Neuroimmune disorders of the central nervous system in children in the molecular era

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Abstract

Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.

Key points

  • Neuroimmune disorders are more prevalent than previously appreciated.

  • Advances in assay development, genetic research, neuroimaging and clinical phenotyping have led to better characterization of the different neuroimmune disorders.

  • Immune signatures have not been identified for all neuroimmune disorders; diagnosis in patients with these disorders relies on the clinical features of acquired neuroinflammation.

  • Prompt diagnosis and immunomodulatory therapy have improved clinical outcomes from neuroimmune disorders, but formal consensus-based treatment protocols or protocols based on evidence from clinical trials are yet to be established.

  • Collaborative research into the pathobiological mechanisms of neuroimmune disorders will further refine relevant treatment strategies, including targeting of key biological pathways.

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Fig. 1: Diagnostic algorithm for a first presentation of acquired demyelinating syndrome in a child without encephalopathy.
Fig. 2: Diagnostic algorithm for patients with neuroimmune disorder with encephalopathy.
Fig. 3: Examples of typical MRI findings in neuroimmune disorders.

Change history

  • 15 November 2018

    In the original version of this Review published online and in print, the contribution of attendees of the International Neuroimmune Meeting to the content of the Review was not acknowledged. The author list has been corrected in the PDF and HTML versions of this article to acknowledge that the Review was written on behalf of attendees of the International Neuroimmune Meeting, and the names of the attendees have been added to the HTML version.

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Acknowledgements

This Review was derived from a meeting of clinicians, scientists and patient advocacy groups that was held in Washington DC in June 2014 and was funded by the Ikaria Fund at Children’s National Health System. A.W. has received research support from the Children’s Hospital of Philadelphia (Foerderer Award), Elise’s Corner (the Akron Community Foundation), the Lynn Saligman League, the US NIH (K23NS069806 and R01NS071463), the National Multiple Sclerosis Society and the Calliope Joy Foundation. B.A. is funded by the US NIH (R01 NR012907, R01 NR014449, R01 NR014449 and R01 NR015738). R.C.D. has received research funding from MS Research Australia, the Australian National Health and Medical Research Council, the Petre Foundation, the Tourette Syndrome Association and the University of Sydney. W.G. receives grant support from the American Epilepsy Society, Citizens United for Research in Epilepsy, the Epilepsy Foundation, the Infantile Epilepsy Research Foundation, the US National Science Foundation, the US NIH and the Patient-Centered Outcomes Research Institute. B.G. has grant support from the Guthy-Jackson Charitable Foundation, the US NIH and the Patient-Centered Outcomes Research Institute. R.C.T. has received funding from the US NIH (R21-NS084264 and U01-NS081041). E.A.Y. has received funding from the Canadian Institute for Health Information, the Canadian Institutes for Health Research, the Mario Batali Foundation, the Multiple Sclerosis Society of Canada, the National Multiple Sclerosis Society, the Patient-Centered Outcomes Research Institute, the Rare Disease Foundation, the SickKids Foundation and the SickKids Innovation Fund. She has received travel support and/or honoraria from the Paediatric Association of Jamaica, the Saudi Arabian Child Neurology Association, the Guthy-Jackson Charitable Foundation and the Nicholas Foundation. S.P. has received support from the Guthy-Jackson Charitable Foundation and the US NIH (R01 NS065829-01) for neuromyelitis optica research.

The names of the attendees of the International Neuroimmune Meeting are as follows; Jessica Carpenter, Irene Cortese, Nathan Dean, Raquel Farias-Moeller, William Gallentine, Carol Glaser, Raphaela Goldbach-Mansky, Ilana Kahn, Bennett Lavenstein, William McClintock, William McDow, Jennifer Murphy, Avindra Nath, Roger Packer, Tova Ronis, David Schleyer, Stephanie Schleyer, Peter Shibuya, Ursula Utz, Gilbert Vezina and David Wessel.

Review criteria

References for this Review were identified through searches of PubMed by use of the search terms “autoimmune”, “inflammatory”, “p(a)ediatrics”, “N-methyl-d-aspartate receptor”, “MOG”, “AQP4”, “aquaporin”, “neuromyelitis”, “transverse myelitis” and “optic neuritis”. Papers published from 1990 to January 2018 were included. Only papers published in English were reviewed. The final reference list was generated on the basis of relevance to the topics covered in this Review.

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Nature Reviews Neurology thanks D. Pohl, M. Riendl and S. Vernino for their contribution to the peer review of this work.

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E.W., Y.H., A.V. and B. Banwell drafted the manuscript. All authors participated in manuscript development and review.

Correspondence to Yael Hacohen or Brenda Banwell.

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Competing interests

A.W. has received research support from Biogen, Chugai, MedImmune, Ionis Pharmaceuticals and Novartis. She has also received speaker’s fees from SUNY Downstate Medical Center and receives publishing royalties from UpToDate. R.C.D. has received research funding from Pfizer and Star Scientific Foundation. He has also received honoraria from Biogen and Bristol-Myers Squibb as an invited speaker. W.G. sits on the editorial board of Epilepsia and holds stock from Eli Lilly, General Electric, GlaxoSmithKline, Johnson and Johnson, Pfizer and Siemens. M.G. has received grant support from Lilly, Novartis, Sobi and Regeneron. B.G. serves on the medical and scientific advisory board of the Transverse Myelitis Association. He has received consulting income from EMD Serono and Novartis. He has grant support from Acorda Therapeutics, Biogen, Chugai and MedImmune. C.A.P. serves on the medical and scientific advisory board of the Transverse Myelitis Association. E.A.Y. has received speaker’s honoraria from EXCEMED, and she is an ACI consultant. S.P. and the Mayo Clinic have a financial interest in patents (#12/678,350 filed in 2010 and #12/573,942 filed in 2008) that relate to functional aquaporin 4 immunoglobulin (IgG) and neuromyelitis optica IgG assays and neuromyelitis optica IgG as a cancer marker. S.P. has consulted for Alexion Pharmaceuticals, Chugai and MedImmune but has received no personal fees or personal compensation for these consulting activities; all compensation for consulting activities is paid directly to the Mayo Clinic. He has also received a research grant from Alexion Pharmaceuticals for an investigator-initiated study. All other authors declare no competing interests.

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