Late cognitive and adaptive outcomes of patients with neuroblastoma-associated opsoclonus-myoclonus-ataxia-syndrome: A report from the Children's Oncology Group.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder of the nervous system presenting with abnormal eye and limb movements, altered gait, and increased irritability. Two to four percent of children diagnosed with neuroblastoma have neuroblastoma-associated OMAS (NA-OMAS). These children typically present with non-high-risk neuroblastoma that is cured with surgery, with or without chemotherapy. Despite excellent overall survival, patients with NA-OMAS can have significant persistent neurological and developmental issues. OBJECTIVE: This study aimed to describe long-term neurocognitive and adaptive functioning of patients with NA-OMAS treated with multimodal therapy, including intravenous immunoglobulin (IVIG) on Children's Oncology Group (COG) protocol ANBL00P3. METHODS: Of 53 children enrolled on ANBL00P3, 25 submitted evaluable neurocognitive data at diagnosis and at least one additional time point within 2 years and were included in the analyses. Adaptive development was assessed via the Vineland Adaptive Behavior Scale, and validated, age-appropriate measures of intellectual function were also administered. RESULTS: Twenty-one of the 25 patients in this cohort ultimately received IVIG. Descriptive spaghetti plots suggest that this cohort demonstrated stable long-term cognitive functioning and adaptive development over time. This cohort also demonstrated decreased OMAS scores over time consistent with improved OMAS symptoms. CONCLUSIONS: While statistical significance is limited by small sample size and loss to follow-up over 10 years, findings suggest stable long-term cognitive and adaptive functioning over time in this treated cohort.

Diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in pediatric opsoclonus myoclonus ataxia syndrome presenting with neuroblastoma.

BACKGROUND: Early precision diagnosis and effective treatment of opsoclonus myoclonus ataxia syndrome (OMAS) patients presenting with neuroblastoma can prevent serious neurological outcomes. OBJECTIVE: To assess the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging in pediatric OMAS with neuroblastoma. MATERIALS AND METHODS: A retrospective evaluation of 45 patients diagnosed with OMAS who underwent 18F-FDG PET/CT was performed. A univariate analysis was performed to compare clinical characteristics between OMAS with and without neuroblastoma. Univariate and multivariate logistic regression analyses were applied to identify independent risk factors for OMAS with neuroblastoma and to develop the clinical model. Finally, independent risk factors and PET/CT were fitted to build the combined model for the diagnosis of OMAS with neuroblastoma and presented as a nomogram. Receiver operating characteristic curve, decision curve, and calibration curve analyses were conducted to evaluate the performance of the models. RESULTS: Among 45 patients, 27 were PET/CT-positive, 23/27 lesions were neuroblastoma, and four were false positives. One of the false positive patients was confirmed to be adrenal reactive hyperplasia by postoperative pathology, and the symptoms of OMAS disappeared in the remaining three cases during clinical follow-up. The average maximal standardized uptake value of PET/CT-positive lesions was 2.6. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT were 100%, 81.8%, 85.2%, 100%, and 91.1%, respectively. Age at diagnosis, lactate dehydrogenase, and neuron-specific enolase showed statistically significant differences between OMAS with and without neuroblastoma. Lactate dehydrogenase was identified as the independent risk factor to develop the clinical model, and the clinical model demonstrated an area under the curve (AUC) of 0.82 for the diagnosis of OMAS with neuroblastoma, with an AUC as high as 0.91 when combined with PET/CT. The decision curve analysis and calibration curve demonstrated that the nomogram had good consistency and clinical usefulness. CONCLUSION: In patients with OMAS, 18F-FDG PET/CT has a high diagnostic accuracy in detecting tumors of the neuroblastoma, especially when combined with the independent risk factor serum lactate dehydrogenase.

Review of Opsoclonus-Myoclonus Ataxia Syndrome in Pediatric Patients.

Opsoclonus-myoclonus ataxia syndrome (OMAS), also known as Kinsbourne syndrome, is a rare disorder that presents with myoclonus, ataxia, abnormal eye movements, irritability, and sleep disruptions, often in young children. We report a case of an infant barely 6 months old, with no significant past medical history, who presented to the emergency department with tremors, jerking motions of the head and arms, and rapid eye movements. After an extensive workup, she was found to have a neuroblastoma, which was subsequently surgically removed via thoracotomy. Despite an initial improvement in symptoms post-resection, the patient's symptoms recurred. She was subsequently treated with dexamethasone, intravenous immunoglobulin (IVIG), and rituximab. After treatment, the patient was noted to have mild global developmental delays but was otherwise well. This case report highlights the rare occurrence of OMAS in an infant barely 6 months old at diagnosis. Using the PubMed database, a systematic review was conducted to highlight the clinical presentation, diagnosis, and management of OMAS.

