We're celebrating
40 years!
Last updated:
10/25/2023
Years published: 1990, 1997, 2005, 2008, 2009, 2012, 2016, 2018, 2019, 2023
NORD gratefully acknowledges Wendy Mitchell, MD, Professor of Clinical Neurology, University of Southern California Keck School of Medicine, Acting Division Head of Neurology, Children’s Hospital Los Angeles; Mark P. Gorman, MD, Department of Neurology, Boston Children’s Hospital, Harvard Medical School; Timothy Lotze, MD, Texas Children’s Hospital, Professor of Pediatrics and Neurology, Baylor College of Medicine; OMSLife Foundation and Michael R. Pranzatelli, MD, for assistance in the preparation of this report.
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an inflammatory neurological disorder, often caused by the immune system reacting to a cancerous tumor (paraneoplastic etiology). It is characterized by associated ocular, motor, behavioral, sleep and language disturbances. The onset is usually abrupt, often severe, and it can become chronic.
The component features of OMAS include repeated, random and rapid eye movements in both horizontal, vertical and diagonal directions (opsoclonus); unsteady gait or loss of ability to stand and walk (ataxia); brief, repeated, shock-like spasms of several muscles within the arms and legs (myoclonus), or tremor interfering with hand use. Behavioral and sleep disturbances, including extreme irritability, inconsolable crying, reduced and fragmented sleep (insomnia) and rage attacks are common. Difficulty articulating speech (dysarthria), sometimes with complete loss of speech and language may occur. Additional symptoms such as decreased muscle tone (hypotonia) and vomiting are common.
The most common cause of OMS in young children is paraneoplastic. A small, often hidden tumor presumably provokes the immune system into attacking the nervous system, which may also control the tumor or even cause it to regress. Tumors are not in the brain, but are in other areas of the body, usually in chest or abdomen. In 50-80% of affected young children, a tumor of embryonic nerve cells (neuroblastoma or ganglioneuroblastoma) is responsible for the symptoms associated with OMS. In other affected individuals, the disorder has been designated ‘idiopathic’ or attributed to various mostly viral infections. However, the high rate of spontaneous tumor regression means that the tumor may be gone before it is looked for. In older children or teens, viral infections are the most frequent apparent cause of OMAS. In adults, paraneoplastic etiology is more common, mostly due to lung or breast cancers. In contrast to paraneoplastic OMAS in infants and young children, whose tumors are biologically inactive and often benign, the tumors in adults are commonly malignant, often disseminated.
OMAS is a rare disorder with a prevalence of 1 per million individuals worldwide. It usually affects infants and young children, although it is also known to affect adults. The peak age in children is about 18 months, with very few diagnosed before 1 year, and a few children diagnosed between 5–6 years. Occurrence of opsoclonus in infants under 6 months old is quite uncommon, and opsoclonus in that age group, when isolated, is usually from another cause. OMAS occurs slightly more often in girls than boys. It occurs in about 3% of all children with neuroblastomas.
The diagnosis is clinical; there is no diagnostic test yet, as the antigen remains unidentified. The presence of the ‘dancing eyes’, the shock-like muscle spasms, and the impairment of gait, especially if accompanied by irritability, are highly reliable indicators of this syndrome. To detect a tumor in children, either a CT scan with oral and IV contrast or MRI with gadolinium of the neck, chest, abdomen and pelvis need to be done. PET scanning is often done in adults with OMAS looking for other occult tumors. In addition, a spinal tap to detect neuroinflammation is necessary. Besides routine tests for infection, recommended CSF studies include so-called “MS panel”, to include oligoclonal bands (with paired serum sample), looking for antibodies secreted by B cells in the CSF. Also, CSF lymphocyte subset analysis (flow cytometry) using immunophenotyping reveals an increased frequency of CSF CD 19+ B cells, which is an invaluable biomarker of OMAS disease activity. Autoantibodies in some children with OMAS have been detected in research laboratories, but commercial autoantibody testing is not cost-effective and best reserved for atypical cases.
Treatment
The goal of treatment of OMAS is early and aggressive immunotherapy with the goal of gaining a durable complete neurological remission. If a tumor is present, surgical resection is standard. The tumors in young children are usually low stage neuroblastomas or ganglioneuroblastomas (stage I or II), and tumor chemotherapy or radiation therapy are not generally indicated. Tumor resection does not usually provide sufficient clinical benefit for OMAS, however. There is no consensus about the order of medications used for treatment: European centers tend to take a stepwise approach, starting with a single agent, adding others if not successful. North American centers generally take a more aggressive approach.
