The diagnosis of ADEM is based on clinical and radiologic characteristics. Unfortunately, there is no specific biologic marker or confirmatory test to specifically identify the disorder, nor is there scientific, randomized, or controlled data 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 will be based on clinical judgment, trying to connect to an expert is critically important.
An ADEM diagnosis is considered when individuals develop multifocal neurologic abnormalities with 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 a vaccination. Physicians must rule out that there is a direct infection of the central nervous system as opposed to an infection that subsequently triggered the immune system to cause the attack. Should a direct infection be suspected, one is often placed on an antibiotic and/or acyclovir (an antiviral drug) to fight the infection.
Laboratory studies include a complete blood count and cultures, and serologic studies are performed on blood and cerebrospinal fluid to detect bacterial and viral organisms. Additionally, viral cultures are obtained from nasopharynx and stool.
A lumbar puncture is also performed. This test is useful because evidence of inflammation is common in cerebrospinal fluid (CSF), with pleocytosis (increased white blood cell count) and/or increased protein concentration. While this is common, sometimes the CSF can be normal. Additionally, although oligoclonal bands are nonspecific and are more often associated with Multiple Sclerosis (MS), they are sometimes also present in ADEM.
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, but can also be asymmetric and are typically poorly marginated. Multiple lesions in the deep and subcortical white matter are common, which is characteristic of demyelination (gray matter lesions sometimes accompany white matter lesions, especially among children). While the number varies, multiple brain lesions are usually present. ADEM lesions are typically large (though smaller ones have also been seen) with diameters ranging from <5 mm to 5 cm. Additionally, brainstem and spinal cord abnormalities on MRI are common in ADEM. In the spinal cord, there are typically large confluent intramedullary lesions that extend over multiple segments of the cord.
It is possible that the MRI may be normal early in the course of the disorder and may have to be repeated. Some physicians recommend repeating MRIs on follow-up to ensure there are no new lesions, which could change the diagnosis from ADEM to multiphasic ADEM (see below) or MS.
In a situation where nonspecific cerebrospinal fluid abnormalities and MRI evidence of white matter lesions are present, it is important that other inflammatory demyelinating disorders be considered. These include: Multiple Sclerosis (MS), Optic Neuritis (ON), Transverse Myelitis (TM), and Neuromyelitis Optica Spectrum Disorder (NMOSD).
An important paper was recently published by the International Pediatric Multiple Sclerosis Study Group, which proposed diagnostic criteria for ADEM in children.2 The criteria are important for the purpose of arriving at better decisions about treatments and are meant to facilitate research on ADEM. The major criteria include:
1. A first clinical attack of central nervous system demyelinating disease with acute or subacute onset, polysymptomatic neurologic features, and encephalopathy
2. Brain MRI showing focal or multifocal lesions, predominantly involving the white matter, without evidence of previous white matter changes
3. 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:
1. 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.
2. 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.
3. 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 an excellent comparison across a number of variables for making the differential diagnosis between ADEM and MS. ADEM more frequently occurs among younger age groups (<10 years) and there does not seem to be a higher incidence between boys or girls. MS occurs more frequently in adolescents and the incidence is higher for girls than for boys. A prior flu-like illness is typically the case in ADEM, while it is variable for MS. Encephalopathy is required to arrive at a diagnosis of ADEM while it is rare in the early stages of MS. Seizures are variable in ADEM and rare in MS. A single event in ADEM can fluctuate over the course of three months, while in MS a discrete event is separated by at least four weeks. Large lesions involving gray and white matter are frequently evident from MRI in ADEM and rare in MS. MRI frequently shows enhancement in both ADEM and MS. Over time, lesions typically appear to resolve in ADEM, while in MS, there is typically development of new lesions. CSF pleocytosis (presence of a greater number of cells than normal) is variable in ADEM and extremely rare in MS (white blood cell count 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.