Paraneoplastic cerebellar and brainstem disorders.

Paraneoplastic cerebellar and brainstem disorders are a heterogeneous group that requires prompt recognition and treatment to help prevent irreversible neurologic injury. Paraneoplastic cerebellar degeneration is best characterized by Yo antibodies in patients with breast or ovarian cancer. Tr (DNER) antibodies in patients with Hodgkin lymphoma can also present with a pure cerebellar syndrome and is one of the few paraneoplastic syndromes found with hematological malignancy. Opsoclonus-myoclonus-ataxia syndrome presents in both pediatric and adult patients with characteristic clinical findings. Other paraneoplastic brainstem syndromes are associated with Ma2 and Hu antibodies, which can cause widespread neurologic dysfunction. The differential for these disorders is broad and also includes pharmacological side effects, infection or postinfectious processes, and neurodegenerative diseases. Although these immune-mediated disorders have been known for many years, mechanisms of pathogenesis are still unclear, and optimal treatment has not been established.

A rare clinical presentation of COVID 19: opsoclonus-myoclonus ataxia syndrome.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) can have symptoms like many neurological diseases, and one of the rare forms of these presentations is opsoclonus-myoclonus ataxia syndrome (OMAS). The pathogenesis of OMAS in adults has not been clearly elucidated and OMAS can be fatal. CASE PRESENTATION: We present a 71-year-old male patient who was admitted to the emergency department with complaints of involuntary tremor-like movements in his hands, feet and mouth, and speech impediment for three days, and was followed up with COVID-19. The patient was diagnosed with OMAS and clonazepam treatment was started. He died three days later due to respiratory arrest. Our case is the first case diagnosed with COVID-19-associated OMAS in Turkey. DISCUSSION: OMAS has no definitive treatment. Early diagnosis and initiation of corticosteroids and intravenous immunoglobulin (IVIG) therapy, if necessary, can be life-saving. In COVID-19 patients with unexplained clinical findings, awareness of different and rare diseases and a multidisciplinary approach has vital importance.

Successful use of tacrolimus for treatment-refractory neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome: A case series.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an autoimmune central nervous system disorder, primarily manifesting as a paraneoplastic sequalae to neuroblastoma, and characterized by motor disorders and behavioral disturbances. OMAS is typified by aberrant B-cell and T-cell activation. Current treatment involves immunosuppression using corticosteroids, intravenous immunoglobulin, and rituximab. However, these approaches often lead to treatment-related toxicities and symptomatic recurrences with chronic neurocognitive impairment. We treated three children with refractory neuroblastoma-associated OMAS with tacrolimus, a T-cell-targeting calcineurin inhibitor, effectively controlling symptoms within a month and enabling the discontinuation of immunosuppression with minimal side effects. Tacrolimus shows promise as a therapeutic option for refractory OMAS.

Opsoclonus-Myoclonus-Ataxia Syndrome Due to Covid-19.

Opsoclonus-myoclonus syndrome (OMS) as a rare neurological encephalopathic entity associated with non-specific infections or cancer processes has been repeatedly described in the setting of SARS-CoV-2 infection. We report a case of a 53-year-old man with SARS-CoV-2 infection, who developed clinical features of opsoclonus-myoclonus ataxia syndrome including cognitive impairments with a prolonged course of disease. Of particular note, cerebrospinal fluid (CSF) analysis revealed the production of myelin oligodendrocyte glycoprotein (MOG) antibodies, suggesting an underlying neuroimmunological mechanism associated with infection with the novel SARS-CoV-2 virus.

Immune-mediated ataxias: Guide to clinicians.

Immune-mediated cerebellar ataxias were initially described as a clinical entity in the 1980s, and since then, an expanding body of evidence has contributed to our understanding of this topic. These ataxias encompass various etiologies, including postinfectious cerebellar ataxia, gluten ataxia, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus-ataxia syndrome and primary autoimmune cerebellar ataxia. The increased permeability of the brain-blood barrier could potentially explain the vulnerability of the cerebellum to autoimmune processes. In this manuscript, our objective is to provide a comprehensive review of the most prevalent diseases within this group, emphasizing clinical indicators, pathogenesis, and current treatment approaches.

