Review Article
Update on Pediatric Opsoclonus Myoclonus Syndrome Barbara Hero1
Gudrun Schleiermacher2
1 Department of Pediatric Oncology, Children’s Hospital, University of
Cologne, Köln, Germany 2 Institut Curie, Paris, France
Address for correspondence Barbara Hero, MD, Department of Pediatric Oncology, Children’s Hospital, University of Cologne, Kerpener Strasse 62, 50924 Köln, Germany (e-mail: [email protected]).
Neuropediatrics 2013;44:324–329.
Abstract
Keywords
► opsoclonus myoclonus syndrome ► dancing eye syndrome ► neuroblastoma
Opsoclonus myoclonus syndrome (dancing eye syndrome) is a rare paraneoplastic syndrome characterized by opsoclonus, myoclonus, and ataxia, usually accompanied by behavioral abnormalities. In adults, opsoclonus myoclonus syndrome has been reported in association with different types of cancer; whereas in children, the syndrome may be associated with neuroblastic tumors. Although a direct proof is lacking, the syndrome is assumed to be of autoimmune origin. The treatment is corticosteroid based with the addition of other immunosuppressive or immunomodulating drugs if intensification seems necessary. Because of the rarity of the disease, international collaborations as well on research as on therapeutic strategies are urgently needed. A European consortium just started a trial for this rare condition.
Clinical Presentation In 1963, Kinsbourne first described opsoclonus myoclonus syndrome (dancing eye syndrome) on the basis of the observation of six children with the main symptoms ataxia, myoclonus, and opsoclonus.1 Most patients present a movement disorder with acute onset or subacute onset, consisting of gait or truncal ataxia and myoclonus. Age of onset is typically in the second year of life, and only occasionally is the syndrome reported at the end of infancy or beyond the third year of life.2–4 Often, the toddlers, just having learned to walk, lose the ability to walk or sit within days. Myoclonus may involve all body parts including limbs, trunk, and face, varies from tremulous polymyoclonia to coarse multifocal jerks, and may be exacerbated by attempts to move or by emotional distress. Distinguishing the myoclonic and ataxic components of the condition may be difficult. Opsoclonus is a rapid, conjugate, multidirectional eye movement which is usually intermittent. It is rarely seen in other childhood conditions. It tends to occur in bursts and can sometimes be provoked by change in gaze
received July 17, 2013 accepted after revision September 5, 2013 published online November 7, 2013
Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.
fixation, usually from far to near. The movement disorder is frequently accompanied by behavioral signs reaching from severe irritability of the inconsolable children, developmental regression, for example, loss of speech, and sleep disturbances, to apathy and reduction of social and playing activities. The neurological signs may vary widely in their expression and are not necessarily all present together. Opsoclonus, in particular, may be intermittent or late in onset, sometimes appearing as late as a few weeks after the onset of ataxia. On the contrary, some discrete signs or behavioral change may be observed several weeks before the onset of the typical symptoms. Occult neuroblastoma may present with some but not all, of the symptoms.5–8 Thus, the diagnosis of opsoclonus myoclonus syndrome may be difficult in some patients and should be considered even when only some of the features are present. International consensus has been reached that three of the following four diagnostic criteria should be present to describe the typical syndrome: (1) opsoclonus, (2) myoclonus/ataxia, (3) behavioral change and/or sleep disturbance, and (4) neuroblastoma.9
© 2013 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1358604. ISSN 0174-304X.
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Update on Pediatric Opsoclonus Myoclonus Syndrome
In adults, opsoclonus myoclonus syndrome has been reported in association with different types of cancer, particularly, breast and lung cell cancer, but also testicular and ovarian tumors.10–12 In childhood, opsoclonus myoclonus syndrome may be associated with neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, or ganglioneuroma). It has only occasionally been described to be associated with other entities as ovarian teratoma or hepatoblastoma.13,14 In a few rare patients, the syndrome seemed to be caused by infections with identifiable agents as mycoplasma pneumonia or hepatitis C virus.15,16 However, these patients were older than the typical toddlers observed with paraneoplastic opsoclonus myoclonus syndrome. Currently, no exact data on the incidence of opsoclonus myoclonus syndrome in childhood exist. A prospective study in the United Kingdom over a 2-year-period identified an incidence of 0.2 per million of the total population per year,17 a figure which was higher than that calculated from incidence figures based on neuroblastoma registries that are available in many countries. Two to four percent of the neuroblastoma patients will develop opsoclonus myoclonus syndrome.3,18 Several studies suggest that at least in about half of the patients with opsoclonus myoclonus syndrome an underlying neuroblastoma will be found.9,19 Lower figures have been reported, however, with a wide spectrum of the investigation protocols used to identify a neuroblastoma.17,20,21 Compared with neuroblastoma in patients without opsoclonus myoclonus syndrome, tumors in patients with the syndrome are smaller, are located more often in paravertebral regions including thoracic regions, and may present less often with elevated catecholamine metabolites.2–4 Such small tumors may escape ultrasound imaging and will not be detected by screening of urinary catecholamine metabolites but may need a more meticulous approach using thin-cut imaging modalities. From these observations, one may hypothesize that the real percentage of neuroblastoma-associated opsoclonus myoclonus syndromes is much higher. In patients in whom no neuroblastoma has been found, a previous virus infection is discussed to be responsible for the autoimmune attack. However, even in many patients with underlying neuroblastoma, infectious episodes, often of viral origin, are reported before the disease and may have triggered the onset of the symptoms. In rare patients, opsoclonus myoclonus syndrome has been diagnosed several months after the diagnosis of neuroblastoma.22,23 As it is a wellknown phenomenon that neuroblastoma may regress spontaneously,24–27 opsoclonus myoclonus syndrome may have occurred after regression of the neuroblastoma in those patients where no tumor is detected. The features of the disease as age at onset, detection of autoantibodies, response to immunosuppressive treatment, and long-term outcome do not differ between patients with or without evidence of neuroblastoma. Only in one series, neurological symptoms at diagnosis were slightly worse in patients with opsoclonus myoclonus syndrome and neuroblastoma.28 These observa-
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tions imply that both forms of opsoclonus myoclonus represent the same disease showing just a different time course in relation to the underlying tumor. Neuroblastoma associated with opsoclonus myoclonus syndrome is most frequently of low-stage and low-risk disease with excellent prognosis.2–4 In most of the patients, surgical resection is the only oncologic treatment needed. Unfavorable molecular risk factors, such as, amplification of the oncogene MYCN, have been reported in a few cases.29 The tumors often show lymphoid cell infiltration and signs of differentiation.30,31 Differentiation of neuroblastoma is a phenomenon, often observed in low-risk neuroblastoma, that may occur during observation or after chemotherapy. This raises the question whether either the immune system may play a role in the differentiation process or whether differentiation in the tumor goes along with changing of antigen expression, thus providing a substrate for the immune answer.
