11 Postgrad Med J: first published as 10.1136/pmj.79.927.11 on 1 January 2003. Downloaded from REVIEW Acute disseminated encephalomyelitis R K Garg ............................................................................................................................. Postgrad Med J 2003;79:11–17 Acute disseminated encephalomyelitis (ADEM) is an mortality and morbidity. Because of significant acute demyelinating disorder of the central nervous advances in infectious disease control ADEM in developed countries is now seen most frequently system, and is characterised by multifocal white matter after non-specific upper respiratory tract infec- involvement. Diffuse neurological signs along with tions and the aetiological agent remains un- multifocal lesions in brain and spinal cord characterise known. In a recent study by Murthy et al, despite vigorous attempts to identify microbial pathogens the disease. Possibly, a T cell mediated autoimmune in 18 patients, only one patient had Epstein-Barr response to myelin basic protein, triggered by an virus isolated as the definite microbial cause of infection or vaccination, underlies its pathogenesis. ADEM. Of the other two patients with rotavirus disease, in one patient infection was considered ADEM is a monophasic illness with favourable long term as possibly associated with ADEM. Failure to prognosis. The differentiation of ADEM from a first identify a viral agent suggests that the inciting attack of multiple sclerosis has prognostic and agents are unusual or cannot be recovered by standard laboratory procedures.1 In developing therapeutic implications; this distinction is often difficult. and poor countries, because of poor implementa- Most patients with ADEM improve with tion of immunisation programmes, measles and methylprednisolone. If that fails immunoglobulins, other viral infections are still widely prevalent and account for frequent occurrences of postin- plasmapheresis, or cytotoxic drugs can be given. Recent fectious demyelinating diseases. ADEM in devel- literature suggests that a significant proportion of oping countries is much more frequent than patients with ADEM will later develop multiple sclerosis; reported.2 In the past it had been observed that ADEM occurred in one out of 1000 measles infec- however, follow up experience from developing tions. ADEM was relatively uncommon after vari- countries does not support this view. cella infection and the incidence that had been .......................................................................... reported was about one per 10 000 patients. The incidence of ADEM after rubella infection was approximately one per 500 infections. Mortality cute disseminated encephalomyelitis and major neurological sequelae of ADEM after http://pmj.bmj.com/ (ADEM) is an acute widespread demyeli- varicella and rubella infections were much lower Anating condition, which principally affects in comparison with ADEM after measles infec- brain and spinal cord (box 1). It usually follows tion. ADEM found after measles was associated an infection or vaccination. The disease is charac- with mortality rates as high as 25% and 25%–40% terised by multifocal white matter lesions on of survivors were left with permanent neurologi- neuroimaging. ADEM is a monophasic disease. cal sequelae.3–5 The main bacterial infection, Uncommonly ADEM can relapse frequently. If which has been implicated with the occurrence of on September 28, 2021 by guest. Protected copyright. these relapses are thought to represent part of the ADEM, is mycoplasma. Other viral and bacterial same acute monophasic illness, the term mul- infections that have been implicated with ADEM tiphasic ADEM is used. Any recurrences beyond are listed in box 2. the first few months of initial clinical illness sug- Another common variant of ADEM is that gest the presence of a chronic immune process which follows vaccination (postimmunisation and a diagnosis of multiple sclerosis should be encephalomyelitis). This form is clinically indis- considered. Devic’s disease or neuromyelitis op- tinguishable from the postinfectious variety ex- tica is characterised by simultaneous attacks of cept the former more often involves the periph- optic neuritis and myelitis with no evidence of eral nervous system. When rabies vaccine was involvement of other parts of the central nervous generated from virus grown in rabbit brain, the system. Precisely what relationship these distinct rate of neurological complications was estimated entities have with each other is a subject of to be as high as one in 400 vaccinations. ....................... intense controversy. In the recent past a lot of new The reported incidence of neuroparalytic information about ADEM and its association with complications with the