A Rare Case of Opsoclonus Myoclonus Ataxia Syndrome Post Viral Illness.

Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare inflammatory neurological disorder characterized by ocular, motor, behavioral, language, and sleep disturbances. It usually affects infants and young children but may affect adults. A 28-year-old male was brought to our emergency ward with complaints of involuntary spontaneous eye movements and jerky movements of limbs with imbalance while walking. He had a history of short febrile illness 10 days prior. His magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid (CSF) analysis, and other routine investigations were normal. The patient was treated with injectable methylprednisolone (1 g) given for five days along with other supportive therapy. A significant reduction in the opsoclonus, myoclonus, and ataxia was seen on a six-month follow-up. OMAS should be identified early to avoid the use of inappropriate medications, and immunotherapy must be provided as early as possible in order to prevent irreversible neurological damage.

Síndrome opsoclono-mioclono: características clínicas, aspectos terapéuticos y factores pronósticos en una cohorte pediátrica española / Opsoclonus-myoclonus syndrome: clinical characteristics, therapeutic considerations, and prognostic factors in a Spanish paediatric cohort

Introducción: El síndrome opsoclono-mioclono-ataxia es un raro trastorno de inicio pediátrico; de base neuroinflamatoria y origen paraneoplásico, parainfeccioso o idiopático. Actualmente no hay biomarcadores, siendo el diagnóstico clínico. El pronóstico cognitivo parece estar relacionado con el inicio temprano de la terapia inmunomoduladora.MétodoSe describen las características epidemiológicas, clínicas, terapéuticas y pronósticas a largo plazo de una cohorte de 20 pacientes españoles.ResultadosLa edad media de debut fue de 21 meses (2-59 meses). La ataxia y el opsoclonus fueron los síntomas de inicio más frecuentes y predominantes en la evolución. El tiempo medio desde los primeros síntomas hasta el diagnóstico fue de 1,1 mes. Un tumor de extirpe neuroblástica fue detectado en el 45%, realizándose resección quirúrgica en siete y quimioterapia en dos pacientes. En el estudio de líquido cefalorraquídeo se constató pleocitosis en cuatro (25%), con negatividad de anticuerpos antineuronales y bandas oligoclonales en todos los casos estudiados. En el 100% se emplearon fármacos inmunomoduladores. En nueve pacientes el tratamiento combinado inmunomodulador se inició desde el momento del diagnóstico, y en cinco el tiempo medio de implementación fue de 2,2 meses. A largo plazo, seis de 10 pacientes con seguimiento superior a cinco años presentaban secuelas cognitivas leves o moderadas; cuatro pacientes presentaron recaídas, generalmente coincidiendo con el descenso de la corticoterapia.ConclusionesEl inicio precoz de la inmunoterapia, así como de la triple terapia en los casos que lo precisaron, se relacionó con una menor frecuencia de afectación cognitiva a los dos años del debut. (AU)

Introduction: Opsoclonus-myoclonus-ataxia syndrome is a rare neuroinflammatory disorder with onset during childhood; aetiology may be paraneoplastic, para-infectious, or idiopathic. No biomarkers have yet been identified, and diagnosis is clinical. Better cognitive prognosis appears to be related to early onset of immunomodulatory therapy.MethodsWe describe the epidemiological, clinical, therapeutic, and long-term prognostic characteristics of a cohort of 20 Spanish patients.ResultsThe mean age of onset was 21 months (range, 2-59). Ataxia and opsoclonus were the most frequent symptoms both at disease onset and throughout disease progression. The mean time from onset to diagnosis was 1.1 months. Neuroblast lineage tumours were detected in 45% of patients; these were treated with surgical resection in 7 cases and chemotherapy in 2. Cerebrospinal fluid analysis revealed pleocytosis in 4 cases (25%) and neither antineuronal antibodies nor oligoclonal bands were detected in any patient. Immunomodulatory drugs were used in all cases. Nine patients started combined immunomodulatory treatment at the time of diagnosis, and 5 patients after a mean of 2.2 months. In the long term, 6 of the 10 patients followed up for more than 5 years presented mild or moderate cognitive sequelae. Four patients presented relapses, generally coinciding with the decrease of corticosteroid doses.ConclusionsEarly initiation of immunotherapy, as well as triple combination therapy, where needed, was associated with a lower frequency of cognitive impairment 2 years after onset. (AU)

Opsoclonus-myoclonus syndrome: Clinical characteristics, therapeutic considerations, and prognostic factors in a Spanish paediatric cohort.

