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

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

Novel cystatin B mutation and diagnostic PCR assay in an unverricht-lundborg progressive myoclonus epilepsy patient

Two mutations in the cystatin B gene, a 3′ splice mutation and a stop codon mutation, were previously found in patients with progressive myoclonus epilepsy of Unverricht-Lundborg type [Pennacchio et al. (1996): Science 271:1731–1734]. We present here a new mutation 2404δTC: a 2-bp deletion within the third exon of the cystatin B gene in an Unverricht-Lundborg patient. This mutation results in a frameshift and consequently premature termination of protein synthesis. Complete sequencing of the coding region and splice junctions of the cystatin B gene showed that neither of the two previously known mutations was present in this patient. The level of cystatin B mRNA in an immortalized cell line was found to be decreased, as had been reported for other Unverricht-Lundborg patients. The new mutation further supports the argument that defects in the cystatin B gene cause the Unverricht-Lundborg form of progressive myoclonus epilepsy. We describe a simple PCR method which can detect the 2404δTC deletion. This assay, together with previously described PCR assays for the other two known mutations, should prove useful in confirming clinically difficult diagnoses of Unverricht-Lundborg disease. Am. J. Med. Genet. 74:467–471, 1997. © 1997 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38271/1/1_ftp.pd

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells—often subtype specific—that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules (“neutraligands”) that are not receptor antagonists, high-affinity neuroligands (“decoy molecules”), as well as neutralizing “nanobodies” (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. “Fusokines” (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

The concept and recognized components of neuroinflammation are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron-glia interactions and other mechanisms affecting neurotransmission. They issue the help me cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells-often subtype specific-that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules ( neutraligands ) that are not receptor antagonists, high-affinity neuroligands ( decoy molecules ), as well as neutralizing nanobodies (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. Fusokines (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers