The diagnosis of ADEM is based on clinical and radiologic characteristics. Unfortunately, there is no specific biological marker or confirmatory test to specifically identify the disorder, nor have there been large-scale, randomized, controlled studies focused on the diagnosis and treatment of ADEM. Decisions about the diagnosis and treatment of this disorder are based primarily on the opinions of experts. Since decisions are often based on clinical judgment, management of ADEM by a healthcare provider who is familiar with the syndrome is critically important.
A diagnosis of ADEM is considered when individuals develop multifocal neurological abnormalities such as confusion, excessive irritability, or altered level of consciousness (encephalopathy), especially if the onset of symptoms occurs within 1 to 2 weeks after a viral/bacterial infection or, rarely, after a vaccination. Physicians must rule out that there is a direct infection of the central nervous system as opposed to an infection that subsequently triggers a misdirected immune response. Should a direct infection be suspected, an antibiotic and/or antiviral drug should be initiated to treat the presumed infection.
Laboratory studies include a complete blood count and blood and cerebrospinal fluid (CSF) cultures, and serological (antibody) studies are performed on blood and CSF to detect bacterial and viral organisms. Additionally, viral cultures can be obtained from nasopharynx and stool. Testing for myelin oligodendrocyte glycoprotein (MOG) and neuromyelitis optica (NMO)/aquaporin-4 antibodies should be completed to evaluate for ADEM mimics that can cause relapsing demyelination.
A lumbar puncture is also performed to evaluate for evidence of inflammation in the cerebrospinal fluid (CSF). Common findings include pleocytosis (increased white blood cell count) and/or increased protein concentration, but normal CSF findings do not exclude the diagnosis of ADEM. Increased and unique antibody production in the CSF can be assessed with measuring IgG index and oligoclonal bands, respectively. While the latter is most commonly associated with multiple sclerosis (MS), these tests can sometimes be abnormal in ADEM as well.
An MRI of the brain and spine is important to establish a diagnosis of ADEM. Abnormalities are best defined by T2-weighted images, FLAIR sequences, and contrast-enhanced MRI with gadolinium. Abnormalities on MRI usually vary in location. Lesions associated with ADEM tend to be bilateral, asymmetric, and have poorly defined margins. Multiple lesions in the deep and subcortical white matter are common. Involvement of cortical and deep gray matter structures can also be seen, especially among children. ADEM lesions are typically large, with diameters ranging from <5 mm to 5 cm, and multiple in number, while presentations with few and/or small lesions are also possible. Additionally, brainstem and spinal cord abnormalities on MRI are common in ADEM. In the spinal cord, large confluent intramedullary lesions extending over multiple vertebral segments of the spinal cord are typical.
It is possible that the MRI may be normal early in the course of the illness and abnormalities only be visualized on subsequent imaging studies. After the acute period, physicians often will repeat the MRI, usually 3-6 months after ADEM presentation, to follow up on the evolution of prior brain lesions and survey for new lesions, which could change the diagnosis from ADEM to multiphasic ADEM (see below) or MS.
In making the diagnosis of ADEM, it is important to consider other inflammatory demyelinating disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and MOG antibody disease (MOGAD), in which an ADEM-like presentation may be the first manifestation of a relapsing, demyelinating disease.
An important paper published by the International Pediatric Multiple Sclerosis Study Group proposed diagnostic criteria and provided treatment recommendations to facilitate improved medical decision-making and formalize research on ADEM in children.2
The major criteria include:
- A first clinical attack of central nervous system demyelinating disease with acute or subacute onset, polysymptomatic neurologic features, and encephalopathy
- Brain MRI showing focal or multifocal lesions, predominantly involving the white matter, without evidence of previous white matter changes
- Encephalopathy as a presenting symptom, with the onset of encephalopathy corresponding with the occurrence of the disease state (encephalopathy is defined to include behavioral changes, such as lethargy or irritability, or severe changes in the level of consciousness such as coma)
These features help distinguish ADEM from other clinically isolated syndromes, which have a greater risk for recurrence and subsequent diagnosis of MS. The authors of the publication define three different categories of ADEM:
- Monophasic ADEM is a one-time episode that can develop over a period for as long as three months. Any new or changing symptoms within this three-month period is considered as one event. Symptoms that might occur during an oral steroid taper or within one month of the completion of the taper are also classified as one single episode. Recurrent and multiphasic ADEM episodes must occur more than three months after the initial event and more than one month after the completion of steroids.
- Recurrent ADEM is defined as a subsequent attack that involves the same symptoms that occurred during the initial attack. The MRI findings tend to be similar to the initial attack, and there are no lesions, but there could be an enlargement of the lesions from the original episode.
- Multiphasic ADEM is defined as an attack that involves new areas of the central nervous system from the initial or previous attacks. There must be signs of encephalopathy, but symptoms and neuroimaging findings are in different areas from the initial attack. There might be new lesions evident on MRI, and there might also be evidence of partial or complete resolution of the lesions associated with the first episode.
The International Pediatric MS Study Group authors also provide guidance on the variables that might distinguish ADEM and MS. ADEM more frequently occurs among younger age groups (<10 years), and there does not seem to be a difference between male versus female incidence. MS occurs more frequently in adolescents and young adults, and the incidence is higher for females than for males. A prior flu-like illness is reported in ADEM but is less common with MS. Encephalopathy is required to satisfy the diagnosis of ADEM, while it is rare in initial presentations of MS. Seizures can occur in ADEM but is not typical with MS. A single event in ADEM is defined as symptoms confined to three months, while in MS, discrete events are separated by at least four weeks. Large lesions involving gray and white matter are frequently evident from MRI in ADEM and rare in MS, which usually manifests as smaller, well-defined, ovoid lesions. MRI can reveal contrast enhancement in both ADEM- and MS-related lesions. Over time, lesions may regress and even resolve completely in ADEM, while in MS, old lesions often evolve but do not disappear, and new lesions develop over time if the disease is untreated. Significant CSF pleocytosis (presence of a greater number of cells than normal) is variable in ADEM but extremely rare in MS (white blood cell count is almost always <50). Finally, the presence of oligoclonal bands in the spinal fluid is variable in ADEM and frequently found in MS.
(2) Krupp LB, Banwell B, Tenembaum S, et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007; 68:S7-S12.