OMAS treatment, which is usually continued over at least 1-2 years, should involve combined immunotherapies as soon as possible after diagnosis. In North America, a three-agent protocol involving initial use of either pulse dose corticosteroids (IV or orally), or high-dose ACTH (corticotropin), along with IVIg, and rituximab has the best-documented outcomes for moderately severe and severe cases. Rituximab is a monoclonal antibody against B cells (anti-CD20). Almost all patients (80-90%) show improvement with this treatment but maintaining sustained improvement may require additional treatment and very gradual weaning. Over time, treatment with daily oral corticosteroids or ACTH may have substantial cortisol-related adverse effects that must be monitored carefully, particularly weight gain, hypertension and reductions in bone density. Monthly pulse dose dexamethasone instead of ACTH is an option in mild and more moderate cases. The use of prednisolone-type oral steroids is not generally recommended, because they are the least effective of the steroids for pediatric OMAS. For OMAS relapses, low-dose IV cyclophosphamide (3-6 cycles) or repeated courses of rituximab (1-2 cycles) are given. Oral weekly methotrexate may be a useful steroid sparer in chronic relapse.
Outcome
Almost all children with neuroblastoma and OMAS survive their tumor, which usually does not behave aggressively, though some tumors may be large and pose difficulties for resection. In contrast, the tumors that are associated with OMAS in adults are often aggressive and are sometimes fatal. The OMAS relapse rate in children treated with only conventional agents is 50-75%. Increased immunosuppression has improved neurodevelopmental outcomes in OMAS. With more aggressive initial therapies in children, the relapse rate appears to be much lower. OMAS onset in the first two years of life is particularly damaging to expressive speech and language development and may result in a higher incidence of residual cognitive impairment. The best responders appear to be those who received early combination therapy and were only of mild to moderate severity. Failure to achieve complete neurological remission and multiple relapses may result in chronic-progressive OMAS, with permanent deficits, such as attention deficient disorder (ADD) attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) and irreversible cognitive impairment (low IQ). Children who are chronically sick can become oppositional, depressed and aggressive, and attention to these issues often helps to improve quality of life. Parents with a severely ill infant or child may develop “fragile child syndrome” and have difficulty ever seeing their child as a normal, thriving individual, with “ordinary” behavioral issues of childhood. These parents may benefit from counselling to gradually adjust their management of their child’s ongoing behavioral and developmental issues.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu
JOURNAL ARTICLES
Rossor T, Yeh EA, Khakoo Y, et al. Diagnosis and management of opsoclonus-myoclonus-ataxia syndrome in children: An international perspective. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1153. Published 2022 Mar 8. doi:10.1212/NXI.0000000000001153
Pranzatelli MR, Tate ED. Trends and tenets in relapsing and progressive pediatric opsoclonus-myoclonus. Brain & Development. Brain Dev. 2016 May;38(5):439-48.
Mitchell WG, Wooten AA, O’Neil SH, Rodriquez JG, Cruz RE, Wittern R. Effect of increased immunosuppression on developmental outcome of opsoclonus myoclonus syndrome (OMS). J Child Neurol 2015;30:976-82.
Panzer JA, Anand R, Dalmau J, Lynch DR. Antobodies to dendritic neuronal surface antigens in opsoclonus myoclonus ataxia syndrome. J Neuroimmunol 2015;286:86-92.
Fuhlhuber V, Bicks S, Tschernatsch M, Dharmalingam B, Kaps M, Preissner KT, Blaes F. Autoantibody-mediated cytotoxicity in paediatric opsoclonus-myoclonus syndrome is dependent in ERK-1/2 phosphorylation. J Neuroimmunol 2015;289:182-6.
Anand G, Bridge H, Rackstraw P, Chekroud AM, Yong J, Stagg CJ, et al. Cerebellar and cortical abnormalities in paediatric opsoclonus-myoclonus syndrome. Dev Med Child Neurol 2015;57:265-72.
