High-throughput Omic Technology for Identification of Biomarkers of Relapsing Acute Disseminated Encephalomyelitis in Immune Cell Network

High-throughput Omic Technology for Identification of Biomarkers of Relapsing Acute Disseminated Encephalomyelitis in the Immune Cell Network

Acute disseminated encephalomyelitis (ADEM) is a neuroinflammatory disorder of the central nervous system, manifesting itself as impaired consciousness, even to the point of coma, and multifocal neurological deficits. ADEM is the most common encephalitis in children. Moreover, 50-65% of ADEM in children is associated with the presence of anti-MOG antibodies (MOGAD). In fact, ADEM is the most frequent clinical presentation of MOGAD in children, 50-75% before the age of 10. The risk of recurrence is higher in pediatric MOGAD of ADEM manifestation, up to 30%, compared to myelitis or optic neuritis. Multiphasic MOGAD are more frequently associated with sequelae in 50-69% of cases, versus 4-32% for monophasic forms. In ADEM, cognitive and epileptic sequelae predominate. The 2020 European consortium and the 2022 national diagnosis and care protocol recommend the introduction of disease-modifying therapies as early as the second attack of the disease, or in the event of distant sequelae, in order to limit relapses and sequelae. However, these treatments take several months to take effect.

There is currently no reliable predictive factor for MOGAD recurrence other than the persistence of an elevated blood anti-MOG antibody level (≥1:1280) at 1 year. The aim of this study is therefore to identify biomarkers associated with MOGAD recurrence from the first attack. To this end, we will study the transcriptome of circulating blood mononuclear cells by single-cell next-generation RNA sequencing in children with anti-MOGAD neuroinflammatory relapses. Anticipating the multiphasic trajectory of the disease would enable the introduction of early disease-modifying therapy to prevent recurrences and long-term sequelae. Furthermore, the discovery of a molecular and/or cellular signature would provide a better understanding of the pathophysiology of ADEM and MOGAD.

Inclusion criteria:

Prospective recruitment Pre-inclusion criteria

• Age at inclusion between 1 and 18 years (included)
• First demyelinating event at inclusion, such as ADEM encephalitis, optic neuritis (NORB) or myelitis, or a combination of these conditions.
• Informed consent signed by patient's legal representative
• Patient affiliated to or benefiting from a social security scheme Inclusion criteria (confirmation of inclusion and follow-up in one of 3 groups)
• MOGAD/ADEM group: presence of serum anti-MOG antibodies and diagnosis of ADEM (according to the International Pediatric Multiple Sclerosis Society Group (IPMSSG) criteria revised in 2013) at the first demyelinating attack.
• Non-MOGAD/ADEM group: anti-MOG antibodies negative and diagnosis of ADEM at first demyelinating attack.
• MOGAD/non-ADEM group: presence of serum anti-MOG antibodies and diagnosis of myelitis and/or NORB at first demyelinating attack.

Retrospective recruitment General inclusion criteria

• Age at inclusion between 1 and 18 years (inclusive)
• Inclusion (signed consent of the patient's legal representative) in the biocollection from which the samples were taken at the latest at the time of management of a first demyelinating event of the ADEM encephalitis, optic neuritis (NORB) or myelitis type, or a combination of these disorders.
• PBMC collected at the time of the first demyelinating event before any immunomodulatory treatment, cryopreserved and available in the biocollection.
• Depending on the date of inclusion (if inclusion beyond 6 to 24 months after the first demyelinating event), samples taken at 6 months and then 24 months after the first demyelinating event available in the biocollection for the analyses planned in the study.
• Informed consent signed by patient's legal representative
• Patient affiliated to or benefiting from a social security scheme

Inclusion criteria specific to the 3 study groups

• MOGAD/ADEM group: presence of serum anti-MOG antibodies and diagnosis of ADEM (according to the International Pediatric Multiple Sclerosis Society Group (IPMSSG) criteria revised in 2013) at the first demyelinating attack.
• Non-MOGAD/ADEM group: anti-MOG antibodies negative and diagnosis of ADEM at first demyelinating attack.
• MOGAD/non-ADEM group: presence of serum anti-MOG antibodies and diagnosis of myelitis and/or NORB at first demyelinating attack.

Non-inclusion criteria (prospective or retrospective recruitment):

• Immunosuppressive therapy in the 6 months prior to treatment for a first demyelinating event.
• Systemic corticosteroid therapy or immunomodulating doses of IV polyvalent immunoglobulin or plasma exchange within 3 months prior to treatment for a first demyelinating event.
• Brain MRI not performed at diagnosis of first demyelinating event
• Poor understanding of the French language