Pathophysiology Clinical features and research results point to an autoimmune origin of the disease, however direct proof of an autoimmune process is lacking and the underlying target has not yet been identified. The observation of frequent autoimmune disorders in families of patients with opsoclonus myoclonus syndrome and a correlation with human leukocyte antigen class II locus DR B101 indicate a genetic predisposition to autoimmunity in the patients affected.32,33 An immune response generated by tumor-associated antigens with cross-reactivity to structures of the central nervous system has been postulated. The symptoms observed hint to cerebellum and brain stem as target structures attacked by the immune system. This is supported by a few clinical observations where involvement of the cerebellum has been claimed by increased activity in single photon emission computed tomography at active disease and by significant cerebellar atrophy at long-term follow-up, interpreted as damage caused by the immunological-mediated disease mechanisms.34,35 In the late 20th century, research on the pathophysiological mechanisms of opsoclonus myoclonus syndrome focused on the search for autoantibodies. Antineuronal antibodies have been detected in adults with paraneoplastic opsoclonus myoclonus syndrome.36,37 Anti-Hu, anti-Ri, and anti-Yo, the antibodies most often reported in adult patients with opsoclonus myoclonus syndrome, are found rarely in children with the disease.38,39 Instead, antineurofilament antibodies (NF210K antibody), anti-Purkinje cell antibodies, and immunoglobulin G autoantibodies binding to the surface of isolated rat cerebellar granular neurons have been isolated.40–42 However, the antigen specificity of the autoantibodies was low.43 Of interest, antineuronal antibodies were also found in age and stage-matched case control patients with neuroblastoma without opsoclonus myoclonus syndrome, albeit to a significant lower percentage.38 An antibody identified in the serum IgG fraction of opsoclonus myoclonus patients with or without neuroblastoma showed significant antiproliferative and cytotoxic effects on neuroblastoma cell lines. This Neuropediatrics
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Opsoclonus Myoclonus Syndrome and Neuroblastoma
Hero, Schleiermacher
Update on Pediatric Opsoclonus Myoclonus Syndrome antibody was absent in sera of neuroblastoma patients without OMS and in the sera of healthy children.44 The hypothesis of a B-cell–mediated disease is further encouraged by the fact that elevated populations of B-cells have been demonstrated in the cerebrospinal fluid (CSF) of children with opsoclonus myoclonus syndrome, indicating an intrathecal B-cell expansion. The B-cell expansion correlates with disease severity and with response to treatment with rituximab.45,46 B-cell activating factor (BAFF), a key molecule necessary for B-cell survival, seems to be involved in the intrathecal B-cell expansion: elevated CSF-levels of BAFF have recently been reported by the two different groups.47,48 Of interest, neuroblastoma cells are also able to produce BAFF as well as to express CXCL12 and CXCL13, chemokines involved in lymphocyte attraction.49,50 Although these observations support a central role of Bcells in the pathogenesis of the disease, there are several facts indicating an involvement of T-cells as well, one of which is the poorly defined specificity of the autoantibodies detected. Histological and immunohistological investigations of neuroblastoma tissue of patients with opsoclonus myoclonus syndrome showed interstitial or perivascular lymphoid infiltrates not only with B-lymphocytes but also with T-lymphocytes.30,31 In addition to B-cell expansion, increased intrathecal numbers of gamma/delta T-cell subsets and of activated CD8þ T-cells were observed.45 The current understanding is that T-cell–dependent response to tumor-associated antigens leads to subsequent B-cell activation and antibody production (reviewed by Matthay et al9 and Posner51).
Long-Term Neurological Outcome Although few children seem to develop normally after opsoclonus myoclonus syndrome, the long-term follow-up of most patients demonstrates significant cognitive or neuropsychological deficits including language, attention, memory, visuomotor, and working memory deficits, often with normal or near-normal motor outcome.2–4,8,20,28,35,52–57 Several series addressing long-term outcome have been published reporting neuropsychological deficits in approximately 80% of the patients investigated (reviewed by Gorman58). Although the results may be hampered by the retrospective nature of most of the series, the diversity of the treatment given, the small number of patients investigated, and by potential referral bias, these studies indicate a substantial long-term neuropsychological morbidity in this patient group, which is of great importance for the daily life of the families and for the planning of appropriate school accommodations. In the same way, the analysis of risk factors for long-term outcome is impaired by the factors discussed above. Currently, no data exist addressing the long-term follow-up of sufficient numbers of uniformly treated patients. Better long-term outcome was reported after treatment with chemotherapy2,9 or in patients with advanced tumor stage.3 This might be explained by a positive effect of the strong immunosuppression by the chemotherapy given. However, it is also Neuropediatrics
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Hero, Schleiermacher discussed that patients with more advanced oncological disease may present a subtype of opsoclonus myoclonus syndrome with lower activation of the immune system. Delayed immunosuppressive treatment, severe initial presentation, younger age, and relapses with steroid dose tapering have been discussed as risk factors for worse neuropychological outcome.53,55,57 The cerebellum does not only play a major role in motor control and in motor learning, but is also involved in cognitive development (reviewed by Timmann59). Cognitive delay and neuropsychological impairment after opsoclonus myoclonus syndrome are thought to be caused by damage to the cerebellum during phases of active disease. Delayed treatment start and relapses may lead to longer exposure of the cerebellum to attacks of the immune system and thus to long-term damage.
Therapy The poor neurological outcome in many children despite steroid-based treatment and the possible beneficial effect of chemotherapeutic intervention led to the current hypothesis that prompt and potent immunosuppression is necessary for patients with opsoclonus myoclonus syndrome. In few patients, spontaneous recovery from opsoclonus myoclonus syndrome was reported, some of them associated with identifiable infections.17,60 Resection of the neuroblastoma may improve the acute symptoms for a short period in some patients, but complete resolution of symptoms after resection without any further immunosuppressive treatment has only rarely been reported.4 Aside from these relatively uncommon cases, most patients will require immunosuppressive treatment. Multiple different therapeutic strategies have been reported including the use of various steroids, adrenocorticotropic hormone (ACTH), immunoglobulins, azathioprine, rituximab, mycophenolate, plasmapheresis, and cyclophosphamide, either given alone or in combination.61–68 However, there is no objective data confirming the efficacy of any of these interventions in altering long-term outcome. Classic treatment consisted of long-term corticosteroids or ACTH. Exacerbations or relapses of neurological symptoms may occur with weaning of the drugs or intercurrent viral illness. ACTH seems to produce a more rapid response and was effective in some patients with insufficient response to prednisone or prednisolone, although reports published so far could not prove a benefit in terms of long-term outcome.8,20 Promising short-term results have been observed in a subgroup of patients with opsoclonus myoclonus treated with dexamethasone pulses.62 There are several reports showing a good response after treatment with high-dose intravenous immunoglobulin (IVIG),63–66 but the patients addressed in long-term studies did not benefit from IVIG therapy.3,4,8 However, IVIG may have been used in patients with severe symptoms or with steroid dependency, thus making it difficult to draw conclusions out of these observations. The Children’s Oncology Group has very recently finished recruitment for a randomized trial addressing the
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role of IVIG in patients with neuroblastoma and opsoclonus myoclonus syndrome (NCT00033293) and the results are awaited soon. Rituximab has recently gained attention in the treatment of opsoclonus myoclonus syndrome. Several case reports and series of children treated with Rituximab in addition to steroids, cyclophosphamide, or IVIG have been published, mostly showing significant clinical improvement,69–73 whereas, in one case report no effect was observed.74 B-cell expansion in the CSF is discussed to be associated with response to rituximab, although not proven in greater series.72 As discussed earlier, it seems necessary to minimize the phases of active immune attacks, that is, to start treatment promptly and to avoid exacerbations of the disease. On the contrary, not all patients seem to need a maximum of treatment. Some patients show a monophasic course with good response to first line immunosuppressive treatment without relapses. Thus, it might be useful to tailor the therapy according to the patient’s needs and to take the long-term side effects of the treatment into account, which are not negligible for most of the drugs used: Steroids and ACTH can cause, for example, hypertension, weight gain, osteopenia, aseptic bony necrosis, growth retardation, and cataracts. IVIG is a blood-derived product bearing the risk of allergic reactions and of transmission of blood-borne infection. Impairment of spermiogenesis and second malignancies have been reported after treatment with higher doses of cyclophosphamide. Rituximab causes long-term B-cell depletion with the increased risk of infections. Although infectious complications in general are thought to be rare,75 single cases of severe CNS infections, or progressive multifocal leukoencephalopathy have been reported.76,77 Once the acute symptoms in the very beginning of the disease are resolved by the immunomodulatory treatment, other therapeutic measures as speech therapy, physiotherapy, and occupational therapy might find their place in management of the patients and should be installed according to the individual needs.
