoms resemble the symptoms of [[multiple sclerosis]] (MS), so the disease itself is sorted into the classification of the [[multiple sclerosis borderline]] diseases. However, ADEM has several features that distinguish it from MS.<ref>Lauren B. Krupp et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders, 2007 by AAN Enterprises, Inc. [http://www.mc.vanderbilt.edu/documents/neurology/files/Consensus%20definitions%20proposed%20for%20pediatric%20multiple%20sclerosis%20and%20related%20disorders%20(International%20Pediatric%20MS%20Study%20Group,%20Neurology,%202007)(1).pdf]</ref> Unlike MS, ADEM occurs usually in children and is marked with rapid fever, although adolescents and adults can get the disease too. ADEM consists of a single flare-up whereas MS is marked with several flare-ups (or relapses), over a long period of time. Relapses following ADEM are reported in up to a quarter of patients, but the majority of these 'multiphasic' presentations following ADEM likely represent MS.<ref name=":0">{{Cite journal|last=Koelman|first=Diederik L. H.|last2=Chahin|first2=Salim|last3=Mar|first3=Soe S.|last4=Venkatesan|first4=Arun|last5=Hoganson|first5=George M.|last6=Yeshokumar|first6=Anusha K.|last7=Barreras|first7=Paula|last8=Majmudar|first8=Bittu|last9=Klein|first9=Joshua P.|date=2016-05-31|title=Acute disseminated encephalomyelitis in 228 patients A retrospective, multicenter US study|journal=Neurology|language=en|volume=86|issue=22|pages=2085–2093|doi=10.1212/WNL.0000000000002723|issn=0028-3878|pmid=27164698}}</ref> ADEM is also distinguished by a loss of consciousness, coma and death, which is very rare in MS, except in severe cases.
-It affects about 8 per 1,000,000 people per year.<ref name="Leake et al. 2004">{{cite journal |vauthors=Leake JA, Albani S, Kao AS |title=Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features |journal=Pediatr. Infect. Dis. J. |volume=23 |issue=8 |pages=756–64 |date=August 2004 |pmid=15295226 |doi= 10.1097/01.inf.0000133048.75452.dd|url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0891-3668&volume=23&issue=8&spage=756 |displayauthors=etal  }}</ref> Although it occurs in all ages, most reported cases are in children and [[Adolescence|adolescents]], with the average age around 5 to 8 years old.<ref>{{cite journal |vauthors =Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ |title=Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children |journal=Neurology |volume=56 |issue=10 |pages=1308–12 |date=May 2001 |pmid=11376179 |doi= 10.1212/WNL.56.10.1308|url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11376179}}</ref><ref name="Anlar B, Basaran C, Kose G, et al. 2003 194–9">{{cite journal |vauthors=Anlar B, Basaran C, Kose G |title=Acute disseminated encephalomyelitis in children: outcome and prognosis |journal=Neuropediatrics |volume=34 |issue=4 |pages=194–9 |date=August 2003 |pmid=12973660 |doi=10.1055/s-2003-42208 |url= |displayauthors=etal  }}</ref><ref name=":1">{{cite journal |vauthors =Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B |title=Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients |journal=Neurology |volume=56 |issue=10 |pages=1313–8 |date=May 2001 |pmid=11376180 |doi= 10.1212/WNL.56.10.1313|url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11376180}}</ref> The disease affects males and females almost equally.<ref name=":2">{{Cite journal|last=Koelman|first=Diederik L. H.|last2=Mateen|first2=Farrah J.|date=2015-03-13|title=Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome|journal=Journal of Neurology|language=en|volume=262|issue=9|pages=2013–2024|doi=10.1007/s00415-015-7694-7|pmid=25761377|issn=0340-5354}}</ref> The mortality rate may be as high as 5%; however, full recovery is seen in 50 to 75% of cases with increase in survival rates up to 70 to 90% with figures including minor residual disability as well.<ref name="Menge et al. 2007">{{cite journal |vauthors =Menge T, Kieseier BC, Nessler S, Hemmer B, Hartung HP, Stüve O |title=Acute disseminated encephalomyelitis: an acute hit against the brain |journal=Curr. Opin. Neurol. |volume=20 |issue=3 |pages=247–54 |date=June 2007 |pmid=17495616 |doi=10.1097/WCO.0b013e3280f31b45 |url=http://mediatum.ub.tum.de/doc/675607/document.pdf}}</ref> The average time to recover from ADEM flare-ups is one to six months.