Tate ED, McGee NM, Pranzatelli MR. Clinical and demographic features of 389 children with OMS: an international cohort. Proceedings of
the 13th International Child Neurology Congress, Iguazu Falls, Brazil, May 4-9, 2014. JICNA 1(Suppl 1):27 (FP79).
Pike M. Opsoclonus-myoclonus syndrome. Handb Clin Neurol. 2013;112:1209-11.
Pranzatelli MR, Tate ED, McGee NR, Travelstead AL, Colliver JA, Ness JM, et al. BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy. J Neuroinflammation 2013;10:10.
Ketterl TG, Messinger YH, Niess DR, Gilles E, Engel WK, Perkins JL. Ofatumumab for refractory opsoclonus-myoclonus syndrome following neuroblastoma. Pediatr Blood Cancer 2013;60:E163-5.
Battaglia T, De Grandis E, Mirabelli-Badenier M, Boeri L, Morcaldi G, Barabino P, et al. Response to rituximab in 3 children with opsoclonus-myoclonus syndrome resistant to conventional treatments. Eur J Paediatr Neurol 2012;16:192-5.
Pranzatelli MR, Tate ED, McGee NR, et al. Key role of CXCL13/CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric OMS. J Neuroimmunol. 2012;243(1-2):81-8.
Brunklaus A, Pohl K, Zuberi SM, de Souza C. Outcome and prognostic features in opsoclonus-myoclonus syndrome from infancy to adult life. Pediatrics 2011;128:e388-94.
Pranzatelli MR, Tate ED, Travelstead AL, Verhulst SJ. Chemokine/cytokine profiling after rituximab: reciprocal expression of BCA-1/CXCL13 and BAFF in childhood OMS. Cytokine. 2011;53:384-389.
Pranzatelli MR, Slev PR, Tate ED, Travelstead AL, Colliver JA, Joseph SA. Cerebrospinal fluid oligoclonal bands in childhood opsoclonus-myoclonus. Pediatric Neurology. 2011;45(1):27-33.
Pranzatelli MR, Tate ED, Swan JA, et al. B cell depletion therapy for new-onset opsoclonus-myoclonus. Movement Disorders. 2010;25(2):238-242.
Pranzatelli MR, Tate ED, Verhulst SJ, et al. Pediatric dosing of rituximab: serum concentrations in opsoclonus-myoclonus syndrome. Journal of Pediatric Hematology and Oncology. 2010;32(5):e167-e172.
Sakuma H, Shimizu Y, Saito Y, Sugai K, Inagaki M, Kaga M, et al. Electrophysiological evidence of cerebral dysfunction in childhood opsoclonus-myoclonus syndrome. Mov Disord 2010;25:940-5.
Wilken B, Baumann M, Bien CG, Hero B, Rostasy K, Hanefeld F. Chronic relapsing opsoclonus-myoclonus syndrome: combination of cyclophosphamide and dexamethasone pulses. Eur J Paediatr Neurol 2008;12:51-5
Blaes F, Pike MG, Lang B. Autoantibodies in childhood opsoclonus-myoclonus syndrome. J Neuroimmunol. 2008;201-202:221-6.
Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol. 2006;28;585-593.
Turkel SB, Brumm VL, Mitchell WG, Tavare CJ. Mood and behavioral dysfunction with opsoclonus-myoclonus ataxia. J Neuropsychiatry Clin Neurosci 2006;18:239-41.
Tate ED, Allison TJ, Pranzatelli MR, et al. Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs. 2005;22:8-19.
Pranzatelli MR, Tate ED, Dukart WS, Flint MJ, Hoffman MT, Oksa AE. Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone. J Pediatr 2005;147:372-8.
Mitchell WG, Brumm VL, Azen CG, et al. Longitudinal neurodevelopmental evaluation of children with opsoclonus-ataxia. Pediatrics. 2005;116:901-907.
Pranzatelli MR, Travelstead AL, Tate ED, et al. B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes. Neurology. 2004;62:1526-32.
Kinsbourne, M. Myoclonic encephalopathy of infants. J Neurol Neurosurg Psychiatry 1962;25:271-6.
INTERNET
Opsoclonus Myoclonus. NINDS/NIH. Date last modified: Jan 20, 2023. Opsoclonus Myoclonus | National Institute of Neurological Disorders and Stroke (nih.gov)
Accessed Oct 25, 2023.
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