The European Trial Prospective studies are urgently needed to address the question of optimal therapy to improve neurological and neuropsychological outcome in this rare condition and to determine favorable and unfavorable prognostic factors. Because of the rarity of the disease, international collaboration is needed. A European trial protocol, brought on the way by specialists of SIOPEN (SIOP [Société Internationale d’Oncologie Pédiatrique] Europe Neuroblastoma), GPOH (Gesellschaft für Pädiatrische Hämatologie und Onkologie), and EPNS (European Pediatric Neurology Society), started recruitment in 2013 (NCT01868269, Sponsor: Institut Curie, Paris, principal coordinating investigator: Gudrun Schleiermacher). This trial will investigate an escalating treatment schedule starting with dexamethasone pulses (first step). In case of insufficient response to dexamethasone after 3 months of
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treatment, cyclophosphamide will be added (second step). Cyclophosphamide will be replaced by rituximab, if still no sufficient improvement is seen after 3 further months (third step). Treatment intensification will be decided on the basis of standardized scoring scales for opsoclonus myoclonus severity, which have been established by international discussion and already been in use for retrospective assessment (reviewed by Gorman58). Pulsed dexamethasone will be used as a first step because of the previous experience in patients with opsoclonus myoclonus syndrome62,74 and because of relatively low side effects. The pulsed treatment has the advantage not to inhibit the adrenal function, so that the corticoid therapy can be stopped without tapering the drug. In addition, the pulses can be tailored according to the patient’s symptoms, for example, the interval may be shortened in case of deterioration before the next scheduled pulse. The rationale for the use of cyclophosphamide is its wide use in other autoimmune disorders, the response seen in pilot patients and the better outcome in patients treated with chemotherapy in retrospective studies. Rituximab is used because of its action on B-cells, its use in other (antibodymediated) autoimmune diseases, and because of the response reported in opsoclonus myoclonus patients. It will only be introduced as a third step, as long-term late effect data are mostly missing so far. This escalating schedule provides a standardized therapy intensification for patients with insufficient response. On the contrary, patients responding well to dexamethasone alone are not exposed to potentially toxic treatment they do not need. This is the first prospective trial including patients with opsoclonus myoclonus syndrome with and without neuroblastoma. Detailed guidelines for the search for neuroblastoma have been elaborated so that data on the real prevalence of neuroblastoma in patients with opsoclonus myoclonus syndrome will be generated. In parallel to the collection of data, plasma, CSF, and—in case of neuroblastoma—tumor tissue will be collected for research purposes, as further insight in the complex pathophysiology of this disease—with the hope to improve treatment options by better knowledge of the pathophysiology— can only be achieved by close international collaboration with collection of biological samples in sufficient quality and quantity. The trial will open in several European countries. For each participating country, a national coordinator as well for pediatric oncology as for pediatric neurology is identified. More detailed information on the trial, the respective national coordinators, and the options to participate are available by contacting Gudrun Schleiermacher ([email protected]) or Barbara Hero ([email protected]).
Acknowledgments The contribution of the members of the European Opsoclonus Myoclonus Collaboration Group (SIOPEN, GPOH, and EPNS) in finalizing the trial protocol is greatly appreciated. Neuropediatrics
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Update on Pediatric Opsoclonus Myoclonus Syndrome
Update on Pediatric Opsoclonus Myoclonus Syndrome References
Hero, Schleiermacher 23 Jamroz E, Głuszkiewicz E, Madziara W, Kiełtyka A. [Opsoclonus-
1 Kinsbourne M. Myoclonic encephalopathy of infants. J Neurol 2
3
4
5 6
7
8
9
10
11 12
13
14
15
16 17
18 19
20 21
22
Neurosurg Psychiatry 1962;25:271–276 Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 1997;28(4):284–288 Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonusataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children’s Cancer Group Study. Med Pediatr Oncol 2001;36(6):612–622 Plantaz D, Michon J, Valteau-Couanet D, et al; Study of the French Society of Pediatric Oncologists. [Opsoclonus-myoclonus syndrome associated with non-metastatic neuroblastoma. Longterm survival]. Arch Pediatr 2000;7(6):621–628 Roberts KB. Cerebellar ataxia and “occult neuroblastoma” without opsoclonus. Pediatrics 1975;56:464–465 Herman TE, Siegel MJ. Ataxia without opsoclonus: right lumbar sympathetic trunk neuroblastoma. Clin Pediatr (Phila) 2009; 48:336–340 Wolff M, Schoning M, Niemann G, Krageloh-Mann I. Late detection of neuroblastoma in a patient with prolonged cerebellar ataxia without opsoclonus. Neuropediatrics 2001;32:101–103 Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al. Opsoclonusataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics 2002;109(1):86–98 Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Lett 2005;228(1-2):275–282 Bataller L, Graus F, Saiz A, Vilchez JJ; Spanish Opsoclonus-Myoclonus Study Group. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 2001;124(Pt 2):437–443 Grant R, Graus F. Paraneoplastic movement disorders. Mov Disord 2009;24(12):1715–1724 Titulaer MJ, Soffietti R, Dalmau J, et al; European Federation of Neurological Societies. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011;18(1): 19–e3 Fitzpatrick AS, Gray OM, McConville J, McDonnell GV. Opsoclonusmyoclonus syndrome associated with benign ovarian teratoma. Neurology 2008;70(15):1292–1293 Wilfong AA, Parke JT, McCrary JA III. Opsoclonus-myoclonus with Beckwith-Wiedemann syndrome and hepatoblastoma. Pediatr Neurol 1992;8(1):77–79 Huber BM, Strozzi S, Steinlin M, Aebi C, Fluri S. Mycoplasma pneumoniae associated opsoclonus-myoclonus syndrome in three cases. Eur J Pediatr 2010;169(4):441–445 Ertekin V, Tan H. Opsoclonus-myoclonus syndrome attributable to hepatitis C infection. Pediatr Neurol 2010;42(6):441–442 Pang KK, de Sousa C, Lang B, Pike MG. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom. Eur J Paediatr Neurol 2010;14(2):156–161 Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 1992;15(3):186–228 Tate ED, Allison TJ, Pranzatelli MR, Verhulst SJ. Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs 2005;22(1):8–19 Pohl KR, Pritchard J, Wilson J. Neurological sequelae of the dancing eye syndrome. Eur J Pediatr 1996;155(3):237–244 Brunklaus A, Pohl K, Zuberi SM, de Sousa C. Investigating neuroblastoma in childhood opsoclonus-myoclonus syndrome. Arch Dis Child 2012;97(5):461–463 Mutch LS, Johnston DL. Late presentation of opsoclonus-myoclonus-ataxia syndrome in a child with stage 4S neuroblastoma. J Pediatr Hematol Oncol 2005;27(6):341–343
Neuropediatrics
Vol. 44
No. 6/2013
24
25
26 27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
myoclonus syndrome in a 2. year old boy with prenatally diagnosed retroperitoneal tumour]. Med Wieku Rozwoj 2011;15(2): 151–156 Evans AE, D’Angio GJ, Randolph J. A proposed staging for children with neuroblastoma. Children’s cancer study group A. Cancer 1971;27(2):374–378 D’Angio GJ, Evans AE, Koop CE. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet 1971;1(7708): 1046–1049 Evans AE, Baum E, Chard R. Do infants with stage IV-S neuroblastoma need treatment? Arch Dis Child 1981;56(4):271–274 Hero B, Simon T, Spitz R, et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 2008;26(9):1504–1510 Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol 2010;14(5):400–409 Hiyama E, Yokoyama T, Ichikawa T, et al. Poor outcome in patients with advanced stage neuroblastoma and coincident opsomyoclonus syndrome. Cancer 1994;74(6):1821–1826 Gambini C, Conte M, Bernini G, et al. Neuroblastic tumors associated with opsoclonus-myoclonus syndrome: histological, immunohistochemical and molecular features of 15 Italian cases. Virchows Arch 2003;442(6):555–562 Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-myoclonusataxia syndrome in neuroblastoma: histopathologic features-a report from the Children’s Cancer Group. Med Pediatr Oncol 2001;36(6):623–629 Hero B, Radolska S, Gathof BS. Opsomyoclonus syndrome in infancy with or without neuroblastoma is associated with HLA DRB101 (abstract). Ped Blood Cancer 2005:45 Krasenbrink I, Fühlhuber V, Juhasz-Boess I, et al. Increased prevalence of autoimmune disorders and autoantibodies in parents of children with opsoclonus-myoclonus syndrome (OMS). Neuropediatrics 2007;38(3):114–116 Oguro K, Kobayashi J, Aiba H, Hojo H. Opsoclonus-myoclonus syndrome with abnormal single photon emission computed tomography imaging. Pediatr Neurol 1997;16(4):334–336 Hayward K, Jeremy RJ, Jenkins S, et al. Long-term neurobehavioral outcomes in children with neuroblastoma and opsoclonus-myoclonus-ataxia syndrome: relationship to MRI findings and anti-neuronal antibodies. J Pediatr 2001;139(4):552– 559 Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29(3):241–251 Dalmau J, Graus F, Cheung NK, et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 1995; 75(1):99–109 Antunes NL, Khakoo Y, Matthay KK, et al. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonusmyoclonus. J Pediatr Hematol Oncol 2000;22(4):315–320 Fisher PG, Wechsler DS, Singer HS. Anti-Hu antibody in a neuroblastoma-associated paraneoplastic syndrome. Pediatr Neurol 1994;10(4):309–312 Connolly AM, Pestronk A, Mehta S, Pranzatelli MR III, Noetzel MJ. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. J Pediatr 1997;130(6):878–884 Noetzel MJ, Cawley LP, James VL, Minard BJ, Agrawal HC. Antineurofilament protein antibodies in opsoclonus-myoclonus. J Neuroimmunol 1987;15(2):137–145 Blaes F, Fühlhuber V, Korfei M, et al. Surface-binding autoantibodies to cerebellar neurons in opsoclonus syndrome. Ann Neurol 2005;58(2):313–317
Downloaded by: Universidad de Barcelona. Copyrighted material.