+It affects about 8 per 1,000,000 people per year.<ref name="Leake et al. 2004">{{cite journal |vauthors=Leake JA, Albani S, Kao AS |title=Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features |journal=Pediatr. Infect. Dis. J. |volume=23 |issue=8 |pages=756–64 |date=August 2004 |pmid=15295226 |doi= 10.1097/01.inf.0000133048.75452.dd|url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0891-3668&volume=23&issue=8&spage=756 |displayauthors=etal  }}</ref> Although it occurs in all ages, most reported cases are in children and [[Adolescence|adolescents]], with the average age around 5 to 8 years old.<ref>{{cite journal |vauthors =Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ |title=Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children |journal=Neurology |volume=56 |issue=10 |pages=1308–12 |date=May 2001 |pmid=11376179 |doi= 10.1212/WNL.56.10.1308}}</ref><ref name="Anlar B, Basaran C, Kose G, et al. 2003 194–9">{{cite journal |vauthors=Anlar B, Basaran C, Kose G |title=Acute disseminated encephalomyelitis in children: outcome and prognosis |journal=Neuropediatrics |volume=34 |issue=4 |pages=194–9 |date=August 2003 |pmid=12973660 |doi=10.1055/s-2003-42208 |url= |displayauthors=etal  }}</ref><ref name=":1">{{cite journal |vauthors =Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B |title=Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients |journal=Neurology |volume=56 |issue=10 |pages=1313–8 |date=May 2001 |pmid=11376180 |doi= 10.1212/WNL.56.10.1313}}</ref> The disease affects males and females almost equally.<ref name=":2">{{Cite journal|last=Koelman|first=Diederik L. H.|last2=Mateen|first2=Farrah J.|date=2015-03-13|title=Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome|journal=Journal of Neurology|language=en|volume=262|issue=9|pages=2013–2024|doi=10.1007/s00415-015-7694-7|pmid=25761377|issn=0340-5354}}</ref> The mortality rate may be as high as 5%; however, full recovery is seen in 50 to 75% of cases with increase in survival rates up to 70 to 90% with figures including minor residual disability as well.<ref name="Menge et al. 2007">{{cite journal |vauthors =Menge T, Kieseier BC, Nessler S, Hemmer B, Hartung HP, Stüve O |title=Acute disseminated encephalomyelitis: an acute hit against the brain |journal=Curr. Opin. Neurol. |volume=20 |issue=3 |pages=247–54 |date=June 2007 |pmid=17495616 |doi=10.1097/WCO.0b013e3280f31b45 |url=http://mediatum.ub.tum.de/doc/675607/document.pdf}}</ref> The average time to recover from ADEM flare-ups is one to six months.
 ADEM produces multiple [[Inflammation|inflammatory]] [[lesion]]s in the brain and [[spinal cord]], particularly in the [[white matter]]. Usually these are found in the subcortical and central white matter and cortical gray-white junction of both [[cerebral hemispheres]], [[cerebellum]], [[brainstem]], and spinal cord,<ref>{{cite journal |author =Wingerchuk DM |title=Postinfectious encephalomyelitis |journal=Curr Neurol Neurosci Rep |volume=3 |issue=3 |pages=256–64 |date=May 2003 |pmid=12691631 |doi= 10.1007/s11910-003-0086-x|url=}}</ref> but periventricular white matter and gray matter of the [[Cerebral cortex|cortex]], [[thalami]] and [[basal ganglia]]  may also be involved.
