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Michael R. Pranzatelli - One of the best experts on this subject based on the ideXlab platform.
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multifactorial analysis of Opsoclonus Myoclonus Syndrome etiology tumor vs no tumor in a cohort of 356 us children
Pediatric Blood & Cancer, 2018Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Nathan R McgeeAbstract:Background Pediatric Opsoclonus-Myoclonus Syndrome (OMS) presents a paradox of etiopathogenesis: A neuroblastic tumor (NB) is found in only one half of the cases, the others are ascribed to infections or designated as idiopathic. Method From an IRB-approved observational study of 356 US children with OMS, secondary analysis of "etiology" and related factors was performed on a well-characterized cohort. The "Tumor" (n = 173) and "No Tumor" groups (n = 183), as defined radiologically, were compared according to multiple factors considered potentially differentiating. Data were analyzed retrospectively using parametric and nonparametric tests as indicated. Results Patients with NB were not distinguishable by prodromal symptoms, OMS onset age, gender, race/ethnicity, OMS severity, rank order of neurological sign appearance, or geographic distribution. Various CSF immunologic biomarker abnormalities of OMS did not vary in the presence or absence of a detectable tumor: frequency of six lymphocyte subsets, or concentrations of 18 cytokines/chemokines, cytokine antagonists, chemokine receptors, cell adhesion molecules, or neuronal/glial markers. Prior responsiveness to conventional immunotherapy was not contingent on tumor/no tumor designation. Conclusions Multiple convergent factors provide compelling empirical evidence and rationalize the concept that OMS is one neurological disorder, regardless of apparent etiology. Limitations to the current clinical etiologic classifications as paraneoplastic, parainfectious/post-infectious, and idiopathic etiology require antigen-based biological solutions to tease out the molecular pathophysiology of viral/tumoral mechanisms. Systematic studies, regardless of presumed etiology, will be necessary to find the highest-yield combination of imaging approaches, screening for infectious agents, and new biomarkers. Two testable hypotheses for future research are presented.
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evaluation of responsiveness to reduced dose rituximab in corticotropin intravenous immunoglobulin rituximab combination immunotherapy for Opsoclonus Myoclonus Syndrome
Pediatric Neurology, 2018Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Nathan R Mcgee, Craig MacarthurAbstract:Abstract Background Rituximab (anti-CD20) has been used as B-cell-targeted intervention to treat Opsoclonus-Myoclonus Syndrome. Due to isolated reports of chronic hypogammaglobulinemia and B lymphopenia following rituximab in several disorders, and rapid B-cell depletion after a few doses, we reduced the dosage 20% in our clinical practice. Methods In this Institutional Review Board-approved retrospective study, 32 children with Opsoclonus-Myoclonus Syndrome and cerebrospinal fluid B-cell expansion had received front-loaded adrenocorticotropic hormone, intravenous immunoglobulin, and rituximab combination immunotherapy for de novo Opsoclonus-Myoclonus Syndrome. Parametric statistical analysis compared 10 children receiving 1200 mg/m2 of rituximab (300 mg/m2 × 4) and 22 receiving 1500 mg/m2 (375 mg/m2 × 4). Clinical response had been video documented and scored by a blinded observer. Results In both groups, motor severity (total score) lessened by ≥76% and cerebrospinal fluid B cells were similarly depleted (≥95%) six months after treatment. None of the treated patients remained unable to walk independently. Serum IgM depletion was analogous in the 1200 mg/m2 (−73%) and 1500 mg/m2 group (−64%). The relapse frequency was similar in both groups. Side effects were principally steroidal, tolerable, and transient. Circulating B-cell repopulation was comparable. Conclusions The reduced-dose of rituximab in rituximab combination immunotherapy was as effective and well tolerated as the standard dose, and provided rapid, early therapeutic intervention in Opsoclonus-Myoclonus Syndrome. Pending a long-term prospective study, these are proof-of-concept data in support of challenging the dose of rituximab in various disorders, which may have different dose requirements.
