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Effect of Increased Immunosuppression on Developmental Outcome of Opsoclonus Myoclonus Syndrome (OMS)
Abstract
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.
... As noted above, the ROHHAD phenotype, like OMS in most cases, continues to unfold even after surgical resection of the tumor, variably receiving immunomodulatory therapy. With earlier diagnosis and aggressive treatment, outcomes in patients with OMS have significantly improved, although many patients experience some long-term sequelae [63]. ...
Purpose:
To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents.
Methods:
The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause.
Results:
ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions.
Conclusion:
ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.
... Existen múltiples direcciones en uso de terapias para el SOM, donde se encuentra el uso de terapias a base de diferentes esteroides, de hormona adrenocorticotropa (ACTH), inmunoglobulinas, rituximab, y el uso de quimioterapia tal como la ciclofosfamida, ya sea en forma única o terapias mixtas (16). Históricamente, se utilizan los esteroides y la ACTH (1,16), donde los primeros en ciclos extensos exponen a los pacientes a múltiples efectos secundarios y un detrimento de su calidad de vida (17), además, de las frecuentes recaídas que presentan cuando se documenta una mejora y se inicia la disminución de las dosis (7,18). Se utilizan dos esquemas descritos con prednisona a dosis 1-2mg/kg/día (19) o dexametasona mensual en pulsos de 20 mg/metro 2 /día por 3 días (1). ...
El síndrome opsoclonus-mioclonus es una condición rara, asociada con una etiología de carácter autoinmune, tanto paraneoplásica, parainfecciosa o idiopática. Estos pacientes se presentan con ataxia del tronco y extremidades, con caídas, opsoclonus, mioclonías, y se puede acompañar de diversos grados de encefalopatía, signos cerebelosos y alteraciones del sueño. En el caso de la población pediátrica, se debe evaluar por neuroblastoma; y en adultos con encefalopatía asociada se debe realizar una evaluación exhaustiva para detectar malignidad oculta. Mientras que los síntomas neurológicos agudos pueden controlarse mediante inmunoterapia, y se ha visto respuesta parcial a tratamiento antitumoral, el resultado a largo plazo se caracteriza por la presencia de déficit neuropsicológico.
... Генез заболевания до конца неясен, как и факторы, влияющие на тяжесть его течения, успешность лечения и прогноз. В структуре дефекта при данном синдроме описываются совокупность неврологических нарушений, а также отдельные клинико-психологические симптомы [3][4][5][6][7][8]. ...
Objective: to investigate and analyze the specific features of mental development in children with opsoclonus-myoclonus syndrome (OMS) in relation to the number of exacerbations. Patients and methods. A total of 19 infants (8 boys and 11 girls) aged 1 year 7 months to 10 years 7 months with OMS were examined. The investigation included an analysis of medical records, a follow-up of the children with evaluation of their behavior, emotional responses, and mental functions, and an interview with their parents. Pathopsychological and neuropsychological examinations were used separately for children under 5 years and for those over 5 years, respectively. Results and discussion. It was established that a larger number of OMS exacerbations increased the severity of mental developmental disorders in children if they had >5 deteriorations; there was a severe developmental retardation. The children with OMS were found to have the features of an emotional state and motor behavior and a stable set of the most vulnerable mental processes and functions in the presence of the disease: the neurodynamic features of mental processes; impairments in the motor component of mental functions, including speech; visual and spatial deficits. Positive trends in mental development (as general cognitive interest, readiness for communication with adults) are suggestive of the potential compensation resources that should be used for the psychocorrection and rehabilitation of children with OMS. Conclusion. Mental retardation is seen in children with OMS, the severity of which increases with the number of disease relapses. There is a need for further studies of children with OMS.
... В связи с этим ученые пришли к выводу, что дан- ный диагноз правомерно выставлять при выявлении хотя бы трех из четырех признаков: опсоклонус, мио- клонус/атаксия, поведенческие изменения/наруше- ния сна и наличие нейробластомы [5]. Выявление нейробластомы -важное звено для постановки ди- агноза, особенно при наличии атипичного течения. ...
Optimization of the choice of rehabilitation methods in children with the oploskonus myoclonus syndrome on the basis of the analysis of stabilometric parameters. The study included 48 children of both sexes in the age range from 3 to 7 years with the diagnosis of «opsclonus-myoclonus syndrome». All patients were separated into 4 groups according to applied rehabilitation methods: in the first group (12 patients) patients received craniosacral therapy, in the II group - modified Vojta therapy (13 patients), in the third group patients underwented an isolated course of Galileo vibration therapy (10 patients), in the fourth group patients received modified Vojta therapy together with Galileo vibration therapy (13 patients). Patients underwented the course of craniosacral therapy demonstrated the increases rates of speed (V) in 1.48 times and statokinesiogram square in 1.94 times after fifth procedure as compared with data before. In the second group 1.32 times speed decrease (V) and 1.56 statokinesiogram square decrease (S) were marked. In the third group there were 1.73 times statokinesiogram square increase (S) and the displacement of pressure center midposition in frontal plane (X) to the left after implementation of 10 manipulation. In the fourth group 1.42 times speed decrease (V) and 2.7 times statokinesiogram square decrease (S) were marked after implementation of 10 manipulation, as well as displacement of pressure center midposition (X) in frontal plane to the right and tendency to displacement of pressure center in sagittal plane to the front after conducted manipulations. Modified Vojta therapy together with Galileo vibration therapy can be applied in the capacity of most effective rehabilitation methods for children with opsoclonus-myoclonus syndrome leading to useful increase of stabilometric parameteres.
... 163 Newer studies using combinations of immunotherapy have shown encouraging results. A recent trial of steroids, IVIg, and rituximab or cyclophosphamide revealed better outcomes than prior historical controls, 164 with further evidence of the effectiveness of multimodal immunotherapy in a subsequent retrospective review. 165 Another study showed that adding rituximab to ACTH and/or IVIg therapy yields motor improvement, with a relapse rate of only twenty percent with ACTH wean. ...
Over the last decade, there have been significant advances in the identification, characterization, and treatment of autoimmune neurologic disorders in children. Many of these diseases include a typical movement disorder that can be a powerful aid to diagnosis. Frequently, movement disorders in autoimmune conditions are the sole or among a few presenting symptoms, allowing for earlier diagnosis of an underlying malignancy or systemic autoimmune disease. Given that early detection and treatment with immunotherapy may confer improved outcomes, recognizing these patterns of abnormal movements is essential for child neurologists. The purpose of this review is to summarize the clinical characteristics, diagnosis, and treatment of movement disorders that occur in pediatric autoimmune disorders.
... Mitchell and co-workers, in their recent long-term follow-up report of OMA, showed a correlation of outcome and intensity of therapy consistent with the hypothesis that more intensive immunosuppression may be associated with improved long-term neurologic outcome. (30) Other studies have also indicated that a more aggressive treatment approach may lead to improved neurologic outcome for patients with OMA.(5;13) Our study demonstrates the addition of IVIG to prednisone and risk-adapted chemotherapy improves OMA response, indicating that IVIG+ will serve as an effective treatment back-bone to test future strategies. ...
Background
No clinical trial has been done for patients with neuroblastoma-associated opsoclonus myoclonus ataxia syndrome (OMA) and existing treatment is based on case reports and small retrospective studies. We aimed to assess OMA response to prednisone and risk-adapted chemotherapy and to establish whether the addition of intravenous immunoglobulin (IVIG) further improves response.
Methods
We did a randomised, open-label, phase 3 trial in 92 Children's Oncology Group institutions in North America, Australia, and New Zealand with patients younger than 8 years with biopsy-proven, newly diagnosed neuroblastoma or ganglioneuroblastoma associated with OMA. Randomisation was stratified according to the clinical stage of neuroblastoma. We randomly assigned eligible patients through use of computer generated randomisation to receive 12 cycles of IVIG (1 g/kg, day 0 and 1, cycle one; day 0, cycles two to six; day 0, cycles eight, ten, and 12; each cycle lasting 28 days) or no IVIG, in addition to prednisone (2 mg/kg per day divided twice a day for a minimum of two cycles) and neuroblastoma risk-adapted chemotherapy (cyclophosphamide 25 mg/kg for children ≤20 kg and 750 mg/m² for children >20 kg, day 0 for the first six cycles in patients with low-risk disease). The primary outcome was OMA response, defined as the best score of the three neurological assessments assessed at months 2, 6, and 12 with a scale developed by Mitchell and Pike; baseline versus best response scores were compared. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00033293.
Findings
Of the 53 patients enrolled in the study between May 15, 2004, and Feb 4, 2013, 33 (62%) were female. 44 patients had low-risk, seven had intermediate-risk, and two had high-risk neuroblastoma. 26 patients were randomly assigned to IVIG and 27 to no IVIG. One patient did not have a neurological assessment and was excluded from OMA response analysis. 21 (81%) of 26 patients in the IVIG group had an OMA response, compared with 11 [41%] of 27 in the no IVIG group (odds ratio 6·1, 95% CI 1·5–25·9, p=0·0029). Median follow-up for patients who were OMA progression-free was 6·1 years (IQR 3·6–8·7, range 1 day to 10·3 years) for both groups. For most patients, the IVIG regimen combined with cyclophosphamide or other risk-based chemotherapy was well tolerated. 28 patients reported grade 3 or higher adverse events, with the most frequent ones being anaemia, neutropenia, vomiting, infectious diseases, nystagmus, ataxia, and agitation. One patient with high-risk neuroblastoma died of a severe adenovirus infection after high-dose chemotherapy followed by autologous stem cell reconstitution.