@@ Line 27: / Line 27: @@
 *A preceding antigenic challenge can be identified in approximately two-thirds of people.<ref name=":2" /> Some viral infections thought to induce ADEM include [[Orthomyxoviridae|influenza virus]], [[dengue]],<ref>16.	Kamel MG, Nam NT, Han NHB, El-Shabouny AE, Makram AM, Abd-Elhay FA, Dang TN, Hieu NLT, Huong VTQ, Tung TH, Hirayama K, Huy NT†. (2017 Jun) Post-dengue acute disseminated encephalomyelitis: A case report and meta-analysis. PLoS Negl Trop Dis. 11(6):e0005715, PMC5509372, 10.1371/journal.pntd.0005715</ref> [[enterovirus]], [[measles]],<ref>{{cite journal|last=Fisher |first=DL |last2=Defres |first2=S |last3=Solomon |first3=T|title=Measles-induced encephalitis|journal=QJM|year=2015|volume=108|issue=3 |pmid=24865261|doi=10.1093/qjmed/hcu113 |pages=177–182|doi-access=free}}</ref> [[mumps]], [[rubella]], [[varicella zoster]], [[Epstein Barr virus]], [[cytomegalovirus]], [[herpes simplex virus]], [[hepatitis A]], and [[coxsackievirus]]; while the bacterial infections include [[Mycoplasma pneumoniae]], [[Borrelia burgdorferi]], [[Leptospira]], and [[Streptococcus#Beta-Hemolytic Streptococci|beta-hemolytic Streptococci]].<ref name="Tenembaum et al. 2007">{{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 |url=|others=International Pediatric MS Study Group }}</ref>
-*Exposure to vaccines: The only vaccine proven related to ADEM is the Semple form of the [[rabies]] vaccine, but [[hepatitis B]], [[pertussis]], [[diphtheria]], measles, mumps, rubella, [[pneumococcus]], [[varicella]], influenza, [[Japanese encephalitis]], and [[polio]] vaccines have all been implicated. The majority of the studies that correlate vaccination with ADEM onset use small samples or case studies.{{citation needed|date=August 2014}} Large scale epidemiological studies (e.g., of MMR vaccine or smallpox vaccine) do not show increased risk of ADEM following vaccination.<ref name="Leake et al. 2004" /><ref name="Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P 1987 369–74">{{cite journal |vauthors =Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P |title=Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination |journal=N. Engl. J. Med. |volume=316 |issue=7 |pages=369–74 |date=February 1987 |pmid=2433582 |doi= 10.1056/NEJM198702123160703|url=}}</ref><ref>{{cite journal |vauthors =Hemachudha T, Griffin DE, Johnson RT, Giffels JJ |title=Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine |journal=Neurology |volume=38 |issue=1 |pages=42–4 |date=January 1988 |pmid=2447520 |doi= 10.1212/WNL.38.1.42|url=}}</ref><ref name="Murthy 2002">{{cite journal |author =Murthy JM |title=Acute disseminated encephalomyelitis |journal=Neurol India |volume=50 |issue=3 |pages=238–43 |date=September 2002 |pmid=12391446 |doi= |url=http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2002;volume=50;issue=3;spage=238;epage=43;aulast=Murthy}}</ref><ref name="Tenembaum et al. 2002">{{cite journal |vauthors =Tenembaum S, Chamoles N, Fejerman N |title=Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients |journal=Neurology |volume=59 |issue=8 |pages=1224–31 |date=October 2002 |pmid=12391351 |doi= 10.1212/WNL.59.8.1224|url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12391351}}</ref><ref name="Fenichel 1982">{{cite journal |author =Fenichel GM |title=Neurological complications of immunization |journal=Ann. Neurol. |volume=12 |issue=2 |pages=119–28 |date=August 1982 |pmid=6751212 |doi=10.1002/ana.410120202 |url=}}</ref><ref>{{cite journal |vauthors =Takahashi H, Pool V, Tsai TF, Chen RT |title=Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. The VAERS Working Group |journal=Vaccine |volume=18 |issue=26 |pages=2963–9 |date=July 2000 |pmid=10825597 |doi= 10.1016/S0264-410X(00)00111-0|url=http://linkinghub.elsevier.com/retrieve/pii/S0264410X00001110}}</ref><ref>{{cite journal |vauthors=Tourbah A, Gout O, Liblau R |title=Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? |journal=Neurology |volume=53 |issue=2 |pages=396–401 |date=July 1999 |pmid=10430433 |doi= 10.1212/WNL.53.2.396|url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10430433 |displayauthors=etal  }}</ref><ref>{{cite journal |vauthors=Karaali-Savrun F, Altintaş A, Saip S, Siva A |title=Hepatitis B vaccine related-myelitis? |journal=Eur. J. Neurol. |volume=8 |issue=6 |pages=711–5 |date=November 2001 |pmid=11784358 |doi=10.1046/j.1468-1331.2001.00290.