Acute disseminated encephalomyelitis 967 222101847 2008-06-27T15:49:50Z 64.223.230.30 /* Acute Hemorrhagic Leukoencephalitis */ {{Infobox_Disease | Name = Acute disseminated encephalomyelitis | Image = | Caption = | DiseasesDB = 158 | ICD10 = {{ICD10|G|04|0|g|00}} | ICD9 = {{ICD9|323.61}} | ICDO = | OMIM = | MedlinePlus = | eMedicineSubj = neuro | eMedicineTopic = 500 | MeshID = D004673 | }} '''Acute disseminated encephalomyelitis''' ('''ADEM''') is an immune mediated [[disease]] of the [[human brain|brain]]<ref>Dale RC. (2003). Acute disseminated encephalomyelitis. ''Seminars in pediatric infectious diseases'' '''14''':90-­95.</ref><ref>Garg RK. (2003) Acute disseminated encephalomyelitis. ''Postgraduate medical journal'' '''79''':11-­17.</ref><ref>Jones CT. (2003). Childhood autoimmune neurologic diseases of the central nervous system. ''Neurologic Clinics'' '''21''':745­-764.</ref>. It usually occurs following a [[virus (biology)|viral]] [[infection]] but may appear following [[vaccination]], [[bacteria]]l or [[Parasitism|parasitic]] infection, or even appear spontaneously. As it involves [[autoimmune]] [[demyelination]], it is similar to [[multiple sclerosis]], and is considered part of the [[Multiple sclerosis borderline]]<ref>Rust RS (2000). Multiple sclerosis, acute disseminated encephalomyelitis, and related conditions. ''Seminars in Pediatric Neurology'' '''7''':66­-90.</ref><ref name="Poser and Brinar 2007">Poser CM & Brinar VV (2007). Disseminated encephalomyelitis and multiple sclerosis: two different diseases ­ a critical review. Acta Neurologica Scandinavica '''116''':201-­206.</ref> The incidence rate is about 0.8 per 100,000 people per year<ref name="Leake et al 2004">Leake JAD, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 2004;23:756–764.</ref><!--<ref>Menge (2005) ''Archives of Neurology''</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>Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS & Kean MJ. (2001). Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. ''Neurology'' '''56''':1308-­1312.</ref><ref>Anlar B, Basaran C, Kose G, et al. (2003). Acute disseminated encephalomyelitis in children: outcome and prognosis. ''Neuropediatrics'' '''34''':194-­199.</ref><ref>Schwarz S, Mohr A, Knauth M, Wildemann B & Storch-Agenlocher B. (2001). Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. ''Neurology'' '''56''':1313-­1318.</ref>. The mortality rate may be as high as 5%, full recovery is seen in 50 to 75% of cases, while up to 70 to 90% recover with some minor residual disability<ref name="Menge et al 2007">Menge T, Kieseier BC, Nessler S, Hemmer B, Hartung HP, & Stuve O (2007). Acute disseminated encephalomyelitis: an acute hit against the brain. ''Current Opinion in Neurology'' '''20''':247-­254</ref>. The average time to recover 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>Wingerchuk DM. (2003). Postinfectious encephalomyelitis. ''Current Neurology and Neuroscience Reports'' '''3''':256–264.</ref>, but periventricular white matter<!----> and gray matter of the [[Cerebral cortex|cortex]], [[thalami]] and [[basal ganglia]] <!----> may also be involved. When the patient suffers more than one demyelinating episode, it is called '''Recurrent disseminated encephalomyelitis'''<ref>{{cite journal |author=Poser CM |title=Multiple sclerosis and recurrent disseminated encephalomyelitis are different diseases |journal=Arch. Neurol. |volume=65 |issue=5 |pages=674; author reply 674–5 |year=2008 |month=May |pmid=18474749 |doi=10.1001/archneur.65.5.674-a |url=}}</ref> or '''Multiphasic disseminated encephalomyelitis'''<ref>{{cite journal |author= |title= |journal= |volume= |issue= |pages= |year= |pmid= |doi= |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11099444}}</ref>(MDEM). ==Causes, Antecedent History== Viral infections thought to induce ADEM include [[Orthomyxoviridae|influenza virus]], [[enterovirus]], [[measles]], [[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">Tenembaum S, Chitnis T, Ness J, Hahn JS (2007). Acute disseminated encephalomyelitis. ''Neurology'' '''68''' (Suppl 2):S23-­S36.</ref>. The only vaccine proven to induce ADEM in 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<ref>Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, & Phanuphak P. (1987). Myelin basic protein as an encephalitogen in encephalomy elitis and polyneuritis following rabies vaccination. ''New England Journal of Medicine'' '''316''':369–374.</ref><ref>Hemachudha T, Griffin DE, Johnson RT, Giffels JJ. (1988). Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine. ''Neurology'' '''38''':42–44.</ref><ref name="Murthy 2002">Murthy JM. (2002), Acute disseminated encephalomyelitis. ''Neurol India'' '''50''':238–243.</ref><ref name="Leake et al 2004"/><ref name="Tenembaum et al 2002">Tenembaum S, Chamoles N, & Fejerman N. (2002). Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. ''Neurology'' '''59''':1224-­1231.</ref><ref name="Fenichel 1982">Fenichel GM. (1982). Neurological complications of immunization. ''Annals of Neurology'' '''12''':119–128.