Interpretation
The addition of IVIG to prednisone and risk-adapted chemotherapy improved OMA response, and this regimen constitutes a backbone on which to build additional therapy.
Funding
US National Cancer Institute, National Institutes of Health.
... The outcomes achieved with the standard treatments (tumor therapy, corticosteroids or ACTH in pediatric patients, often combined with IVIG; if required, plasma exchange) are often unsatisfactory and associated with residual deficits [73]. More aggressive therapeutic strategies, such as rituximab and cyclophosphamide, can improve long-term prognosis, including cognitive and behavioral deficits [74,75]. ...
Zusammenfassung
Die paraneoplastischen neurologischen Erkrankungen sind insgesamt selten und zeichnen sich durch eine mannigfaltige klinische Präsentation aus. Sie können sowohl das zentrale und periphere Nervensystem als auch den neuromuskulären Übergang und die Muskulatur betreffen. In zweidrittel der Fälle ist der Tumor zum Zeitpunkt des Auftretens der neurologischen Symptome noch nicht bekannt. Für die Diagnosestellung sind eine Testung der antineuronalen Antikörper und eine gezielte Tumorsuche notwendig. Eine schnellstmögliche adäquate Tumortherapie in Kombination mit einer Immuntherapie sind die Grundpfeiler der Behandlung von paraneoplastischen Erkrankungen. Aufgrund des Fehlens von kontrollierten Studien basieren die Therapieempfehlungen auf Fallserien und Expertenmeinungen. Im Akutstadium werden meist eine Steroidstoßtherapie, intravenöse Immunglobuline oder die therapeutische Apherese angewendet. Angesichts des potenziell irreversiblen Schadens muss diese Therapie früh, ggf. bereits während der Tumordiagnostik, begonnen werden. Für die Langzeittherapie werden je nach Krankheitsbild unterschiedliche Immunsuppressiva empfohlen.
Neben der Tumorprognose hängt der Krankheitsverlauf weitgehend davon ab, ob die Antikörper gegen intrazelluläre Antigene oder gegen Oberflächenantigene gerichtet sind. Letztere Erkrankungen sprechen auf B-Zell gerichtete Therapien gut an und sind mit einer deutlich besseren Prognose assoziiert. Diese Übersichtsarbeit fasst die aktuellen Therapieempfehlungen zusammen und gibt einen Ausblick auf einige noch nicht validierte, aber perspektivisch interessante Ansätze.
... The outcomes achieved with the standard treatments (tumor therapy, corticosteroids or ACTH in pediatric patients, often combined with IVIG; if required, plasma exchange) are often unsatisfactory and associated with residual deficits [73]. More aggressive therapeutic strategies, such as rituximab and cyclophosphamide, can improve long-term prognosis, including cognitive and behavioral deficits [74,75]. ...
Paraneoplastic neurological disorders are rare and clinically heterogeneous diseases. They can affect both the central and peripheral nervous system as well as the neuromuscular junction and muscle. Neurological deficits develop in 2/3 of cases prior to cancer diagnosis. The diagnostic approach includes screening for antineuronal antibodies and a search for the underlying tumor. A prompt tumor therapy in combination with immunotherapy is the cornerstone in the management of these diseases. Due to lack of clinical trials, treatment recommendations are based on case series and expert opinions. High-dose corticosteroids, intravenous immunoglobulins and apheresis therapies are often used in the acute stage of the disease. These therapies should be started as early as possible, e. g., during tumor screening, in order to prevent irreversible damage. Long-term treatment is mostly immunosuppressive and depends on the specific paraneoplastic syndrome. Outcomes vary depending upon the prognosis of the underlying cancer and the nature of the antineuronal antibodies. Disorders with antibodies directed against antigens on the neuronal cell surface are highly sensitive to B cell-directed therapies and mostly associated with a favorable outcome. A thorough review of published data on actual treatment recommendation is provided along with discussion of currently not validated, but potentially effective new therapies.
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.
Background and Objectives
Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children.
Methods
Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification.
Results
Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58–7.58) years. The initial hospitalization recorded a median score of 12 (7–14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0–5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17–7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3–4), reducing to 1 (0–4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy).
Discussion
OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.
A previously healthy 12-year-old girl presented to the emergency department due to her vision “jumping” while trying to focus or read for the past 2 weeks. Six weeks before, she experienced fever and sore throat, followed by generalized seizures, and she was evaluated in the emergency department by the neurology service. Magnetic resonance imaging (MRI) of the brain demonstrated broad areas of increased T2 signal in the left frontal, parietal, and occipital lobes with diffusion restriction. A lumbar puncture revealed lymphocytic pleocytosis, elevated protein, elevated IgG synthesis rate, and elevated opening pressure. She was ultimately diagnosed with aseptic meningoencephalitis and discharged from the hospital on a regimen of levetiracetam and acyclovir with follow-up in the neurology outpatient clinic.KeywordsOpsoclonus-myoclonus syndromeOcular flutterParaneoplasticAutoimmuneNeuro-immunologyEncephalitisNeuroblastoma
Aim:
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder. Approximately half of the cases are associated with neuroblastoma in children. This study's aim is to review management of our cases with OMAS-associated neuroblastoma for treatment approach as well as long-term follow-up.
Methods:
Age at onset of symptoms and tumor diagnosis, tumor location, histopathology, stage, chemotherapy, OMAS protocol, surgery, and follow-up period were evaluated retrospectively in six patients between 2007 and 2022.
Results:
Mean age of onset of OMAS findings was 13.5 months and mean age at tumor diagnosis was 15.1 months. Tumor was located at thorax in three patients and surrenal in others. Four patients underwent primary surgery. Histopathological diagnosis was ganglioneuroblastoma in three, neuroblastoma in two, and undifferentiated neuroblastoma in one. One patient was considered as stage 1 and rest of them as stage 2. Chemotherapy was provided in five cases. The OMAS protocol was applied to five patients. Our protocol is intravenous immunoglobulin (IVIG) 1 g/kg/d for 2 consecutive days once a month and dexamethasone for 5 days (20 mg/m2/d for 1-2 days, 10 mg/m2/d for 3-4 days, and 5 mg/m2/d for the fifth day) once a month, alternatively by 2-week intervals. Patients were followed up for a mean of 8.1 years. Neuropsychiatric sequelae were detected in two patients.
Conclusion:
In tumor-related cases, alternating use of corticosteroid and IVIG for suppression of autoimmunity as the OMAS protocol, total excision of the tumor as soon as possible, and chemotherapeutics in selected patients seem to be related to resolution of acute problems, long-term sequelae, and severity.
Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare disorder that causes significant neurodevelopmental sequelae in children. Approximately half of pediatric OMAS cases are paraneoplastic, typically associated with localized neuroblastic tumors. Since early persistence or relapse of OMAS symptoms is common even after tumor resection, OMAS relapses may not routinely prompt reevaluation for recurrent tumors. We report a 12-year-old girl with neuroblastic tumor recurrence associated with OMAS relapse a decade after initial treatment. Providers should be aware of tumor recurrence as a trigger for distant OMAS relapse, raising intriguing questions about the role of immune surveillance and control of neuroblastic tumors.
The neurological sign, ataxia, is defined as a disturbance in smooth coordination of movements. While ataxia is usually due to a disturbance in the cerebellum, it can be caused by abnormalities anywhere in the neuroaxis. Evaluation of ataxia requires a careful history and physical examination focused on localizing the cause. The differential diagnosis of ataxia is broad and best approached by dividing it into acute/subacute, recurrent/episodic and chronic static or progressive etiologies. Postinfectious cerebellar ataxia is the most common cause of childhood ataxia and usually has a favorable outcome. However, it is important to rule out serious and potentially life-threatening causes such as posterior fossa malignancies. Recurrent episodes of ataxia can be due to a migrainous etiology or from metabolic and genetic causes. Causes of chronic ataxia include structural, genetic or metabolic causes. Management includes symptom-based treatment to ensure safety of the child, while specific treatments usually depend on the underlying etiology.
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.
Opsoclonus-myoclonus syndrome associated with neuroblastoma (OMS-NB) is a refractory paraneoplastic syndrome which often remain neurological sequelae, and detailed pathogenesis has remained elusive. We encountered a pediatric patient with OMS-NB treated by immunosuppressed therapy who showed anti-glutamate receptor δ2 antibody and increased B-cells in cerebrospinal fluid (CSF), and multiple lymphoid follicles containing abundant Bcells in tumor tissue. Unbiased B-cell receptor repertoire analysis revealed identical B-cell clone was identified as the dominant clone in both CSF and tumor tissue. These identical B-cell clone may contribute to the pathogenesis of OMS-NB. Our results could facilitate the establishment of pathogenesis-based treatment strategies for OMS-NB.
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.
Background
Dancing eye syndrome or opsoclonus-myoclonus syndrome (OMS) is a very rare disease (incidence <1/5,000,000 per year), which is more prevalent in young children. Although it is not usually a cause of mortality, the aftermaths are not rare.