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1351-5101&date=2001&volume=8&issue=6&spage=711 |archive-url=https://archive.is/20120729154913/http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1351-5101&date=2001&volume=8&issue=6&spage=711 |dead-url=yes |archive-date=2012-07-29 }}</ref><ref>{{cite journal |vauthors =Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, Lane JM |title=Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004 |journal=JAMA |volume=294 |issue=21 |pages=2744–50 |date=December 2005 |pmid=16333010 |doi=10.1001/jama.294.21.2744 |url=}}</ref><ref>{{cite journal |vauthors =Ozawa H, Noma S, Yoshida Y, Sekine H, Hashimoto T |title=Acute disseminated encephalomyelitis associated with poliomyelitis vaccine |journal=Pediatr. Neurol. |volume=23 |issue=2 |pages=177–9 |date=August 2000 |pmid=11020647 |doi= 10.1016/S0887-8994(00)00167-3|url=http://linkinghub.elsevier.com/retrieve/pii/S0887-8994(00)00167-3}}</ref>
+*Exposure to vaccines: The only vaccine proven related to ADEM is the Semple form of the [[rabies]] vaccine, but [[hepatitis B]], [[pertussis]], [[diphtheria]], measles, mumps, rubella, [[pneumococcus]], [[varicella]], influenza, [[Japanese encephalitis]], and [[polio]] vaccines have all been implicated. The majority of the studies that correlate vaccination with ADEM onset use small samples or case studies.{{citation needed|date=August 2014}} Large scale epidemiological studies (e.g., of MMR vaccine or smallpox vaccine) do not show increased risk of ADEM following vaccination.<ref name="Leake et al. 2004" /><ref name="Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P 1987 369–74">{{cite journal |vauthors =Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P |title=Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination |journal=N. Engl. J. Med. |volume=316 |issue=7 |pages=369–74 |date=February 1987 |pmid=2433582 |doi= 10.1056/NEJM198702123160703|url=}}</ref><ref>{{cite journal |vauthors =Hemachudha T, Griffin DE, Johnson RT, Giffels JJ |title=Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine |journal=Neurology |volume=38 |issue=1 |pages=42–4 |date=January 1988 |pmid=2447520 |doi= 10.1212/WNL.38.1.42|url=}}</ref><ref name="Murthy 2002">{{cite journal |author =Murthy JM |title=Acute disseminated encephalomyelitis |journal=Neurol India |volume=50 |issue=3 |pages=238–43 |date=September 2002 |pmid=12391446 |doi= |url=http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2002;volume=50;issue=3;spage=238;epage=43;aulast=Murthy}}</ref><ref name="Tenembaum et al. 2002">{{cite journal |vauthors =Tenembaum S, Chamoles N, Fejerman N |title=Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients |journal=Neurology |volume=59 |issue=8 |pages=1224–31 |date=October 2002 |pmid=12391351 |doi= 10.1212/WNL.59.8.1224}}</ref><ref name="Fenichel 1982">{{cite journal |author =Fenichel GM |title=Neurological complications of immunization |journal=Ann. Neurol. |volume=12 |issue=2 |pages=119–28 |date=August 1982 |pmid=6751212 |doi=10.1002/ana.410120202 |url=}}</ref><ref>{{cite journal |vauthors =Takahashi H, Pool V, Tsai TF, Chen RT |title=Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. The VAERS Working Group |journal=Vaccine |volume=18 |issue=26 |pages=2963–9 |date=July 2000 |pmid=10825597 |doi= 10.1016/S0264-410X(00)00111-0}}</ref><ref>{{cite journal |vauthors=Tourbah A, Gout O, Liblau R |title=Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? |journal=Neurology |volume=53 |issue=2 |pages=396–401 |date=July 1999 |pmid=10430433 |doi= 10.1212/WNL.53.2.396|displayauthors=etal  }}</ref><ref>{{cite journal |vauthors=Karaali-Savrun F, Altintaş A, Saip S, Siva A |title=Hepatitis B vaccine related-myelitis? |journal=Eur. J. Neurol. |volume=8 |issue=6 |pages=711–5 |date=November 2001 |pmid=11784358 |doi=10.1046/j.1468-1331.2001.00290.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1351-5101&date=2001&volume=8&issue=6&spage=711 |archive-url=https://archive.is/20120729154913/http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1351-5101&date=2001&volume=8&issue=6&spage=711 |dead-url=yes |archive-date=2012-07-29 }}</ref><ref>{{cite journal |vauthors =Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, Lane JM |title=Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004 |journal=JAMA |volume=294 |issue=21 |pages=2744–50 |date=December 2005 |pmid=16333010 |doi=10.1001/jama.294.21.2744 |url=}}</ref><ref>{{cite journal |vauthors =Ozawa H, Noma S, Yoshida Y, Sekine H, Hashimoto T |title=Acute disseminated encephalomyelitis associated with poliomyelitis vaccine |journal=Pediatr. Neurol. |volume=23 |issue=2 |pages=177–9 |date=August 2000 |pmid=11020647 |doi= 10.1016/S0887-8994(00)00167-3|url=http://linkinghub.elsevier.com/retrieve/pii/S0887-8994(00)00167-3}}</ref>
