Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
1.
J Neuroimmunol ; 355: 577570, 2021 06 15.
Article in English | MEDLINE | ID: mdl-33862421

ABSTRACT

Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder. The pathogenesis is thought to be immune-mediated. In adults, it may be idiopathic or paraneoplastic in origin. However, most cases of paraneoplastic OMS in adults are not associated with well-characterized antibodies, except for a small subgroup who have anti-Ri antibodies. Herein, we provide the first detailed description of a case of OMS associated with a Kelch-like protein-11 antibody, a newly discovered biomarker for paraneoplastic neurological syndromes associated with germ-cell tumors. This was a young female patient in whom no tumor was ever detected and who had an excellent response to rituximab.


Subject(s)
Autoantibodies/blood , Carrier Proteins/blood , Neoplasms , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/diagnostic imaging , Adult , Female , HEK293 Cells , Humans
2.
Neurology ; 96(7): e1082-e1087, 2021 02 16.
Article in English | MEDLINE | ID: mdl-33443132

ABSTRACT

OBJECTIVE: A recent study showed glutamate receptor delta 2 antibodies (GluD2-ab) in sera of patients with opsoclonus-myoclonus syndrome (OMS). Inconsistencies between cerebellar immunoreactivity and expression of GluD2 led us to hypothesize that these antibodies are not biomarkers of OMS. METHODS: Serum of 45 children with OMS (10 [22%] with neuroblastoma), 158 adults with OMS (53 [34%] with tumors), and 172 controls including 134 patients with several types of neurologic disorders, 18 with neuroblastoma without OMS, and 20 healthy participants were investigated. Antibodies were determined with 3 different techniques: (1) rat brain immunohistochemistry, (2) a live cell-based assay using a standard secondary antibody (2-step CBA), and (3) a similar CBA with a secondary and tertiary antibodies (3-step CBA). Two plasmids were used in the CBA studies. Three commercial GluD2-ab and 2 human sera with GluD2-ab served as controls for expression of GluD2. RESULTS: The 3 commercial GluD2-ab showed predominant reactivity with the molecular and Purkinje cell layers (where GluD2 is highly enriched), and were also positive with the indicated CBAs. Substantially milder reactivity with brain tissue and CBA was obtained with the 2 control human sera containing GluD2-ab. None of the 203 patients with OMS and 172 controls showed immunoreactivities consistent with GluD2-abs. Compared with a standard 2-step CBA, the 3-step assay did not improve antibody detection and showed more frequent nonspecific reactivity that was not immunoabsorbed with GluD2. CONCLUSION: We did not find GluD2-ab in a large cohort of patients with OMS. GluD2-ab should not be considered diagnostic biomarkers of OMS.


Subject(s)
Autoantibodies/blood , Glutamate Dehydrogenase/immunology , Opsoclonus-Myoclonus Syndrome/immunology , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Opsoclonus-Myoclonus Syndrome/blood
3.
J Pediatr Hematol Oncol ; 43(2): e176-e179, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33060390

ABSTRACT

Pediatric opsoclonus-myoclonussyndrome (OMS) is a rare autoimmune disorder of which 50% are associated with neuroblastoma (NB). We investigated whether surface-binding autoantibodies in OMS can enhance natural killer (NK) cell-mediated cytotoxicity in these patients. OMS immunoglobulin G (IgG) bound to NB cell lines and NK cell-mediated cytotoxicity to NB cells was enhanced after preincubation with OMS-IgG, but not IgG from NB without OMS or healthy controls. Activation of NK cells by surface-binding autoantibodies may be an additional mechanism of antitumor immunity in children with NB and OMS.


Subject(s)
Apoptosis , Autoantibodies/immunology , Immunoglobulin G/adverse effects , Killer Cells, Natural/pathology , Neuroblastoma/pathology , Opsoclonus-Myoclonus Syndrome/pathology , Autoantibodies/blood , Autoantibodies/drug effects , Child, Preschool , Female , Follow-Up Studies , Humans , Immunoglobulin G/immunology , Infant , Killer Cells, Natural/immunology , Male , Neuroblastoma/blood , Neuroblastoma/complications , Neuroblastoma/immunology , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/complications , Opsoclonus-Myoclonus Syndrome/immunology , Prognosis
4.
Neurology ; 91(8): e714-e723, 2018 08 21.
Article in English | MEDLINE | ID: mdl-30045961

ABSTRACT

OBJECTIVE: To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology. METHODS: OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data. RESULTS: Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections. CONCLUSION: Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.


Subject(s)
Antibodies/blood , Opsoclonus-Myoclonus Syndrome/blood , Receptors, Glutamate/immunology , Adolescent , Animals , Animals, Newborn , Cerebellum/metabolism , Child , Child, Preschool , Encephalitis/blood , Extracellular Fluid/metabolism , Female , HEK293 Cells , Humans , Immunoprecipitation , Infant , Male , Mass Spectrometry , Neuroblastoma/metabolism , Neuroblastoma/pathology , Opsoclonus-Myoclonus Syndrome/pathology , Proteomics/methods , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/immunology , Receptors, Glutamate/genetics , Transfection
5.
J Neuroimmunol ; 321: 150-156, 2018 08 15.
Article in English | MEDLINE | ID: mdl-29685330

ABSTRACT

In 208 children with opsoclonus-myoclonus syndrome (OMS), CSF IgG oligoclonal bands (OCB) and 22 immunomarkers in CSF and 21 in serum/blood were measured. In 36 untreated OMS, 58% were OCB(+), whereas 55% of treated OMS were OCB(-). OCB positivity or negativity did not alter concentrations or frequencies of immunomarkers. The phenotypes of OCB(+) and OCB(-) patients were not distinctive. CSF B cells were expanded in untreated OMS regardless of OCB positivity. These data reveal a much higher frequency of OCB positivity in untreated OMS than previously realized and a disconnect between intrathecal OCB and inflammatory mediator production.


Subject(s)
Immunotherapy/methods , Inflammation Mediators/blood , Inflammation Mediators/cerebrospinal fluid , Oligoclonal Bands/blood , Oligoclonal Bands/cerebrospinal fluid , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Humans , Immunologic Factors/blood , Immunologic Factors/cerebrospinal fluid , Male , Opsoclonus-Myoclonus Syndrome/drug therapy , Retrospective Studies , Treatment Outcome
6.
Pediatr Neurol ; 65: 86-89, 2016 12.
Article in English | MEDLINE | ID: mdl-27707529

ABSTRACT

BACKGROUND: Opsoclonus-myoclonus syndrome is a rare clinical condition that has been associated with neuroblastoma. There are few reported examples of ANNA-1/anti-Hu antibodies in children with neuroblastoma and opsoclonus-myoclonus, all in children aged less than three years of age. METHODS: We describe the new onset of focal seizures without alteration of consciousness and opsoclonus-myoclonus in an 11-year-old girl with ANNA-1/anti-Hu positivity and a paraspinal ganglioneuroblastoma. A systematic review of the literature of children with ANNA-1/anti-Hu positivity and malignancy was also performed. RESULTS: Fourteen patients were identified, eight of whom had opsoclonus-myoclonus. Although epilepsia partialis continua has been described in association with several neuronal autoantibodies, association with ANNA-1/anti-Hu has not been reported. CONCLUSIONS: We describe epilepsia partialis continua in a child with ANNA-1/anti-Hu antibodies and neuroblastoma. Testing for antineuronal antibodies should be considered in children presenting with either opsoclonus-myoclonus or epilepsia partialis continua.


Subject(s)
Antibodies, Neoplasm , Autoantibodies , ELAV Proteins , Epilepsia Partialis Continua/diagnostic imaging , Opsoclonus-Myoclonus Syndrome/diagnostic imaging , Spinal Neoplasms/diagnostic imaging , Antibodies, Neoplasm/blood , Antibodies, Neoplasm/cerebrospinal fluid , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Child , ELAV Proteins/blood , ELAV Proteins/cerebrospinal fluid , Epilepsia Partialis Continua/blood , Epilepsia Partialis Continua/cerebrospinal fluid , Female , Humans , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Spinal Neoplasms/blood , Spinal Neoplasms/cerebrospinal fluid
8.
JAMA Neurol ; 73(4): 417-24, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26856612

ABSTRACT

IMPORTANCE: Most studies on opsoclonus-myoclonus syndrome (OMS) in adults are based on small case series before the era of neuronal cell surface antibody discovery. OBJECTIVE: To report the clinical and immunological features of idiopathic OMS (I-OMS) and paraneoplastic OMS (P-OMS), the occurrence of antibodies to cell surface antigens, and the discovery of a novel cell surface epitope. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study and laboratory investigations of 114 adult patients with OMS at a center for autoimmune neurological disorders done between January 2013 and September 2015. MAIN OUTCOMES AND MEASURES: Review of clinical records. Immunohistochemistry on rat brain and cultured neurons as well as cell-based assays were used to identify known autoantibodies. Immunoprecipitation and mass spectrometry were used to characterize novel antigens. RESULTS: Of the 114 patients (62 [54%] female; median age, 45 years; interquartile range, 32-60 years), 45 (39%) had P-OMS and 69 (61%) had I-OMS. In patients with P-OMS, the associated tumors included lung cancer (n = 19), breast cancer (n = 10), other cancers (n = 5), and ovarian teratoma (n = 8); 3 additional patients without detectable cancer were considered to have P-OMS because they had positive results for onconeuronal antibodies. Patients with I-OMS, compared with those who had P-OMS, were younger (median age, 38 [interquartile range, 31-50] vs 54 [interquartile range, 45-65] years; P < .001), presented more often with prodromal symptoms or active infection (33% vs 13%; P = .02), less frequently had encephalopathy (10% vs 29%; P = .01), and had better outcome (defined by a modified Rankin Scale score ≤ 2 at last visit; 84% vs 39%; P < .001) with fewer relapses (7% vs 24%; P= .04). Onconeuronal antibodies occurred in 13 patients (11%), mostly Ri/ANNA2 antibodies, which were detected in 7 of 10 patients (70%) with breast cancer. Neuronal surface antibodies were identified in 12 patients (11%), mainly glycine receptor antibodies (9 cases), which predominated in P-OMS with lung cancer (21% vs 5% in patients with OMS without lung cancer; P = .02); however, a similar frequency of glycine receptor antibodies was found in patients with lung cancer without OMS (13 of 65 patients [20%]). A novel cell surface epitope, human natural killer 1 (HNK-1), was the target of the antibodies in 3 patients with lung cancer and P-OMS. CONCLUSIONS AND RELEVANCE: Patients with I-OMS responded better to treatment and had fewer relapses than those with P-OMS. Older age and encephalopathy, significantly associated with P-OMS, are clinical clues suggesting an underlying tumor. Glycine receptor antibodies occur frequently in P-OMS with lung cancer, but the sensitivity and specificity are low. The HNK-1 epitope is a novel epitope in a subset of patients with P-OMS and lung cancer.


Subject(s)
Antigens, Surface/immunology , Autoantibodies/immunology , Neurons/immunology , Opsoclonus-Myoclonus Syndrome/immunology , Adult , Antigens, Surface/blood , Antigens, Surface/cerebrospinal fluid , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Cohort Studies , Female , Humans , Male , Middle Aged , Neurons/metabolism , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Retrospective Studies
9.
J Neuroimmunol ; 286: 86-92, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26298330

ABSTRACT

Opsoclonus myoclonus ataxia syndrome (OMAS) is an autoimmune disorder characterized by rapid, random, conjugate eye movements (opsoclonus), myoclonus, and ataxia. Given these symptoms, autoantibodies targeting the cerebellum or brainstem could mediate the disease or be markers of autoimmunity. In a subset of patients with OMAS, we identified such autoantibodies, which bind to non-synaptic puncta on the surface of live cultured cerebellar and brainstem neuronal dendrites. These findings implicate autoimmunity to a neuronal surface antigen in the pathophysiology of OMAS. Identification of the targeted antigen(s) could elucidate the mechanisms underlying OMAS and provide a biomarker for diagnosis and response to therapy.


Subject(s)
Antigens, Surface/immunology , Dendrites/metabolism , Neurons/cytology , Opsoclonus-Myoclonus Syndrome/immunology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Animals , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Brain Stem/cytology , Cells, Cultured , Cerebellum/cytology , Child , Child, Preschool , Dendrites/drug effects , Disks Large Homolog 4 Protein , ELAV Proteins/metabolism , Embryo, Mammalian , Guanylate Kinases/metabolism , Humans , Infant , Membrane Proteins/metabolism , Mice , Middle Aged , Neurons/drug effects , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Rats , Young Adult
11.
Neurology ; 81(17): 1500-6, 2013 Oct 22.
Article in English | MEDLINE | ID: mdl-24068784

ABSTRACT

OBJECTIVE: To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies. METHODS: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported. RESULTS: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms. CONCLUSION: Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.


Subject(s)
Autoantibodies/biosynthesis , Limbic Encephalitis/immunology , Lung Neoplasms/immunology , Receptors, GABA-B/immunology , Small Cell Lung Carcinoma/immunology , Adolescent , Adult , Aged , Ataxia/blood , Ataxia/cerebrospinal fluid , Ataxia/immunology , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Female , Follow-Up Studies , Humans , Limbic Encephalitis/blood , Limbic Encephalitis/cerebrospinal fluid , Lung Neoplasms/blood , Lung Neoplasms/cerebrospinal fluid , Male , Middle Aged , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Opsoclonus-Myoclonus Syndrome/immunology , Prognosis , Retrospective Studies , Small Cell Lung Carcinoma/blood , Small Cell Lung Carcinoma/cerebrospinal fluid , Status Epilepticus/blood , Status Epilepticus/cerebrospinal fluid , Status Epilepticus/immunology , Young Adult
12.
Cytokine ; 64(1): 331-6, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23764550

ABSTRACT

Identifying and blocking chemokine inflammatory mediators in pediatric opsoclonus-myoclonus syndrome (OMS) is critical to the treatment of this autoimmune, paraneoplastic, neurological disorder. In a prospective, case-control, clinico-scientific study of children with OMS compared to non-inflammatory neurological controls and other inflammatory neurological disorders, CCL19 (n=369) and CCL21 (n=312) were quantified in CSF and serum, respectively, by ELISA. Both cross-sectional and longitudinal effects of OMS and various immunotherapies were evaluated. Significant upregulation of CCL21 concentration (mean ± SD) (+32%) was found in serum of untreated OMS (630 ± 133 pg/mL), compared to controls (478 ± 168 pg/mL), (p<0.0001). Both corticosteroids and ACTH (corticotropin) significantly lowered CCL21 to control levels, as they did in combination with IVIg, rituximab, cyclophosphamide or other treatments, without additional reduction attributable to the other agents. In a pilot longitudinal study of ACTH-based triple therapy, the mean serum CCL21 concentration fell 59% from elevated to less than 1 SD below controls 1 week after high-dose ACTH, gradually returning to the control mean with ACTH tapering by 3 weeks and out to 12 weeks (p<0.0001). In contrast, CCL19, detectable in CSF, was not significantly altered by OMS or various immunotherapies. In the "high" CCL21 subgroup, higher serum concentrations of CCL22 (+57%) and CXCL13 (+40%), as well as the CSF concentration of BAFF (+64%), also were found. Elevated serum CCL21, not CSF CCL19, correlates with OMS severity and duration in pediatric OMS. Corticosteroids and ACTH were the only immunotherapies evaluated that down-regulated CCL21 production. Validation studies are needed to assess treatment biomarker status.


Subject(s)
Adrenal Cortex Hormones/metabolism , Adrenocorticotropic Hormone/metabolism , Chemokine CCL21/blood , Opsoclonus-Myoclonus Syndrome/metabolism , Receptors, CCR7/metabolism , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adrenocorticotropic Hormone/therapeutic use , Antibodies, Monoclonal, Murine-Derived/pharmacology , B-Cell Activating Factor/cerebrospinal fluid , Biomarkers/blood , Case-Control Studies , Chemokine CCL19/cerebrospinal fluid , Chemokine CCL21/metabolism , Chemokine CCL22/blood , Chemokine CXCL13/blood , Child , Child, Preschool , Cross-Sectional Studies , Cyclophosphamide/pharmacology , Down-Regulation , Female , Humans , Immunoglobulins, Intravenous/pharmacology , Immunologic Factors/pharmacology , Immunosuppressive Agents/pharmacology , Immunotherapy , Infant , Inflammation , Male , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/drug therapy , Prospective Studies , Receptors, CCR7/blood , Rituximab , Young Adult
13.
Clin Exp Immunol ; 172(3): 427-36, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23600831

ABSTRACT

Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder associated with remote cancer. To understand more clearly the role of inflammatory mediators, the concentration of CXCR3 ligands CXCL10, CXCL9 and CXCL11 was measured in 245 children with OMS and 81 paediatric controls using enzyme-linked immunosorbent assay (ELISA), and CXCR3 expression on CD4(+) T cells was measured by flow cytometry. Mean cerebrospinal fluid (CSF) CXCL10 was 2·7-fold higher in untreated OMS than controls. Intrathecal production was demonstrated by significantly different CXCL10 CSF : serum ratios. The dichotomized 'high' CSF CXCL10 group had higher CSF leucocyte count (P = 0·0007) and B cell activating factor (BAFF) and CXCL13 concentrations (P < 0·0001). CSF CXCL10 did not correlate with clinical severity or relapse using grouped data, although it did in some patients. Among seven types of immunotherapy, including rituximab or chemotherapy, only adrenocorticotrophic hormone (ACTH) monotherapy showed reduced CSF CXCL10, but prospective longitudinal studies of ACTH combination therapies indicated no reduction in CXCL10 despite clinical improvement (P < 0·0001). CXCL10 concentrations were 11-fold higher in CSF and twofold higher in serum by multiplexed fluorescent bead-based immunoassay than enzyme-linked immunosorbent assay, but the two correlated (r = 0·7 and 0·83). In serum, no group differences for CXCL9 or CXCL11 were found. CXCR3 expression on CD4(+) T cells was fivefold higher in those from CSF than blood, but was not increased in OMS or altered by conventional immunotherapy. These data suggest alternative roles for CXCL10 in OMS. Over-expression of CXCL10 was not reduced by clinical immunotherapies as a whole, indicating the need for better therapeutic approaches.


Subject(s)
Chemokine CXCL10/cerebrospinal fluid , Chemokine CXCL11/blood , Chemokine CXCL9/blood , Opsoclonus-Myoclonus Syndrome/immunology , Receptors, CXCR3/metabolism , Adrenocorticotropic Hormone/administration & dosage , B-Cell Activating Factor/cerebrospinal fluid , CD4-Positive T-Lymphocytes/immunology , Case-Control Studies , Chemokine CXCL10/blood , Chemokine CXCL13/cerebrospinal fluid , Child , Child, Preschool , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoassay , Immunotherapy , Infant , Inflammation Mediators/blood , Inflammation Mediators/cerebrospinal fluid , Male , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Opsoclonus-Myoclonus Syndrome/therapy , Receptors, CXCR3/blood , Steroids/administration & dosage
14.
J Neurol Sci ; 326(1-2): 53-8, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23380454

ABSTRACT

OBJECTIVE: To test for hypothesized disease- and treatment-induced changes in cytokines and adhesion molecules in children with opsoclonus-myoclonus syndrome (OMS). METHODS: Multiplex bead assay technology was used for simultaneous measurement of 34 soluble cytokines in cerebrospinal fluid (CSF) and serum. Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA. In total, there were 388 children (239 OMS, 114 controls, and 35 other inflammatory neurological disorders (OIND)). RESULTS: In untreated OMS, mean CSF IL-6 was elevated 2.3-fold, but 67-fold in OIND, without significant differences in other CSF cytokines. Mean serum concentrations of sIL-2Ra (+50%) and CXCL1 (+70%) (p<0.0001) were also raised. CSF CCL5 was more often detected in untreated OMS than controls (p=0.005), as was serum CCL11 and IL-13 in treated OMS. Mean CSF CCL4 and IL-1Ra were selectively higher in IVIg-treated OMS (p≤0.0001). CSF sICAM-1 was elevated only in OIND (3.3-fold); serum sICAM-1 was higher in untreated OMS (+21%); and sVCAM-1 was not affected. No correlations with OMS severity or duration were identified. CONCLUSIONS: Novel cytokine, cytokine antagonist, and soluble adhesion molecule abnormalities due to OMS or treatment were found. However, the normality of much of the data strengthens previous findings implicating B cell mechanisms.


Subject(s)
Cell Adhesion Molecules/blood , Cell Adhesion Molecules/cerebrospinal fluid , Cytokines/blood , Cytokines/cerebrospinal fluid , Inflammation Mediators/physiology , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Adolescent , Biomarkers/blood , Cell Adhesion Molecules/physiology , Child , Child, Preschool , Cytokines/antagonists & inhibitors , Female , Humans , Immunoglobulins, Intravenous/administration & dosage , Infant , Inflammation/blood , Inflammation/cerebrospinal fluid , Inflammation/drug therapy , Inflammation Mediators/blood , Inflammation Mediators/cerebrospinal fluid , Male , Opsoclonus-Myoclonus Syndrome/drug therapy
15.
J Clin Immunol ; 33(4): 817-25, 2013 May.
Article in English | MEDLINE | ID: mdl-23340773

ABSTRACT

PURPOSE: To study the role of Th2-attracting chemokines in opsoclonus-myoclonus syndrome (OMS), a serious neurological paraneoplastic disorder in need of better immunological understanding and therapy. METHODS: The CCR4 agonists CCL22 and CCL17 were measured in serum by ELISA in children with OMS (238 and 260, respectively), pediatric controls (115 and 143), and other inflammatory neurological disorders (33 and 24). RESULTS: Both CCL22 (+55 %) and CCL17 (+121 %) were significantly elevated in untreated OMS compared to controls and inter-correlated (p < 0.0001). Their concentrations in untreated OMS also were higher than in OIND (21 %, 41 %). The concentration of CCL22 in ACTH and steroids groups (not IVIg) was 51 % lower than in controls, but only a smaller effect of ACTH on CCL17 was found. Prospective longitudinal studies revealed a precipitous 81 % drop in CCL22 even by the first week of high-dose ACTH therapy, staying below control mean for at least 12 weeks, and a 34 % reduction after 8 months of combined treatment. Response to ACTH was dose-related (r = -0.50, p < 0.0001). Luminex detection confirmed the ELISA results for CCL22, which were about 200 % higher. CONCLUSIONS: These data reveal an elevated serum concentration of Th2-attracting chemokines CCL22 and CCL17 in OMS. Marked and rapid reduction in CCL22, not CCL17, with either ACTH or steroid therapy suggests differential regulation and cellular sources of CCR4 ligands, and CCL22 as a potential candidate biomarker for ACTH or corticosteroid effect.


Subject(s)
Chemokine CCL17/blood , Chemokine CCL22/blood , Opsoclonus-Myoclonus Syndrome/immunology , Th2 Cells/immunology , Adolescent , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Adrenocorticotropic Hormone/administration & dosage , Adrenocorticotropic Hormone/adverse effects , Chemokine CCL17/genetics , Chemokine CCL17/metabolism , Chemokine CCL22/genetics , Chemokine CCL22/metabolism , Child , Child, Preschool , Down-Regulation , Female , Humans , Infant , Male , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/drug therapy , Prospective Studies , Receptors, CCR4/agonists , Th2 Cells/drug effects , Up-Regulation
16.
J Neuroinflammation ; 10: 10, 2013 Jan 16.
Article in English | MEDLINE | ID: mdl-23324534

ABSTRACT

BACKGROUND: B-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder. OBJECTIVE: To assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS. METHODS: Soluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally. RESULTS: The mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (-61%) or corticosteroids (-38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into 'high' versus 'normal' CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003). CONCLUSIONS: Striking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.


Subject(s)
B-Cell Activating Factor/blood , Immunotherapy/methods , Inflammation Mediators/blood , Opsoclonus-Myoclonus Syndrome/blood , Severity of Illness Index , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Adolescent , B-Cell Activating Factor/cerebrospinal fluid , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Case-Control Studies , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Infant , Inflammation Mediators/cerebrospinal fluid , Longitudinal Studies , Male , Opsoclonus-Myoclonus Syndrome/pathology , Opsoclonus-Myoclonus Syndrome/therapy , Prospective Studies , Tumor Necrosis Factor Ligand Superfamily Member 13/cerebrospinal fluid
17.
J Neurol Sci ; 320(1-2): 61-5, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22818114

ABSTRACT

BACKGROUND: Opsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. METHODS: We recorded eye movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. RESULTS: In all patients but one the opsoclonus resolved within 2weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4-10Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. CONCLUSIONS: The clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus.


Subject(s)
Autoantibodies/metabolism , Cerebellum/immunology , Eye Movements/immunology , Opsoclonus-Myoclonus Syndrome/diagnosis , Opsoclonus-Myoclonus Syndrome/immunology , Adult , Animals , Autoantibodies/blood , COS Cells , Cell Line, Transformed , Cerebellum/metabolism , Chlorocebus aethiops , Eye Movements/physiology , Female , Humans , Male , Middle Aged , Opsoclonus-Myoclonus Syndrome/blood , Purkinje Cells/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Glutamate/genetics , Receptors, Glutamate/metabolism
18.
Cytokine ; 53(3): 384-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21211990

ABSTRACT

The aim of the study was to test the hypothesis that B-cell repopulation following rituximab (anti-CD20) therapy is orchestrated by chemokines and non-chemokine cytokines. Twenty-five children with opsoclonus-myoclonus syndrome (OMS) received rituximab with or without conventional agents. A comprehensive panel of 40 chemokines and other cytokines were measured in serum by ELISA and multiplexed fluorescent bead-based immunoassay. Serum BAFF concentration changed dramatically (even after first infusion) and inversely with B-cell depletion/repopulation and CXCL13 concentration at 1, 3, and 6 months. Negative correlations were found for BAFF concentration vs blood B cell percentage and serum CXCL13 concentration; positive correlations with serum rituximab concentrations. Six months after initiation of therapy, no significant difference in the levels of APRIL, CXCL10, IL-6, or 17 other cytokines/chemokines were detected. These data reveal a major role for BAFF in peripheral B cell repopulation following rituximab-induced B-cell depletion, and novel changes in CXCL13. ClinicalTrials.gov NCT0024436.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Chemokines/blood , Cytokines/blood , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/drug therapy , Adrenocorticotropic Hormone/administration & dosage , Adrenocorticotropic Hormone/therapeutic use , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/blood , B-Cell Activating Factor/blood , B-Lymphocytes/drug effects , B-Lymphocytes/pathology , Chemokine CXCL13/blood , Child , Drug Administration Schedule , Drug Therapy, Combination , Enzyme-Linked Immunosorbent Assay , Humans , Immunoassay/methods , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/administration & dosage , Immunologic Factors/blood , Immunologic Factors/therapeutic use , Rituximab , Time Factors , Treatment Outcome
19.
J Clin Immunol ; 30(1): 106-13, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19838774