Methods
We performed an observational retrospective review of children diagnosed with OMS in our neuropediatric department from 1996 to 2020, with the objective of assessing the prognostic value of initial clinical features. All medical data from diagnosis to last follow-up were reviewed. We defined unfavorable evolution of OMS as persistence or worsening of symptoms. Subsequently, based on a literature review, our results and experience, a diagnostic algorithm was developed.
Results
A total of 13 OMS patients were included: 61.5% were male (n = 8), median age at diagnosis was 18 months (IR = 76), median treatment delay was 14 days (IR = 146) and OMS score at onset was 8 (IR = 11). The most frequent etiologies were neuroblastoma-associated and idiopathic OMS (38.46%; n = 5) of the patients, followed by post-infectious OMS (n = 3). All the patients were treated with corticosteroids, five required a surgical intervention (neuroblastoma group), and three required adjunctive immune therapy (immunoglobulins, cyclophosphamide and/or rituximab). We detected neurodevelopmental disorders in 38.46% (n = 5) of the patients, mainly attention deficit (n = 4), and persistent sleep disturbances (n = 4). The median OMS score at the end of follow-up was 1 (IR = 3).
An important diagnostic delay, OMS score of ≥10 and age >1 year at onset may correlate with a higher risk of aftermaths. We detected a better prognosis in the post-infectious OMS, with full recovery occurring in 2/3 of patients.
Conclusions
Early clinical suspicion is key to guarantee maximum response of treatment.
Background:
Neuroblastoma with opsoclonus-myoclonus syndrome (OMS-NB) is a rare disease in children. Few studies of long-term outcome of children with OMS-NB were conducted. This study aimed to review the rate of recovery of neurological symptoms and the long-term neurological outcomes of children with OMS-NB.
Methods:
This study retrospectively assessed 14 children with OMS-NB diagnosed at Peking University First Hospital from May 2011 to November 2019. Demographic data, neurological symptoms, oncological status and treatments were retrospectively reviewed from the records. Neurological sequelae were recorded by clinical and remote follow-up.
Results:
During the acute stage, myoclonus and ataxia were observed in all children while opsoclonus was observed in 10/14 children. The median durations of neurological symptoms were 15 months (range, 5-48 months). Approximately 93% (13/14) children revealed neurological sequelae. Significant correlations were as follows: motor retardation with female gender (P<0.001) and residual tumors (P<0.05); language impairment with non-adrenal-gland-located tumors (P<0.05). There were no obvious factors that had a statistical relationship with cognitive disorder or behavioral changes.
Conclusions:
Children with OMS-NB have favorable outcomes in terms of neurological symptoms. Neurological sequelae occurred in almost all children. Children with different features tend to reveal different sequalae. Features of female gender and residual tumors tend to reveal motor retardation while that of non-adrenal-gland-located tumors tend to reveal language impairment.
Background and Objectives
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen.
Methods
Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae.
Results
The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided.
Discussion
OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.
Opsoclonus-myoclonus syndrome (OMS) is a neurological non-fatal disease that usually responds to immunotherapies. However, the real challenge is to counteract the high frequency of relapses and long-term developmental sequelae. Since the OMS is extremely rare, a common consensus regarding therapeutic guidelines is still lacking. The goals of this study were to test whether ACTH was superior to other immunotherapies and to investigate whether an early treatment could improve the outcome. Sixteen children affected by OMS were retrospectively reviewed. Eight children had a neuroblastic tumor. The other eight patients were affected by non-paraneoplastic OMS. Overall, the most commonly used treatment was corticotherapy (n = 11). However, ACTH (n = 10), rituximab (n = 7), immunoglobulins (n = 4), cyclophosphamide (n = 3), and mycophenolate (n = 2) were also administered. ACTH was associated with a high percentage of patients who healed (80%) and, as a first-line therapy, was associated with a lower incidence of relapses. An early treatment was associated with a favorable long-term outcome. Long-term sequelae occurred in 42% of patients who were treated early and in all of those who were treated late. It is advisable for the affected children to be identified at an early time, as they may benefit from an early treatment. ACTH represents an effective treatment with a high probability of recovery and low rate of relapses.
Objective: To study the clinical characteristics and treatment of pediatric opsoclonus-myoclonus syndrome (OMS).
Methods: We analyzed the clinical data of nine children OMS between June 2017 and Nov 2020.
Results: Nine children (M/F = 3:6, median onset age was 18 months) diagnosed with OMS were included in the study. Before onset, human rhinovirus and respiratory syncytial virus were seen in one patient, respectively. And one patient received Japanese encephalitis vaccination. Three patients had neuroblastoma, and one patient had ganglioneuroblastoma. All patients' symptoms were improved after receiving surgery (for four patients with tumor), intravenous human immunoglobulin and pulsed methylprednisolone. However, four patients without mass relapsed and became relapse free after rituximab treatment. The relapse rate was 44.4% (4/9). The OMS severity score at the last follow-up was significantly lower than the OMS severity score at onset (3.0 ± 1.0 vs. 11.0 ± 2.2, paired-samples t-test, P < 0.001). All patients had at least one item of neurological symptoms or neuropsychological disturbances.
Conclusion: For pediatric OMS, human rhinovirus infection and respiratory syncytial virus infection can be seen before onset. Rituximab is effective in reducing relapse. Improving recognition and long-term prognosis in OMS is urgent.
Introduction:
Paraneoplastic neurological syndromes (PNS) are a rare heterogeneous group of neurological diseases associated with tumors. These syndromes are the result of a cross-reactive immune response against antigens shared by the tumor and the nervous system. The discovery of an increasing number of autoantigens and the identification of tumoral factors leading to a substantial antitumoral immune response makes this topic highly innovative.
Areas covered:
This review covers the clinical, oncological, pathophysiological aspects of both immunological PNS groups. One is associated with autoantibodies against intracellular onconeural antibodies, which are highly specific for an underlying tumor, although the disease is mainly T-cell mediated. In contrast, PNS associated with pathogenic surface-binding/receptor autoantibodies, which are often responsive to immunosuppressive treatment, may manifest as paraneoplastic and non-paraneoplastic diseases. The most frequent tumors associated with PNS are (small cell) lung cancer, gynecological tumors, thymoma, lymphoma, and, in children, neuroblastoma. A special interest is given to PNS, induced by immune checkpoint-inhibitors (ICIs).
Expert opinion:
Research in PNS, including the group of ICI-induced PNS provide new insights in both the pathophysiology of PNS and tumor immune interactions and offers new treatment options for this group of severe neurological diseases.
Background and Objectives: The opsoclonus-myoclonus syndrome (OMS) is characterised by opsoclons, myoclons and impaired balance, often concomitant with sleep disorder and behavioural difficulties. The symptoms develop as a result of autoimmune response triggered by a neuroblastic tumour (NT). OMS can also develop secondarily to a viral infection or as an immune response triggered by an unknown agent. This leads to the activation of B- and T-cells, which produce and release autoantibodies or cytokines directly within the central nervous system (CNS), thus damaging the neurons within the cerebellum and the brain stem. The available OMS treatments aim at decreasing lymphocyte, cytokine and autoantibody production or accelerating the utilisation of the latter. Another treatment option for OMS involves using cytostatic agents, which damage T- and B-cells causing their depletion and impaired function, which reduces their ability to produce antibodies and cytokines. Materials and Methods: We present a single-centre experience in treating OMS secondary to NT in 7 children. Results: The combined treatment with cyclophosphamide plus dexamethasone resulted in a complete resolution of OMS symptoms in 4 children, and a significant improvement in the 3 children. Two of them periodically present hyperactivity, and one girl requires an additional support at school due to special educational needs (SEN). Conclusions: NT resection does not resolve OMS in children with OMS secondary to NT. The combined treatment with dexamethasone plus cyclophosphamide seems to be an effective treatment of OMS.
Opsoclonus-myoclonus syndrome (OMS) or Kinsbourne encephalopathy is a unique, rare neurological disease that causes difficulties in diagnosis, examination and treatment tactics. This article presents some organizational clinical, psychological and rehabilitation issues.
The aim of the study was to develop treatment tactics and means of preventing the recurrent development of neurological, behavioral and cognitive impairment in this pathology.
Results. Diagnosis of the disease was carried out based on a detailed study of anamnestic, molecular genetic, scintigraphic, neuroimaging, ultrasound, lymphocytic and neurological (opsoclonus, myoclonus, ataxia, behavioral and sleep disorders) signs. The severity of a child condition was determined using the Pranzatelli M. and Matthay K. scales. The clinical picture was represented by specific involuntary, arrhythmic, chaotic, multidirectional saccadic eye movements with horizontal, vertical, torsional components, behavioral changes, sleep disturbances, motor coordination dysfunction, the presence of myoclonic seizures, myoclonic jerks in the limbs and trunk, cerebellar ataxia and tremor. Slight cerebrospinal fluid lymphocytic pleocytosis was noted in the child, as it was described in the literature. Due to the fact that Kinsbourne encephalopathy has a paraneoplastic etiology in most cases, the child underwent brain MRI and CT as well as laboratory and instrumental examinations of the internal organs. The neuroimaging examination of the child’s brain indicated no focal density changes.
To rule out neuroblastoma, the child underwent ultrasound examination of the abdominal cavity organs and retroperitoneal space, a blood test for tumor markers, and measurements of catecholamine levels. To rule out parainfection and autoimmune processes, serum antibodies to various viruses were studied. Diagnosis of OMS was based on the analysis of the clinical picture, medical history and screening tests for oncopathology which was ruled out after a cytological study.
