Understanding early brain inflammation in children who develop MS

Dr Fabienne Brilot-Turville

The University of Sydney, NSW

| Causes and Prevention | Immunology | Neurobiology | Project | 2012 | Investigator Led Research |


MS is an inflammatory disease in which the fatty myelin sheaths around the axons (nerve fibres) of the central nervous system are damaged, leading to demyelination. Up to 10% of adult MS sufferers have their first episode of demyelination when they are young, and MS is being increasingly diagnosed in children. Dr Brilot-Turville, Associate Professor Dale, and their colleagues will identify the earliest immune responses against the brain in children who develop MS. Identifying these early immune responses will allow early and directed treatments to prevent disability and death in the future.

Primary investigator Dr Brilot-Turville’s study is the largest follow-up study of Australian children after a first episode of CNS demyelination and has provided a unique insight into both childhood and adult MS. This study will define a subgroup of demyelination patients who have antibodies against one of the most significant myelin proteins in MS, MOG. Her study will define the importance of anti-MOG antibodies as a predictor of MS, and will investigate the effect of the anti-MOG antibody on the myelin-producing cells, oligodendrocytes.

This project also aimed to investigate the link between anti-MOG antibody detection and the presence and activation of immune cells in cerebrospinal fluid. Based on results obtained, the detection of the anti-MOG antibody in children may define a subgroup of patients that could benefit from therapy targeting these self-directed immune cells with the aim of preventing progression to MS.

This research will greatly improve the knowledge of CNS demyelination and progression to MS and will have an impact on the care of these patients.

Project Outcomes

The follow-up of the Australian children affected by a first episode of demyelination is now completed. The aim was to follow-up these children for the longest time possible, and study how many of them progressed to MS. The mean follow-up time for the cohort is around 5 years, which is quite long compared to what has been previously published. At this time, 14% of children with a first episode of demyelination have progressed to MS (cut-off 16 years). The team have also been able to show that the McDonald 2010 MS diagnostic criteria (which were developed to assist with the diagnosis of MS in adults) performed well in this cohort with a sensitivity of 91% and specificity of 93%.

Dr Brilot-Turville then analysed correlations between MS progression, immune cells in the cerebrospinal fluid, and presence of serum MOG antibody in the cohort of children. The whole cohort and prospective patients were tested for MOG antibody in the serum using a new cell-based assay to detect MOG antibody based on a fluorescent green lentivirus, optimised by the team.

These analyses have also detected autoantibody anti-MOG (myelin oligodendrocyte glycoprotein) in the serum of these patients. Unexpectedly, anti-MOG antibody-positive patients did not have CSF intrathecal oligoclonal bands (a typical feature of MS), and did not fulfill McDonald MRI criteria for MS. Dr Brilot-Turville’s results in the cohort of children with inflammatory demyelination has demonstrated that anti-MOG antibody is a useful biomarker that strongly associates with a “new” demyelinating syndrome that is separate from MS.

The final aim of this project was to explore whether the MOG-antibody could be associated with structural changes in the brain. Dr Brilot-Turville and colleagues optimised assays in order to study the functional effect of the binding of MOG-antibody to the MOG protein on the surface of cells. This study identified that MOG-antibodies may disrupt the structural skeleton inside brain cells that produce myelin.

Dr Brilot-Turville and Associate Professor Dale have achieved remarkable outcomes in this project, publishing six high quality manuscripts in peer-reviewed journals, with another currently submitted for publication.


  • Sudarshini Ramanathan, Stephen W. Reddel,  Andrew Henderson,  John D.E. Parratt,  Michael Barnett,  Prudence N. Gatt, Vera Merheb, Raani-Yogeeta Anusuiya Kumaran, Karrnan Pathmanandavel, Nese Sinmaz, Mahtab Ghadiri, Con Yiannikas, Steve Vucic, Graeme Stewart, Andrew F. Bleasel, David Booth, Victor S.C. Fung, Russell C. Dale, Fabienne Brilot. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm December 2014 vol. 1 no. 4 e40
  • Dale RC, Tantsis EM, Merheb V, Kumaran RY, Sinmaz N, Pathmanandavel K, Ramanathan S, Booth DR, Wienholt LA, Prelog K, Clark DR, Guillemin GJ, Lim CK, Mathey EK, Brilot F. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Accepted for publication, Neurology: Neuroimmunology & Neuroinflammation.
  • Dale RC, Tantsis E, Merheb V, Brilot F. Cerebrospinal fluid B-cell expansion in longitudinally extensive transverse myelitis associated with neuromyelitis optica immunoglobulin G. Dev Med Child Neurol 2011; 53(9): 856-60 (I.F.: 2.776)
  • Pröbstel AK, Dornmair K, Bittner R, Sperl P, Jenne D, Magalhaes S, Villalobos A, Breithaupt C, Weissert R, Jacob U, Krumbholz M, Kümpfel T, Blaschek A, Stark W, Gärtner J, Pohl D, Rostasy K, Weber F, Forne I, Khademi M, Olsson T, Brilot F, Tantsis E, Dale RC, Wekerle H, Hohlfeld R, Banwell B, Bar-Or A, Meinl E, and Derfuß T. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 2011; 77(6): 580-8 (I.F.: 8.249)
  • Dale RC, Banwell B, Bar-Or A, Brilot F. (2012) Autoantibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein in paediatric CNS demyelination: Recent developments and future directions. Multiple Sclerosis and Related Disorders. 1(3):116-122.
  • Tantsis EM, Prelog K, Ouvrier RA, Brilot F and Dale RC. Risk of Multiple Sclerosis after a first demyelinating episode in an Australian Paediatric Cohort: Clinical, radiological features and application of the McDonald 2010 MRI criteria. Multiple Sclerosis Journal (underway).
  • Mayer MC, Breithaupt C, Reindl M, Schanda K, Rostásy K, Berger T, Dale RC, Brilot F, Olsson T, Jenne D, Pröbstel AK, Dornmair K, Wekerle H, Hohlfeld R, Banwell B, Bar-Or A, Meinl E. Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol. 2013 191(7):3594-604.

Another manuscript is currently being considered for publication.

Updated: 30 June 2014

Updated: 06 January, 2012


Grant Awarded

  •  Project Grant

Total Funding

  • $50,000


  • 2 years over 2012 - 2013

Funding Partner

  • MS Angels
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Understanding early brain inflammation in children who develop MS