Clinical features of neuromyelitis optica in children

Objective: To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases. Methods: Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified. Results: Thirty-eight cases of NMOwere identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p 5 0.02) and borderline findings for sex (p 5 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vsMS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS. Conclusion: The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment. Neurology® 2016;86:245–252 GLOSSARY ADEM 5 acute disseminated encephalomyelitis; DD-NOS 5 recurrent demyelinating disease not otherwise specified; EDSS 5 Expanded Disability Status Scale; IgG 5 immunoglobulin G; IPMSSG 5 International Pediatric Multiple Sclerosis Study Group; IPND 5 International Panel for NMO Diagnosis; IQR 5 interquartile range; IT 5 infratentorial; LETM 5 longitudinally extensive transverse myelitis; MOG 5 myelin oligodendrocyte glycoprotein; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica; ON 5 optic neuritis; PLEX 5 plasma exchange. Approximately 4% of neuromyelitis optica (NMO) cases are reported to be pediatric onset. Early differentiation of NMO from other childhood demyelinating disorders including acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) is critical for instituting appropriate therapy. Reports on pediatric NMO are often limited to small series or case reports, most of which have focused on NMO immunoglobulin G (IgG)–seropositive patients. The largest series from the Mayo Clinic described a cohort of 88 children seropositive for NMO From Partners Multiple Sclerosis Center (T.C.), Department of Neurology, Brigham and Women’s Hospital, Brookline; Partners Pediatric Multiple Sclerosis Center (T.C.), Massachusetts General Hospital for Children, Boston; University of Alabama Center for Pediatric Onset Demyelinating Disease (J.N.), Children’s Hospital of Alabama, Birmingham; the Lourie Center for Pediatric MS, Stony Brook Children’s Hospital (L.K., A.B.), New York, NY; the Department of Neurology (E.W., J.G.) and the Department of Pediatrics, Benioff Children’s Hospital (E.W.), University of California, San Francisco; the Departments of Pediatrics (T.H., C.S.O., T.C.C.) and Neurology (J.W.R.), University of Utah, Salt Lake City; Mayo Clinic’s Pediatric MS Center (M.R., M.P.), Rochester, MN; Blue Bird Circle Multiple Sclerosis Center (T.L.), Baylor College of Medicine, Houston, TX; Boston Children’s Hospital (M.G., L.B.), MA; the Pediatric Multiple Sclerosis Center (B.W.-G.), Jacobs Neurological Institute, SUNY Buffalo, New York, NY; and Pediatric MS Center at Loma Linda University Children’s Hospital (G.A.), CA. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by the Guthy-Jackson Charitable Foundation. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. © 2015 American Academy of Neurology 245 a 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. IgG antibody. Another series of 9 children with demyelinating disease included a description of children with relapsing NMO phenotype, 7 of whom were seropositive for NMO IgG antibody. The goal of this study was to characterize the demographic and clinical features in pediatric patients with NMO spectrum disorders relative toMS and ADEM and to test diagnostic criteria for NMO, including the recently proposed International Panel for NMODiagnosis (IPND 2015) criteria. METHODS Study setting. The US Network of Pediatric MS Centers is a group of 9 centers funded by the National MS Society that serve as regional referral centers for children and adolescents with demyelinating diseases of the CNS. These sites include Boston Children’s Hospital, Loma Linda Children’s Hospital, Massachusetts General Hospital, Mayo Clinic, SUNY-StonyBrook, SUNY-Buffalo, Texas Children’s Hospital, University of Alabama, and University of California San Francisco. Clinical data have been prospectively collected from pediatric patients with acquired CNS demyelinating diseases since May 2011, using standardized case report forms, including demographic features, neurologic examinations at visits, attack characteristics, and treatment information. Data are entered into an OpenClinica database, housed at the University of Utah Data Coordinating and Analysis Center. Patients. Four groups of patients were identified