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rituximab ivig and tetracosactide acth1 24 combination immunotherapy rite ci for pediatric Opsoclonus Myoclonus Syndrome immunomarkers and clinical observations
Neuropediatrics, 2017Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Michael Alber, Maha Awadalla, Lubov Blumkin, Elena S Lina, S Leiz, J MoserAbstract:Opsoclonus-Myoclonus Syndrome (OMS) is a neuroinflammatory disorder with pervasive morbidity that warrants better treatments. Twelve children with moderate/severe OMS (total score 23 ± 6) who did not remit to multiple immunotherapies were evaluated for neuroinflammation in a case-control study using cerebrospinal fluid (CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immunofixation with isoelectric focusing. Observations made on empirical treatment with rituximab, IVIg, and tetracosactide combination immunotherapy (coined "RITE-CI") were analyzed. All of the patients tested for multiple inflammatory markers were positive; 75% had ≥3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell expansion; and 50 to 100%, elevated concentrations of multiple chemokines and neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped significantly in the group (-85%, p < 0.0001) from moderate to trace, and by 2 to 4 severity categories in each patient. The 24-week schedule was well tolerated and clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is feasible and effective as rescue therapy and presents an initial option for children with moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient severity, propensity for relapse, and other factors.
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demographic clinical and immunologic features of 389 children with Opsoclonus Myoclonus Syndrome a cross sectional study
Frontiers in Neurology, 2017Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Nathan R McgeeAbstract: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 IQR), 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 < .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 = .004) and stage (P = .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 CSF leukocyte count was minimally elevated in 14% (≤ 11/cu mm) with normal differential, and commercially-screened serum autoantibodies were negative, but CSF oligoclonal bands 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 < .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 oligoclonal bands and B cells, not by routine CSF or commercial antibody studies.
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dexamethasone intravenous immunoglobulin and rituximab combination immunotherapy for pediatric Opsoclonus Myoclonus Syndrome
Pediatric Neurology, 2017Co-Authors: Michael R. Pranzatelli, Elizabeth D TateAbstract:Abstract Background Although pulse-dose dexamethasone is increasingly favored for treating pediatric Opsoclonus-Myoclonus Syndrome (OMS), and multimodal immunotherapy is associated with improved clinical response, there have been no neuroimmunologic studies of dexamethasone-based multimodal disease-modifying therapy. Methods In this observational retrospective study, 19 children with OMS (with or without associated neuroblastoma) underwent multibiomarker evaluation for neuroinflammation. Nine children of varying OMS severity, duration, and treatment status were treated empirically with pulse dexamethasone, intravenous immunoglobulin (IVIg), and rituximab combination immunotherapy (DEXIR-CI). Another 10 children on dexamethasone alone or with IVIg at initial evaluation only provided a comparison group. Motor severity (total score) was scored rater-blinded via videotapes using the validated OMS Evaluation Scale. Results DEXIR-CI was associated with a 69% reduction in group total score ( P = 0.004) and was clinically well tolerated. Patients given the dexamethasone combination exhibited significantly lowered B cell frequencies in cerebrospinal fluid (−94%) and blood (−76%), normalizing the cerebrospinal fluid B cell percentage. The number of patients with positive inflammatory markers dropped 87% ( P = 0.002) as did the number of markers. Cerebrospinal fluid oligoclonal bands were positive in four of nine pretreatment patients but zero of six post-treatment patients. In the comparison group, partial response to dexamethasone alone or with IVIg was associated with multiple positive markers for neuroinflammation despite an average of seven months of treatment. Conclusions Multimechanistic dexamethasone-based combination immunotherapy increases the therapeutic armamentarium for OMS, providing a viable option for less severely affected individuals. Partial response to dexamethasone with or without IVIg is indicative of ongoing neuroinflammation and should be treated promptly and accordingly.
Michael Pike - One of the best experts on this subject based on the ideXlab platform.
