The initial neurological symptoms of ADEM may include fever, headache, and vomiting. Encephalopathy (abnormal functioning of the brain) is a characteristic feature of ADEM. It usually develops rapidly and results in symptoms such as altered level of consciousness, acute cognitive dysfunction, behavioral changes, and seizures in about a third of cases. The altered consciousness can range greatly from sleepiness to 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 coordination), and cranial neuropathies (abnormalities in eye and face movement). ADEM is multifocal, which means inflammation can occur in the brain, optic nerves (optic neuritis or ON) and/or spinal cord (transverse myelitis, or TM). Thus, a child or adult with ADEM can have the symptoms of ON such as impaired vision and eye pain, and/or TM such as motor and sensory abnormalities. TM symptoms may 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. ADEM symptoms can persist for a few days or several weeks. Peak severity of the syndrome is typically reached within 4 to 7 days, though acute symptoms may last 2 to 4 weeks.