Long-term follow-up of neuromyelitis optica with a pediatric onset

Neuromyelitis optica (NMO) is a rare inflammatory disease occurring at an average age of 35 years (range 4–66).^1–3 Apart from case reports,^4,5 only 2 recent retrospective studies have contributed to epidemiologic and laboratory data on children with NMO: one on 17 children fulfilling the 1999 NMO criteria followed up for an average of 3 years and the other on 9 children fulfilling the 2006 NMO criteria followed up for an average of 4 years.^1,6

Pediatric-onset NMO (p-NMO) is especially characterized by frequent brain involvement at presentation, expressed clinically by encephalopathy or seizure associated with multiple sclerosis (MS)–like lesions on brain MRI.^1,6 Laboratory findings revealed a high prevalence of NMO-immunoglobulin G (IgG) positivity (78%) in the relapsing population but NMO-IgG positivity was estimated at 12.5% in the population with a monophasic disease course.¹

However, there are currently no data on time to disability in patients with p-NMO during a long follow-up. Furthermore, no study has compared p-NMO with adult-onset NMO (a-NMO), analyzed with the same design and using the same inclusion criteria.

We report the clinical and paraclinical features and long-term outcome of patients with p-NMO and compare them with a large a-NMO cohort.

METHODS

We retrospectively studied patients with p-NMO in 25 pediatric and adult medical centers in France. Through the Club Francophone de la Sclérose en Plaques, a French network of MS centers, we identified 200 patients with suspected NMO from September 2007 through August 2008, the study endpoint. Seventy-five experienced isolated optic neuritis/longitudinal extensive transverse myelitis (LETM) or MS. The remaining 125 fulfilled the 2006 criteria for NMO, namely optic neuritis, myelitis, and at least 2 of the following 3 items: LETM, NMO-IgG seropositivity, and brain MRI not meeting Paty criteria for MS.⁷ In this cohort, we identified 12 patients with p-NMO (onset before 18 years of age) and 113 with a-NMO. Data were collected from hospital files or using standardized assessment forms designed for NMO and have been entered in the European Database for MS, adapted to NMO specificities.⁸ Ethical approval, data confidentiality, and security were ensured in keeping with the recommendations of the French data protection authority, which approved the study.

For each patient, we recorded demographic data (gender, race, age at onset, follow-up), medical history of attacks and disability, laboratory data (NMO-IgG, CSF), MRI data (number and location of lesions), and treatments (type and number). Brain MRIs were classified as either not fulfilling or fulfilling MS criteria (Barkhof or Paty) and were performed a mean 84 ± 139 months after the first clinical event. Spinal cord MRIs were performed a mean 26 ± 13 months after the first clinical event. Sera of 111 patients were tested for NMO-IgG in Lyon, France, using an indirect immunofluorescence assay, as previously described.⁹ Residual disability was assessed during at least 6 months in terms of Expanded Disability Status Scale (EDSS) score and severe residual visual loss (SRVL), defined as a visual acuity ≤1/10 (corresponding to +1 on logMAR or 20/200 on Snellen visual acuity charts).

Categorical data were compared using the χ² test and quantitative data using the Mann-Whitney test. The Kaplan-Meier technique was used to estimate time to assignment of EDSS scores. Survival curves were compared using the log-rank test. Two-sided p values <0.05 were considered significant. All computations were performed using SPSS for Windows, version 14.0.

RESULTS

Characteristics and long-term outcome of patients with p-NMO.

Twelve children were followed up during a mean 19.3 years. Table 1 shows their clinical and paraclinical characteristics. Three patients (25%) fulfilled Paty criteria for MS on first brain MRI, including one patient with acute disseminated encephalomyelitis. During the course of the disease, patient 10 developed LETM and patient 8 experienced a regression of the brain MRI lesions, and both were also considered as NMO. The course of NMO was relapsing-remitting in all p-NMO cases. The median interval between onset and disability was 20.7 years for EDSS score 4, 26 years for EDSS score 6, and 28.7 years for EDSS score 7, and was 1.3 years for SRVL (figure). The median interval between the first myelitis and the assignment of EDSS scores 4, 6, and 7 was as follows: 15 years for score 4, 23.7 years for score 6, and 27 years for score 7. No patient reached an EDSS score ≥4 immediately after the first myelitis. After the first optic neuritis, median time to SRVL was 1.3 years.

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Table 1 Demographic, clinical, and paraclinical characteristics of patients with pediatric-onset NMO

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Figure Actuarial survival analysis of patients with neuromyelitis optica (NMO), according to age at onset

Kaplan-Meier estimates of time from NMO onset to the assignment of Expanded Disability Status Scale (EDSS) scores 4 (A), 6 (B), and 7 (C) and to severe residual visual loss (SRVL) (D) in patients with NMO with pediatric (p-NMO) or adult onset (a-NMO). Compared to patients with a-NMO (n = 101), patients with p-NMO (n = 12) had a longer median time to EDSS 4 (20.7 vs 5.3 years; p < 0.01) and EDSS 6 (26 vs 8.5 years; p < 0.01), whereas no difference was found for median time to either EDSS 7 (28.7 vs 21.4; p = 0.17) or SRVL (1.3 vs 15.1; p = 0.1). *Log-rank test was used to compare survival curves.