The prolonged multiple use of a combination of glucocorticoid, immunosuppressive and immunoglobulin therapy has been the essence of successful treatment. Currently, relative improvements in the emotional-volitional sphere can be reported - age-appropriate intelligence and vocabulary skills, pulls himself up to stand and walks without support. Ocular opsoclonus rarely occurs – more often in jitteriness.
Conclusions. The rare occurrence and anatomical and biological characteristics of this disease emphasize the importance of search for new specific methods of diagnosis and treatment to implement timely measures aimed at slowing the disease progression.
Aim
To determine predictors of full‐scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort.
Method
In this retrospective and prospective cohort study at three academic medical centers (2006–2013), the primary outcome measure, FSIQ, was categorized based on z‐score: above average (≥+1), average (+1 to –1), mildly impaired (–1 to –2), and impaired (<–2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike’s information criterion was performed to understand the relationship between exposures and FSIQ.
Results
Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40–114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow‐up (p<0.001) predicted FSIQ (adjusted R²=0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse.
Interpretation
Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes.
Opsoclonus-myoclonus syndrome (OMS) is a rare and often relapsing neurologic illness with onset in early childhood. Patients with OMS have longitudinal mental development disturbances and features of emotional and behavioral state. Interruption of the normative mental development is determined by movement disorders (primary defect), which establish new conditions for child's life for a long time. Case study of the child with OMS and the discussion of movement disorders in the structure of the different mental processes types in this disease are presented. Movement disorders (primary defect) and their effects (secondary and other defects) affecting mental development are discussed (based on the levels of movements coordination concept by N.A. Bernstein). The research detects mistmatch between levels of movements coordination (intactness of higher levels and disturbance of lower levels), which important for prospective analysis of the mental disorders mechanisms in children with OMS.
Resumen
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.
Método
Se describen las características epidemiológicas, clínicas, terapéuticas y pronósticas a largo plazo de una cohorte de 20 pacientes españoles.
Resultados
La 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.
Conclusiones
El 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.
Objective
To review the treatment and revaccination of neuroblastoma‐associated opsoclonus‐myoclonus‐ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK).
Procedure
Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma‐associated OMAS followed at MSK from 2000 to 2016.
Results
Fourteen patients (nine female) were 9‐21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n = 12), stage 2B, or intermediate‐risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in two, and unknown in one patient. No patient had amplified MYCN . All patients underwent tumor resection at diagnosis. Anti‐neuroblastoma treatment was limited to chemotherapy in one patient. Overall survival is 100% at 3‐16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab, and one received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, five patients received low‐dose cyclophosphamide and two received rituximab. The mean total OMAS treatment was 20‐96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other six experienced OMAS relapse. To date, six patients have been revaccinated at a minimum of 2 years after completion of OMAS therapy without OMAS recurrence.
Conclusions
Patients with neuroblastoma‐associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg, and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.
Purpose Rituximab is increasingly used as a second-line treatment of neuroinflammatory disorders to improve clinical outcomes in cases refractory to conventional immunotherapy and to reduce relapses. This study aimed to demonstrate the efficacy and safety of rituximab used for pediatric autoimmune neuroinflammatory disorders. Methods We retrospectively reviewed the medical records of 32 patients (median age, 8.5 years; range, 1.1 to 17.1; 23 girls) who received rituximab treatment at Seoul National University Children’s Hospital. The disease subgroups were anti-N-methyl-D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis (n=11), opsoclonus-myoclonus ataxia syndrome (OMAS) (n=10), other suspected autoimmune encephalitis (n=5), neuromyelitis optica spectrum disorder (n=4), and chronic inflammatory demyelinating polyneuropathy (n=2). Efficacy was measured by modified Rankin Scale (mRS) scores at the initiation of rituximab administration, at 2 months after initiation, and at the last follow-up. A favorable clinical outcome was defined as an improvement of ≥2 in the mRS score or achievement of an mRS score ≤2. Safety was assessed by reviewing infusion-related adverse events and infectious complications, including progressive multifocal leukoencephalopathy. Results Two months after the initiation of rituximab therapy, 21patients (65.6%) had a favorable response, while 26 (82.1%) had a favorable response at the last follow-up. Among the disease subgroups, anti-NMDAR encephalitis and OMAS showed especially good responses. Rituximab infusion-related adverse events were identified in nine patients (28.1%). All complications recovered spontaneously or with only symptomatic treatment. Conclusion Rituximab can be used safely for various pediatric autoimmune neuroinflammatory diseases. Rituximab is expected to improve clinical outcomes in pediatric patients with anti-NMDAR encephalitis and OMAS.
Autoimmune central nervous system (CNS) affection comprises an expanding group of potentially treatable disorders that should be included in the differential diagnosis of any type of encephalitis or myelitis. The extent of CNS involvement in systemic immunopathic disorders such as lupus erythematosus, rheumatoid arthritis (RA), or sarcoidosis has been recognized since long. However, the identification of underlying pathogenic mechanisms has led to the development of revolutionary antibody (Ab)-based therapies improving the prognosis of this group of patients. Further advances in autoimmune involvement of the nervous system have led to the identification of new clinical syndromes, associated with antineuronal Abs that have transformed the diagnostic and therapeutic approach to these disorders. Starting with auto-Abs to the acetylcholine receptor for myasthenia gravis and against intracellular antineuronal nuclear Ab 1 (ANNA-1) (Hu) antigen, there is still a continuous expansion of the number of cell surface, synaptic, and intracellular molecules, which expose antigenic epitopes for autoimmune neurological disorders. Numerous of these Abs were associated with an extraneural malignancy, causing “paraneoplastic neurological syndromes,” while others occur as primary autoimmune diseases. Furthermore, identification of several Abs targeting glial antigens, such as aquaporin-4 (AQP4), has enabled the classification of these disorders as distinct clinical entities. The particular focus of this chapter is on autoimmune disorders associated with encephalitis or myelitis, subdivided into two groups: (1) systemic diseases with CNS manifestations and (2) Ab-associated disorders of the CNS.
Background
Treatment of opsoclonus‐myoclonus syndrome (OMS) has historically involved corticosteroids and intravenous immunoglobulin (IVIG) for a duration of 6‐12 months or longer. This study evaluated whether a brief upfront immunomodulatory therapy protocol with rituximab reduces the duration of OMS therapy without adversely affecting OMS outcomes.
Procedure
Retrospective chart review was performed for consecutive children diagnosed with OMS from 2006 to 2019 at The Hospital for Sick Children (Toronto, Canada). Children treated within 3 months of diagnosis with a treatment protocol involving pulse methylprednisolone (3‐5 days, followed by an oral steroid taper), IVIG and/or plasma exchange, and rituximab (protocol group, n = 7) were compared to a historical group treated primarily with prednisone and IVIG (n = 8).
Results
The duration of corticosteroid treatment was shorter in the protocol (median 4.5 [range 3‐12] months) compared to that in the historical group (median 21.5 [range 6‐70] months, P = .005), and subjects in the protocol group received fewer cycles of IVIG (median 1 [range 0‐7] cycle vs 7 [range 1‐70] cycles, P = .01). The proportion of children with OMS relapse was similar between the protocol and historic groups (2/6 vs 5/8, P = .59). OMS symptom rating scales at 12‐month follow‐up were similar in the protocol group (median 2.5, range 0‐3) compared to that in the historical group (median 1, range 0‐7; P = .66).
Conclusions
An upfront immunomodulatory therapy protocol with rituximab permits reduction in the duration of corticosteroid and IVIG therapy without a detrimental effect on OMS outcomes. Future studies with longer follow‐up will have to determine whether neurocognitive and psychosocial outcomes are improved by this approach.
Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early‐onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease‐modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease‐modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha‐adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of “disease‐specific” therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood‐onset movement disorders. © 2019 International Parkinson and Movement Disorder Society
Opsoclonus–myoclonus syndrome in adults is a rare and heterogeneous disorder with the clinical features of opsoclonus, myoclonus, ataxia, and behavioral and sleep disturbances. The pathophysiology is thought to be immunological on the basis of paraneoplastic or infectious etiologies. Immunomodulatory therapies should be performed although the response may be incomplete. A number of autoantibodies have been identified against a variety of antigens, but no diagnostic immunological marker has yet been identified. This review focuses on underlying mechanisms of opsoclonus–myoclonus syndrome, including findings that have been identified recently, and provides an update on the clinical features and treatments of this condition.
Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder with unknown etiology and pathogenesis. There is not enough knowledge about psychological development of children with OMS.
Aim:
To study an influence of the time of disease onset and children's age and type of disease course on psychological development of children with OMS.
Material and methods:
The study included 26 children with OMS of age between 1 year 7 months and 13 years, 10 boys and 16 girls. The following methods were used: analysis of patient's development records, psychological interview with parents, assessment of emotional, behavioral, motion state and interpersonal relations.
Results and conclusion:
The disease onset at the early stage of ontogenesis (before 3 years) results into severe psychological disorders. Patients at the age between 3 and 5 years demonstrate the maximal number of developmental delays with possibilities of compensation. The article discusses a possible role of psychotraumatic and psychosocial factors in psychological disorders in children with OMS. The influence of age should be taken into account in planning of treatment and rehabilitation and evaluation of disease prognosis.