from the US Network of Pediatric MS Centers database seen between May 1, 2011, and December 31, 2013: those with a treating physician diagnosis of (1) NMO, (2) MS, (3) ADEM, or (4) any recurrent forms of CNS demyelinating disease not falling into the prior categories (recurrent demyelinating disease not otherwise specified [DD-NOS]). Summary case report forms were generated including age at onset, diagnoses at visits, relapse features, results of NMO IgG testing in serum and CSF, presence of CSF oligoclonal bands, and treatment history. Qualitative MRI review was performed by site investigators on NMO cases including the presence of a longitudinally extensive transverse myelitis (LETM) and the fulfillment of Paty or Barkhof brain MRI criteria. Each case was reviewed by at least 2/4 members of a clinical review panel (T.C., J.N., L.K., E.W.) and assigned the following diagnostic categories: 1. NMO meeting 2006 Wingerchuk criteria or consensus by the clinical review panel (n 5 38). 2. Pediatric MS meeting International Pediatric Multiple Sclerosis Study Group (IPMSSG) 2013 consensus criteria (n 5 150). 3. ADEM meeting IPMSSG consensus criteria and with at least 2 years of follow-up with no further attacks (n 5 24). 4. Recurrent DD-NOS: demyelinating disorders with.1 attack, not meeting definitions 1–3 (n 5 26). We assessed whether NMO cases met the updated IPND 2015 diagnostic criteria for NMO, which divide patients into NMO-IgG seropositive and NMO-IgG seronegative. Seropositive patients are required to have at least one of the following core clinical characteristics: optic neuritis (ON), transverse myelitis, area postrema syndrome, acute brainstem syndrome, narcolepsy or diencephalic syndrome, or cerebral syndrome with NMO spectrum disorder–typical brain lesions. Only the first 4 of these criteria could be assessed in our cohort, as the last 2 are not collected as part of the standard dataset. Seronegative patients are required to have at least 2 core clinical characteristics of the following: (1a) at least 1 core clinical characteristic must be ON, acute myelitis with LETM, or area postrema syndrome; (1b) dissemination in space; (1c) fulfillment of additional MRI requirements, as applicable; (2) negative test for aquaporin-4 IgG using best available assay, or testing unavailable; (3) no better explanation for the clinical syndrome. Statistical analysis. We described study populations using counts and relative frequencies for categorical variables, and means and standard deviations, or medians and interquartile ranges (IQR, or 75th percentile–25th percentile), for continuous variables. We reported the number of patients with available data for each description due to varying rates of unknown data. Descriptions included demographics, laboratory results, first attack locations and symptoms, and disease course. History of other autoimmune diseases of the patient and first-degree relatives (i.e., mother, father, full sibling), treatments, and timing of those treatments are also described. We tested for associations between diagnosis classifications using Fisher exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Differences between patients with seronegative and seropositive NMO were tested using the same methods. Differences were considered significant when p , 0.05. Analyses were conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, NC). Standard protocol approvals, registrations, and patient consents. Ethics committees of participating institutions approved this study. The University of Utah Data Coordinating and Analysis Center maintains the human subject research protocol for the centralized collection and storage of data from all participating sites. RESULTS Patient groups. We identified 38 patients with pediatric NMO, 150MS, 24 ADEM, and 26 recurrent DD-NOS, according to our reviewer classification criteria (table 1). Fulfillment of diagnostic criteria for NMO. We tested recent NMO criteria in 37/38 patients. One patient did not have sufficient information. Only 49% (18/ 37) of the reviewer-classified patients with NMO met the 2006 Wingerchuk diagnostic criteria for NMO. Thirteen patients were NMO IgG seropositive, yet had only one of the 2 core symptoms of ON or transverse myelitis. A total of 28/37 patients with NMO had LETM on their first available MRI scans. Of the