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cerebellar and cortical abnormalities in paediatric Opsoclonus Myoclonus Syndrome
Developmental Medicine & Child Neurology, 2015Co-Authors: Geetha Anand, Holly Bridge, Peter Rackstraw, Adam M Chekroud, Jean Yong, Charlotte J Stagg, Michael PikeAbstract:AIM: Paediatric Opsoclonus-Myoclonus Syndrome (OMS) is a poorly understood condition with long-term cognitive, behavioural, and motor sequelae. Neuroimaging has indicated cerebellar atrophy in the chronic phase, but this alone may not explain the cognitive sequelae seen in many children with OMS. This study aimed to determine the extent of structural change throughout the brain that may underpin the range of clinical outcomes. METHOD: Nine participants with OMS (one male, eight females; mean age [SD] 14y, [6y 5mo], range 12-30y) and 10 comparison individuals (three males, seven females; mean age 12y 6mo, [4y 9mo], range 10-23y) underwent magnetic resonance imaging to acquire T1-weighted structural images, diffusion-weighted images, and magnetic resonance spectroscopy scans. Neuroblastoma had been present in four participants with OMS. Voxel-based morphometry was used to determine changes in grey matter volume, tract-based spatial statistics to analyze white matter integrity, and Freesurfer to analyze cortical thickness across visual and motor cortices. RESULTS: Whole-brain analysis indicated that cerebellar grey matter was significantly reduced in the patients with OMS, particularly in the vermis and flocculonodular lobe. A region-of-interest analysis indicated significantly lower cerebellar grey matter volume, particularly in patients with the greatest OMS scores. Diffusion-weighted images did not show effects at a whole brain level, but all major cerebellar tracts showed increased mean diffusivity when analysis was restricted to the cerebellum. Cortical thickness was reduced across the motor and visual areas in the OMS group, indicating involvement beyond the cerebellum. INTERPRETATION: Across individuals with OMS, there is considerable cerebellar atrophy, particularly in the vermis and flocculonodular lobes with atrophy severity associated with persistent symptomatology. Differences in cerebral cortical thickness indicate disease effects beyond the cerebellum.
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Opsoclonus Myoclonus Syndrome
Handbook of Clinical Neurology, 2013Co-Authors: Michael PikeAbstract:Opsoclonus-Myoclonus Syndrome is a very rare disorder with onset usually in the second year of life, and the clinical features of Opsoclonus, Myoclonus, ataxia, irritability, sleep disturbance, and, often but by no means invariably, an associated neuroblastoma. There is no diagnostic test; brain imaging is normal and other investigations produce nonspecific results; the diagnosis is clinical and the condition is not infrequently mistaken for acute cerebellar ataxia. The pathophysiology is thought to be immunological on the basis of the paraneoplasticity and the symptomatic (though often incomplete) response to immunomodulatory therapies; a number of autoantibodies have been identified to a variety of antigens and cerebrospinal fluid B-cell numbers found to be increased but no diagnostic immunological marker has yet been identified. Therapeutic benefit has been described with steroids, intravenous immunoglobulin, cyclophosphamide, azathioprine, and rituximab, but randomized trials are extremely difficult because of the rarity of the condition. Successful treatment of the tumor, when present, does not usually improve neurological outcome. Disease course may be monophasic or chronic relapsing and children are often left with long-term motor, behavioral, and cognitive sequelae.
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a prospective study of the presentation and management of dancing eye Syndrome Opsoclonus Myoclonus Syndrome in the united kingdom
European Journal of Paediatric Neurology, 2010Co-Authors: K K Pang, Bethan Lang, Carlos De Sousa, Michael PikeAbstract:Abstract The incidence, mode of presentation and management of Dancing Eye Syndrome/Opsoclonus–Myoclonus Syndrome (DES/OMS) was prospectively evaluated in 20 United Kingdom (UK) paediatric neurology centres by questionnaire over a 24-month period between 2003 and 2005. Nineteen children were notified, giving an incidence of 0.18 cases per million total population per year. Mean age at presentation was 18 months (range 3–42 months). Fifteen families consented to participate in the study. Atypical features were present in 6/15 cases including very delayed presentation of Opsoclonus, dysphagia, and rapid spontaneous improvement without treatment. Only 4/15 cases were associated with neuroblastoma (NB) but current practice in excluding this is diverse and a standardised approach is suggested.
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autoantibodies in childhood Opsoclonus Myoclonus Syndrome
Journal of Neuroimmunology, 2008Co-Authors: Franz Blaes, Michael Pike, Bethan LangAbstract:Opsoclonus-Myoclonus Syndrome or Dancing Eye Syndrome (OMS/DES) is a rare neurological disorder of children, which associates with neuroblastoma (NB) in approximately 50% of cases. We examined sera from five patients with (OMS-NB(+)) and five without NB (OMS-NB(-)) for autoantibodies. OMS-NB(-) IgG bound to the surface of a NB cell line, whereas IgG from OMS-NB(+) and from NB patients without OMS/DES bound only to permeabilised cells. Both OMS-NB(+) and OMS-NB(-) reduced proliferation of NB cells. We also present a case report of a child with OMS/DES without NB who made a complete recovery without treatment. Serum antibodies at presentation bound to the surface and decreased NB cell proliferation but had decreased 9 weeks later when the child was asymptomatic. These results demonstrate that sera from some OMS/DES patients contain IgG antibodies that are potentially pathogenic.
