Response to rituximab in a child with neuroblastoma and opsoclonus-myoclonus

Opsoclonus-myoclonus (OM) is a paraneoplastic syndrome of probable autoimmune origin. Despite current therapies aimed at decreasing autoantibody formation, OM is difficult to control and may impact long-term neurologic outcome. We present a case of a 19-month-old patient who initially presented with OM, neuroblastoma and a constitutional cytogenetic abnormality t(5;12)(q11.2;q15). The patient's OM was recalcitrant to conventional therapies, but showed significant improvement following treatment with rituximab.     

Rituximab for treatment of opsoclonus-myoclonus syndrome in neuroblastoma

Opsoclonus-myoclonus syndrome (OMS) is a rare paraneoplastic syndrome that occurs in 2%-3% of patients with neuroblastoma. The cause of this syndrome is believed to be immune mediated, but the exact mechanism still remains unclear. There is an urgent need to improve our current strategies for treating patients with OMS, as many patients have significant long-term neurologic deficits and behavior disorders with current treatment approaches. Therapies that have shown to improve symptoms in these patients have ranged from ACTH and corticosteroids, to intravenous gammaglobulin and plasmapheresis. We report our experience with Rituximab in a patient with neuroblastoma and OMS.     

Paraneoplastic gastro-intestinal anti-Hu syndrome in neuroblastoma

The anti-Hu syndrome is a well-known paraneoplastic syndrome and may be rarely seen in patients with neuroblastoma. However, it is relatively unknown that anti-Hu antibodies can cause gastro-intestinal signs and symptoms. We report on a child with neuroblastoma who presented with gastro-intestinal disturbances as a result of the anti-Hu syndrome and summaries two similar case reports reported in literature. Neuroblastoma patients with gastro-intestinal disturbances, ranging from constipation to a paralytic ileus, might suffer from the gastro-intestinal anti-Hu syndrome. The causative antibodies can be determined to diagnose or exclude this syndrome, and successful treatment is possible.     

Paraneoplastic limbic encephalitis in a teenage girl with an immature ovarian teratoma

Paraneoplastic limbic encephalitis (PLE) is an unusual disorder that is characterized by the association of clinical limbic system abnormalities with neoplasia, usually malignancy. It has rarely been reported in children and then manifests during the teenage years. Diagnosis is often delayed, especially when the tumor has not been recognized. In adults, the diagnosis can be revealed by the presence of antineuronal antibodies. We describe an unusual case of behavioral disturbance leading rapidly to coma in a 14-year-old girl with CSF pleocytosis who was found 10 weeks later to have an immature ovarian teratoma. Although her symptoms eventually improved slightly after tumor excision, she died while in rehabilitation. PLE is an important diagnosis to consider in the teenage girl with symptoms of a progressive limbic disorder and CSF pleocytosis, and whose brain MR imaging demonstrates no abnormality or mild T2-weighted temporal lobe signal abnormality. When this constellation of findings presents in a teenage girl, the possibility of an underlying ovarian teratoma should be considered.     

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

1 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.

2 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.

3 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.

4 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.     

Neuroblastoma-Associated Paraneoplastic Syndrome with anti-Hu Antineuronal Antibodies Presenting at the Time of Recurrence

A 27-month-old girl presented with chest pain. Further evaluation confirmed posterior mediastinal neuroblastoma with bone marrow infiltration, which was treated with a combination of chemotherapy and surgery. Four months after completing treatment, she presented with myoclonus and weakness of her right arm. The myoclonus eventually subsided but her right arm weakness progressed to a right hemiplegia. High titers of antineuronal nuclear antibodies identified as anti-Hu were found in both serum and cerebrospinal fluid. One month later she presented with a relapse of her original tumor, from which she died. Identification of anti-Hu antineuronal nuclear antibodies in this neuroblastoma-associated paraneoplastic syndrome supports the hypothesis that the syndrome is due to autoimmune disease.     

Therapeutic plasma exchange for a case of refractory opsoclonus myoclonus ataxia syndrome

Opsoclonus myoclonus ataxia syndrome (OMAS) can be refractory to standard therapies and devastating. Alternative treatments are imperative. A 14‐month‐old male diagnosed with neuroblastoma and paraneoplastic OMAS achieved complete cancer remission with chemotherapy. The OMAS, however, persisted over the subsequent 4 years despite numerous immune‐modulatory and immunosuppressive therapies. The patient ultimately achieved complete remission following therapeutic plasma exchange (TPE) combined with rituximab and intravenous immunoglobulin. After three asymptomatic years, he relapsed. Upon reintroducing TPE and rituximab plus oral prednisolone, the patient rapidly achieved a second complete remission. This case offers proof‐of‐principle for the potential efficacy of TPE for neuroblastoma‐associated OMAS.     

Paraneoplastic opsoclonus myoclonus syndrome associated with inflammatory myofibroblastic tumor in a pediatric patient

Opsoclonus myoclonus syndrome (OMS) is a rare neurological syndrome caused by a paraneoplastic autoimmune process that affects children with neuroblastic tumors. Treatment includes corticosteroids, intravenous gamma globulin (IVIG), rituximab, and other immunosuppressive therapies. Here, we describe a patient diagnosed with OMS associated with a localized inflammatory myofibroblastic tumor. The patient has no evidence of tumor recurrence following surgical resection with 8‐month follow‐up. The neurologic symptoms resolved with corticosteroids and IVIG. This case demonstrates that in children, neoplasms other than neuroblastoma may be associated with this paraneoplastic syndrome, and highlights the importance of evaluating patients with OMS for underlying malignancies.     

Paraneoplastic limbic encephalitis masquerading as chronic behavioural disturbance in an adolescent girl

AIM: To describe an unusual but treatable cause of behavioural disturbance in adolescence. METHODS: The case is reported of a 15-y-old girl presenting with acute confusion, memory problems and psychotic symptoms following an 18-mo history of change in personality, school failure and running away from home. A review of the literature is also presented. RESULTS: Microbiology, toxicology, computed tomography and magnetic resonance imaging did not show any pathology of the central nervous system. Bilateral ovarian immature teratomas were eventually diagnosed and removed. The rapid improvement in the patient's mental and cognitive functions after corticosteroid treatment and the abnormality shown on the single photon emission computed tomography suggested a diagnosis of paraneoplastic limbic encephalitis. CONCLUSION: Paediatricians and neurologists should be aware of this rare disease entity among the more common conditions of behavioural problems and substance abuse in adolescents.     

False positive results in a neuroblastoma screening programme

Twenty thousand, eight hundred and twenty-nine babies were screened for neuroblastoma at 6 months of age by measuring homovanillic (HVA) and vanillylmandelic (VMA) acid in urine and ratioing these to creatinine. Using a ?cut off”? of the mean + 3 SD, 10 were found to be positive. Two were found on evaluation to have neuroblastoma and in the remaining 8 the raised levels of HVA and/or VMA returned to normal. Only one of the 8 false positive babies was absolutely normal, most having a chronic disorder or illness. Utilising new centiles which relate HVA and VMA to creatinine, only 3 of the 8 would have remained positive, a false positive rate of 0.01%. The false negative rate would have remained unchanged.     

High-dose iv human immunoglobulin in a case with infantile opsoclonus polymyoclonia syndrome

We report a 14-month-old male with infantile opsoclonus polymyoclonia syndrome. His clinical disabilities responded favorably to high-dose human immunoglobulin therapy. High dose immunoglobulin therapy is one of the therapies for patients with this syndrome.