reviewer-classified patients with NMO, approximately 1/3 (12/37) met Paty MRI criteria, including 9 who also met Barkhof MRI criteria: 7/37 (Paty) and 3/37 (Barkhof) on their first available scan. Updated diagnostic criteria for NMO have been proposed recently. Using this subset of criteria features as described in the methods, 36/37 (97%) reviewerdefined patients with NMO fit the updated diagnostic criteria. Demographic characteristics. The youngest patient within the pediatric NMO group was 16 months at 246 Neurology 86 January 19, 2016 a 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. onset. Mean age at onset (years) was 10.2 6 4.7 in NMO, 13.5 6 3.8 in MS, and 4.8 6 2.9 in ADEM (table 1). Onset prior to age 11 years was more common in ADEM (96%) and less common in MS (20%) and NMO (54%, p , 0.0001 both comparisons). Figure 1 presents the distribution of age at onset for all diagnosis classifications. The percentage of male participants was similar in the NMO (32%) and MS (37%) groups. In contrast, the ADEM cases were more frequently male (58%) compared to NMO cases (p 5 0.06). The ratio of female to male in patients with NMO,11 years was 1.5:1, and in those $11 years, 3.25:1 (figure 2). In contrast, the female:male ratio in MS,11 was 1.1:1, and in MS $11 was 1.86:1; in ADEM, the ratio was 0.77:1 (in ,11) and the $11 group was exclusively male. Nonwhite race was reported more frequently in NMO vs MS or ADEM (p , 0.01, both comparisons). Table 1 shows patient’s reported race and ethnicity by group. Among patients with NMO, 37% were African American, while 11% were Asian. Hispanic/Latino ethnicity was reported in 13% NMO, 31% MS, and 21% ADEM cases. History of other autoimmune disease. Frequency of other autoimmune diseases occurring in the patients as well as first-degree relatives is reported in figures e-1 and e-2 on the Neurology® Web site at Neurology.org. Patients with NMO (16%) and MS (9%) had similar rates of additional autoimmune disorders. Of patients with NMO, 42% had firstdegree relatives with an autoimmune disease compared with 32% of patients with MS. NMO-IgG results. A total of 37/38 patients with NMO had serum or CSF tested for NMO-IgG. NMO-IgG was present in 65% (24/37) of NMO cases: 60% (21/35) in serum and 50% (7/14) in CSF. No patient had positive CSF NMO-IgG and negative serum NMO-IgG in contemporaneous samples. Two patients had positive CSF NMO-IgG without contemporaneous serum testing performed. One of these patients had positive CSF 2 years after negative serum samples; however, a concomitant serum sample was not drawn at the time of CSF analysis. Of the 24 seropositive patients with NMO, 19 (79%) were positive the first time they were tested (mean time after disease onset 11.3 months; SD 15.0; range: 0–48 months), 4 became positive the 2nd time (mean time after disease onset 26.5 months; SD 17.4; range 3–45 months), and 1 the 3rd time (39.0 months from onset). Of 23 seropositive patients with information about the timing of the test, 57% tested positive within 12 months of disease onset, 13% within 12–23 months, 13% within 24–35 months, and 17% at 36 months or more. NMO-IgG was absent in patients with MS (44% tested, 0/66), patients with ADEM (42% tested, 0/10) and patients with recurrent DD-NOS (81% tested, 0/21). CSF results. Results of first CSF analysis are presented in table 2 (NMO,MS, andADEM) and table e-1 (recurrent DD-NOS). Mean CSF leukocyte count was higher in NMO vsMS (p5 0.01), but not different vs ADEM (p 5 0.88). Percent CSF neutrophils were highest in ADEM, but not different from the other groups (NMO 6.96 12.5, MS 8.16 11.5, p5 0.53; ADEM 21.26 22.9, p5 0.06). When all documented CSF laboratory results were included in the analysis, CSF oligoclonal bands were differentially present in NMO (31%), MS (68%), and ADEM (0%) (p , 0.01 comparing NMO and MS; p 5 0.08 comparing NMO and ADEM). Similarly, IgG index was elevated in 30% of NMO cases, 63% of MS cases (p 5 0.01 vs NMO), and 22% of ADEM cases (p 5 1.0 vs NMO). First attack features. We compared first symptoms as well as first attack locations in the different groups (table 3). Visual, motor, and constitutional symptoms Table 1 Demographics of patients with neuromyelitis optica (NMO), multiple sclerosis (MS), or acute disseminated encephalomyelitis (ADEM) NMO (n 5 38) MS (n 5 150) ADEM (n 5 24)