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43 Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J.
61 Emir S, Akyüz C, Büyükpamukçu M. Correspondence: treatment of
Autoantigen diversity in the opsoclonus-myoclonus syndrome. Ann Neurol 2003;53(3):347–353 Korfei M, Fühlhuber V, Schmidt-Wöll T, Kaps M, Preissner KT, Blaes F. Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonus-syndrome. J Neuroimmunol 2005;170(1-2):150–157 Pranzatelli MR, Travelstead AL, Tate ED, Allison TJ, Verhulst SJ. CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity. Mov Disord 2004;19(7):770–777 Pranzatelli MR, Tate ED, Travelstead AL, Colliver JA. Long-term cerebrospinal fluid and blood lymphocyte dynamics after rituximab for pediatric opsoclonus-myoclonus. J Clin Immunol 2010; 30(1):106–113 Pranzatelli MR, Tate ED, McGee NR, et al. BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy. J Neuroinflammation 2013;10:10 Fühlhuber V, Bick S, Kirsten A, et al. Elevated B-cell activating factor BAFF, but not APRIL, correlates with CSF cerebellar autoantibodies in pediatric opsoclonus-myoclonus syndrome. J Neuroimmunol 2009;210(1-2):87–91 Raffaghello L, Fuhlhuber V, Bianchi G, et al. Role of BAFF in Opsoclonus-Myoclonus syndrome, a bridge between cancer and autoimmunity. J Leukoc Biol 2013;94(1):183–191 Raffaghello L, Conte M, De Grandis E, Pistoia V. Immunological mechanisms in opsoclonus-myoclonus associated neuroblastoma. Eur J Paediatr Neurol 2009;13(3):219–223 Posner JB. Paraneoplastic opsoclonus/myoclonus: B cells, T cells, both, or neither? Neurology 2004;62(9):1466–1467 Klein A, Schmitt B, Boltshauser E. Long-term outcome of ten children with opsoclonus-myoclonus syndrome. Eur J Pediatr 2007;166(4):359–363 De Grandis E, Parodi S, Conte M, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics 2009;40(3):103–111 Catsman-Berrevoets CE, Aarsen FK, van Hemsbergen ML, van Noesel MM, Hakvoort-Cammel FG, van den Heuvel-Eibrink MM. Improvement of neurological status and quality of life in children with opsoclonus myoclonus syndrome at long-term follow-up. Pediatr Blood Cancer 2009;53(6):1048–1053 Mitchell WG, Brumm VL, Azen CG, Patterson KE, Aller SK, Rodriguez J. Longitudinal neurodevelopmental evaluation of children with opsoclonus-ataxia. Pediatrics 2005;116(4):901–907 Turkel SB, Brumm VL, Mitchell WG, Tavare CJ. Mood and behavioral dysfunction with opsoclonus-myoclonus ataxia. J Neuropsychiatry Clin Neurosci 2006;18(2):239–241 Brunklaus A, Pohl K, Zuberi SM, de Sousa C. Outcome and prognostic features in opsoclonus-myoclonus syndrome from infancy to adult life. Pediatrics 2011;128(2):e388–e394 Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr 2010; 22(6):745–750 Timmann D. [Contribution of the cerebellum to cognition]. Fortschr Neurol Psychiatr 2012;80(1):44–52 Ki Pang K, Lynch BJ, Osborne JP, Pike MG. Dancing Eye Syndrome associated with spontaneous recovery and normal neurodevelopment. Eur J Paediatr Neurol 2010;14(2):178–181
the neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome with high-dose methylprednisolone. Med Pediatr Oncol 2003;40(2):139 Rostásy K, Wilken B, Baumann M, et al. High dose pulsatile dexamethasone therapy in children with opsoclonus-myoclonus syndrome. Neuropediatrics 2006;37(5):291–295 Borgna-Pignatti C, Balter R, Marradi P, Colamaria V. Treatment with intravenously administered immunoglobulins of the neuroblastoma-associated opsoclonus-myoclonus. J Pediatr 1996; 129(1):179–180 Petruzzi MJ, de Alarcon PA. Neuroblastoma-associated opsoclonus-myoclonus treated with intravenously administered immune globulin G. J Pediatr 1995;127(2):328–329 Pless M, Ronthal M. Treatment of opsoclonus-myoclonus with high-dose intravenous immunoglobulin. Neurology 1996;46(2): 583–584 Veneselli E, Conte M, Biancheri R, Acquaviva A, De Bernardi B. Effect of steroid and high-dose immunoglobulin therapy on opsoclonus-myoclonus syndrome occurring in neuroblastoma. Med Pediatr Oncol 1998;30(1):15–17 Yiu VW, Kovithavongs T, McGonigle LF, Ferreira P. Plasmapheresis as an effective treatment for opsoclonus-myoclonus syndrome. Pediatr Neurol 2001;24(1):72–74 Pranzatelli MR, Tate ED, Travelstead AL, et al. Insights on chronicrelapsing opsoclonus-myoclonus from a pilot study of mycophenolate mofetil. J Child Neurol 2009;24(3):316–322 Pranzatelli MR, Tate ED, Travelstead AL, Longee D. Immunologic and clinical responses to rituximab in a child with opsoclonusmyoclonus syndrome. Pediatrics 2005;115(1):e115–e119 Bell J, Moran C, Blatt J. Response to rituximab in a child with neuroblastoma and opsoclonus-myoclonus. Pediatr Blood Cancer 2008;50(2):370–371 Burke MJ, Cohn SL. Rituximab for treatment of opsoclonus-myoclonus syndrome in neuroblastoma. Pediatr Blood Cancer 2008; 50(3):679–680 Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (antiCD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2006;28(9):585–593 Pranzatelli MR, Tate ED, Verhulst SJ, et al. Pediatric dosing of rituximab revisited: serum concentrations in opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2010;32(5): e167–e172 Ertle F, Behnisch W, Al Mulla NA, et al. Treatment of neuroblastoma-related opsoclonus-myoclonus-ataxia syndrome with highdose dexamethasone pulses. Pediatr Blood Cancer 2008;50(3): 683–687 Tam C, Seymour JF, Brown M, et al. Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies. Haematologica 2005;90(5):700–702 Quartier P, Tournilhac O, Archimbaud C, et al. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003;36(3):e47–e49 Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9(4):425–437
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Update on Pediatric Opsoclonus Myoclonus Syndrome
Update on Pediatric Opsoclonus Myoclonus Syndrome Barbara Hero1
Gudrun Schleiermacher2
1 Department of Pediatric Oncology, Children’s Hospital, University of
Cologne, Köln, Germany 2 Institut Curie, Paris, France
Address for correspondence Barbara Hero, MD, Department of Pediatric Oncology, Children’s Hospital, University of Cologne, Kerpener Strasse 62, 50924 Köln, Germany (e-mail: [email protected]).