INTRODUCTION: Opsoclonus-myoclonus-ataxia syndrome is a rare neuroinflammatory disorder with onset during childhood; aetiology may be paraneoplastic, para-infectious, or idiopathic. No biomarkers have yet been identified, and diagnosis is clinical. Better cognitive prognosis appears to be related to early onset of immunomodulatory therapy. METHODS: We describe the epidemiological, clinical, therapeutic, and long-term prognostic characteristics of a cohort of 20 Spanish patients. RESULTS: The mean age of onset was 21 months (range, 2-59). Ataxia and opsoclonus were the most frequent symptoms both at disease onset and throughout disease progression. The mean time from onset to diagnosis was 1.1 months. Neuroblast lineage tumours were detected in 45% of patients; these were treated with surgical resection in 7 cases and chemotherapy in 2. Cerebrospinal fluid analysis revealed pleocytosis in 4 cases (25%) and neither antineuronal antibodies nor oligoclonal bands were detected in any patient. Immunomodulatory drugs were used in all cases. Nine patients started combined immunomodulatory treatment at the time of diagnosis, and 5 patients after a mean of 2.2 months. In the long term, 6 of the 10 patients followed up for more than 5 years presented mild or moderate cognitive sequelae. Four patients presented relapses, generally coinciding with the decrease of corticosteroid doses. CONCLUSIONS: Early initiation of immunotherapy, as well as triple combination therapy, where needed, was associated with a lower frequency of cognitive impairment 2 years after onset.

Clinical features and outcomes of opsoclonus myoclonus ataxia syndrome.

OBJECTIVES AND METHODS: Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare neuroinflammatory disorder. We aimed to retrospectively evaluate clinical and laboratory data and outcomes of 23 children diagnosed with OMAS in two children's hospitals between 2010 and 2021. RESULTS: There were 14 boys and 9 girls aged 4-113 months, median 24 months. Ten (43.5%) children had paraneoplastic causes: neuroblastoma/ganglioneuroblastoma (n = 9), acute lymphoblastic leukemia (n = 1). Three children had a postinfectious cause (upper respiratory tract infection in 2, EBV infection in 1) and two had a history of vaccination (varicella in 1, hepatitis A and meningococcal in 1). No underlying factor was identified in 8 (34.8%) children. Speech disorders were more frequent in patients with neural tumors than in those without (p = 0.017). Intravenous immunoglobulin and steroids were effective as initial treatment in most children. Rituximab resulted in at least mild improvement in all 6 children with persistent or recurrent symptoms. Nine (39%) children experienced at least one relapse. Neurological sequelae were detected in 13 (57%) children. There was no significant correlation between clinical characteristics and outcome, except for higher risk of relapse in case of incomplete recovery after first attack (p = 0.001). CONCLUSIONS: Acute lymphoblastic leukemia, vaccines against hepatitis A and meningococci can be included among antecedent factors in OMAS. Among clinical symptoms, speech problems might point to the likelihood of an underlying neoplasm in OMAS. Intravenous immunoglobulin and steroids may be chosen for initial treatment while rituximab can increase the chance of recovery in case of persistent or recurrent symptoms. The presence of relapse was associated with poor outcome.

Surgical considerations for neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome: a series of 14 patients from a single institution.

INTRODUCTION: Neuroblastoma is a childhood cancer of neural crest cells occasionally associated with opsoclonus-myoclonus-ataxia syndrome (OMAS), a paraneoplastic process characterized by ataxia, rapid eye movements, and muscle twitching. OMAS treatment and outcomes are well studied, but prior reports do not detail how the presence of OMAS should impact surgical approach, particularly for tumors with image defined risk factors (IDRF). METHODS: We reviewed patients with neuroblastoma and OMAS at our institution from January 2009 to December 2020 and recorded tumor characteristics, operative details, OMAS therapies, and outcomes. RESULTS: We identified 14 patients with neuroblastoma and OMAS out of 212 patients referred for surgery. There were 11 gross total resections and three partial resections. Two patients with partial resections developed OMAS after initial resection. One patient with gross total resection developed tumor recurrence 10 years later with OMAS redevelopment signaling recurrence. Three patients were positive for IDRFs and the one receiving neoadjuvant therapy achieved a gross total resection. CONCLUSIONS: OMAS development after partial resection and OMAS recurrence following tumor recurrence indicates a correlation between tumor bulk and the paraneoplastic process. This justifies an aggressive resection even for low-risk tumors. Neoadjuvant therapy should be considered for potentially unresectable tumors with image defined risk factors. LEVEL OF EVIDENCE: IV.