 *In rare cases, ADEM seems to follow from [[organ transplant]]ation.<ref name="Tenembaum et al. 2002" /> An upper bound for the risk of ADEM from measles vaccination, if it exists, can be estimated to be 10 per million,<ref name=NAP_vaccination>{{cite book|title=Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality|editor-last1=Stratton|editor-first1=Kathleen R.|editor-last2=Howe|editor-first2=Cynthia J.|editor-last3=Johnston Jr.|editor-first3=Richard B.|date=1994|publisher=The National Academies Press|isbn=978-0-309-07496-4|pages=125–126|url=http://www.nap.edu/read/2138/chapter/7#124|accessdate=6 December 2015}}</ref> which is far lower than the risk of developing ADEM from an actual measles infection, which is about 1 per 1,000 cases. For a rubella infection, the risk is 1 per 5,000 cases.<ref name="Fenichel 1982" /><ref>{{cite journal |vauthors=Miller HG, Stanton JB, Gibbons JL |title=Parainfectious encephalomyelitis and related syndromes |journal=Quarterly Journal of Medicine |volume=25 |issue= 100|pages=427–505 |year=1956 |pmid=13379602}}</ref> Some early vaccines, later shown to have been contaminated with host animal [[Central nervous system|CNS]] tissue, had ADEM incident rates as high as 1 in 600.<ref name="Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P 1987 369–74"/>
@@ Line 38: / Line 38: @@
 ===Differential diagnosis===
 ====Multiple sclerosis====
-While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects.<ref name=":2" /><ref>{{cite journal |vauthors=Wingerchuk DM, Lucchinetti CF |title=Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis |journal=Curr. Opin. Neurol. |volume=20 |issue=3 |pages=343–50 |date=June 2007 |pmid=17495631 |doi=10.1097/WCO.0b013e3280be58d8 |url=}}</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>Weinshenker B, Miller D. (1999). Multiple sclerosis: one disease or many? In: Siva A, Kesselring J, Thompson A, eds. Frontiers in multiple sclerosis. London: Dunitz, p37-46.</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|url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11376169}}</ref> while others consider them discretely different diseases.<ref name="Poser and Brinar 2007" />
+While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects.<ref name=":2" /><ref>{{cite journal |vauthors=Wingerchuk DM, Lucchinetti CF |title=Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis |journal=Curr. Opin. Neurol. |volume=20 |issue=3 |pages=343–50 |date=June 2007 |pmid=17495631 |doi=10.1097/WCO.0b013e3280be58d8 |url=}}</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>Weinshenker B, Miller D. (1999). Multiple sclerosis: one disease or many? In: Siva A, Kesselring J, Thompson A, eds. Frontiers in multiple sclerosis. London: Dunitz, p37-46.</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}}</ref> while others consider them discretely different diseases.<ref name="Poser and Brinar 2007" />
 Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults,<ref name=":0" /><ref name=":1" /> and can also be clinically multiphasic.<ref>{{cite journal | vauthors=Krupp LB, Banwell B, Tenembaum S, ((International Pediatric MS Study Group)) | year = 2007 | title = Consensus definitions proposed for pediatric multiple sclerosis and related disorders | url = | journal = Neurology | volume = 68 | issue = Suppl 2| pages = S7–S12 |pmid=17438241 | doi=10.1212/01.wnl.0000259422.44235.a8}}</ref>
@@ Line 44: / Line 44: @@
 Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis.<ref name="pmid20129937">{{cite journal | author = Lassmann H | title = Acute disseminated encephalomyelitis and multiple sclerosis | url = | journal = Brain | volume = 133 | issue = Pt 2| pages = 317–319 | doi = 10.1093/brain/awp342 | pmid=20129937 | date=Feb 2010| doi-access = free}}</ref> If MS were defined just 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 |author1-link=W. Ian McDonald |author2-link=Alastair Compston |title=Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis|url=|journal=[[Ann. Neurol.]] |volume=50 |issue=1 |pages=121–7 |year=2001 |pmid=11456302 |doi= 10.1002/ana.1032|display-authors=etal|citeseerx=10.1.1.466.5368 }}</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 separation line in the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination".<ref name="pmid20129937" /><ref name="Young">{{cite journal | vauthors = Young NP, etal | year = 2010 | title = Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis | url = http://www.medscape.com/medline/abstract/20129932 | journal = Brain | volume = 133 | issue = 2| pages = 333–48 | doi=10.1093/brain/awp321| doi-access = free | pmid=20129932 | pmc=2822631}}</ref>