ABSTRACT

INTRODUCTION: Opsoclonus-myoclonus syndrome (OMS) is an autoimmune paraneoplastic disorder characterized by B and T cell abnormalities in cerebrospinal fluid (CSF) and propensity for relapse. The study aim was to assess whether rituximab-induced B cell ablation in CSF outlasts repopulation in blood and if there are changes in other lymphocyte subsets. MATERIALS AND METHODS: In 25 children with OMS, the expression of CSF and blood lymphocyte surface antigens was evaluated by flow cytometry before and at intervals after rituximab therapy. RESULTS: The reduction in CSF CD27+ memory, CD38+ activated, CD5+, and other B cell subsets was profound (p < 0.0001), comparable across groups (-94%), and sustained over 12-18 months despite repopulation in blood. The observed lag in memory B cell pool recovery in the CSF compared to peripheral blood may be clinically relevant. T cell phenotypic changes involved frequency, not absolute counts, and were transient. Co-treatment with IVIg or ACTH did not significantly alter B cell depletion or repletion. DISCUSSION: These data indicate that rituximab affords long-term protection against CSF B cell expansion in OMS (ClinicalTrials.gov NCT00244361).


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antigens, CD/metabolism , B-Lymphocytes/drug effects , Lymphocyte Subsets/drug effects , Opsoclonus-Myoclonus Syndrome/drug therapy , T-Lymphocytes/drug effects , Adolescent , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antigens, CD/genetics , Antigens, CD/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Cell Proliferation/drug effects , Cells, Cultured , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Immunologic Memory/drug effects , Immunophenotyping , Infant , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/pathology , Male , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Opsoclonus-Myoclonus Syndrome/immunology , Opsoclonus-Myoclonus Syndrome/pathology , Rituximab , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Time Factors
20.
J Neuroimmunol ; 210(1-2): 87-91, 2009 May 29.
Article in English | MEDLINE | ID: mdl-19339060

ABSTRACT

Childhood opsoclonus-myoclonus syndrome (OMS) occurs idiopathic or, in association with a neuroblastoma, as a paraneoplastic syndrome. Since autoantibodies were identified in some patients, an autoimmune pathogenesis has been suspected. While the newly discovered B-cell activating factors BAFF and APRIL are involved in systemic autoimmune diseases, their association with neuroimmunological diseases is hardly understood. We here investigated the BAFF and APRIL levels in serum and cerebrospinal fluid (CSF) of OMS patients and their correlation with surface-binding autoantibodies. BAFF and APRIL were both determined by ELISA, and autoantibodies to cerebellar granular neurons (CGN) have been investigated by flow cytometry in 17 OMS patients, 16 neuroblastoma (NB) patients, 13 controls and 11 children with inflammatory neurological diseases (IND). BAFF, but no APRIL, was elevated in the CSF of OMS children and IND children. However, in contrast to IND patients, OMS patients did not have a blood-brain-barrier disturbance, indicating that BAFF was produced intrathecally in OMS patients, but not in IND patients. CSF BAFF levels showed a correlation with CSF CGN autoantibodies (r(2)=0.58, p<0.05). These data indicate that an activated B-cell system in the cerebrospinal fluid is involved in the pathogenesis of OMS, and BAFF may be a candidate parameter for the activation of B-cell immune system.


Subject(s)
Autoantibodies/cerebrospinal fluid , B-Cell Activating Factor/analysis , Cerebellar Diseases/immunology , Lymphocyte Activation/immunology , Opsoclonus-Myoclonus Syndrome/immunology , Antibody Formation/immunology , Autoantibodies/analysis , B-Cell Activating Factor/blood , B-Cell Activating Factor/cerebrospinal fluid , Biomarkers/analysis , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Blood-Brain Barrier/immunology , Cerebellar Diseases/cerebrospinal fluid , Cerebellar Diseases/physiopathology , Cerebellum/immunology , Cerebellum/pathology , Cerebellum/physiopathology , Child, Preschool , Female , Humans , Male , Opsoclonus-Myoclonus Syndrome/blood , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Predictive Value of Tests , Subarachnoid Space/immunology , Subarachnoid Space/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/analysis , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Up-Regulation/immunology
SELECTION OF CITATIONS
SEARCH DETAIL
...