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Opsoclonus Myoclonus Syndrome in neuroblastoma a report from a workshop on the dancing eyes Syndrome at the advances in neuroblastoma meeting in genoa italy 2004
Cancer Letters, 2005Co-Authors: Katherine K Matthay, Wendy G Mitchell, Barbara Hero, Franz Blaes, Michael Pike, Dominique Plantaz, Pedro A De Alarcon, Vito PistoiaAbstract:Opsoclonus-Myoclonus Syndrome (OMS) is a rare neurologic Syndrome that, in children, associates with neuroblastoma in more than half of the cases. The etiology of this condition is thought to be immune mediated, but, though immunosuppressive therapies may ameliorate the acute symptoms, no effective treatment to prevent the common neuropsychologic sequelae has been established. This paper summarizes the results obtained at the 2004 Advances in Neuroblastoma Research meeting, providing status of the art information on immune pathogenesis, clinical features, acute and chronic neurologic manifestations, current and novel therapeutic approaches. It is emphasized that, due to the rarity of OMS in general and neuroblastoma-associated OMS in particular, international collaborations are needed to better define the pathogenesis and therapy of this disease, propose common evaluation criteria and identify new treatment modalities.
Elizabeth D Tate - One of the best experts on this subject based on the ideXlab platform.
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evaluation of responsiveness to reduced dose rituximab in corticotropin intravenous immunoglobulin rituximab combination immunotherapy for Opsoclonus Myoclonus Syndrome
Pediatric Neurology, 2018Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Nathan R Mcgee, Craig MacarthurAbstract:Abstract Background Rituximab (anti-CD20) has been used as B-cell-targeted intervention to treat Opsoclonus-Myoclonus Syndrome. Due to isolated reports of chronic hypogammaglobulinemia and B lymphopenia following rituximab in several disorders, and rapid B-cell depletion after a few doses, we reduced the dosage 20% in our clinical practice. Methods In this Institutional Review Board-approved retrospective study, 32 children with Opsoclonus-Myoclonus Syndrome and cerebrospinal fluid B-cell expansion had received front-loaded adrenocorticotropic hormone, intravenous immunoglobulin, and rituximab combination immunotherapy for de novo Opsoclonus-Myoclonus Syndrome. Parametric statistical analysis compared 10 children receiving 1200 mg/m2 of rituximab (300 mg/m2 × 4) and 22 receiving 1500 mg/m2 (375 mg/m2 × 4). Clinical response had been video documented and scored by a blinded observer. Results In both groups, motor severity (total score) lessened by ≥76% and cerebrospinal fluid B cells were similarly depleted (≥95%) six months after treatment. None of the treated patients remained unable to walk independently. Serum IgM depletion was analogous in the 1200 mg/m2 (−73%) and 1500 mg/m2 group (−64%). The relapse frequency was similar in both groups. Side effects were principally steroidal, tolerable, and transient. Circulating B-cell repopulation was comparable. Conclusions The reduced-dose of rituximab in rituximab combination immunotherapy was as effective and well tolerated as the standard dose, and provided rapid, early therapeutic intervention in Opsoclonus-Myoclonus Syndrome. Pending a long-term prospective study, these are proof-of-concept data in support of challenging the dose of rituximab in various disorders, which may have different dose requirements.
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multifactorial analysis of Opsoclonus Myoclonus Syndrome etiology tumor vs no tumor in a cohort of 356 us children
Pediatric Blood & Cancer, 2018Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Nathan R McgeeAbstract:Background Pediatric Opsoclonus-Myoclonus Syndrome (OMS) presents a paradox of etiopathogenesis: A neuroblastic tumor (NB) is found in only one half of the cases, the others are ascribed to infections or designated as idiopathic. Method From an IRB-approved observational study of 356 US children with OMS, secondary analysis of "etiology" and related factors was performed on a well-characterized cohort. The "Tumor" (n = 173) and "No Tumor" groups (n = 183), as defined radiologically, were compared according to multiple factors considered potentially differentiating. Data were analyzed retrospectively using parametric and nonparametric tests as indicated. Results Patients with NB were not distinguishable by prodromal symptoms, OMS onset age, gender, race/ethnicity, OMS severity, rank order of neurological sign appearance, or geographic distribution. Various CSF immunologic biomarker abnormalities of OMS did not vary in the presence or absence of a detectable tumor: frequency of six lymphocyte subsets, or concentrations of 18 cytokines/chemokines, cytokine antagonists, chemokine receptors, cell adhesion molecules, or neuronal/glial markers. Prior responsiveness to conventional immunotherapy was not contingent on tumor/no tumor designation. Conclusions Multiple convergent factors provide compelling empirical evidence and rationalize the concept that OMS is one neurological disorder, regardless of apparent etiology. Limitations to the current clinical etiologic classifications as paraneoplastic, parainfectious/post-infectious, and idiopathic etiology require antigen-based biological solutions to tease out the molecular pathophysiology of viral/tumoral mechanisms. Systematic studies, regardless of presumed etiology, will be necessary to find the highest-yield combination of imaging approaches, screening for infectious agents, and new biomarkers. Two testable hypotheses for future research are presented.
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rituximab ivig and tetracosactide acth1 24 combination immunotherapy rite ci for pediatric Opsoclonus Myoclonus Syndrome immunomarkers and clinical observations
Neuropediatrics, 2017Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Michael Alber, Maha Awadalla, Lubov Blumkin, Elena S Lina, S Leiz, J MoserAbstract:Opsoclonus-Myoclonus Syndrome (OMS) is a neuroinflammatory disorder with pervasive morbidity that warrants better treatments. Twelve children with moderate/severe OMS (total score 23 ± 6) who did not remit to multiple immunotherapies were evaluated for neuroinflammation in a case-control study using cerebrospinal fluid (CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immunofixation with isoelectric focusing. Observations made on empirical treatment with rituximab, IVIg, and tetracosactide combination immunotherapy (coined "RITE-CI") were analyzed. All of the patients tested for multiple inflammatory markers were positive; 75% had ≥3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell expansion; and 50 to 100%, elevated concentrations of multiple chemokines and neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped significantly in the group (-85%, p < 0.0001) from moderate to trace, and by 2 to 4 severity categories in each patient. The 24-week schedule was well tolerated and clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is feasible and effective as rescue therapy and presents an initial option for children with moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient severity, propensity for relapse, and other factors.
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demographic clinical and immunologic features of 389 children with Opsoclonus Myoclonus Syndrome a cross sectional study
Frontiers in Neurology, 2017Co-Authors: Michael R. Pranzatelli, Elizabeth D Tate, Nathan R McgeeAbstract: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 IQR), 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 < .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 = .004) and stage (P = .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 CSF leukocyte count was minimally elevated in 14% (≤ 11/cu mm) with normal differential, and commercially-screened serum autoantibodies were negative, but CSF oligoclonal bands 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 < .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 oligoclonal bands and B cells, not by routine CSF or commercial antibody studies.
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dexamethasone intravenous immunoglobulin and rituximab combination immunotherapy for pediatric Opsoclonus Myoclonus Syndrome
Pediatric Neurology, 2017Co-Authors: Michael R. Pranzatelli, Elizabeth D TateAbstract:Abstract Background Although pulse-dose dexamethasone is increasingly favored for treating pediatric Opsoclonus-Myoclonus Syndrome (OMS), and multimodal immunotherapy is associated with improved clinical response, there have been no neuroimmunologic studies of dexamethasone-based multimodal disease-modifying therapy. Methods In this observational retrospective study, 19 children with OMS (with or without associated neuroblastoma) underwent multibiomarker evaluation for neuroinflammation. Nine children of varying OMS severity, duration, and treatment status were treated empirically with pulse dexamethasone, intravenous immunoglobulin (IVIg), and rituximab combination immunotherapy (DEXIR-CI). Another 10 children on dexamethasone alone or with IVIg at initial evaluation only provided a comparison group. Motor severity (total score) was scored rater-blinded via videotapes using the validated OMS Evaluation Scale. Results DEXIR-CI was associated with a 69% reduction in group total score ( P = 0.004) and was clinically well tolerated. Patients given the dexamethasone combination exhibited significantly lowered B cell frequencies in cerebrospinal fluid (−94%) and blood (−76%), normalizing the cerebrospinal fluid B cell percentage. The number of patients with positive inflammatory markers dropped 87% ( P = 0.002) as did the number of markers. Cerebrospinal fluid oligoclonal bands were positive in four of nine pretreatment patients but zero of six post-treatment patients. In the comparison group, partial response to dexamethasone alone or with IVIg was associated with multiple positive markers for neuroinflammation despite an average of seven months of treatment. Conclusions Multimechanistic dexamethasone-based combination immunotherapy increases the therapeutic armamentarium for OMS, providing a viable option for less severely affected individuals. Partial response to dexamethasone with or without IVIg is indicative of ongoing neuroinflammation and should be treated promptly and accordingly.
