ADEM's symptoms are similar to multiple sclerosis (MS) and is considered part of the multiple sclerosis borderline diseases. ADEM has several differentiating features from MS. Unlike MS, ADEM occurs usually in children and is marked with rapid fever. ADEM consists of a single episode whereas MS is marked with several episodes over a long period of time. ADEM is also distinguished by a loss of consciousness.
The incidence rate is about 8 per 1,000,000 people per year. Although it occurs in all ages, most reported cases are in children and adolescents, with the average age around 5 to 8 years old. 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. The average time to recover is one to six months.
ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1–3 weeks after infection. Major symptoms include fever, headache, 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. Additional symptoms include hemiparesis, paraparesis, and cranial nerve palsies.
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, 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. Oral tapers of less than three weeks duration show a higher chance of relapsing, and tend to show poorer outcomes. Other antiinflamatory and immunosuppressive therapies have been reported to show beneficial effect, such as plasmapheresis, high doses of intravenous immunoglobulin (IVIg),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 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. 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. 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. 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.
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. The mortality rate may be as high as 5%. 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. 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.
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.
Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability. 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. 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.
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. 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.
ADEM and multiple sclerosis
While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course, while others consider them discretely different diseases.
Problems for differential diagnosis increase due to the lack of agreement for a definition of Multiple Sclerosis. For some people MS should be considered a clinical entity based in inflammatory lesions separated in time and space. As some cases of ADEM satisfy these conditions, they should be considered inside the MS spectrum. Using a pathological definition instead, they would be apart (plaques in the white matter in MS are sharply delineated, while the inflammation in ADEM is widely disseminated and ill-defined).
Acute hemorrhagic leukoencephalitis
Acute hemorrhagic leukoencephalitis (AHL, or AHLE), also known as acute necrotizing encephalopathy (ANE), 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]), it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema. Death is common in the first week and overall mortality is about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the magnitude of the white matter affected. This disease has been occasionally associated with ulcerative colitis and Crohn's disease, malaria,septicemia associated with immune complex deposition, methanol poisoning, and other underlying conditions.
Experimental allergic encephalomyelitis (EAE) is an animal model of CNS inflammation and demyelination frequently used to investigate potential MS treatments. An acute monophasic illness, EAE is far more similar to ADEM than MS.
^ abHemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P; Griffin; Giffels; Johnson; Moser; Phanuphak (February 1987). "Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination". N. Engl. J. Med.316 (7): 369–74. doi:10.1056/NEJM198702123160703. PMID2433582.
^Hemachudha T, Griffin DE, Johnson RT, Giffels JJ; Griffin; Johnson; Giffels (January 1988). "Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine". Neurology38 (1): 42–4. doi:10.1212/WNL.38.1.42. PMID2447520.
^Miller HG, Stanton JB, Gibbons JL (1956). "Parainfectious encephalomyelitis and related syndromes". Quarterly Journal of Medicine25 (100): 427–505. PMID13379602.
^Allmendinger A, Krauthamer A, Spektor V (2009). "Case of the month". Diagnostic Imaging31 (12): 10.
^ abcShahar 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. PMID12585719.
^ abRavaglia 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. PMID17965959.
^Feasby T, Banwell B, Benstead T, et al. (April 2007). "Guidelines on the use of intravenous immune globulin for neurologic conditions". Transfus Med Rev21 (2 Suppl 1): S57–107. doi:10.1016/j.tmrv.2007.01.002. PMID17397768.
^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. PMID15351018.
^McDonald WI, Compston A, Edan G, et al. (2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Ann. Neurol.50 (1): 121–7. doi:10.1002/ana.1032. PMID11456302.
^ abDavies NW, Sharief MK, Howard RS; Sharief; Howard (July 2006). "Infection-associated encephalopathies: their investigation, diagnosis, and treatment". J. Neurol.253 (7): 833–45. doi:10.1007/s00415-006-0092-4. PMID16715200.
^Venugopal V, Haider M; Haider (2013). "First case report of acute hemorrhagic leukoencephalitis following Plasmodium vivax infection". Indian J Med Microbiol31 (1): 79–81. doi:10.4103/0255-0857.108736. PMID23508437.