 [[File:PMC4574135_12974_2015_398_Fig1_HTML.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 perivenular inflammation with limited "sleeves of demyelination".<ref>{{cite journal | author = Young NP | date = Feb 2008 | title = Acute Disseminated Encephalomyelitis: Current Understanding and Controversies. Thieme Medical Publishers | url = https://www.orpha.net/data/patho/Pro/en/AcuteDisseminatedEncephalomyelitisr-FRenPro11590v01.pdf | format = PDF | journal = Semin Neurol | volume = 28 | issue = 1| pages = 84–94 | doi=10.1055/s-2007-1019130| pmid = 18256989 }}</ref><ref name=":2" /> Nevertheless, MS-like plaques (confluent demyelination) can appear<ref>{{cite journal | vauthors = Guenther AD, Munoz DG | year = 2013 | title = Plaque-like demyelination in acute disseminated encephalomyelitis (ADEM) - an autopsy case report | url = | journal = Clinical Neuropathology | volume = 32 | issue = 6| pages = 486–491 | doi = 10.5414/NP300634 | pmid = 23863345 }}</ref>
+The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenular inflammation with limited "sleeves of demyelination".<ref>{{cite journal | author = Young NP | date = Feb 2008 | title = Acute Disseminated Encephalomyelitis: Current Understanding and Controversies. Thieme Medical Publishers | url = https://www.orpha.net/data/patho/Pro/en/AcuteDisseminatedEncephalomyelitisr-FRenPro11590v01.pdf | journal = Semin Neurol | volume = 28 | issue = 1| pages = 84–94 | doi=10.1055/s-2007-1019130| pmid = 18256989 }}</ref><ref name=":2" /> Nevertheless, MS-like plaques (confluent demyelination) can appear<ref>{{cite journal | vauthors = Guenther AD, Munoz DG | year = 2013 | title = Plaque-like demyelination in acute disseminated encephalomyelitis (ADEM) - an autopsy case report | url = | journal = Clinical Neuropathology | volume = 32 | issue = 6| pages = 486–491 | doi = 10.5414/NP300634 | pmid = 23863345 }}</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 | year = 2011 | title = Comparative Brain Stem Lesions on MRI of Acute Disseminated Encephalomyelitis, Neuromyelitis Optica, and Multiple Sclerosis | journal = PLoS ONE | volume = 6 | issue = 8| page = e22766 | doi = 10.1371/journal.pone.0022766 |display-authors=etal| doi-access = free | pmid=21853047 | pmc=3154259}}</ref>
@@ Line 56: / Line 56: @@
 It has been found that anti-[[Myelin oligodendrocyte glycoprotein|MOG]] auto-antibodies are related to this kind of ADEM<ref>M. Baumann, E.M. Hennes, K. Schanda, M. Karenfort, B. Bajer-Kornek, K. Diepold, B. Fiedler, I. Marquardt, J. Strautmanis, S. Vieker, M. Reindl, K. Rostásy. "Clinical characteristics and neuroradiological findings in children with multiphasic demyelinating encephalomyelitis and MOG antibodies. ''European Journal of Paediatric Neurology'', Volume 19, Supplement 1, May 2015, Pages S21, Abstracts of the 11th EPNS Congress. 22 May 2015. {{DOI|10.1016/S1090-3798(15)30066-0}}</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"/> It has been classified inside the [[anti-MOG associated inflammatory demyelinating diseases]].<ref>{{cite journal | author = Baumann M |display-authors=etal | year = 2016 | title = Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): Extending the spectrum of MOG antibody positive diseases | url = | journal = Mult Scler | volume =  | issue = | page =  }}</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"/> It has been classified inside the [[anti-MOG associated inflammatory demyelinating diseases]].<ref>{{cite journal | author = Baumann M |display-authors=etal | year = 2016 | title = Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): Extending the spectrum of MOG antibody positive diseases | url = | journal = Mult Scler | volume =  22| issue = 14|pages=1821–1829 |doi=10.1177/1352458516631038 |pmid=26869530 }}</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 et al. 2006">{{cite journal |vauthors =Davies NW, Sharief MK, Howard RS |title=Infection-associated encephalopathies: their investigation, diagnosis, and treatment |journal=J. Neurol. |volume=253 |issue=7 |pages=833–45 |date=July 2006 |pmid=16715200 |doi=10.1007/s00415-006-0092-4 |url=}}</ref> it is seen in about 2% of ADEM cases,<ref name="Tenembaum et al. 2002" /> and is characterized by [[necrosis|necrotizing vasculitis]] of [[venules]] and hemorrhage, and edema.