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.

Keywords: ROHHAD syndrome; anti-ANNA-1/anti-Hu syndrome; cerebrospinal fluid B cells; neuroblastic tumors; neuroinflammation; opsoclonus-myoclonus syndrome; paraneoplastic syndrome; pediatric neuroimmunological disorders.

Figure 1

US pin map of residential locations of children with opsoclonus-myoclonus syndrome (OMS) in the study sample. Some dots overlie each other. Our former center locations drew from the Mid-Atlantic States and Midwest. Fewer cases came from Southern California, where there is another OMS center.

Figure 2

Prodromal symptoms in patients with opsoclonus-myoclonus syndrome (OMS) per history. Patients may have more than one prodromal symptom.

Figure 3

(A) Frequency of opsoclonus-myoclonus syndrome (OMS) by age of OMS onset. N = 389. Data are displayed at 0.25-year increments. (B) Frequency of various neuroblastic tumors by OMS onset age. N = 177. Abbreviations—NB, neuroblastoma; GNB, ganglioneuroblastoma; GN, ganglioneuroma. (C) Frequency of neuroblastoma INSS stages by OMS onset age. N = 118. Classification—Stage 1: localized unilateral tumor, negative lymph nodes outside tumor; Stage 2: not all visible tumor could be resected but negative lymph nodes outside tumor (2A) or positive ipsilateral nodes (2B); Stage 3: not completely resected, tumor crossed midline, or positive contralateral lymph nodes, or tumor midline and spread to both sides; Stage 4: metastatic; Stage 4S: metastatic in infants <1 years old, unilateral tumor, no contralateral positive nodes (<10% marrow cells positive). (D) Frequency of neuroblastoma without OMS from published statistics (3). N = 643. Visual comparison of (C,D) reveals that the frequency of paraneoplastic OMS and of neuroblastoma is not a mere function of each other.

Figure 4

Ten presenting neurological signs of opsoclonus-myoclonus syndrome (OMS) by order of appearance per parents. The data are median ranks with interquartile range: the lower the rank, the earlier the sign. In Dunn’s multiple comparisons test, staggering occurred significantly before other signs (P < 0.0001). Refusing to walk and inability to sit were similar in occurring significantly later than falling, body jerks, and irritability, but earlier than loss of speech. Falling and body jerks occurred earlier than loss of speech or drooling. Loss of speech and drooling occurred later than irritability.