Recommendations for Neuroblastoma Associated Opsoclonus-myoclonus-ataxia Syndrome in Childhood / 罕见病研究

@#Opsoclonus-myoclonus-ataxia syndrome(OMAS) is a rare neurological disorder. This disease is often associated with neuroblastoma(NB). OMAS and neuroblastoma in children in China are treated separately by neurology, medical and surgical oncology. In this group of children, NB usually has a good prognosis, while OMAS is prone to sequelae, but the lack of standardized evaluation and follow-up is not conducive to the diagnosis and treatment of the disease. In this study, experts from multidisciplinary fields worked together to develop recommendations for the diagnosis, treatment and follow-up of NB associated OMAS in children, hoping to improve the prognosis of children through standardized management of this group of children.

Corrigendum: CSF HIV RNA Escape in Opsoclonus-Myoclonus-Ataxia Syndrome: Case Report and Review of the Literature.

[This corrects the article DOI: 10.3389/fneur.2020.585527.].

Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS) Associated with SARS-CoV-2 Infection: Post-Infectious Neurological Complication with Benign Prognosis.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is the cause of the COVID-19 pandemic [5]. SARS-Cov-2 demonstrates partial resemblance to SARS-CoV and MERS-CoV in phylogenetic analysis, clinical manifestations, and pathological findings [6, 7]. Reports emerging from China have described ataxia as a neurological symptom of the SARS-CoV-2 infection [5]. Opsoclonus consists of back-to-back multidirectional conjugate saccades without an inter-saccadic interval [8]. Myoclonus is defined as a sudden, brief, "shock-like", nonepileptic involuntary movement [9], which has been described as a symptom of SARS-CoV-2 infection [10]. Opsoclonus-Myoclonus-Ataxia syndrome (OMAS) associated COVID-19 infection has been reported recently [1112].

CSF HIV RNA Escape in Opsoclonus-Myoclonus-Ataxia Syndrome: Case Report and Review of the Literature.

Background: Human immunodeficiency viruses (HIV) infection is associated with a broad range of neurological manifestations, including opsoclonus-myoclonus ataxia syndrome (OMAS) occurring in primary infection, immune reconstitution syndrome or in case of opportunistic co-infection. Case: We report the exceptional case of a 43-year-old female under HIV treatment for 10 years who presented initially with suspected epileptic seizure. Although the clinical picture slightly improved under anti-epileptic treatment, it was rapidly attributed to OMAS. The patient exhibited marked opsoclonus, mild dysarthria, upper limbs intermittent myoclonus, ataxia in 4 limbs, truncal ataxia, and a severe gait ataxia (SARA score: 34). The diagnostic work-up showed radiological and biological signs of central nervous system (CNS) inflammation and cerebral venous sinus thromboses. The HIV viral load was higher in cerebrospinal fluid (CSF) than in the blood (4,560 copies/ml vs. 76 copies/ml). She was treated for 5 days with pulsed corticotherapy. Dolutegravir and anticoagulation administration were initiated. Follow-ups at 2 and 4 months showed a dramatic improvement of clinical neurologic status (SARA score at 4 months: 1), reduction of CNS inflammation and revealed undetectable CSF and serum viral loads. Conclusion: This case underlines the importance of the evaluation of the CSF viral load in HIV patients developing OMAS and suggests CSF HIV RNA escape as a novel cause for OMAS.

Brain paraneoplastic syndromes in a patient with mediastinal ganglioneuroma.

Paraneoplastic neurologic syndromes are a rare and heterogeneous group of immune-mediated syndromes caused by underlying solid and nonsolid tumors. We present a case of 8-year-old female with long history of mild headaches and central instability who presented multiple poorly defined signal abnormalities at the subcortical white matter of both cerebral hemispheres and cerebellar atrophy on brain magnetic resonance imaging. Further studies revealed a posterior mediastinum ganglioneuroma derived from a mature ganglioneuroblastoma that was treated with surgery. Two paraneoplastic neurologic syndromes were considered: Anti-N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis due to the resolution of subcortical signal abnormalities after mediastinal mass resection and opsoclonus-myoclonus-ataxia syndrome due to cerebellar atrophy. Intertnational guideline established the criteria for definite diagnosis of paraneoplastic neurologic syndromes and detection of onconeural antibodies is not mandatory for their diagnosis. Paraneoplastic neurologic syndromes may appear several years before the tumor is detected.