What would be the best treatment option?


In this clinical dilemma, researchers are determining how best to treat patients with opsoclonus-myoclonus-associated neuroblastoma with bone marrow metastases.

A 1.9-year-old girl was presented to hospital with dancing eye movements, ataxia and behavioral disturbances. MRI showed a retroperitoneal tumor (transverse size: 3.9 x 2.5 cm, craniocaudal size: 4.6 cm) extending from vertebral bodies T12 to L3 (Figure), which was suspected of neuroblastoma. Then, a biopsy of the lesion and of the bone marrow was performed. The initial pathological evaluation (CD56 +, PHOX2B +, NKX2-, Ki67 50% -55%, NSE +, CD99-) of the tumor and bone marrow confirmed the diagnosis of low-differentiated high-risk neuroblastoma.

What would be the best choice for the continuation of the management of this patient?


“Dancing eye syndrome”, or opsoclonus-myoclonus syndrome (OMS), is a rare disease that affects the nervous system. WHO is characterized by rapid, multidirectional eye movements (opsoclonus), rapid and involuntary muscle twitching, sleep disturbances, cognitive dysfunction, and changes in behavior.1 WHO usually occurs in association with tumors, usually with neuroblastoma (NB). About half of the pediatric OMS is related to New Brunswick. The incidence of DMS is rare; one of the prospective studies in the UK estimated 0.18 cases per million per year.2

The literature indicates that OMS is caused by an autoimmune process for which early immunosuppressive therapy is recommended.3 In addition to corticosteroids, intravenous immunoglobulins (IVIG), cyclophosphamide, or rituximab can also be used. However, there is no combination or standard duration of immunomodulatory therapy.4

Cancer patients with paraneoplastic MSO tend to have a higher survival than those without paraneoplastic MSO.5

An earlier study has shown that the typical features of neuroblastoma differ in children WHO. In particular, the frequency of OMS associated with NB is lowest in children 6 months or less.6

NB is the most common solid extracranial tumor in childhood. It can be classified into different prognostic groups according to age, histological subtype, tumor grade, stage, condition of MYCN oncogene, chromosome 11q status, and DNA ploidy. In addition, according to the revised classification, segmental chromosomal aberrations (loss or gain of part of a chromosomal arm) also play a role in the classification system and are associated with an unfavorable prognosis. Accurate staging plays a crucial role in treatment planning, as it is provided based on assigned risk groups.7

There is a wide range of therapeutic approaches for patients with NB: observation, chemotherapy, myeloablative consolidation therapy (single or tandem), surgery, radiotherapy, immunotherapy. Surgical resection of the tumor is an essential part of treatment for NB, however, in some cases induction chemotherapy is required in order to make the tumor susceptible to surgical resection.8 Therefore, initial surgical resection with negative margins and without any loss of neurological function is not always feasible. Performing surgery in patients with disseminated disease does not guarantee performing gross total resection of the primary tumor. In addition, in case of initial surgical treatment, as the radiation volume is fixed at the resection, the radiation field is much larger. Despite this, some recent studies suggest better treatment results for complete resection. Surgery alone is a preferable option for most patients with low risk disease. However, based on several studies, resection should be performed after several cycles of induction chemotherapy when the tumor becomes smaller and less invasive. Therefore, the initial surgical treatment would lead to a number of complications and would not improve the survival of this patient, which would make answer B (surgical resection of the primary tumor) a bad choice.9

Despite the fact that WHO is associated with better outcome and low risk disease, in this particular case the patient had disseminated disease and an unfavorable histological type according to Shimada’s classification. Patients over 18 months of age and those with disease spread or localized disease with unfavorable markers, such as MYCN amplification, are most at risk for disease progression and mortality. Therefore, answer C (observation) is not the preferred route for the management of this patient since only observation would lead to progression of the disease.ten

Radiation therapy is another option for local control, along with surgical resection, and is a necessary part of treatment for high-risk neuroblastoma. However, its benefit is greater when administered after surgical resection as part of subsequent treatment. In addition, radiation therapy at this young age would lead to a number of side effects and complications. Therefore, answer D (radiotherapy) is not the preferred option for this child.11

The standard approach for high-risk neuroblastoma includes initial chemotherapy with additional surgical treatment and aHSCT. These patients usually present with unresectable diseases.12 Thus, it is essential to provide induction chemotherapy to reduce tumor burden and continue local control. In order to reduce disease recurrence and reduce nervous system symptoms, children with NBOMS should be treated with combination therapy, including surgery, chemotherapy, HSCT, and / or radiation therapy. Current WHO therapeutic approaches include immunomodulatory therapies, including steroids, IVIG, cyclophosphamide and, more recently, rituximab.13 In view of this information, to respond to (chemotherapy with additional treatment including surgery and aHSCT) is the best treatment option for this patient.