Pediatric movement disorders (PMDs) are common and have recently received increasing attention. As these disorders have special clinical features, the selection of appropriate behavioral assessment tools that can clearly distinguish movement disorders from other diseases (eg, epilepsy and neuromuscular disorders) is crucial for achieving an accurate diagnosis and treatment. However, few studies have focused on behavioral assessments in children. The present report attempts to provide a critical review of the available subjective and objective assessment tests for common PMDs. We believe that the principles of objectification, multi‐purpose use, and simplification are also applicable to the selection and development of satisfactory pediatric behavioral assessment tools. We expect that the development of wearable sensors, virtual reality, and augmented reality will lead to the establishment of more reliable and simple tests. In addition, more rigorous randomized controlled trials that have been specifically designed to evaluate behavioral testing in children are also expected in the future.
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.
Introduction:
Flow cytometric cerebrospinal fluid (CSF) lymphocyte subset analysis has improved the diagnosis of neuroinflammation and identified multiple markers of inflammation in opsoclonus-myoclonus syndrome (OMS). The aim of this exploratory, retrospective study was to analyze the effect of immunotherapy on these markers to determine which agents are disease modifying.
Methods:
Cross-sectional immunological observations were made in an IRB-approved case-control study, and patients were treated empirically. Ten different CSF lymphocyte subpopulations from 18 children with persistent OMS had been measured by flow cytometry before and after clinical treatment with cyclophosphamide/ACTH/IVIG combination (n = 7) or ACTH/IVIG alone (n = 11). Clinical severity of OMS was scored from videotapes by a blinded observer using the OMS Evaluation Scale.
Results:
Only cyclophosphamide combination therapy (mean dose 26 ± 3 mg/kg or 922 ± 176 mg/m2x 6 cycles) significantly decreased the percentage of CSF B cells. The mean reduction was 65%, with CSF B cell frequency normalized at 7-8 months in 70%. Other abnormalities of the CSF immunophenotype, such as the low CD4/CD8 T cell ratio, persisted, and there were no therapeutic changes in T cell activation/maturation markers. Effects on relative and absolute size of PBMC subsets were similar. Clinical improvement was 70% and 55% in respective treatment groups. The relapse rates of the two groups did not significantly differ.
Discussion:
The main effect of cyclophosphamide combination therapy on neuroinflammation in OMS was moderate reduction in CSF B cell expansion. Though exploratory, it may provide a steroid sparer option in partially-responsive OMS.
Immune mediated movement disorders include movement disorders in the context of autoimmune encephalitis such as anti-NMDAR encephalitis, post-infectious autoimmune movement disorders such as Sydenham chorea, paraneoplastic autoimmune movement disorders such as opsoclonus myoclonus ataxia syndrome, and infection triggered conditions such as paediatric acute neuropsychiatric syndrome. This review focuses on the approach to treatment of immune mediated movement disorders, which requires an understanding of the immunopathogenesis, whether the disease is destructive or 'altering', and the natural history of disease. Factors that can influence outcome include the severity of disease, the delay before starting therapy, use of multimodal therapy and whether the course is monophasic or relapsing. Although the four main conditions listed above have different pathophysiological processes, there are general themes that broadly apply including: early diagnosis and treatment is better, minimise the severity of disease, escalate treatment if the patient is not responding to initial treatments, and minimise relapse.
Nonparaneoplastic opsoclonus–myoclonus ataxia syndrome is a rare neuroinflammatory condition featured by opsoclonus, myoclonus, ataxia, and cognitive behavioral disturbance. The authors report an observation of enterovirus 71-associated opsoclonus–myoclonus ataxia syndrome evolving toward full recovery on intravenous intravenous immunoglobulin (IG) treatment. Based on this case report, enterovirus 71 should be added to the list of infectious agents likely involved in opsoclonus–myoclonus ataxia syndrome, including the emerging subgroup of opsoclonus–myoclonus ataxia syndrome recovering without aggressive or prolonged immunosuppressive intervention. Further studies are mandatory to define the precise role, incidence, treatment, and outcome of enterovirus 71 and other infectious agents in benign forms of 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.
Pediatric-onset opsoclonus-myoclonus syndrome (OMS) is a devastating neuroinflammatory, often paraneoplastic, disorder. The objective was to characterize demographic, clinical, and immunologic aspects in the largest cohort reported to date. Cross-sectional data were collected on 389 children in an IRB-approved, observational study at the National Pediatric Myoclonus Center. Non-parametric statistical analysis was used. OMS manifested in major racial/ethnic groups, paralleling US population densities. Median onset age was 1.5 years (1.2–2 interquartile range), inclusive of infants (14%), toddlers (61%), and youngsters (25%). The higher female sex ratio of 1.2 was already evident in toddlers. Time to diagnosis was 1.2 months (0.7–3); to treatment, 1.4 months (0.4–4). Irritability/crying dominated prodromal symptomatology (60%); overt infections in <35%. Acute cerebellar ataxia was the most common misdiagnosis; staggering appeared earliest among 10 ranked neurological signs (P < 0.0001). Some untreated youngsters had no words (33%) or sentences (73%). Remote neuroblastic tumors were detected in 50%; resection was insufficient OMS treatment (58%). Age at tumor diagnosis related to tumor type (P = 0.004) and stage (P = 0.002). A novel observation was that paraneoplastic frequency varied with patient age—not a mere function of the frequency of neuroblastoma, which was lowest in the first 6 months of life, when that of neuroblastoma without OMS was highest. The cerebrospinal fluid (CSF) leukocyte count was minimally elevated in 14% (≤11/mm³) with normal differential, and commercially screened serum autoantibodies were negative, but CSF oligoclonal bands (OCB) and B cells frequency were positive (58 and 93%). Analysis of patients presenting on immunotherapy revealed a shift in physician treatment practice patterns from monotherapy toward multi-agent immunotherapy (P < 0.001); the number of agents/sequences varied. In sum, a major clinical challenge is to increase OMS recognition, prevent initial misdiagnosis, and shorten time to diagnosis/treatment. The index of suspicion for an underlying tumor must remain high despite symptoms of infection. The disparity in onset age of neuroblastoma frequency with that of neuroblastoma with OMS warrants further studies of potential host/tumor factors. OMS neuroinflammation is best diagnosed by CSF OCB and B cells, not by routine CSF or commercial antibody studies.
Opsoclonus-myoclonus syndrome is characterized by abnormal lymphocyte trafficking into brain. The authors hypothesized that mycophenolate mofetil, a lymphocyte proliferation inhibitor, might be therapeutic. The cerebrospinal fluid and blood immunophenotypes of 15 children with predominantly chronic-relapsing opsoclonus-myoclonus syndrome were compared before and after treatment by flow cytometry. Mycophenolate mofetil reduced the cerebrospinal fluid expansion of HLA-DR+ activated T cells (-40%); the frequency of other T-cell or natural killer cell subsets remained unchanged, but cerebrospinal fluid B cells increased significantly. Adrenocorticotropic hormone dose was lowered by 64% over an average of 1.5 years, yet 73% eventually relapsed despite therapeutic drug levels. Prior treatment with rituximab prevented relapse-associated increase in cerebrospinal fluid B cells, without hindering mycophenolate mofetil-induced reduction in T-cell activation. These data demonstrate resistant immunologic problems in chronic-relapsing opsoclonus-myoclonus syndrome. Mycophenolate mofetil did not prevent relapse. The novel effect of mycophenolate mofetil on chronically activated T cells may contribute to its efficacy in T-cell mediated neurological disorders.
Little is known about the relations of fitness and fatness to left ventricular structure and function in obese adolescents. This project had 2 purposes: 1) to determine the correlations of cardiovascular fitness and adiposity to left ventricular parameters in obese adolescents; and 2) to see the effect of 8 months of physical training (PT) at low and high intensities.
Obese 13- to 16-year-olds (N = 81) were tested at baseline and then randomly assigned to lifestyle education (LSE) alone, LSE plus moderate-intensity PT, or LSE plus high-intensity PT. Follow-up testing was conducted 8 months later. Because no significant differences were found between moderate-intensity and high-intensity PT, the groups were combined to form a LSE + PT group.
Eight months of PT, offered 5 days per week with the target energy expenditure for all PT participants being 250 kcal/session, and LSE every 2 weeks. Outcome Measures. Left ventricular mass divided by height to the 2.7th power (LVM/Ht(2.7)), midwall fractional shortening (MFS), and relative wall thickness (RWT) were measured using M-mode echocardiography. Cardiovascular fitness was measured by a maximal multistage treadmill test; percent body fat (%BF) with dual-energy radiograph absorptiometry; and visceral adipose tissue (VAT) with magnetic resonance imaging.
At baseline, high levels of VAT were associated with higher RWT (r = 0.30) and lesser MFS (r = -0.29). Compared with the LSE-alone group, the LSE + PT group significantly improved in cardiovascular fitness and decreased in %BF and VAT. However, there were no significant differences between groups on changes in LVM/Ht(2.7), MFS, or RWT. Individual changes in cardiovascular fitness, %BF, and VAT did not correlate significantly with interindividual changes in left ventricular structure and function.