Semple type of antirabies Correspondence to: other demyelinating disorders has been made vaccine varied between one per 600 to one per Dr R K Garg, Department available. In this article all this information will of Neurology, King 1575 vaccinations. Such complications are now George’s Medical College, be reviewed. Lucknow 226003, India; ................................................. [email protected] EPIDEMIOLOGY Abbreviations: ADEM, acute disseminated Submitted The exact incidence of ADEM is not known. In the encephalomyelitis; EAE, experimental allergic encephalomyelitis; FLAIR, fluid attenuated inversion 15 January 2002 past ADEM commonly followed common child- Accepted recovery sequence; HEAE, hyperacute experimental 16 October 2002 hood infections (like measles, smallpox, and allergic encephalomyelitis; MHC, major histocompatibility ....................... chickenpox) and was associated with significant complex; MRI, magnetic resonance imaging www.postgradmedj.com 12 Garg invasion by inflammatory cells, perivascular oedema, and Postgrad Med J: first published as 10.1136/pmj.79.927.11 on 1 January 2003. Downloaded from Box 1: Acute disseminated encephalomyelitis and haemorrhage. These changes are present in the small blood related disorders vessels of both white and grey matter. As the lesions become Acute disseminated encephalomyelitis older, the macrophages increase and lymphocytes decrease in • Postinfectious. number. At a late stage of disease foci of fibrillary fibrosis can • Postvaccinial. also be seen in adjacent brain tissue. Although postinfectious Acute haemorrhagic leucoencephalitis encephalomyelitis typically involves the white matter, lesions Restricted form of acute, inflammatory demyelinating in grey matter have also been seen. Basal ganglia, thalamus, diseases and even cortical grey matter may be involved.14 15 • Transverse myelitis. The pathological findings described in ADEM are very simi- • Optic neuritis. lar to experimental allergic encephalomyelitis (EAE). EAE is • Cerebellitis. an autoimmune encephalomyelitis that can be induced • Brain stem encephalitis. experimentally in susceptible animals by exposing them to a Multiphasic form of acute disseminated myelin antigen such as myelin basic protein, proteolipid encephalomyelitis and multiple sclerosis protein, and myelin oligodendrocyte glycoprotein. In complete Freund’s adjuvant these myelin antigens can produce a diffuse white matter encephalomyelitis. Myelin basic protein and proteolipid protein are the most encephilitogenic. The existing Box 2: Preceding infectious illnesses evidence suggests that ADEM results from a transient autoimmune response against myelin or other autoantigens, A. Infections possibly, via molecular mimicry or by non-specific activation Viral of an autoreactive T cell clone. Peptides from microbial • Measles. proteins that have sufficient structural similarity with the • Mumps. host’s self peptides can activate autoreactive T cells; this • Influenza A or B. mechanism is referred to as molecular mimicry. EAE, in the • Hepatitis A or B. Theiler’s murine encephalomyelitis model, is initiated by • Herpes simplex. CD4+ T helper cells by infiltrating the central nervous system • Human herpes virus E. and subsequently recruiting additional lymphocytes and • Varicella, rubella. mononuclear cells to cross the blood-brain barrier, resulting in • Epstein-Barr virus. inflammation and demyelination. CD8+ T cells have also been • Cytomegalovirus. implicated in a secondary autoimmune response.16–19 Disease • HIV. can be transferred to susceptible mice by injection of T cells Others that recognise myelin-associated protein. Semple antirabies • Mycoplasma pneumoniae. vaccine contains a fair amount of neural antigens that can • Chlamydia. excite a cross reactive T cell response.20 Probably genetic • Legionella. • Campylobacter. susceptibility explains why encephalomyelitic complications • Streptococcus. develop in only a small minority of patients who have received rabies vaccine prepared from rabbit brain, or have had B. Vaccines measles. Of the many candidate polymorphic major histocom- • Rabies. patibility complex (MHC) and non-MHC genes, which • Diphtheria, tetanus, pertussis. contribute to disease susceptibility, including those which http://pmj.bmj.com/ • Smallpox. encode for effector (cytokines and chemokines) or receptor • Measles. molecules within the immune system, human leucocyte anti- • Japanese B encephalitis. gen class II genes have the most significant influence.21 • Polio. Acute haemorrhagic leucoencephalitis is a more severe and • Hepatitis B. frequently fatal hyperacute variant of ADEM. The pathological • Influenza. features of acute haemorrhagic leucoencephalitis are similar to that of hyperacute experimental allergic