Diagnosis and Management of Children With Atypical Neuroinflammation

Pediatric neuroimmune disorders comprise a heterogeneous group of immune-mediated CNS inflammatory conditions. Some, such as multiple sclerosis, are well defined by validated diagnostic criteria. Others, such as anti-NMDA receptor encephalitis, can be diagnosed with detection of specific autoantibodies. This review addresses neuroimmune disorders that neither feature a diagnosis-defining autoantibody nor meet criteria for a distinct clinicopathologic entity. A broad differential in these cases should include CNS infection, noninflammatory genetic disorders, toxic exposures, metabolic disturbances, and primary psychiatric disorders. Neuroimmune considerations addressed in this review include seronegative autoimmune encephalitis, seronegative demyelinating disorders such as neuromyelitis optica spectrum disorder, and genetic disorders of immune dysregulation or secondary neuroinflammation. In such cases, we recommend a broad diagnostic workup to support the presence of neuroinflammation, exclude non-neuroimmune disorders, detect autoantibodies and other biomarkers of known diseases, identify any potential genetic drivers of neuroinflammation, and provide case-specific insights into pathophysiologic mechanisms of inappropriate immune pathway activation or dysregulation. This review includes an extensive list of useful diagnostic tests and potential implications thereof, as well as a proposed algorithm for the diagnosis and management of the pediatric patient with atypical neuroimmune disorders. In general, first-line acute treatment of neuroimmune disorders begins with steroids, along with consideration of plasmapheresis or IV immunoglobulin. Selection of second-line or maintenance therapy is challenging without a definite, specific diagnosis and the associated benefit of established evidence-based treatment options. Immunotherapies may be considered based on the suspected mechanism of neuroinflammation and the likelihood of relapse. For example, rituximab may be considered for possible antibody-mediated or B-cell-mediated inflammation while anti-interleukin (IL)-6 agents, anti-IL-1 agents, or JAK inhibitors may be considered for certain cases of cytokine-mediated inflammation or innate immune system dysregulation. Care should be taken to monitor response and disease activity, revisit the differential diagnosis in the case of unexpected findings or poor treatment response, and weigh the risks of immunotherapy with the benefits of empiric treatment. Over time, further advancements in biomarker identification and omics research may define specific new clinicopathologic diagnoses and thus obviate the need for "n of 1" approaches to what are currently heterogeneous groups of atypical seronegative neuroimmune disorders.