High levels of VAT were associated with unfavorable left ventricular structure and function. However, no evidence was provided that an 8-month PT program, which improved cardiovascular fitness and reduced general and visceral adiposity, improved left ventricular structure and function. Future studies consisting of longer training programs and/or greater weight reductions are needed to see whether the adverse left ventricular effects of obesity can be ameliorated by exercise training.
Opsoclonus-myoclonus syndrome (OMS) is an autoimmune disorder with serious neurodevelopmental morbidity and limited treatment options. We treated a toddler with moderately severe OMS with rituximab, a monoclonal anti-B cell antibody. The patient's clinical response was documented on videotape and scored with the OMS Evaluation Scale. Cerebrospinal fluid lymphocyte subsets were evaluated by flow-cytometric immunophenotyping, with a comprehensive panel of monoclonal antibodies. Eradication of cerebrospinal fluid B cells, which previously were expanded, was associated with dramatic clinical improvement. There also were secondary changes in other lymphocyte subsets that might be relevant to the clinical response and lack of serious infections. In addition to clarifying the immune response to B-cell depletion, these data reveal a promising new therapy for OMS that warrants a phase I clinical trial.
A retrospective data collection was performed on 29 children diagnosed with neuroblastoma and opsoclonus‐myoclonus between 1983–1993 from Pediatric Oncology Group institutions. The aim was to describe neurologic outcome in children with neuroblastoma and opsoclonus‐myoclonus.
Age at diagnosis ranged from one month to 4 years (median age, 18 months). The duration of opsoclonus‐myoclonus symptoms prior to the diagnosis of neuroblastoma ranged from 6 days to 17 months (median duration, 6 weeks). There was a prevalence of low stage disease according to the POG staging system; stage A (n = 18), stage B (n = 3), stage C (n = 7), stage D (n = 1). There was a predominance of paraspinal primary tumors. There was no case of N‐myc amplification (0/17), and 2/8 cases were diploid.
Treatment for neuroblastoma consisted of surgery alone in 19/29 (18 stage A, 1 stage C in thorax), and surgery plus chemotherapy in 10/29. No patient received radiotherapy.
Treatment for opsoclonus‐myoclonus ranged varied. Six children received no treatment for opsoclonus‐myoclonus. The following agents were used aCTH (n = 14), prednisone (n = 12), IV IgG (n = 6), immuran (n = 2), depakote (n = 1), and inderal (n = 1). Eighteen of 29 children (62%) had resolution of opsoclonus‐myoclonus symptoms. The range of time for recovery was a few days to 3 years. However the majority recovered over several months.
Twenty of 29 children (69%) had persistent neurologic deficits including speech delay, cognitive deficits, motor delay, and behavioral problems. Of the 9 children who had complete recovery of opsoclonus‐myoclonus without neurologic sequelae, age at diagnosis and duration of symptoms were not different from the entire group. Interestingly, 6/9 children with complete recovery received chemotherapy as part of their treatment. In conclusion, persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonusmyoclonus. Treatment with chemotherapy may improve the neurologic outcome. Med. Pediatr. Oncol. 28:284–288. © 1997 Wiley‐Liss, Inc.
Childhood opsoclonus‐myoclonus syndrome (OMS) is a movement disorder which typically strikes children in the early preschool years, seriously affecting intellectual, social‐emotional and general adaptive development. This series of 13 cases with well‐documented neurological histories, aged 1.7 to 16.3 years, provides an initial systematic evaluation of these children's neuropsychological, psychosocial and adaptive status. As expected, children with OMS had significantly reduced intelligence and severe speech and motor output problems; however, most of them also demonstrated a range of preserved neurocognitive abilities and impressive goal‐directedness and communicative effort. Psychosocial problems included mild behavioral impairment on the Achenbach Child Behavior Checklist, and severe adaptive limitations on the Vineland Adaptive Behavior Scales despite relatively strong social skills. Developmental factors and likelihood of subcortical localization are discussed, and practical guidelines are provided for behavioral and educational management of these children.
RÉSUMÉ
Caractéristiques neurocomporiementales el psychosocials du syndrome opsoclonies‐myoclonies
Le syndrome infantile opsoclonies‐myoclonies (OMS) est un trouble moteur qui frappe les enfants dans les premières années préscolaires. affectant gravement le développement intellectuel, socio‐affectif et d'adaptation générate. Cette serie de 13 cas âgés de 1,7 à 16,3 ans, avec une histoire neurologique bien documentée fournit un début d'ébut d'évaluation systématique de l'état neuropsychologique, psychosocial et adaptatif. Comme on pouvait s'y attendre les enfants avec OMS ont une intelligence significativement réduite et des problèmes graves de langagc et de motricité; néanmoins, la plupart d'entre eux conservaient des aptitudes neurocognitives, la capacité d'agir avec un but et de communiquer. Les problèmes psychosociaux incluaient un trouble comportemental modéréà la Achenbach Child Behavior Checklist et de graves limitations aux Vineland Adaptive Behavior Scales en dépit d'activités sociales relativement évoluées. Les facteurs de développement et la localisation sous corticale vraisemblable sont discutés et des conseils sont donnés pour la prise en charge comportementale et pédagogique de ces enfants.
ZUSAMMENFASSUNG
Verhaltensneurologischer mid psychosozialer Status bei Kindren mit Opsoklonus‐Myoklonus Syndrom
Das Opsoklonus‐Myuoklonus Syndrom (OMS) ist eine Bewegungsstörung, die typischerweise bei Kindern im frühen Schulalter auftritt und die intellektuelle, sozio‐emotionale und allgemeine adaptive Entwicklung schwer beeinträchtigt. Diese Studie beinhaltet 13 Fälle im Alter von 1,7–16,3 Jahren mit gut dokumentierten neurologischen Anamnesen und liefert eine erste systematische Beurteilung des neuropsychologischen, psychosozialen und adaptiven Status dieser Kinder. Wie erwartet hatten OMS Kinder eine signifikant verminderte Intelligenz und schwere sprachliche und molorische Problems, jedoch zeigten die meisten von ihnen auch eine Reihe erhaltener neurokognitiver Fähigkeiten und eindrucksvolle Zielrichtung und Kommunikationsversuche. Die psychosozialen Probleme beinhalteten eine leichte Verhaltensstörung bei der Achenback Child Behavior Checklist und schwere adaptive Einschränkungen bei den Vineland Adaptive Behavior Scales trotz relativ starker sozialer Fahigkeiten. Es wird über Entwicklungsfaktoren und die Wahrscheinlichkeit einer subkortikalen Loalisation diskutiert und es werden Richtlinien für die Verhaltens‐ und Erziehungsbctreuung dieser Kinder gegeben.
RESUMEN
Funcionamienio neuroevolutivo y psicosocial de niños con el síndrome de opsoclonus‐mioclonus
El síndrome infantil de osoelonus‐miolonus (SOM) es una alteración del movimiento que afeta típicamcnte a los niños en edad prcescolar. afectando seriamente el desarrollo intelectual, social‐emocional y adaptativo general. Esta serie de 13 casos con historias neurológicas bien documentadas, de 1,7 a 16,3 años de edad, proporciona una evaluación inicial sistemática del estado neuropsicológico, psiocosocial y adaptativo de estos niños. Tal como se esperaba, los niños con SOM tenían una reducción significativa de la inteligencia y problemas graves de lenguaje y motores. Sin embargo la mayoria mostraban una buena presenvación de las habilidades cognitivs y un impresionantc esfuerzo en la comunicación y en orientación de finalidades. Los problemas psicosociales, consistían en una alteración moderada del comportamiento en la Achenbach Child Behavior Checklist y graves limitaciones adaptativas en las escales Vineland Adaptive Behavior Scales, a pesar de unas habilidades sóciales relativamente sólidas. Se discuten los factores de desarrollo y la posibilidad de una localización subcortical y se proporcionan lineas maestras prácticas para el manejo conductual y educacional de estos niños.
Background
Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2–3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies.ProcedureQuestionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies.ResultsOf the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV).Conclusions
Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification. Med. Pediatr. Oncol. 36:612–622, 2001. © 2001 Wiley-Liss, Inc.
The authors describe a case of an 8-month-old boy with opsoclonus-myoclonus syndrome (OMS) and coincident unresectable neuroblastoma (NB). He achieved a complete remission for NB after 6 courses of standard-dose chemotherapy without significant neurological improvement despite the use of steroids and high-dose immunoglobulin (HIG), administered separately. Only the combined treatment withthese two drugs induced a complete disappearance of neurological symptoms. On the basis of this experience, the authors suggest the association of steroids plus HIG for the treatment of OMS in patients not responsive to conventional first line therapy with steroids. Med. Pediatr. Oncol. 30:15–17, 1998. © 1998 Wiley-Liss, Inc.