<ref name="Stone & Hawkins 2007">{{cite journal |vauthors =Stone MJ, Hawkins CP |title=A medical overview of encephalitis |journal=Neuropsychol Rehabil |volume=17 |issue=4–5 |pages=429–49 |year=2007 |pmid=17676529 |doi=10.1080/09602010601069430 |url=}}</ref> Death is common in the first week<ref name="Archer & Wall 2003">{{cite journal |vauthors =Archer H, Wall R |title=Acute haemorrhagic leukoencephalopathy: two case reports and review of the literature |journal=J. Infect. |volume=46 |issue=2 |pages=133–7 |date=February 2003 |pmid=12634076 |doi= 10.1053/jinf.2002.1096|url=http://linkinghub.elsevier.com/retrieve/pii/S0163445302910960}}</ref> and overall mortality is about 70%,<ref name="Davies et al. 2006" /> but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange.<ref name="Tenembaum et al. 2007" /> About 70% of survivors show residual neurological deficits,<ref name="Stone & Hawkins 2007" /> but some survivors have shown surprisingly little deficit considering the magnitude of the white matter affected.<ref name="Archer & Wall 2003" />
+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 et al. 2006">{{cite journal |vauthors =Davies NW, Sharief MK, Howard RS |title=Infection-associated encephalopathies: their investigation, diagnosis, and treatment |journal=J. Neurol. |volume=253 |issue=7 |pages=833–45 |date=July 2006 |pmid=16715200 |doi=10.1007/s00415-006-0092-4 |url=}}</ref> it is seen in about 2% of ADEM cases,<ref name="Tenembaum et al. 2002" /> and is characterized by [[necrosis|necrotizing vasculitis]] of [[venules]] and hemorrhage, and edema.<ref name="Stone & Hawkins 2007">{{cite journal |vauthors =Stone MJ, Hawkins CP |title=A medical overview of encephalitis |journal=Neuropsychol Rehabil |volume=17 |issue=4–5 |pages=429–49 |year=2007 |pmid=17676529 |doi=10.1080/09602010601069430 |url=}}</ref> Death is common in the first week<ref name="Archer & Wall 2003">{{cite journal |vauthors =Archer H, Wall R |title=Acute haemorrhagic leukoencephalopathy: two case reports and review of the literature |journal=J. Infect. |volume=46 |issue=2 |pages=133–7 |date=February 2003 |pmid=12634076 |doi= 10.1053/jinf.2002.1096}}</ref> and overall mortality is about 70%,<ref name="Davies et al. 2006" /> but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange.<ref name="Tenembaum et al. 2007" /> About 70% of survivors show residual neurological deficits,<ref name="Stone & Hawkins 2007" /> but some survivors have shown surprisingly little deficit considering the magnitude of the white matter affected.<ref name="Archer & Wall 2003" />
 This disease has been occasionally associated with [[ulcerative colitis]] and [[Crohn's disease]], [[malaria]],<ref name=Venugopal2013>{{cite journal | vauthors = Venugopal V, Haider M | year = 2013 | title = First case report of acute hemorrhagic leukoencephalitis following ''Plasmodium vivax'' infection | url = | journal = Indian J Med Microbiol | volume = 31 | issue = 1| pages = 79–81 | doi = 10.4103/0255-0857.108736 | pmid = 23508437 }}</ref> [[septicemia]] associated with immune complex deposition, [[methanol]] poisoning, and other underlying conditions. Also anecdotal association with MS has been reported<ref>{{cite journal | author = Yildiz O. | date = Sep 2015 | title = Acute hemorrhagic leukoencephalitis (Weston-Hurst syndrome) in a patient with relapse-remitting multiple sclerosis | url = | journal = J Neuroinflammation | volume = 12 | issue = 1| page = 175 | doi = 10.1186/s12974-015-0398-1 | pmid = 26376717 | pmc = 4574135 |display-authors=etal| doi-access = free}}</ref>
@@ Line 79: / Line 79: @@
 ===Neurocognitive===
-Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability.<ref>{{cite journal |vauthors=Foong J, Rozewicz L, Quaghebeur G |title=Executive function in multiple sclerosis. The role of frontal lobe pathology |journal=Brain |volume=120 |issue= 1|pages=15–26 |date=January 1997 |pmid=9055794 |doi= 10.1093/brain/120.1.15|url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9055794|display-authors=etal}}</ref> Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery.<ref>{{cite journal |vauthors=Hahn CD, Miles BS, MacGregor DL, Blaser SI, Banwell BL, Hetherington CR |title=Neurocognitive outcome after acute disseminated encephalomyelitis |journal=Pediatr. Neurol. |volume=29 |issue=2 |pages=117–23 |date=August 2003 |pmid=14580654 |doi= 10.1016/S0887-8994(03)00143-7|url=http://linkinghub.elsevier.com/retrieve/pii/S0887899403001437}}</ref> All six children performed in the normal range on most tests, including [[Wechsler Adult Intelligence Scale#Verbal Subtests|verbal IQ]] and [[Wechsler Adult Intelligence Scale#Performance Subtests|performance IQ]], but performed at least one [[standard deviation]] below age norms in at least one cognitive domain, such as complex attention (one child), [[Wechsler Adult Intelligence Scale#Working memory|short-term memory]] (one child) and internalizing behaviour/[[Affect (psychology)|affect]] (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS.<ref>{{cite journal |vauthors=Banwell BL, Anderson PE |title=The cognitive burden of multiple sclerosis in children |journal=Neurology |volume=64 |issue=5 |pages=891–4 |date=March 2005 |pmid=15753431 |doi=10.1212/01.WNL.0000152896.35341.51 }}</ref>
+Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability.<ref>{{cite journal |vauthors=Foong J, Rozewicz L, Quaghebeur G |title=Executive function in multiple sclerosis. The role of frontal lobe pathology |journal=Brain |volume=120 |issue= 1|pages=15–26 |date=January 1997 |pmid=9055794 |doi= 10.1093/brain/120.1.15|url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9055794|display-authors=etal}}</ref> Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery.<ref>{{cite journal |vauthors=Hahn CD, Miles BS, MacGregor DL, Blaser SI, Banwell BL, Hetherington CR |title=Neurocognitive outcome after acute disseminated encephalomyelitis |journal=Pediatr. Neurol. |volume=29 |issue=2 |pages=117–23 |date=August 2003 |pmid=14580654 |doi= 10.1016/S0887-8994(03)00143-7}}</ref> All six children performed in the normal range on most tests, including [[Wechsler Adult Intelligence Scale#Verbal Subtests|verbal IQ]] and [[Wechsler Adult Intelligence Scale#Performance Subtests|performance IQ]], but performed at least one [[standard deviation]] below age norms in at least one cognitive domain, such as complex attention (one child), [[Wechsler Adult Intelligence Scale#Working memory|short-term memory]] (one child) and internalizing behaviour/[[Affect (psychology)|affect]] (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS.<ref>{{cite journal |vauthors=Banwell BL, Anderson PE |title=The cognitive burden of multiple sclerosis in children |journal=Neurology |volume=64 |issue=5 |pages=891–4 |date=March 2005 |pmid=15753431 |doi=10.1212/01.WNL.0000152896.35341.51 }}</ref>
 Another study compared nineteen children with a history of ADEM, of which 10 were five years of age or younger at the time (average age 3.8 years old, tested an average of 3.9 years later) and nine were older (mean age 7.7y at time of ADEM, tested an average of 2.2 years later) to nineteen matched controls.<ref>{{cite journal |vauthors=Jacobs RK, Anderson VA, Neale JL, Shield LK, Kornberg AJ |title=Neuropsychological outcome after acute disseminated encephalomyelitis: impact of age at illness onset |journal=Pediatr. Neurol. |volume=31 |issue=3 |pages=191–7 |date=September 2004 |pmid=15351018 |doi=10.1016/j.pediatrneurol.2004.03.008 |url=}}</ref> Scores on IQ tests and educational achievement were lower for the young onset ADEM group (average IQ 90) compared to the late onset (average IQ 100) and control groups (average IQ 106), while the late onset ADEM children scored lower on verbal processing speed. Again, all groups means were within one standard deviation of the controls, meaning that while effects were statistically reliable, the children were as a whole, still within the normal range. There were also more behavioural problems in the early onset group, although there is some suggestion that this may be due, at least in part, to the stress of hospitalization at a young age.<ref>{{cite journal |author =Douglas JW |title=Early hospital admissions and later disturbances of behaviour and learning |journal=Dev Med Child Neurol |volume=17 |issue=4 |pages=456–80 |date=August 1975 |pmid=1158052 |doi= 10.1111/j.1469-8749.1975.tb03497.x|url=}}</ref><ref>{{cite journal |vauthors=Daviss WB, Racusin R, Fleischer A, Mooney D, Ford JD, McHugo GJ |title=Acute stress disorder symptomatology during hospitalization for pediatric injury |journal=J Am Acad Child Adolesc Psychiatry |volume=39 |issue=5 |pages=569–75 |date=May 2000 |pmid=10802974 |doi= 10.1097/00004583-200005000-00010|url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0890-8567&volume=39&issue=5&spage=569}}</ref>

Classification	D ICD-10: G04.0 ICD-9-CM: 323.61, 323.81 MeSH: D004673 DiseasesDB: 158
External resources	eMedicine: neuro/500