Consensus definitions for pediatric MS and other demyelinating disorders in childhood

Clinically isolated syndromes.

Five reports evaluated the accuracy of the 2010 McDonald criteria to diagnose MS in children, with similar results despite methodologic differences.^3,–,7 At time of first CIS, after application of the 2010 McDonald criteria to the initial brain MRI, the diagnosis of MS was met in 53%–63% of the children who subsequently developed a clinical relapse. DIT was less frequently present at initial brain MRI than DIS, which was observed in more than 80% of children. Interestingly, the inclusion of spinal cord imaging did not increase accuracy of MS diagnosis.^4,6 A follow-up MRI performed at 3 months, demonstrating new lesions, increased the identification of MS to 84%–100% of children who later had clinical relapse.^4,6

Three points are discussed:

1. The 2012 IPMSSG criteria (but not the Mc Donald 2010 criteria) required an age of 12 years or older for applying DIS and DIT criteria to diagnose MS at the time of the initial CIS.¹ However, subsequent studies^3,–,6 found that MS diagnostic criteria at CIS are applicable in younger children, provided that clinicians are aware that 2010 McDonald criteria have a lower positive predictive power and a higher false-positive rate.⁵ Documentation of new lesions on serial images or evidence of clinical relapses is strongly supportive of an MS diagnosis in all patients.

2. The fulfilment of DIS and DIT: DIS criteria are not specific for MS, nor sufficient for MS diagnosis in absence of a clinically relevant history, even in patients who accrue new lesions on serial MRI scans. The diagnosis of MS should also not be made, even if lesions are numerous on the baseline scan, in absence of radiologic signs of DIT (enhancing and nonenhancing clinically silent lesions at baseline or a single new T2 lesion or enhancing lesion on a scan performed more than 30 days from baseline).² In daily clinical practice, it has not yet been established when it is best to repeat an MRI after a first CIS for clinically stable patients. Two studies on follow-up MRI performed at 3 months^3,6 suggest that this time interval is both efficient (most patients will be recognized) and safe (treatment will not be excessively delayed). As such, we recommend a repeat MRI 3 months after a diagnosis of pediatric CIS.

3. Other diagnosis such as vasculitis might fulfil DIS and DIT criteria: a clinically relevant history is mandatory to diagnose MS.

Acute disseminated encephalomyelitis.

In children presenting with ADEM (in whom the presence of multiple lesions is likely to meet DIS and the presence of enhancing and nonenhancing lesions would also meet DIT), the criteria for a MS diagnosis using baseline DIT and DIS imaging criteria are not appropriate.⁵ As an ADEM-like attack is the first MS event in only 5%–15% of children,¹ the diagnosis of MS in such children requires a second non-ADEM attack as well as either further MRI findings of clinically silent new lesions or a third attack also not meeting criteria for ADEM.

Radiologically isolated syndrome (RIS).

RIS refers to individuals with incidental MS-typical MRI findings in whom clinical history or signs of MS are lacking. The following adult criteria⁸ are believed to be appropriate for pediatric RIS but should be validated:

1. MRI showing ovoid, well-circumscribed, and homogenous T2 hyperintensities fulfilling at least 3 Barkhof criteria (at least 1 gadolinium-enhancing lesion or 9 T2-hyperintense lesions; at least 1 infratentorial lesion; at least 1 juxtacortical lesion; at least 3 periventricular lesions).

2. No historical account of remitting symptoms of neurologic dysfunction indicating MS.

3. MRI findings do not account for symptoms for which the individual was imaged.

4. MRI findings are not better explained by another disease process.

In adults, male sex and an MRI lesion in the spinal cord increase the likelihood that RIS will be associated with a subsequent clinical attack⁹ but data are lacking for children. Published experience of pediatric RIS is limited to 5 cases (2–13 years): none developed a clinical event during 5–15 years of follow-up.¹⁰ The prevalence of cognitive deficits in children with RIS is unknown but worthy of investigation as adults with RIS have a cognitive profile similar to those with remitting-relapsing MS.¹¹

CNS-directed antibodies as potential biomarkers for distinct demyelinating disease phenotypes.

The identification of anti-aquaporin 4 antibodies as a relevant biomarker for neuromyelitis optica spectrum disorders emphasizes the potential for antibodies to aid in the diagnosis of CNS inflammatory disorders. Key considerations for antibodies as biomarkers include (1) fidelity with clinical features (see chapter 9); (2) persistent detection if such persistence distinguishes a specific disorder from transient immune recognition of multiple CNS antigens; and (3) pathogenicity of the antibodies within the CNS (required if the antibodies are thought to contribute to the disease directly). The assays used to measure antibodies must also be carefully validated (the increased sensitivity of cell-based assays now used for detection of aquaporin-4 antibodies emphasizes this point).

Anti–myelin oligodendroglial glycoprotein (MOG) antibodies have been detected in 18%–35% of children with a first acute episode of inflammatory demyelination^12,–,14 (see “Immunopathophysiology of pediatric CNS inflammatory demyelinating disease” on page S12). The transient detection of anti-MOG antibodies is more frequent in children at onset of ADEM, optic neuritis, and relapsing optic neuritis, and anti-MOG positivity predicts a non-MS disease course.^13,–,16 MOG-positive children have clinical and radiologic features typical for ADEM and elevated lymphocyte counts in CSF, suggesting a high degree of inflammation.^16,17 Persistence of anti-MOG antibodies has been associated with MS, although fewer than 25% of pediatric patients with MS have detectable anti-MOG antibodies.¹² Demonstrating the pathogenicity of anti-MOG antibodies and following larger cohorts of pediatric patients who have been tested for them are needed for the presence of MOG antibodies to serve as a disease-specific biomarker and to guide patient care.