A retrospective data collection was performed on 29 children diagnosed with neuroblastoma and opsoclonus-myoclonus between 1983–1993 from Pediatric Oncology Group institutions. The aim was to describe neurologic outcome in children with neuroblastoma and opsoclonus-myoclonus.Age at diagnosis ranged from one month to 4 years (median age, 18 months). The duration of opsoclonus-myoclonus symptoms prior to the diagnosis of neuroblastoma ranged from 6 days to 17 months (median duration, 6 weeks). There was a prevalence of low stage disease according to the POG staging system; stage A (n = 18), stage B (n = 3), stage C (n = 7), stage D (n = 1). There was a predominance of paraspinal primary tumors. There was no case of N-myc amplification (0/17), and 2/8 cases were diploid.Treatment for neuroblastoma consisted of surgery alone in 19/29 (18 stage A, 1 stage C in thorax), and surgery plus chemotherapy in 10/29. No patient received radiotherapy.Treatment for opsoclonus-myoclonus ranged varied. Six children received no treatment for opsoclonus-myoclonus. The following agents were used aCTH (n = 14), prednisone (n = 12), IV IgG (n = 6), immuran (n = 2), depakote (n = 1), and inderal (n = 1). Eighteen of 29 children (62%) had resolution of opsoclonus-myoclonus symptoms. The range of time for recovery was a few days to 3 years. However the majority recovered over several months.Twenty of 29 children (69%) had persistent neurologic deficits including speech delay, cognitive deficits, motor delay, and behavioral problems. Of the 9 children who had complete recovery of opsoclonus-myoclonus without neurologic sequelae, age at diagnosis and duration of symptoms were not different from the entire group. Interestingly, 6/9 children with complete recovery received chemotherapy as part of their treatment. In conclusion, persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonusmyoclonus. Treatment with chemotherapy may improve the neurologic outcome. Med. Pediatr. Oncol. 28:284–288. © 1997 Wiley-Liss, Inc.
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 corticosteroid-based therapy, and overall tolerability.
Opsoclonus-myoclonus syndrome (OMS) is a serious, often disabling neurological illness of early childhood which is frequently associated with occult neuroblastoma. As investigation methods vary significantly, the authors assessed the usefulness of imaging and metabolic studies in tumour detection.
Retrospective case note review of 101 OMS patients from two paediatric neurology centres over 53 years.
The prevalence of neuroblastoma in OMS was 8% in the 1970s, 16% in the 1980s, 38% in the 1990s and 43% in the 2000s, with tumours being mainly low grade. CT/MR imaging of the chest and abdomen was the most accurate test to detect occult neuroblastoma. Poorer sensitivities were noted for metaiodobenzylguanidine scintigraphy and urine catecholamines, reflecting the low metabolic activity of these tumours.
CT/MR imaging has the highest detection rate of neuroblastoma and this should be reflected in investigation protocols to achieve the best possible outcome for children with OMS.
The aim of this study is to describe the long-term neurological, neuropsychological and neuroradiological sequelae and to determine prognostic factors for neurological outcome in children with neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome.
Data on medical history were collected for the study patients. Examinations with grading of neurological signs, neuropsychological tests and brain magnetic resonance imaging with spectroscopy were performed during a follow-up clinic.
Fourteen subjects entered the study. All had localized neuroblastoma and they were evaluated after a median of 7.8 years. Patients with a chronic/multiphasic neurological course received steroids combined with intravenous immunoglobulins in the majority of cases. 71% presented neurological sequelae and 62% had a full-scale IQ below the normal range. All patients showed at least some deficit in the neuropsychological functions assessed (language, visual-motor integration, memory, attention and motor ability). Long-term deficits were more frequently detected in patients with an interval of more than 2 months between OMA onset and its diagnosis, even if in most comparisons statistical significance was not reached. Cerebellar atrophy, observed in 36% of patients, was not associated with the neurological outcome.
Persisting disability is present in most children with neuroblastoma-associated OMA. However, our results support the role of an early diagnosis of OMA in reducing sequelae and encourage the use of new immunosuppressive therapies.
Case reports of 28 neuroblastoma patients who had opso-myoclonus as their presenting feature are reviewed. As compared with the 30%-34% two-year survival rate for the overall population of patients with neuroblastoma, those who exhibited the opso-myoclonus/neuroblastoma combination had a tumor-free two-year survival rate of 89.3%. This excellent prognosis may be explained partially by earlier diagnosis and a higher percentage (71% vs. 33%) of patients with Stage I, II, and IV-S disease in the opso-myoclonus sub-group. However, these factors are not, of themselves, sufficient to explain totally the differences in survival rate since five of seven patients with Stage III-IV disease also exhibited long-term survival. This raises the question as to whether the neurologic dysfunction in these patients is pathogenetically related to an unknown factor (possibly autoimmune) which also controls growth and spread of the tumor.
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.
Three children with myoclonic encephalopathy (Kinsbourne's disease) are described, in which one of them was shown to have ganglioneuroblastoma. Symptoms were opsoclonus, polymyoclonia of the striated muscles and cerebellar ataxia. Treatment consisted in corticosteroids and adrenocorticotropic hormone respectively in all patients, the patient with ganglioneuroblastoma also had a resection of the tumor. All patients responded to therapy, however recurrence of myoclonia and of the opsoclonus were seen after discontinuation or reduction of the corticosteroid dose, as well as following the course of intercurrent viral infections. Neurologic symptoms eventually disappeared after 3 1/2-5 1/2 years, however in two children behavioural abnormalities and disorders of speech and cognitive development remained.
Fifty-four patients with dancing eye syndrome (DES), presenting over a 25-year period, were reviewed retrospectively. One third of them were on active follow up at the time of the study. Malignancy was uncommon diagnosed in only 4 patients, neuroblastoma in 3 cases and acute lymphoblastic leukaemia (ALL) in 1. An intercurrent illness preceded onset of DES in 51% of the children and was of equivocal significance. There was no clear temporal relationship to immunization. The acute phase of the illness was severe and caused total immobilization in 88% of patients. A favourable initial response to treatment with prednisolone or corticotrophin gel was observed in all patients. Although corticotrophin seemed to produce a more rapid response, overall improvement was similar with both treatments. Long-term neurological morbidity was a major problem with 91% of children suffering either persisting symptoms or repeated relapses. A persisting disability was found in 88% and was considered severe in 61% of patients. No features prognostic of neurological severity or outcome were identified.
Conclusion
Demonstrable malignancy is uncommon in the dancing eye syndrome. The neurological legacy of DES is often evident well into adult life.
The authors describe a case of an 8-month-old boy with opsoclonus-myoclonus syndrome (OMS) and coincident unresectable neuroblastoma (NB). He achieved a complete remission for NB after 6 courses of standard-dose chemotherapy without significant neurological improvement despite the use of steroids and high-dose immunoglobulin (HIG), administered separately. Only the combined treatment withthese two drugs induced a complete disappearance of neurological symptoms. On the basis of this experience, the authors suggest the association of steroids plus HIG for the treatment of OMS in patients not responsive to conventional first line therapy with steroids.
Opsoclonus-ataxia, also called "dancing eye syndrome," is a serious neurologic condition that is often a paraneoplastic manifestation of occult neuroblastoma in early childhood. Despite resection of tumor and immunosuppressive therapy, outcome generally includes significant developmental and behavioral sequelae. There is controversy about how treatment alters outcome. The goals of this study were to understand the ongoing neurologic and developmental deficits of children who are treated for opsoclonus-ataxia with associated neuroblastoma; to relate treatment history to outcome; and to quantify objectively the acute changes in motor function, speech, mood, and behavior related to intravenous immunoglobulin (IVIg) treatment.
Patients were children with opsoclonus-ataxia caused by neuroblastoma, regardless of interval since diagnosis. Records were reviewed, and children underwent comprehensive evaluations, including neurologic examination and tests of cognitive and adaptive function, speech and language, and fine and gross motor abilities. Psychiatric interview and questionnaires were used to assess current and previous behavior. In 6 children, a videotaped standardized examination of eye movements was performed. Additional examinations were performed immediately before and 2 to 3 days after treatment with IVIg in 5 children.
Seventeen children, ages 1.75 to 12.62 years, were examined. All had a stage I or II neuroblastoma resected 3 months to 11 years previously. None received any other treatment for the tumor. All but 1 had received at least 1 year of either oral corticosteroids or corticotropin (ACTH); 12 had received 1 or more courses of IVIg, 2 g/kg. Three had received other immunosuppressive treatment, including cyclophosphamide. Cognitive development and adaptive behavior were delayed or abnormal in nearly all children. Expressive language was more impaired than receptive language. Speech was impaired, including both intelligibility and overall output. Fine and gross motor abilities were impaired. Increased age was strikingly associated with lower scores in all areas. Behavioral problems early in the course included severe irritability and inconsolability in all; later, oppositional behavior and sleep disorders were reported. Opsoclonus abated in all, but abnormalities in pursuit eye movements were found in all 6 children cooperative with standardized examination. Outcome did not differ in children who were treated with ACTH versus oral steroids. Three children who had received cyclophosphamide fared poorly. Immediate versus delayed treatment was not associated with better outcome. IVIg improved both gross and fine motor and speech function acutely, but we could not confirm long-term benefit of IVIg. Total number of courses of IVIg was not associated with outcome.
Opsoclonus-ataxia caused by neuroblastoma causes substantial developmental sequelae that are not adequately prevented by current treatment. The increased deficits in older children raise concern that this represents a progressive encephalopathy rather than a time-limited single insult. Although the study is cross-sectional and neither randomized nor blinded, we were unable to confirm a purported advantage of either ACTH over corticosteroids or of cyclophosphamide. A randomized study is needed but is difficult for this rare condition.
Although many lines of evidence suggest an autoimmune etiology, the pathophysiology of opsoclonus-myoclonus syndrome (OMS) remains poorly understood and no immunologic abnormalities have correlated with neurologic severity. Conventional immunotherapies often do not prevent relapse or permanent sequelae.