Neuropediatrics 2013;44:324–329.
Abstract
Keywords
► opsoclonus myoclonus syndrome ► dancing eye syndrome ► neuroblastoma
Opsoclonus myoclonus syndrome (dancing eye syndrome) is a rare paraneoplastic syndrome characterized by opsoclonus, myoclonus, and ataxia, usually accompanied by behavioral abnormalities. In adults, opsoclonus myoclonus syndrome has been reported in association with different types of cancer; whereas in children, the syndrome may be associated with neuroblastic tumors. Although a direct proof is lacking, the syndrome is assumed to be of autoimmune origin. The treatment is corticosteroid based with the addition of other immunosuppressive or immunomodulating drugs if intensification seems necessary. Because of the rarity of the disease, international collaborations as well on research as on therapeutic strategies are urgently needed. A European consortium just started a trial for this rare condition.
Clinical Presentation In 1963, Kinsbourne first described opsoclonus myoclonus syndrome (dancing eye syndrome) on the basis of the observation of six children with the main symptoms ataxia, myoclonus, and opsoclonus.1 Most patients present a movement disorder with acute onset or subacute onset, consisting of gait or truncal ataxia and myoclonus. Age of onset is typically in the second year of life, and only occasionally is the syndrome reported at the end of infancy or beyond the third year of life.2–4 Often, the toddlers, just having learned to walk, lose the ability to walk or sit within days. Myoclonus may involve all body parts including limbs, trunk, and face, varies from tremulous polymyoclonia to coarse multifocal jerks, and may be exacerbated by attempts to move or by emotional distress. Distinguishing the myoclonic and ataxic components of the condition may be difficult. Opsoclonus is a rapid, conjugate, multidirectional eye movement which is usually intermittent. It is rarely seen in other childhood conditions. It tends to occur in bursts and can sometimes be provoked by change in gaze
received July 17, 2013 accepted after revision September 5, 2013 published online November 7, 2013
Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.
fixation, usually from far to near. The movement disorder is frequently accompanied by behavioral signs reaching from severe irritability of the inconsolable children, developmental regression, for example, loss of speech, and sleep disturbances, to apathy and reduction of social and playing activities. The neurological signs may vary widely in their expression and are not necessarily all present together. Opsoclonus, in particular, may be intermittent or late in onset, sometimes appearing as late as a few weeks after the onset of ataxia. On the contrary, some discrete signs or behavioral change may be observed several weeks before the onset of the typical symptoms. Occult neuroblastoma may present with some but not all, of the symptoms.5–8 Thus, the diagnosis of opsoclonus myoclonus syndrome may be difficult in some patients and should be considered even when only some of the features are present. International consensus has been reached that three of the following four diagnostic criteria should be present to describe the typical syndrome: (1) opsoclonus, (2) myoclonus/ataxia, (3) behavioral change and/or sleep disturbance, and (4) neuroblastoma.9
© 2013 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1358604. ISSN 0174-304X.
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Update on Pediatric Opsoclonus Myoclonus Syndrome
In adults, opsoclonus myoclonus syndrome has been reported in association with different types of cancer, particularly, breast and lung cell cancer, but also testicular and ovarian tumors.10–12 In childhood, opsoclonus myoclonus syndrome may be associated with neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, or ganglioneuroma). It has only occasionally been described to be associated with other entities as ovarian teratoma or hepatoblastoma.13,14 In a few rare patients, the syndrome seemed to be caused by infections with identifiable agents as mycoplasma pneumonia or hepatitis C virus.15,16 However, these patients were older than the typical toddlers observed with paraneoplastic opsoclonus myoclonus syndrome. Currently, no exact data on the incidence of opsoclonus myoclonus syndrome in childhood exist. A prospective study in the United Kingdom over a 2-year-period identified an incidence of 0.2 per million of the total population per year,17 a figure which was higher than that calculated from incidence figures based on neuroblastoma registries that are available in many countries. Two to four percent of the neuroblastoma patients will develop opsoclonus myoclonus syndrome.3,18 Several studies suggest that at least in about half of the patients with opsoclonus myoclonus syndrome an underlying neuroblastoma will be found.9,19 Lower figures have been reported, however, with a wide spectrum of the investigation protocols used to identify a neuroblastoma.17,20,21 Compared with neuroblastoma in patients without opsoclonus myoclonus syndrome, tumors in patients with the syndrome are smaller, are located more often in paravertebral regions including thoracic regions, and may present less often with elevated catecholamine metabolites.2–4 Such small tumors may escape ultrasound imaging and will not be detected by screening of urinary catecholamine metabolites but may need a more meticulous approach using thin-cut imaging modalities. From these observations, one may hypothesize that the real percentage of neuroblastoma-associated opsoclonus myoclonus syndromes is much higher. In patients in whom no neuroblastoma has been found, a previous virus infection is discussed to be responsible for the autoimmune attack. However, even in many patients with underlying neuroblastoma, infectious episodes, often of viral origin, are reported before the disease and may have triggered the onset of the symptoms. In rare patients, opsoclonus myoclonus syndrome has been diagnosed several months after the diagnosis of neuroblastoma.22,23 As it is a wellknown phenomenon that neuroblastoma may regress spontaneously,24–27 opsoclonus myoclonus syndrome may have occurred after regression of the neuroblastoma in those patients where no tumor is detected. The features of the disease as age at onset, detection of autoantibodies, response to immunosuppressive treatment, and long-term outcome do not differ between patients with or without evidence of neuroblastoma. Only in one series, neurological symptoms at diagnosis were slightly worse in patients with opsoclonus myoclonus syndrome and neuroblastoma.28 These observa-
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tions imply that both forms of opsoclonus myoclonus represent the same disease showing just a different time course in relation to the underlying tumor. Neuroblastoma associated with opsoclonus myoclonus syndrome is most frequently of low-stage and low-risk disease with excellent prognosis.2–4 In most of the patients, surgical resection is the only oncologic treatment needed. Unfavorable molecular risk factors, such as, amplification of the oncogene MYCN, have been reported in a few cases.29 The tumors often show lymphoid cell infiltration and signs of differentiation.30,31 Differentiation of neuroblastoma is a phenomenon, often observed in low-risk neuroblastoma, that may occur during observation or after chemotherapy. This raises the question whether either the immune system may play a role in the differentiation process or whether differentiation in the tumor goes along with changing of antigen expression, thus providing a substrate for the immune answer.