The child received 6 cycles of chemotherapy according to the NB2004 protocol, after which a complete surgical resection of the tumor was possible. After the first cycle of chemotherapy, symptoms of DMS disappeared; therefore, no steroids or immunoglobulins were added to the treatment. Pathological examination of the resected tumor showed histological differentiation (ganglioneuroma-, CD56 +, NSE +, Ki67 1% -2%). Then an HSCT was performed. Now the child is disease free and has no neurological abnormalities due to WHO. m

Key points

  • Cancer in children with paraneoplastic OMS appears to have a better prognosis compared to cancer patients without paraneoplastic symptoms.
  • It is believed that OMS is caused by an autoimmune process and early immunosuppressive therapy is recommended.
  • The prognosis for high-risk NB is significantly better with high-dose chemotherapy and / or radiotherapy followed by autologous bone marrow transplant than with chemotherapy alone.

Author affiliations: 1Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center according to Prof. RH Yeolyan, Yerevan, Armenia; 2Yerevan State Medical University, Yerevan, Armenia; 3Department of Pediatric Oncology and Hematology, Yerevan State Medical University, Yerevan, Armenia; 4Institute of Cancer and Crisis, Yerevan, Armenia; 5Pediatric Oncology Clinic, Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center according to Prof. RH Yeolyan, Yerevan, Armenia; 6Musculoskeletal Tumor Working Group, Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center according to Prof. RH Yeolyan, Yerevan, Armenia.

CONFLICT OF INTEREST: All the authors did not disclose any conflict of interest.

Maria T. Bourlon, MD is Associate Professor, Chief Urologic Oncology Clinic; national researcher, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. She is also a member of the ASCO IDEA working group.

E. David Crawford, MD, is Chairman of the Prostate Conditions Education Council; editor-in-chief, Great tours in urology; and professor of urology, University of California at San Diego, La Jolla, CA.

The references

1. Digested KB. Opsoclonus in adults. About three cases and review of the literature. Arche Neurol. 1986; 43 (11): 1165-1175. doi: 10.1001 / archneur.1986.00520110055016

2. Bhatia P, Heim J, Cornejo P, Kane L, Santiago J, Kruer MC. Opsoclonia-myoclonus-ataxia syndrome in children. J Neurol. Published online March 29, 2021. doi: 10.1007 / s00415-021-10536-3

3. Connolly AM, Pestronk A, Mehta S, Pranzatelli MR III, Noetzel MJ. Serum autoantibodies in infantile opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neuronal tissues. J Pediatrician. 1997; 130 (6): 878-884. doi: 10.1016 / s0022-3476 (97) 70272-5

4. Wilbur C, Yea C, Licht C, Irwin MS, Yeh EA. An initial immunomodulatory treatment protocol for pediatric opsoclonus-myoclonus syndrome. Pediatric blood cancer. 2019; 66 (8): e27776. doi: 10.1002 / pbc.27776

5. Russo C, Cohn SL, Petruzzi MJ, of Alarcon PA. Long-term neurologic outcomes in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatrician Oncol. 1997; 28 (4): 284-288. doi: 10.1002 / (sici) 1096-911x (199704) 28: 43.0.co; 2-e

6. Pranzatelli MR, Tate ED, McGee NR. Demographic, clinical and immunological characteristics of 389 children with opsoclonus-myoclonus syndrome: a cross-sectional study. Neurol before. 2017; 8: 468. doi: 10.3389 / fneur.2017.00468

7. Irwin MS, Naranjo A, Zhang FF et al. Revised Neuroblastoma Risk Classification System: A Report from the Children’s Oncology Group. J Clin Oncol. Published online July 28, 2021. doi: 10.1200 / JCO.21.00278

8. Tolbert VP, Matthay KK. Neuroblastoma: clinical and biological approach to risk stratification and treatment. Res Cellular Tissue. 2018; 372 (2): 195-209. doi: 10.1007 / s00441-018-2821-2

9. Ryan AL, Akinkuotu A, Pierro A, Morgenstern DA, Irwin MS. Place of surgery in high-risk neuroblastomas. J Pediatr Hematol Oncol. 2020; 42 (1): 1-7. doi: 10.1097 / MPH.0000000000001607

10. 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 UK. Eur J Pediatrician Neurol. 2010; 14 (2): 156-161. doi: 10.1016 / j.ejpn.2009.03.002

11. Jo JH, Ahn SD, Koh M, et al. Models of recurrence after radiotherapy for high-risk neuroblastoma. Radiat Oncol J. 2019; 37 (3): 224-231. doi: 10.3857 / roj.2019.00353

12. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation and 13-cis-retinoic acid. Childhood cancer group. N English J Med. 1999; 341 (16): 1165-1173. doi: 10.1056 / NEJM199910143411601

13. Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children, whether or not associated with neuroblastoma. Eur J Pediatrician Neurol. 2010; 14 (5): 400-409. doi: 10.1016 / j.ejpn.2009.12.005

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