</ref><ref>Takahashi H, Pool V, Tsai TF, Chen RT. Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. The VAERS Working Group. ''Vaccine'' '''18''':2963–2969.</ref><ref>Tourbah A, Gout O, Liblau R, et al. (1999). Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? Neurology 53:396–401.</ref><ref>Karaali-Savrun F, Altintas A, Saip S, & Siva A. (2001) Hepatitis B vaccine related-myelitis? ''European Journal of Neurology'' '''8''':711–715.</ref><ref>Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, & Lane JM. (2005). Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004. ''Journal of the American Medical Association'' '''294''':2744–2750.</ref> <ref>Ozawa H, Noma S, Yoshida Y, Sekine H, & Hashimoto T. (2000). Acute disseminated encephalomyelitis associated with poliomyelitis vaccine. ''Pediatric Neurology'' '''23''':177–179.</ref>. In rare cases, ADEM seems to follow from [[organ transplant]]ation<ref name="Tenembaum et al 2002"/>. The risk of ADEM from measels vaccination <!--does this mean MMR I wonder--> is about 1 to 2 per million<ref name="Murthy 2002"/>, which is far lower than the risk of developing ADEM from an actual measels infection, which is about 1 per 1000 for measles (and 1 per 5000 for rubella)<ref>Miller HG, Stanton JB, Gibbons JL (1956). Parainfectious encephalomyelitis and related syndromes. ''Quarterly Journal of Medicine'' '''25''':427-505.</ref><ref name="Fenichel 1982"/>. Measels infection also appears to lead to worse ADEM outcomes than cases associated with measels immunization. Some vacines, later shown to have been contaminated with host animal [[Central nervous system|CNS]] tissue, have ADEM incident rates as high as 1 in 600<ref>Hemachudha T, Griffin DE, Giffels JJ, et al. (1987). Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. ''New England Journal of Medicine'' '''316''':369-­374.</ref>. ==Presentation== ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1-3 weeks after infection or vaccination. Major symptoms include [[fever]], [[headache]], drowsiness, [[non-epileptic seizure|seizure]]s 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<ref name="Tenembaum et al 2002"/>. ==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 [[corticosteroid]]s <ref>Shahar E, Andraus J, Savitzki D, et al. (2002). Outcome of severe encephalomyelitis in children: effect of high-dose methylprednisolone and immunoglobulins. ''Journal of Child Neurology'' '''17''':810-­814.</ref>, 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<ref name="Tenembaum et al 2002">Tenembaum S, Chamoles N, Fejerman N. (2002). Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. ''Neurology'' '''59''':1224–1231.</ref>. Oral tapers of less than three weeks duration show a higher chance of relapsing<ref>Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. (2000). Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. ''Brain'' '''123''':2407–2422.</ref><ref>Anlar B, Basaran C, Kose G, et al. (2003). Acute disseminated encephalomyelitis in children: outcome and prognosis. ''Neuropediatrics'' '''34''':194–199.</ref>, and tend to show poorer outcomes{{Fact|date=March 2008}}. Other antiinflamatory and immunosuppressive therapies have been reported to show beneficial effect, such as [[plasmapheresis]], high doses of intravenous [[immunoglobulin]] (IVIG)<ref name="Shahar et al 2002">Shahar E, Andraus J, Savitzki D, et al. (2002). Outcome of severe encephalomyelitis in children: Effect of high-dose methylprednisolone and immunoglobulins. ''Journal of Child Neurology'' '''17''':810-814</ref><ref>Ravaglia S, Piccolo G, Ceroni M, Franciotta D, ichiecchio A, Bastianello S, Tavazzi E, Minoli L, Marchioni E (2007). Severe steroid-resistant post-infectious encephalomyelitis: General features and effects of IVIg. ''Journal of Neurology'' '''254''':1518-1523.</ref>, [[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<ref>Straussberg R, Schonfeld T, Weitz R, Karmazyn B, Harel L. (2001). Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immuneglobulins. ''Pediatric Neurology'' '''24''':139–143.</ref> 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 IVIg; 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<ref name="Shahar et al 2002"/>. 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<ref>Feasby T, et al. (2007). Guidelines on the Use of Intravenous Immune Globulin for Neurologic Conditions. ''Transfusion Medicine Reviews'' '''21''':S57-S107.</ref>. 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<ref>Ravaglia, S. et al. (2007) Severe steroid-resistant post-infectious encephalomyelitis: General features and effects of IVIg. ''Journal of Neurology'' '''254''':1518–1523</ref>. This same study found one subject, a 71 year old man who had not responded to steroids, that responded to a IVIg treatment 58 days after disease onset. ==Prognosis== Full recovery is seen in 50 to 75% of cases, ranging to 70 to 90% recovery with some minor residual disability (typically assessed using measures such as [[Modified Rankin Scale|mRS]] or [[Expanded Disability Status Scale|EDSS]]), average time to recover is one to six months<ref name="Menge et al 2007"/>. The mortality rate may be as high as 5%.