Pathophysiology Clinical features and research results point to an autoimmune origin of the disease, however direct proof of an autoimmune process is lacking and the underlying target has not yet been identified. The observation of frequent autoimmune disorders in families of patients with opsoclonus myoclonus syndrome and a correlation with human leukocyte antigen class II locus DR B101 indicate a genetic predisposition to autoimmunity in the patients affected.32,33 An immune response generated by tumor-associated antigens with cross-reactivity to structures of the central nervous system has been postulated. The symptoms observed hint to cerebellum and brain stem as target structures attacked by the immune system. This is supported by a few clinical observations where involvement of the cerebellum has been claimed by increased activity in single photon emission computed tomography at active disease and by significant cerebellar atrophy at long-term follow-up, interpreted as damage caused by the immunological-mediated disease mechanisms.34,35 In the late 20th century, research on the pathophysiological mechanisms of opsoclonus myoclonus syndrome focused on the search for autoantibodies. Antineuronal antibodies have been detected in adults with paraneoplastic opsoclonus myoclonus syndrome.36,37 Anti-Hu, anti-Ri, and anti-Yo, the antibodies most often reported in adult patients with opsoclonus myoclonus syndrome, are found rarely in children with the disease.38,39 Instead, antineurofilament antibodies (NF210K antibody), anti-Purkinje cell antibodies, and immunoglobulin G autoantibodies binding to the surface of isolated rat cerebellar granular neurons have been isolated.40–42 However, the antigen specificity of the autoantibodies was low.43 Of interest, antineuronal antibodies were also found in age and stage-matched case control patients with neuroblastoma without opsoclonus myoclonus syndrome, albeit to a significant lower percentage.38 An antibody identified in the serum IgG fraction of opsoclonus myoclonus patients with or without neuroblastoma showed significant antiproliferative and cytotoxic effects on neuroblastoma cell lines. This Neuropediatrics
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Opsoclonus Myoclonus Syndrome and Neuroblastoma
Hero, Schleiermacher
Update on Pediatric Opsoclonus Myoclonus Syndrome antibody was absent in sera of neuroblastoma patients without OMS and in the sera of healthy children.44 The hypothesis of a B-cell–mediated disease is further encouraged by the fact that elevated populations of B-cells have been demonstrated in the cerebrospinal fluid (CSF) of children with opsoclonus myoclonus syndrome, indicating an intrathecal B-cell expansion. The B-cell expansion correlates with disease severity and with response to treatment with rituximab.45,46 B-cell activating factor (BAFF), a key molecule necessary for B-cell survival, seems to be involved in the intrathecal B-cell expansion: elevated CSF-levels of BAFF have recently been reported by the two different groups.47,48 Of interest, neuroblastoma cells are also able to produce BAFF as well as to express CXCL12 and CXCL13, chemokines involved in lymphocyte attraction.49,50 Although these observations support a central role of Bcells in the pathogenesis of the disease, there are several facts indicating an involvement of T-cells as well, one of which is the poorly defined specificity of the autoantibodies detected. Histological and immunohistological investigations of neuroblastoma tissue of patients with opsoclonus myoclonus syndrome showed interstitial or perivascular lymphoid infiltrates not only with B-lymphocytes but also with T-lymphocytes.30,31 In addition to B-cell expansion, increased intrathecal numbers of gamma/delta T-cell subsets and of activated CD8þ T-cells were observed.45 The current understanding is that T-cell–dependent response to tumor-associated antigens leads to subsequent B-cell activation and antibody production (reviewed by Matthay et al9 and Posner51).
Long-Term Neurological Outcome Although few children seem to develop normally after opsoclonus myoclonus syndrome, the long-term follow-up of most patients demonstrates significant cognitive or neuropsychological deficits including language, attention, memory, visuomotor, and working memory deficits, often with normal or near-normal motor outcome.2–4,8,20,28,35,52–57 Several series addressing long-term outcome have been published reporting neuropsychological deficits in approximately 80% of the patients investigated (reviewed by Gorman58). Although the results may be hampered by the retrospective nature of most of the series, the diversity of the treatment given, the small number of patients investigated, and by potential referral bias, these studies indicate a substantial long-term neuropsychological morbidity in this patient group, which is of great importance for the daily life of the families and for the planning of appropriate school accommodations. In the same way, the analysis of risk factors for long-term outcome is impaired by the factors discussed above. Currently, no data exist addressing the long-term follow-up of sufficient numbers of uniformly treated patients. Better long-term outcome was reported after treatment with chemotherapy2,9 or in patients with advanced tumor stage.3 This might be explained by a positive effect of the strong immunosuppression by the chemotherapy given. However, it is also Neuropediatrics
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Hero, Schleiermacher discussed that patients with more advanced oncological disease may present a subtype of opsoclonus myoclonus syndrome with lower activation of the immune system. Delayed immunosuppressive treatment, severe initial presentation, younger age, and relapses with steroid dose tapering have been discussed as risk factors for worse neuropychological outcome.53,55,57 The cerebellum does not only play a major role in motor control and in motor learning, but is also involved in cognitive development (reviewed by Timmann59). Cognitive delay and neuropsychological impairment after opsoclonus myoclonus syndrome are thought to be caused by damage to the cerebellum during phases of active disease. Delayed treatment start and relapses may lead to longer exposure of the cerebellum to attacks of the immune system and thus to long-term damage.
Therapy The poor neurological outcome in many children despite steroid-based treatment and the possible beneficial effect of chemotherapeutic intervention led to the current hypothesis that prompt and potent immunosuppression is necessary for patients with opsoclonus myoclonus syndrome. In few patients, spontaneous recovery from opsoclonus myoclonus syndrome was reported, some of them associated with identifiable infections.17,60 Resection of the neuroblastoma may improve the acute symptoms for a short period in some patients, but complete resolution of symptoms after resection without any further immunosuppressive treatment has only rarely been reported.4 Aside from these relatively uncommon cases, most patients will require immunosuppressive treatment. Multiple different therapeutic strategies have been reported including the use of various steroids, adrenocorticotropic hormone (ACTH), immunoglobulins, azathioprine, rituximab, mycophenolate, plasmapheresis, and cyclophosphamide, either given alone or in combination.61–68 However, there is no objective data confirming the efficacy of any of these interventions in altering long-term outcome. Classic treatment consisted of long-term corticosteroids or ACTH. Exacerbations or relapses of neurological symptoms may occur with weaning of the drugs or intercurrent viral illness. ACTH seems to produce a more rapid response and was effective in some patients with insufficient response to prednisone or prednisolone, although reports published so far could not prove a benefit in terms of long-term outcome.8,20 Promising short-term results have been observed in a subgroup of patients with opsoclonus myoclonus treated with dexamethasone pulses.62 There are several reports showing a good response after treatment with high-dose intravenous immunoglobulin (IVIG),63–66 but the patients addressed in long-term studies did not benefit from IVIG therapy.3,4,8 However, IVIG may have been used in patients with severe symptoms or with steroid dependency, thus making it difficult to draw conclusions out of these observations. The Children’s Oncology Group has very recently finished recruitment for a randomized trial addressing the
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role of IVIG in patients with neuroblastoma and opsoclonus myoclonus syndrome (NCT00033293) and the results are awaited soon. Rituximab has recently gained attention in the treatment of opsoclonus myoclonus syndrome. Several case reports and series of children treated with Rituximab in addition to steroids, cyclophosphamide, or IVIG have been published, mostly showing significant clinical improvement,69–73 whereas, in one case report no effect was observed.74 B-cell expansion in the CSF is discussed to be associated with response to rituximab, although not proven in greater series.72 As discussed earlier, it seems necessary to minimize the phases of active immune attacks, that is, to start treatment promptly and to avoid exacerbations of the disease. On the contrary, not all patients seem to need a maximum of treatment. Some patients show a monophasic course with good response to first line immunosuppressive treatment without relapses. Thus, it might be useful to tailor the therapy according to the patient’s needs and to take the long-term side effects of the treatment into account, which are not negligible for most of the drugs used: Steroids and ACTH can cause, for example, hypertension, weight gain, osteopenia, aseptic bony necrosis, growth retardation, and cataracts. IVIG is a blood-derived product bearing the risk of allergic reactions and of transmission of blood-borne infection. Impairment of spermiogenesis and second malignancies have been reported after treatment with higher doses of cyclophosphamide. Rituximab causes long-term B-cell depletion with the increased risk of infections. Although infectious complications in general are thought to be rare,75 single cases of severe CNS infections, or progressive multifocal leukoencephalopathy have been reported.76,77 Once the acute symptoms in the very beginning of the disease are resolved by the immunomodulatory treatment, other therapeutic measures as speech therapy, physiotherapy, and occupational therapy might find their place in management of the patients and should be installed according to the individual needs.