To test the cellular immune hypothesis of OMS in a cross-sectional study and determine if CSF lymphocyte subset analysis provides biomarkers of disease activity.
The expression of lymphocyte surface antigens was investigated in CSF and blood of 36 children with OMS and 18 control subjects, using a comprehensive panel of monoclonal antibodies to adhesion and activation proteins in combination with anti-CD3 and anti-CD45 antibodies in four-color fluorescence-activated cell sorting.
Although most children with OMS had normal CSF cell counts, they exhibited expansion of CD19+ B-cell (up to 29%) and gammadelta T-cell (up to 26%) subsets and a lower percentage of CD4+ T-cells and CD4/CD8 ratio, which persisted even years after disease onset and conventional treatments. The percentage of activated CSF T-cells was also higher. Abnormalities correlated with neurologic severity, as scored blinded from videotapes using a 12-item motor scale, and disease duration. No significant differences were found between tumor and no-tumor groups. In children with neuroblastoma, tumor resection or cancer chemotherapy did not alter immunologic abnormalities.
CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.
Lack of a biomarker of disease activity has hindered the therapy of childhood opsoclonus-myoclonus syndrome (OMS), which is purported to be mediated humorally. To determine if the cerebrospinal fluid (CSF) B lymphocyte, which may traffic into the central nervous system (CNS) to produce antibody locally, is one such biomarker, B lymphocytes were immunophenotyped in the CSF and blood of 56 children with OMS and 26 pediatric controls by dual-laser flow cytometry. Neurological severity was rated blindly from videotapes using a validated 12-item motor evaluation scale. Children with OMS manifested a 4- to 7-fold higher percentage of total B-cells in CSF (P < 0.0001), including CD5(+) (P = 0.001) and CD5(-) (P = 0.0004) B-cell subsets, compared with controls, in whom the percentages were negligible and unchanging with age. CSF expansion of both B-cell subsets increased with disease severity and decreased with disease duration (P </= 0.0001, ANOVA). Previous treatment with conventional immunotherapies, chemotherapy, or tumor resection had not normalized B-cell percentages in those with lingering symptoms. These studies reveal that CSF B-cell expansion in OMS is characteristic and often persistent. Presence of the autoreactive CD5(+) B-cell subset and correlations with neurological severity and disease duration suggest CSF B-cell expansion is a biomarker of disease activity and possible target for B-cell-specific therapy. Immunophenotyping of CSF lymphocytes by flow cytometry yields valuable clinical information missed by routine studies and allows crucial treatment decisions to be made rapidly.
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.
We previously reported on children with opsoclonus-ataxia and found pervasive neurodevelopmental deficits, years after onset, without a clear relationship to treatment modality or timing of treatment. A significant negative correlation of functional status with age at testing raised a question of whether opsoclonus-ataxia is a progressive encephalopathy. We attempted to answer this question with serial testing. In addition, we examined the relationship between clinical course and developmental outcome.
Thirteen of 17 children with opsoclonus-ataxia, all with neuroblastoma, who were previously reported were reevaluated a second time 2 to 4 years after the initial assessment. One subject who lived out of state was partially reevaluated and is included. Five new subjects (2 with neuroblastoma and 3 without) were also enrolled. Each was evaluated twice at a minimum interval of 1 year between sessions. Intercurrent medical course was recorded, emphasizing medication and relapse history. Cognitive, adaptive behavior, academic, speech and language, and motor abilities were assessed.
For the group as a whole, overall standardized, age-adjusted cognitive scores improved. Generally, younger subjects' cognitive and adaptive behavior scores improved more than older subjects. Although all subjects had gains in speech, language, and motor function, some progressed at a slow pace, and in some instances, standard scores dropped. There was a striking influence of clinical course. Although initial presentation was severe and all subjects required high doses of corticosteroids or corticotropin, 5 had a monophasic course and were able to be weaned from treatment without relapses. Fourteen had multiple relapses over the years, generally with reduction of medication or intercurrent illnesses. Of the 5 children with monophasic course, 4 are currently functioning in the average range with a full-scale IQ of > or =90 and age-appropriate academic and adaptive skills.
The results continue to raise concern that opsoclonus-ataxia is sometimes a progressive encephalopathy. A minority of children with opsoclonus-ataxia have a monophasic course. Despite initial severity of symptoms, these children may have a more benign prognosis. For the majority of children with opsoclonus-ataxia, the course includes multiple relapses and requires prolonged treatment. Developmental sequelae are significant in these children with chronic course.
Opsoclonus-myoclonus ataxia syndrome is a paraneoplastic syndrome of cerebellar damage associated with neuroblastoma. The authors assessed psychiatric symptoms of opsoclonus-myoclonus ataxia syndrome in 17 children, who were 16 months to 12(1/2) years of age. Psychiatric symptoms examined included disruptive behavior, affective dysregulation, irritability, impulsivity, cognitive impairment, and poor attention.
To determine if rituximab, an anti-CD20 monoclonal antibody, reduces cerebrospinal fluid (CSF) B-cell expansion in opsoclonus-myoclonus syndrome (OMS) and results in clinical improvement.
Sixteen children with OMS and increased % CD20 B-cells in CSF received 4 rituximab infusions (375 mg/m IV) as add-on therapy to corticotropin (ACTH), intravenous immunoglobulins, or both, and were reevaluated 6 months later. Outcome measures were clinical (motor function, behavior, sleep) and immunologic (CSF and blood immunophenotype and Ig levels). Controls were 16 age-matched and sex-matched children, who did not have OMS.
After rituximab, 81% of OMS had a lower motor severity score, and 44% improved one severity category. Mean total score decreased by 44% (P = 0.0005). Rituximab reduced rage score, nighttime awakenings, and the number of children with opsoclonus, action myoclonus, drooling, gait ataxia, and rage. Despite a 51% reduction in ACTH dose, 9 of 11 children on ACTH did not relapse. The percentage of CSF CD19 (and CD20) B-cells was lowered in all children (undetectable in 6), with a 90% reduction in the group mean (P = 0.00003). CSF B-cells were no longer expanded compared with controls. In blood, CD19 B-cells decreased (-90%, P = 0.0003), as did the CSF:blood CD19 B-cell ratio (P = 0.00003). Serum IgM fell by 69% (below reference range), with no statistically significant change in IgG or IgA.
Rituximab seems efficacious and safe as adjunctive therapy for OMS. Selective targeting of CSF B lymphocytes represents a novel and valuable paradigm shift in the therapy for centrally mediated paraneoplastic disorders.
Opsoclonus-myoclonus syndrome (OMS) in children is a rare neurological condition with opsoclonus, myoclonus, ataxia and irritability in the first 2 years of life. It can be idiopathic, parainfectious, or paraneoplastic with tumours of the neural crest. Few studies of long-term follow-up after OMS have been published. We investigated the motor, cognitive and behavioural outcome of ten patients (eight girls and two boys) seen between 1987 and 2002. We reviewed the records and reassessed the patients. A ganglioneuroma was found in one patient and a neuroblastoma in another. Tumour resection did not influence the OMS. The age at diagnosis was 10-24 months and the follow-up period 1-17 years (average 6.5 years). The interval between the first signs and symptoms and starting treatment was 2-12 weeks: treatment consisted of different immunosupressants. Remission was achieved within 5 months in seven, and relapses were present in seven of ten. At follow-up, only one child had mild ataxia. IQ testing was performed in nine with scores below 75 in four and above 85 in four. Attention deficit and visuomotor difficulties led to school problems with special needs, also in those three children with normal IQs. Only two children were attending regular schools. Behavioural problems were reported in seven, and speech difficulties were present in five. In conclusion, the long-term outcome in our patients with OMS was dominated by cognitive and behavioural problems and not by ataxia. Compared with previous reports, our patients were treated earlier. Larger studies and uniform treatment protocols are needed to demonstrate whether early and prolonged immunosupressant therapy has a favourable influence on outcome.
Opsoclonus-myoclonus syndrome (OMS) is a rare movement disorder characterized by chaotic eye movements, myoclonus, and ataxia associated with severe irritability. Different treatment modalities including steroids and cyclophosphamide have been tried in the past often with significant side effects and variable success. Here we present 11 children, diagnosed with OMS between 1999 and 2005 and treated with high dose dexamethasone pulses. Main symptoms at presentation were opsoclonus (11/11), ataxia and/or myoclonus (11/11), irritability (10/11) associated with a neuroblastoma in four children. Number of dexamethasone pulses ranged from 6 to 60 pulses. No major side effects were reported. In 6/11 children a complete and sustained remission of OMS symptoms was achieved after 6 to 29 pulses of dexamethasone. Two children from this group have a normal development and no neurological sequelae. Two further children have minor delays in fine- and gross-motor skills. Two children despite a complete recovery of OMS symptoms have persisting developmental problems. 5/11 children still require regular dexamethasone pulses in addition to daily prednisolone (n = 1) or have received cyclophosphamide pulses meanwhile (n = 2). All children continue to have developmental and neurological difficulties. In summary treatment with high dose pulsatile dexamethasone appears to be safe and beneficial in a subgroup of patients with OMS.
Active comparator-controlled, rater-blinded study of corticotropin-based
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Tate ED, Pranzatelli MR, Verhulst SJ, et al. Active comparator-controlled, rater-blinded study of corticotropin-based