<ref name="Menge et al 2007"/>. 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<ref>Lin C-H, Jeng J-S, Hsieh S-T, Yip P-K, & Wu R-M (2007) Acute disseminated encephalomyelitis: a follow-up study in Taiwan. ''Journal of Neurology Neurosurgery and Psychiatry'' '''78''':162-­167.</ref>. 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. ===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]] <ref name="Tenembaum et al 2007"/>. ===Neurocognitive=== Patients with demylinating illnesses, such as MS, have been show cognitive deficits even when there is minimal physical disability<ref>Foong J, Rozewicz L, Quaghebeur G, et al. (1997). Executive function in multiple sclerosis. The role of frontal lobe pathology. ''Brain'' '''120''':15-26.</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>Hahn CD, Miles BS, MacGregor DL, Blaser SI, Banwell BL & Hetherington CR. (2003). Neurocognitive outcome after acute disseminated encephalomyelitis. ''Pediatric Neurology'' '''29''':117-123.</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]] (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>Banwell BL & Anderson PE. (2005). The cognitive burden of multiple sclerosis in children. ''Neurology'' '''64''':891-­894.</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>Jacobs RK, Anderson VA, Neale JL, Shield LK, Kornberg AJ. Neuropsychological outcome after acute disseminated encephalomyelitis: impact of age at illness onset. Pediatr Neurol 2004;31:191-­197.</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>Douglas JWB. (1975). Early hospital admissions and later disturbances of behavior and learning. Devel Med Child Neurol 17:456-80.</ref><ref>Daviss WB, Racusin R, Fleischer A, Mooney D, Ford JD & McHugo GJ. (2000). Acute stress disorder symptomatology during hospitalization for pediatric injury. J Am Acad Child Adol Psychiatry 2000;39:569-75.</ref> ==ADEM & MS== While ADEM and MS both involve autoimmune demylenation, they differ in many clinical, genetic, imaging, and histopathological differences<ref>Wingerchuk DM & Lucchinetti CF. (2007). Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. ''Current Opinion in Neurology'' '''20''':343-­350.</ref>. Some authors consider MS and its [[Idiopathic inflammatory demyelinating diseases|borderline forms]] to constitute a spectrum, differing only in chronocity, 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>Hartung H-P, Grossman R. (2001). ADEM: distinct disease or part of the MS spectrum? ''Neurology'' '''56''':1257-12­60.</ref>, while others consider them discretely different diseases<ref name="Poser and Brinar 2007"/>.<!-- Plaques in the white matter in MS are sharply delinated, while the inflammation in ADEM is widely disseminated and ill-defined. Treatment of ADEM and [[Neuromyelitis optica]] with long-term immunomodulatory or immunosuppressive drugs --> ==Acute Hemorrhagic Leukoencephalitis== Acute hemorrhagic leukoencephalitis (AHL, or AHLE) or Acute necrotizing encephalopathy (ANE), Acute hemorrhagic encephalomyelitis (AHEM), Acute necrotizing hemorrhagic leukoencephalitis (ANHLE), or 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<ref name="Davies et al 2006">Davies NWS, Sharief MK & Howard RS (2006). Infection-associated encephalopathies: their investigation, diagnosis, and treatment. ''Journal of Neurology'' '''253''':833-­845.</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">Stone MJ & Hawkins CP (2007) A medical overview of encephalitis. ''Neuropsychological Rehabilitation'' '''17''':429-449.</ref>, death is common in the first week<ref name="Archer & Wall 2003">Archer H & all R (2003). Acute Haemorrhagic Leukoencephalopathy: Two case reports and review of the literature. ''Journal of Infection'' '''46''':133-137.</ref> with mortality rate of 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"/>. ==Experimental Allergic Encephalomyelitis== {{main|Experimental autoimmune encephalomyelitis}} Experimental Allergic Encephalomyelitis (EAE) is an animal model of CNS inflammation and demyelination frequently used to investigate potential MS treatments<ref>Rivers TM & Schwentker FF. (1935). Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. ''Journal of Experimental Medicine'' '''61''':689 –701.</ref>. An acute monophasic illness, EAE is far more similar to ADEM than MS<ref>Sriram S & Steiner I (2005) Experimental Allergic Encephalomyelitis: A misleading model of Multiple Sclerosis. ''Annals of Neurology'' '''58''':939 –945.</ref>. ==See also== * [[Optic neuritis]] * [[Transverse myelitis]] ==References== {{reflist|2}} == External links == * [http://www.myelitis.org/adem.htm Acute Disseminated Encephalomyelitis (ADEM)] at myelitis.org {{Multiple sclerosis}} {{Diseases of the nervous system}} [[Category:multiple sclerosis]] [[Category:Autoimmune diseases]] [[Category:Neurological disorders]] [[Category:Neurology]] [[de:Akute disseminierte Enzephalomyelitis]] [[nl:Acute gedissemineerde encefalomyelitis]] [[fi:Akuutti disseminoitunut enkefalomyeliitti]]