The European Trial Prospective studies are urgently needed to address the question of optimal therapy to improve neurological and neuropsychological outcome in this rare condition and to determine favorable and unfavorable prognostic factors. Because of the rarity of the disease, international collaboration is needed. A European trial protocol, brought on the way by specialists of SIOPEN (SIOP [Société Internationale d’Oncologie Pédiatrique] Europe Neuroblastoma), GPOH (Gesellschaft für Pädiatrische Hämatologie und Onkologie), and EPNS (European Pediatric Neurology Society), started recruitment in 2013 (NCT01868269, Sponsor: Institut Curie, Paris, principal coordinating investigator: Gudrun Schleiermacher). This trial will investigate an escalating treatment schedule starting with dexamethasone pulses (first step). In case of insufficient response to dexamethasone after 3 months of
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treatment, cyclophosphamide will be added (second step). Cyclophosphamide will be replaced by rituximab, if still no sufficient improvement is seen after 3 further months (third step). Treatment intensification will be decided on the basis of standardized scoring scales for opsoclonus myoclonus severity, which have been established by international discussion and already been in use for retrospective assessment (reviewed by Gorman58). Pulsed dexamethasone will be used as a first step because of the previous experience in patients with opsoclonus myoclonus syndrome62,74 and because of relatively low side effects. The pulsed treatment has the advantage not to inhibit the adrenal function, so that the corticoid therapy can be stopped without tapering the drug. In addition, the pulses can be tailored according to the patient’s symptoms, for example, the interval may be shortened in case of deterioration before the next scheduled pulse. The rationale for the use of cyclophosphamide is its wide use in other autoimmune disorders, the response seen in pilot patients and the better outcome in patients treated with chemotherapy in retrospective studies. Rituximab is used because of its action on B-cells, its use in other (antibodymediated) autoimmune diseases, and because of the response reported in opsoclonus myoclonus patients. It will only be introduced as a third step, as long-term late effect data are mostly missing so far. This escalating schedule provides a standardized therapy intensification for patients with insufficient response. On the contrary, patients responding well to dexamethasone alone are not exposed to potentially toxic treatment they do not need. This is the first prospective trial including patients with opsoclonus myoclonus syndrome with and without neuroblastoma. Detailed guidelines for the search for neuroblastoma have been elaborated so that data on the real prevalence of neuroblastoma in patients with opsoclonus myoclonus syndrome will be generated. In parallel to the collection of data, plasma, CSF, and—in case of neuroblastoma—tumor tissue will be collected for research purposes, as further insight in the complex pathophysiology of this disease—with the hope to improve treatment options by better knowledge of the pathophysiology— can only be achieved by close international collaboration with collection of biological samples in sufficient quality and quantity. The trial will open in several European countries. For each participating country, a national coordinator as well for pediatric oncology as for pediatric neurology is identified. More detailed information on the trial, the respective national coordinators, and the options to participate are available by contacting Gudrun Schleiermacher ([email protected]) or Barbara Hero ([email protected]).
Acknowledgments The contribution of the members of the European Opsoclonus Myoclonus Collaboration Group (SIOPEN, GPOH, and EPNS) in finalizing the trial protocol is greatly appreciated. Neuropediatrics
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Update on Pediatric Opsoclonus Myoclonus Syndrome References
Hero, Schleiermacher 23 Jamroz E, Głuszkiewicz E, Madziara W, Kiełtyka A. [Opsoclonus-
1 Kinsbourne M. Myoclonic encephalopathy of infants. J Neurol 2
3
4
5 6
7
8
9
10
11 12
13
14
15
16 17
18 19
20 21
22
Neurosurg Psychiatry 1962;25:271–276 Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 1997;28(4):284–288 Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonusataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children’s Cancer Group Study. Med Pediatr Oncol 2001;36(6):612–622 Plantaz D, Michon J, Valteau-Couanet D, et al; Study of the French Society of Pediatric Oncologists. [Opsoclonus-myoclonus syndrome associated with non-metastatic neuroblastoma. Longterm survival]. Arch Pediatr 2000;7(6):621–628 Roberts KB. Cerebellar ataxia and “occult neuroblastoma” without opsoclonus. Pediatrics 1975;56:464–465 Herman TE, Siegel MJ. Ataxia without opsoclonus: right lumbar sympathetic trunk neuroblastoma. Clin Pediatr (Phila) 2009; 48:336–340 Wolff M, Schoning M, Niemann G, Krageloh-Mann I. Late detection of neuroblastoma in a patient with prolonged cerebellar ataxia without opsoclonus. Neuropediatrics 2001;32:101–103 Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al. Opsoclonusataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics 2002;109(1):86–98 Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Lett 2005;228(1-2):275–282 Bataller L, Graus F, Saiz A, Vilchez JJ; Spanish Opsoclonus-Myoclonus Study Group. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 2001;124(Pt 2):437–443 Grant R, Graus F. Paraneoplastic movement disorders. Mov Disord 2009;24(12):1715–1724 Titulaer MJ, Soffietti R, Dalmau J, et al; European Federation of Neurological Societies. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011;18(1): 19–e3 Fitzpatrick AS, Gray OM, McConville J, McDonnell GV. Opsoclonusmyoclonus syndrome associated with benign ovarian teratoma. Neurology 2008;70(15):1292–1293 Wilfong AA, Parke JT, McCrary JA III. Opsoclonus-myoclonus with Beckwith-Wiedemann syndrome and hepatoblastoma. Pediatr Neurol 1992;8(1):77–79 Huber BM, Strozzi S, Steinlin M, Aebi C, Fluri S. Mycoplasma pneumoniae associated opsoclonus-myoclonus syndrome in three cases. Eur J Pediatr 2010;169(4):441–445 Ertekin V, Tan H. Opsoclonus-myoclonus syndrome attributable to hepatitis C infection. Pediatr Neurol 2010;42(6):441–442 Pang KK, de Sousa C, Lang B, Pike MG. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom. Eur J Paediatr Neurol 2010;14(2):156–161 Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 1992;15(3):186–228 Tate ED, Allison TJ, Pranzatelli MR, Verhulst SJ. Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs 2005;22(1):8–19 Pohl KR, Pritchard J, Wilson J. Neurological sequelae of the dancing eye syndrome. Eur J Pediatr 1996;155(3):237–244 Brunklaus A, Pohl K, Zuberi SM, de Sousa C. Investigating neuroblastoma in childhood opsoclonus-myoclonus syndrome. Arch Dis Child 2012;97(5):461–463 Mutch LS, Johnston DL. Late presentation of opsoclonus-myoclonus-ataxia syndrome in a child with stage 4S neuroblastoma. J Pediatr Hematol Oncol 2005;27(6):341–343
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myoclonus syndrome in a 2. year old boy with prenatally diagnosed retroperitoneal tumour]. Med Wieku Rozwoj 2011;15(2): 151–156 Evans AE, D’Angio GJ, Randolph J. A proposed staging for children with neuroblastoma. Children’s cancer study group A. Cancer 1971;27(2):374–378 D’Angio GJ, Evans AE, Koop CE. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet 1971;1(7708): 1046–1049 Evans AE, Baum E, Chard R. Do infants with stage IV-S neuroblastoma need treatment? Arch Dis Child 1981;56(4):271–274 Hero B, Simon T, Spitz R, et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 2008;26(9):1504–1510 Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol 2010;14(5):400–409 Hiyama E, Yokoyama T, Ichikawa T, et al. Poor outcome in patients with advanced stage neuroblastoma and coincident opsomyoclonus syndrome. Cancer 1994;74(6):1821–1826 Gambini C, Conte M, Bernini G, et al. Neuroblastic tumors associated with opsoclonus-myoclonus syndrome: histological, immunohistochemical and molecular features of 15 Italian cases. Virchows Arch 2003;442(6):555–562 Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-myoclonusataxia syndrome in neuroblastoma: histopathologic features-a report from the Children’s Cancer Group. Med Pediatr Oncol 2001;36(6):623–629 Hero B, Radolska S, Gathof BS. Opsomyoclonus syndrome in infancy with or without neuroblastoma is associated with HLA DRB101 (abstract). Ped Blood Cancer 2005:45 Krasenbrink I, Fühlhuber V, Juhasz-Boess I, et al. Increased prevalence of autoimmune disorders and autoantibodies in parents of children with opsoclonus-myoclonus syndrome (OMS). Neuropediatrics 2007;38(3):114–116 Oguro K, Kobayashi J, Aiba H, Hojo H. Opsoclonus-myoclonus syndrome with abnormal single photon emission computed tomography imaging. Pediatr Neurol 1997;16(4):334–336 Hayward K, Jeremy RJ, Jenkins S, et al. Long-term neurobehavioral outcomes in children with neuroblastoma and opsoclonus-myoclonus-ataxia syndrome: relationship to MRI findings and anti-neuronal antibodies. J Pediatr 2001;139(4):552– 559 Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29(3):241–251 Dalmau J, Graus F, Cheung NK, et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 1995; 75(1):99–109 Antunes NL, Khakoo Y, Matthay KK, et al. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonusmyoclonus. J Pediatr Hematol Oncol 2000;22(4):315–320 Fisher PG, Wechsler DS, Singer HS. Anti-Hu antibody in a neuroblastoma-associated paraneoplastic syndrome. Pediatr Neurol 1994;10(4):309–312 Connolly AM, Pestronk A, Mehta S, Pranzatelli MR III, Noetzel MJ. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. J Pediatr 1997;130(6):878–884 Noetzel MJ, Cawley LP, James VL, Minard BJ, Agrawal HC. Antineurofilament protein antibodies in opsoclonus-myoclonus. J Neuroimmunol 1987;15(2):137–145 Blaes F, Fühlhuber V, Korfei M, et al. Surface-binding autoantibodies to cerebellar neurons in opsoclonus syndrome. Ann Neurol 2005;58(2):313–317
Downloaded by: Universidad de Barcelona. Copyrighted material.