Wendy G Mitchell - One of the best experts on this subject based on the ideXlab platform.
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immunotherapy responsive sars cov 2 infection exacerbating Opsoclonus Myoclonus Syndrome
Multiple sclerosis and related disorders, 2021Co-Authors: Sarah E Wiegand, Wendy G Mitchell, Jonathan D SantoroAbstract:The global pandemic of SARS-CoV-2 has been known to have diverse neurologic complications among adult patients. The neurologic effects of SARS-CoV-2 in the pediatric population is poorly described, especially in those with rare underlying neurologic conditions. We describe the first known case of SARS-CoV-2 in a pediatric patient with refractory Opsoclonus-Myoclonus Syndrome. A 25-month-old female with progressive Opsoclonus-Myoclonus Syndrome secondary to metastatic neuroblastoma status-post resection and chemotherapy presented with worsening Opsoclonus, tremor, and breakthrough seizures. She had no fever or respiratory symptoms at presentation. Urine catecholamines were unchanged, with low suspicion for tumor recurrence. She was found to have SARS-CoV-2 via nasopharnygeal PCR assay. She received intravenous immunoglobulin and dexamethasone therapy with improvement in Opsoclonus-Myoclonus Syndrome symptoms and was discharged home at her neurologic baseline. Patients with Opsoclonus-Myoclonus Syndrome may present with exacerbation of symptoms in the context of SARS-CoV-2. This case describes a sentinel report of a child with Opsoclonus-Myoclonus Syndrome presenting with worsening symptoms with concomitant SARS-CoV-2. Improvement in symptoms was achieved with standard of care therapies.
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effect of increased immunosuppression on developmental outcome of Opsoclonus Myoclonus Syndrome oms
Journal of Child Neurology, 2015Co-Authors: Wendy G Mitchell, Amelia A Wooten, Sharon H Oneil, Jenny Rodriguez, Rosa E Cruz, Rachael WitternAbstract:Opsoclonus Myoclonus Syndrome (OMS) produces long-term cognitive, behavioral, and motor deficits. Objective was to see if more aggressive treatment improved outcome. Assessment included Opsoclonus Myoclonus Syndrome rating, developmental/cognitive and motor assessment, and adaptive behavior. Fourteen subjects completed testing. Nine had neuroblastoma. Onset was at 10 to 35 months; onset to diagnosis: 2 days to 14 months, and onset to first treatment: 5 days to 15 months. Initial treatment was corticotropin (12), oral steroids (3), plus intravenous immunoglobulin in all. Ten received rituximab, 5 cyclophosphamide. Age at testing ranged from 2.5 to 10.3 years. Adaptive Behavior Score (11 subjects), mean 93.5; estimated Intelligence Quotient/Developmental Quotient mean 93.5; Motor: mean 92.8. Residual Opsoclonus Myoclonus Syndrome symptoms at the time of the evaluation were generally minor; Opsoclonus Myoclonus Syndrome scores ranged from 0 to 6. Comparison to previously reported Opsoclonus Myoclonus Syndrome subjects showed improved outcomes: Adaptive behavior, cognitive and motor scores were significantly higher (P < .001) in new subjects. Outcomes have improved with more aggressive immunosuppression, with most Opsoclonus Myoclonus Syndrome survivors now functioning at or near normal.
