Demographic, Clinical, and Immunologic Features of 389 Children with Opsoclonus-Myoclonus Syndrome: A Cross-sectional Study

Abstract

Pediatric-onset opsoclonus-myoclonus syndrome (OMS) is a devastating neuroinflammatory, often paraneoplastic, disorder. The objective was to characterize demographic, clinical, and immunologic aspects in the largest cohort reported to date. Cross-sectional data were collected on 389 children in an IRB-approved, observational study at the National Pediatric Myoclonus Center. Non-parametric statistical analysis was used. OMS manifested in major racial/ethnic groups, paralleling US population densities. Median onset age was 1.5 years (1.2–2 interquartile range), inclusive of infants (14%), toddlers (61%), and youngsters (25%). The higher female sex ratio of 1.2 was already evident in toddlers. Time to diagnosis was 1.2 months (0.7–3); to treatment, 1.4 months (0.4–4). Irritability/crying dominated prodromal symptomatology (60%); overt infections in <35%. Acute cerebellar ataxia was the most common misdiagnosis; staggering appeared earliest among 10 ranked neurological signs (P < 0.0001). Some untreated youngsters had no words (33%) or sentences (73%). Remote neuroblastic tumors were detected in 50%; resection was insufficient OMS treatment (58%). Age at tumor diagnosis related to tumor type (P = 0.004) and stage (P = 0.002). A novel observation was that paraneoplastic frequency varied with patient age—not a mere function of the frequency of neuroblastoma, which was lowest in the first 6 months of life, when that of neuroblastoma without OMS was highest. The cerebrospinal fluid (CSF) leukocyte count was minimally elevated in 14% (≤11/mm3) with normal differential, and commercially screened serum autoantibodies were negative, but CSF oligoclonal bands (OCB) and B cells frequency were positive (58 and 93%). Analysis of patients presenting on immunotherapy revealed a shift in physician treatment practice patterns from monotherapy toward multi-agent immunotherapy (P < 0.001); the number of agents/sequences varied. In sum, a major clinical challenge is to increase OMS recognition, prevent initial misdiagnosis, and shorten time to diagnosis/treatment. The index of suspicion for an underlying tumor must remain high despite symptoms of infection. The disparity in onset age of neuroblastoma frequency with that of neuroblastoma with OMS warrants further studies of potential host/tumor factors. OMS neuroinflammation is best diagnosed by CSF OCB and B cells, not by routine CSF or commercial antibody studies.

Multifactorial analysis of opsoclonus‐myoclonus syndrome etiology (“Tumor” vs. “No tumor”) in a cohort of 356 US children

“…The present study accepts the compelling reason and unique opportunity to study multiple factors that may be involved. To approach the problem, we performed extensive secondary analysis of just the US cases of a well‐defined population of pediatric‐onset OMS . Primary analysis of the data, which did not address this issue, is not reiterated here.…”

“…The opsoclonus‐myoclonus evaluation scale (OMES) used for assessing OMS severity is reprinted in Supplementary Table S1. Extensive methodological details were provided with the primary analysis …”

“…Commercial screening for “paraneoplastic” autoantibodies and antibodies associated with autoimmune encephalitis was so seldom positive, results were not dichotomized.…”

“…The diagnostic paradox is that a paraneoplastic etiology can only be proven presently in about 50% of the cases . One proposed explanation is missed tumors.…”

Current therapies and therapeutic decision making for childhood‐onset movement disorders

“…It is important to recognize immune‐mediated conditions that present with movement disorders in children, given that they are amenable to immune‐modulatory therapies. Opsoclonus myoclonus ataxia syndrome is a recognizable condition which is associated with neural crest tumors in 50% of cases, and the use of corticosteroids, intravenous immunoglobulin, rituximab, and cyclophosphamide has changed the natural history of this disease . As is true for many conditions, early recognition and treatment and inducing a complete clinical remission and minimizing relapse is the therapeutic aim .…”