328
Hero, Schleiermacher
43 Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J.
61 Emir S, Akyüz C, Büyükpamukçu M. Correspondence: treatment of
Autoantigen diversity in the opsoclonus-myoclonus syndrome. Ann Neurol 2003;53(3):347–353 Korfei M, Fühlhuber V, Schmidt-Wöll T, Kaps M, Preissner KT, Blaes F. Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonus-syndrome. J Neuroimmunol 2005;170(1-2):150–157 Pranzatelli MR, Travelstead AL, Tate ED, Allison TJ, Verhulst SJ. CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity. Mov Disord 2004;19(7):770–777 Pranzatelli MR, Tate ED, Travelstead AL, Colliver JA. Long-term cerebrospinal fluid and blood lymphocyte dynamics after rituximab for pediatric opsoclonus-myoclonus. J Clin Immunol 2010; 30(1):106–113 Pranzatelli MR, Tate ED, McGee NR, et al. BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy. J Neuroinflammation 2013;10:10 Fühlhuber V, Bick S, Kirsten A, et al. Elevated B-cell activating factor BAFF, but not APRIL, correlates with CSF cerebellar autoantibodies in pediatric opsoclonus-myoclonus syndrome. J Neuroimmunol 2009;210(1-2):87–91 Raffaghello L, Fuhlhuber V, Bianchi G, et al. Role of BAFF in Opsoclonus-Myoclonus syndrome, a bridge between cancer and autoimmunity. J Leukoc Biol 2013;94(1):183–191 Raffaghello L, Conte M, De Grandis E, Pistoia V. Immunological mechanisms in opsoclonus-myoclonus associated neuroblastoma. Eur J Paediatr Neurol 2009;13(3):219–223 Posner JB. Paraneoplastic opsoclonus/myoclonus: B cells, T cells, both, or neither? Neurology 2004;62(9):1466–1467 Klein A, Schmitt B, Boltshauser E. Long-term outcome of ten children with opsoclonus-myoclonus syndrome. Eur J Pediatr 2007;166(4):359–363 De Grandis E, Parodi S, Conte M, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics 2009;40(3):103–111 Catsman-Berrevoets CE, Aarsen FK, van Hemsbergen ML, van Noesel MM, Hakvoort-Cammel FG, van den Heuvel-Eibrink MM. Improvement of neurological status and quality of life in children with opsoclonus myoclonus syndrome at long-term follow-up. Pediatr Blood Cancer 2009;53(6):1048–1053 Mitchell WG, Brumm VL, Azen CG, Patterson KE, Aller SK, Rodriguez J. Longitudinal neurodevelopmental evaluation of children with opsoclonus-ataxia. Pediatrics 2005;116(4):901–907 Turkel SB, Brumm VL, Mitchell WG, Tavare CJ. Mood and behavioral dysfunction with opsoclonus-myoclonus ataxia. J Neuropsychiatry Clin Neurosci 2006;18(2):239–241 Brunklaus A, Pohl K, Zuberi SM, de Sousa C. Outcome and prognostic features in opsoclonus-myoclonus syndrome from infancy to adult life. Pediatrics 2011;128(2):e388–e394 Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr 2010; 22(6):745–750 Timmann D. [Contribution of the cerebellum to cognition]. Fortschr Neurol Psychiatr 2012;80(1):44–52 Ki Pang K, Lynch BJ, Osborne JP, Pike MG. Dancing Eye Syndrome associated with spontaneous recovery and normal neurodevelopment. Eur J Paediatr Neurol 2010;14(2):178–181
the neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome with high-dose methylprednisolone. Med Pediatr Oncol 2003;40(2):139 Rostásy K, Wilken B, Baumann M, et al. High dose pulsatile dexamethasone therapy in children with opsoclonus-myoclonus syndrome. Neuropediatrics 2006;37(5):291–295 Borgna-Pignatti C, Balter R, Marradi P, Colamaria V. Treatment with intravenously administered immunoglobulins of the neuroblastoma-associated opsoclonus-myoclonus. J Pediatr 1996; 129(1):179–180 Petruzzi MJ, de Alarcon PA. Neuroblastoma-associated opsoclonus-myoclonus treated with intravenously administered immune globulin G. J Pediatr 1995;127(2):328–329 Pless M, Ronthal M. Treatment of opsoclonus-myoclonus with high-dose intravenous immunoglobulin. Neurology 1996;46(2): 583–584 Veneselli E, Conte M, Biancheri R, Acquaviva A, De Bernardi B. Effect of steroid and high-dose immunoglobulin therapy on opsoclonus-myoclonus syndrome occurring in neuroblastoma. Med Pediatr Oncol 1998;30(1):15–17 Yiu VW, Kovithavongs T, McGonigle LF, Ferreira P. Plasmapheresis as an effective treatment for opsoclonus-myoclonus syndrome. Pediatr Neurol 2001;24(1):72–74 Pranzatelli MR, Tate ED, Travelstead AL, et al. Insights on chronicrelapsing opsoclonus-myoclonus from a pilot study of mycophenolate mofetil. J Child Neurol 2009;24(3):316–322 Pranzatelli MR, Tate ED, Travelstead AL, Longee D. Immunologic and clinical responses to rituximab in a child with opsoclonusmyoclonus syndrome. Pediatrics 2005;115(1):e115–e119 Bell J, Moran C, Blatt J. Response to rituximab in a child with neuroblastoma and opsoclonus-myoclonus. Pediatr Blood Cancer 2008;50(2):370–371 Burke MJ, Cohn SL. Rituximab for treatment of opsoclonus-myoclonus syndrome in neuroblastoma. Pediatr Blood Cancer 2008; 50(3):679–680 Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (antiCD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2006;28(9):585–593 Pranzatelli MR, Tate ED, Verhulst SJ, et al. Pediatric dosing of rituximab revisited: serum concentrations in opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2010;32(5): e167–e172 Ertle F, Behnisch W, Al Mulla NA, et al. Treatment of neuroblastoma-related opsoclonus-myoclonus-ataxia syndrome with highdose dexamethasone pulses. Pediatr Blood Cancer 2008;50(3): 683–687 Tam C, Seymour JF, Brown M, et al. Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies. Haematologica 2005;90(5):700–702 Quartier P, Tournilhac O, Archimbaud C, et al. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003;36(3):e47–e49 Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9(4):425–437
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Update on Pediatric Opsoclonus Myoclonus Syndrome