DISCUSSION

Our study underlines 2 points: the first brain MRI in p-NMO can show a diffuse inflammatory process, such as MS lesions (2 patients) or acute disseminated encephalomyelitis (1 patient); similarly to pediatric MS, p-NMO seems to have a better prognosis than a-NMO in terms of disability: time from onset to EDSS scores 4 and 6 was longer in patients with p-NMO, largely explained by the severity of the first myelitis in the a-NMO group.

To date, there is no explanation for the high level of inflammation in the brain of children with NMO.^1,3,6 The short time to SRVL in the patients with p-NMO is in accordance with the predictive role of the number of lesions on brain MRI for SRVL in NMO and a possible susceptibility of the optic nerve to inflammation.²

The good prognosis of patients with p-NMO is in line with a retrospective chart review, in which 9 patients with p-NMO experienced good visual and motor recovery after corticotherapy, with the absence of sequelae during an average 5-year follow-up.¹⁰ However, response to treatment is unlikely to be the sole explanation for the good prognosis, given the long interval before the first treatment in the p-NMO group.

Due to the retrospective design of this study, selection bias may limit the interpretation of the results. We cannot exclude the possibility that patients with severe p-NMO had died or were otherwise lost to follow-up at the time of the study. The predominant recruitment of patients in adult centers may have led to benign forms of p-NMO being underrepresented. No difference was found in the number of brain MRI lesions between the a-NMO and p-NMO groups. This may be due to a lack of statistical power due to the small number of p-NMO cases and the long delay in some cases between the first clinical event and the first brain MRI. Finally, the outcome of treatment is difficult to assess given the many different treatments used in the patients with p-NMO.

Prospective studies are needed to determine the disease course in children and assess the impact of immunosuppressive therapies in p-NMO.

ACKNOWLEDGMENT

The authors thank Vidjeyabaradi Brice for technical and material support, Prof. Pierre Meyer for statistical assistance, and Nick Barton for language editing.

DISCLOSURE

Dr. Collongues, Dr. Marignier, Dr. Zéphir, and Dr. Papeix report no disclosures. Dr. Fontaine serves on the editorial boards of Gene and Immunity, the Journal of Neurology, Neurosurgery and Psychiatry, Revue Neurologique, and the Journal of Neurology; and receives research support from Biogen Idec, Sanofi-Aventis, Merck Serono, INSERM (National Research Agency), the University Pierre and Marie Curie, Association Française contre les myopathies, and Association pour la Recherche sur la Sclérose en Plaques (ARSEP). Dr. Blanc, Dr. Rodriguez, and Dr. Fleury report no disclosures. Dr. Vukusic has received travel expenses and/or honoraria for lectures or educational activities not funded by the industry; has received funding for travel from Biogen Idec and Merck Serono; and has received honoraria from the Serono Symposia MS Foundation. Dr. Pelletier serves on scientific advisory boards for Biogen Idec and Novartis and has received research support from ARSEP. Dr. Audoin reports no disclosures. Dr. Thouvenot receives research support from ARSEP. Dr. Camu has received consulting fees from Sanofi-Aventis and Merck Serono. Dr. Barroso serves on a scientific advisory board for Biogen Idec and has received honoraria from the Serono Foundation. Dr. Ruet reports no disclosures. Dr. Brochet serves on a scientific advisory board for Bayer Schering Pharma; serves as a Associate Editor of SEP et Neurosciences; has received speaker honoraria from Novartis, Teva Pharmaceutical Industries Ltd., and Sanofi-Aventis; and receives research support to his institution from Merck Serono and Bayer Schering Pharma. Dr. Vermersch serves on scientific advisory boards for Merck Serono, Biogen Idec, Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., and Sanofi-Aventis; has received funding for travel and/or speaker honoraria from Merck Serono, Biogen Idec, and Bayer Schering Pharma; and receives research support from Merck Serono and Biogen Idec. Dr. Confavreux has received honoraria from the Serono Symposia Foundation; serves as a consultant for Sanofi-Aventis, Genzyme Corporation, UCB, Roche, and Novartis; and has received research funds from Biogen Idec, Bayer Schering Pharma, Merck Serono, Teva Pharmaceutical Industries Ltd., and Sanofi-Aventis to support the EDMUS project (European Database for multiple Sclerosis). Dr. de Seze serves on scientific advisory boards for and has received honoraria from Biogen Idec, LFB, Merck Serono, Sanofi-Aventis, and Bayer Schering Pharma; and serves on the editorial board of Revue Neurologique.