All of the treatments for ADEM are based largely on opinions from respected authorities based on clinical experience, descriptive studies or reports of expert committees. Standard treatments recommended in acute ADEM are not confirmed from randomized, placebo-controlled trials.

Since patients with ADEM usually present with fever, meningeal signs, acute encephalopathy, and evidence of inflammation in blood and CSF, it is important to first consider a treatment with antibiotics and/or acyclovir until an infectious cause is ruled out. A high dose of intravenous corticosteroids, for 3-5 days is the primary and most common first treatment of ADEM and the corticosteroids can be used concurrently with antibiotics and acyclovir. Plasma Exchange (PLEX) is recommended if there is no response to corticosteroids. Intravenous immunoglobulin (IVIG) is recommended if there is no response to PLEX.

The strength of evidence for the recommendation of corticosteroids and PLEX are graded as moderate. The strength of evidence for a recommendation of IVIG is poor. It should be noted that no studies have compared IVIG treatment with corticosteroids or plasma exchange, and there is debate over whether PLEX or IVIG should be used first when corticosteroids fail to work.