Thursday, February 13, 2020

Myelin oligodendrocyte glycoprotein antibodies in pediatric demyelinating and encephalitic syndromes

Thaís Armangue,  Gemma Olivé-Cirera, Eugenia Martínez-Hernandez, Maria Sepulveda, Raquel Ruiz-Garcia, Marta Muñoz-Batista, et al.  Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study. Lancet Neurology.  Online Fbruary 20, 2020.


Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis.

In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity.

Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7–10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22–67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05–0·59).

The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications.

Myelin oligodendrocyte glycoprotein (MOG) antibodies were associated with a wider spectrum of pediatric autoimmune conditions than previously thought, an observational study in Spain showed.

Of 535 children with central nervous system (CNS) demyelinating disorders or encephalitis, 116 tested positive for MOG antibodies, according to Thais Armangue, MD, of Sant Joan de Deu Children's Hospital, Josep Dalmau, MD, of the University of Barcelona and University of Pennsylvania in Philadelphia, and colleagues. 

About 85% of those 116 children responded to treatment with complete or near-complete recovery, but 15% experienced severe deficits and one patient died, they reported in Lancet Neurology.

Most studies about MOG-antibody associated syndromes have focused on acquired demyelinating diseases, Dalmau said. "There have been only a few case reports, mainly including adult patients, suggesting that these antibodies can also occur in patients with encephalitis without overt clinical or MRI findings suggesting demyelinating features," he noted.

"Our study took a novel approach of prospectively examining two large cohorts of pediatric patients, one including 239 patients with demyelinating syndromes and the other 296 patients with all types of consecutively identified encephalitis in 40 Spanish centers," he told MedPage Today.

Of the 116 children diagnosed with MOG antibodies, 94 (39%) were in the group of demyelinating syndromes and 22 (7%) were in the encephalitis group. In the first group, the researchers confirmed the association of MOG antibodies with demyelinating syndromes previously known, including acute disseminated encephalomyelitis (ADEM), optic neuritis, and myelitis.

"The major surprise came from the group of patients with encephalitis, who had syndromes in which the presence of MOG antibodies is rarely considered or even suspected," Dalmau said. "This is important because nowadays about 40% of patients with encephalitis remain without a clear etiology."

MOG antibodies damage the myelin sheath surrounding nerve fibers, causing symptoms like vision loss, muscle weakness, and pain. Many children may only experience one MOG antibody disease event, but some may relapse months or years later. The full range of diseases associated with MOG antibodies is unknown.

In this study, researchers followed children with a median age of 6 in Spanish hospitals from 2013 to 2018. Children who tested positive for MOG antibodies were assessed over a median of 42 months.

Of the 116 children who tested positive for MOG antibodies, 24% had syndromes not previously associated with MOG antibodies.

During follow-up, 33 children had relapses, including 15 children who had more than one relapse. The likelihood of relapse was similar regardless of syndrome at disease onset. Time to antibody negativity was longer in patients with relapses (HR 0.18, 95% CI 0.05-0.59).

Steroids, intravenous immunoglobulin, or plasma exchange were used in 86% of children at diagnosis and 97% of children at relapse. Rituximab (Rituxan) was used in 11 children at relapse.

Most of the 116 patients who were MOG-positive had substantial recovery (85% had a score of 0 or 1 on the modified Rankin scale, indicating no significant disability). One boy died at 4 days follow-up, and the remaining children had moderate to severe deficits. Patterns associated with poor prognosis included ADEM-like relapses with changes that resembled leukodystrophy, and extensive cortical encephalitis evolving to brain atrophy.

At last follow-up, only five patients (4%) had been diagnosed with multiple sclerosis (MS), supporting the idea that MOG antibody-associated syndromes and MS are different pathological entities, the authors noted.

This research is "a milestone in the understanding of MOG antibody-associated syndromes," wrote Romain Marignier, MD, PhD, of the Hospices Civils de Lyon in France, in an accompanying comment.

"In view of the very broad clinical spectrum now associated with MOG autoimmunity, the next challenge will be to identify the optimal therapeutic strategy for each clinical presentation," he added. "This objective is closely connected to a better understanding of the pathogenic role of MOG antibodies, and the need for early, robust, and specific prognostic factors of relapse and disability." 

This study has several limitations, the researchers noted. It was not registry-based and could not assess the incidence and prevalence of MOG antibody-associated syndromes. Because follow-up was short, the frequency of relapses or MS development may have been underestimated. The study also did not include cognitive evaluations.

Some of the cases in the study "would have been missed if it were not for the systematic screening of our study," the researchers pointed out. "Overall, our findings are important because 85% of patients in this study had substantial recovery, illustrating the need for an update of the existing classification and terminology of MOG antibody-associated syndromes."


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