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acute cerebellar ataxia acute cerebellitis and Opsoclonus Myoclonus Syndrome
Journal of Child Neurology, 2012Co-Authors: Jay Desai, Wendy G MitchellAbstract:Acute cerebellar ataxia and acute cerebellitis represent a process characterized by parainfectious, postinfectious, or postvaccination cerebellar inflammation. There is considerable overlap between these entities. The mildest cases of acute cerebellar ataxia represent a benign condition that is characterized by acute truncal and gait ataxia, variably with appendicular ataxia, nystagmus, dysarthria, and hypotonia. It occurs mostly in young children, presents abruptly, and recovers over weeks. Neuroimaging is normal. Severe cases of cerebellitis represent the other end of the spectrum, presenting with acute cerebellar signs often overshadowed by alteration of consciousness, focal neurological deficits, raised intracranial pressure, hydrocephalus, and even herniation. Neuroimaging is abnormal and the prognosis is less favorable than in acute cerebellar ataxia. Acute disseminated encephalomyelitis may be confused with acute cerebellitis when the clinical findings are predominantly cerebellar, but lesions on neuroimaging are usually widespread. Paraneoplastic Opsoclonus-Myoclonus Syndrome is often initially misdiagnosed as acute cerebellar ataxia, but has very specific features, course, and etiopathogensis.
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active comparator controlled rater blinded study of corticotropin based immunotherapies for Opsoclonus Myoclonus Syndrome
Journal of Child Neurology, 2012Co-Authors: Elizabeth D Tate, Michael R. Pranzatelli, Wendy G Mitchell, Steven Verhulst, Stephen Markwell, David Neal Franz, William D Graf, Anne S Joseph, Yasmin Khakoo, Lalitha SivaswamyAbstract:To test the efficacy and safety of corticotropin-based immunotherapies in pediatric Opsoclonus-Myoclonus Syndrome, 74 children received corticotropin alone or with intravenous immunoglobulin (groups 1 and 2, active controls); or both with rituximab (group 3) or cyclophosphamide (group 4); or with rituximab plus chemotherapy (group 5) or steroid sparers (group 6). There was 65% improvement in motor severity score across groups (P < .0001), but treatment combinations were more effective than corticotropin alone (P = .0009). Groups 3, 4, and 5 responded better than group 1; groups 3 and 5 responded better than group 2. The response frequency to corticotropin was higher than to prior corticosteroids (P < .0001). Fifty-five percent had adverse events (corticosteroid excess), more so with multiagents (P = .03); and 10% had serious adverse events. This study demonstrates greater efficacy of corticotropin-based multimodal therapy compared with conventional therapy, greater response to corticotropin than corticost...
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active comparator controlled rater blinded study of corticotropin based immunotherapies for Opsoclonus Myoclonus Syndrome
Journal of Child Neurology, 2012Co-Authors: Elizabeth D Tate, Michael R. Pranzatelli, Wendy G Mitchell, Steven Verhulst, Stephen Markwell, David Neal Franz, William D Graf, Anne S Joseph, Yasmin Khakoo, Lalitha SivaswamyAbstract:To test the efficacy and safety of corticotropin-based immunotherapies in pediatric Opsoclonus-Myoclonus Syndrome, 74 children received corticotropin alone or with intravenous immunoglobulin (group...
Franz Blaes - One of the best experts on this subject based on the ideXlab platform.
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childhood Opsoclonus Myoclonus Syndrome diagnosis and treatment
Expert Review of Neurotherapeutics, 2016Co-Authors: Franz Blaes, Backialakshmi DharmalingamAbstract:Opsoclonus-Myoclonus Syndrome (OMS) is a rare and primarily immune-mediated disease in children and adults. The main symptoms include Opsoclonus, Myoclonus and ataxia. In children, the symptoms also include irritability, and, over a long-term course, learning and behavioural disturbances. OMS can be idiopathic, parainfectious or occur as a paraneoplastic (tumour-associated) Syndrome. Paraneoplastic OMS in children is almost exclusively associated with neuroblastoma, whereas in adults, small cell lung cancer and breast cancer are the main underlying tumours. An autoimmune pathophysiology is suspected because childhood OMS patients have functionally active autoantibodies, proinflammatory changes in the cytokine network and immunotherapy responses. Children appear to respond regularly to immunosuppressive treatment. However, although the neurological symptoms show a good response, most children continue to show neuropsychological disturbances.
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elevated b cell activating factor baff but not april correlates with csf cerebellar autoantibodies in pediatric Opsoclonus Myoclonus Syndrome
Journal of Neuroimmunology, 2009Co-Authors: V Fuhlhuber, Franz Blaes, Marlene Tschernatsch, Manfred Kaps, Klaus T Preissner, A Kirsten, Sandra M Bick, A Hahn, Tibo Gerriets, S AltenkamperAbstract: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.
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autoantibodies in childhood Opsoclonus Myoclonus Syndrome
Journal of Neuroimmunology, 2008Co-Authors: Franz Blaes, Michael Pike, Bethan LangAbstract:Opsoclonus-Myoclonus Syndrome or Dancing Eye Syndrome (OMS/DES) is a rare neurological disorder of children, which associates with neuroblastoma (NB) in approximately 50% of cases. We examined sera from five patients with (OMS-NB(+)) and five without NB (OMS-NB(-)) for autoantibodies. OMS-NB(-) IgG bound to the surface of a NB cell line, whereas IgG from OMS-NB(+) and from NB patients without OMS/DES bound only to permeabilised cells. Both OMS-NB(+) and OMS-NB(-) reduced proliferation of NB cells. We also present a case report of a child with OMS/DES without NB who made a complete recovery without treatment. Serum antibodies at presentation bound to the surface and decreased NB cell proliferation but had decreased 9 weeks later when the child was asymptomatic. These results demonstrate that sera from some OMS/DES patients contain IgG antibodies that are potentially pathogenic.
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new autoantibodies in pediatric Opsoclonus Myoclonus Syndrome
Annals of the New York Academy of Sciences, 2007Co-Authors: A Kirsten, V Fuhlhuber, Martina Korfei, Manfred Kaps, Klaus T Preissner, S Beck, T Kreutz, Sigrid Schmitt, Franz BlaesAbstract:Opsoclonus-Myoclonus Syndrome (OMS) is a rare neurologic disorder comprising the main symptoms of eye-movement disturbances, muscle jerks, and severe ataxia. In children and adults, some cases are associated with a tumor as a paraneoplastic Syndrome, whereas in children the paraneoplastic form is almost exclusively associated with neuroblastoma. The detection of autoantibodies in some OMS sera led to the hypothesis that the Syndrome is of autoimmune origin. Beside autoantibodies against intracellular proteins, such as anti-Hu, alpha-enolase, and KHSRP, specific binding of autoantibodies to the surface of neuroblastoma cells and cerebellar granular neurons have been found. Antiproliferative and proapoptotic effects of these autoantibodies on neuroblastoma cell lines were noted as well. These results support the concept of a humoral autoimmune process in the pathogenesis of OMS.
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functional characterisation of autoantibodies from patients with pediatric Opsoclonus Myoclonus Syndrome
Journal of Neuroimmunology, 2005Co-Authors: Martina Korfei, V Fuhlhuber, Manfred Kaps, Klaus T Preissner, Thomas Schmidtwoll, Franz BlaesAbstract:Paraneoplastic Opsoclonus-Myoclonus-Syndrome (OMS) both in children and adults is suspected to be the result of an autoimmune response directed against cross-reactive proteins of tumor and neuronal cells. We here characterised the binding and functional activities of anti-neuroblastoma antibodies in IgG fractions from 11 OMS children with and without neuroblastoma. IgG fractions from neuroblastoma without OMS (NB) and healthy children served as controls. Indirect immunofluorescence and Western blot revealed IgG binding to intracellular autoantigens in all OMS patients, but in only one of the controls (p<0.001). Using flow cytometry, we could demonstrate surface binding of IgG fractions in all OMS patients, but only in one of control (p<0.001). Moreover OMS IgG exhibited a significant anti-proliferative and a cytotoxic effect on neuroblastoma cells compared to control IgG (p<0.001 and p<0.01). TUNEL assay revealed increased apoptotic cell death of the neuroblastoma cells after exposure to OMS IgG, but not to NB or control IgG (p<0.01). Preabsorption of membrane binding abandoned the anti-proliferative effect of OMS IgG. These findings indicate that surface-binding autoantibodies are present in OMS patients and these autoantibodies cause inhibition of cell proliferation and induce apoptosis.