NORD gratefully acknowledges Michael R. Pranzatelli, MD, Founder & President, National Pediatric Neuroinflammation Organization, Inc., (Courtesy) Professor of Neurology, University of Central Florida College of Medicine, for assistance in the preparation of this report.
The component features of OMS include repeated, random and rapid eye movements in both horizontal and vertical directions (opsoclonus); unsteady, gait (ataxia); brief, repeated, shock-like spasms of several muscles within the arms, legs (myoclonus). Extreme irritability, reduced and fragmented sleep (insomnia), rage attacks, difficulty articulating speech (dysarthria), or inability to speak (mutism), decreased muscle tone (hypotonia), and vomiting are common.
When opsoclonus and myoclonus occur together, the cause is a tumor until proven otherwise— not a brain tumor, but rather an occult body cavity tumor. In approximately 50 percent of affected children, a tumor of embryonic nerve cells (neuroblastoma) is responsible for the symptoms associated with OMS. In other cases, the disorder has been designated ‘idiopathic’ or attributed to various mostly viral infections, such as Coxsackie virus B3 or St. Louis encephalitis virus, however, the high rate of spontaneous tumor regression means that the tumor may be gone before it is looked for. In adults, the tumors are most often lung and breast cancer.
OMS is a rare disorder: 1 in a 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 a long tail out to about 5 – 6 years. Occurrence in infants under 6 months old is quite uncommon, and opsoclonus in that age group, when isolated, is usually from another cause. OMS occurs in only slightly more 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 stumbling gait, especially if accompanied by irritability, are highly reliable indicators of this syndrome. To detect a tumor in children, both a CT scan of the neck, chest, abdomen, and pelvis (with oral and IV contrast) as well as an MIBG scan need to be done. PET scanning is often done in adults. In addition, a spinal tap to detect neuroinflammation is necessary. Besides routine tests for infection, recommended CSF studies include oligoclonal bands (with paired serum sample), which are autoantibodies secreted by B cells in the CSF. Also, lymphocyte subset analysis using immunophenotyping reveals an increased frequency of CSF B cells, which is an invaluable biomarker of OMS disease activity. Studies of cytokines/chemokines, which are inflammatory mediators, have identified an increase of B-cell attractants (CXCL13) and activators (BAFF) in CSF. Autoantibodies in some children with OMS have been at detected in research laboratories, but commercial autoantibody testing is not cost-effective and best reserved for atypical cases.
The main tenet of treatment for OMS is early and sufficient immunotherapy with the goal of gaining a durable complete neurological remission. If a tumor is present, surgical resection is standard. The tumors are usually low stage (I or II), and tumor chemotherapy or radiation therapy are not indicated. Tumor resection does not usually provide sufficient clinical benefit for OMS, however. OMS treatment, which is usually continued over 1-2 years, should involve combined immunotherapies as soon as possible after diagnosis. FLAIR therapy is a three-agent protocol involving front-loaded high-dose ACTH (corticotropin), IVIg, and rituximab that was developed by the National Pediatric Myoclonus Center for pediatric OMS, and 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. Over time, treatment with ACTH may have mostly cortisol-related adverse effects that must be monitored carefully. Pulse dose dexamethasone instead of ACTH is an option in mild and more moderate cases. The use of prednisone-type oral steroids is not recommended, because they are the least effective of the steroids for pediatric OMS. For OMS relapse, low-dose IV cyclophosphamide (3-6 cycles) or more rituximab (1-2 cycles) are given. Oral weekly methotrexate may be a useful steroid sparer in chronic relapse. A biomarker-guided approach, which led to the introduction of anti-B-cell monoclonal antibodies in OMS, promises to give rise to new therapeutic targets and strategies.
Almost all children with neuroblastoma and OMS 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 afflict adults are sometimes fatal. The OMS relapse rate in children treated with only conventional agents is 50-75%. Increased immunosuppression has improved neurodevelopmental outcomes in OMS. With FLAIR therapy, the relapse rate appears to be much lower. OMS onset in the first year of life is particularly damaging to expressive speech and language development, and may result in a higher incidence of 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 OMS, with permanent deficits, such as ADD/ADHD, OCD, and irreversible cognitive impairment (low IQ). Children in the chronic sick role can become oppositional, depressed, and aggressive, and attention to these issues often helps to improve quality of life.
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Contact for additional information about opsoclonus-myoclonus syndrome:
Michael R. Pranzatelli, MD
Director & President
National Pediatric Neuroinflammation Organization, Inc.
12001 Research Parkway, Suite 236
Orlando, FL 32826
Tel.: 877 359 8599
Fax: 877 369 8488
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Pranzatelli MR, Tate ED. Trends and tenets in relapsing and progressive pediatric opsoclonus-myoclonus. Brain & Development. December 1, 2015.
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.
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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.
NINDS Opsoclonus Myoclonus Information Page. NINDS/NIH. http://www.ninds.nih.gov/disorders/opsoclonus_myoclonus/opsoclonus_myoclonus.htm. Last updated February 14, 2007. Accessed January 11, 2016.
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