The neurological signs from the inflammatory attack often begin with fever, headache, and vomiting. Encephalopathy (damage or malfunction of the brain) is a characteristic feature of ADEM and usually develops rapidly. This results in symptoms, such as altered level of consciousness, acute cognitive dysfunction, behavioral changes, and seizures in about a third of those diagnosed. The altered consciousness can range from lethargy to coma.

In addition to encephalopathy, other common neurologic signs of ADEM include: long tract pyramidal signs (decreased voluntary movement), acute hemiparesis (muscle weakness on one side of the body), cerebellar ataxia (decreased muscle coordination), and cranial neuropathies (damage of cranial nerves). ADEM is multifocal; meaning the inflammatory attack can occur in the brain, as well as occur as Optic Neuritis (ON) and/or Transverse Myelitis (TM). Thus, a child or adult with ADEM can have the symptoms of ON (i.e., impaired vision and eye pain), and/or all of the symptoms from an inflammatory attack in the spinal cord (TM). The TM symptoms depend on the severity and the level of the attack in the spinal cord. These can include: impaired breathing, bowel and bladder dysfunction, paralysis or muscle weakness, spasticity, paresthesias, or nerve pain. The inflammatory attack can go on for a few days or for a few weeks. The most severe symptoms are ordinarily reached within the first 4 to 7 days, and the first 2 to 4 weeks are the most severe period.