Accepted Manuscript

Title: Dexamethasone Based Multimodal Therapy for Pediatric Opsoclonus-

Myoclonus-Ataxia Syndrome: is It Really Superior?

Author: Indar Kumar Sharawat, Renu Suthar

PII: S0887-8994(17)30958-X
DOI: https://doi.org/doi:10.1016/j.pediatrneurol.2017.10.003
Reference: PNU 9244

To appear in: Pediatric Neurology

Please cite this article as: Indar Kumar Sharawat, Renu Suthar, Dexamethasone Based
Multimodal Therapy for Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome: is It Really
Superior?, Pediatric Neurology (2017), https://doi.org/doi:10.1016/j.pediatrneurol.2017.10.003.

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 Title page

Article type: Letter to Editor

Dexamethasone based Multimodal Therapy for Pediatric Opsoclonus-Myoclonus-Ataxia

Syndrome: Is it really Superior?

Authors and affiliations:

Indar Kumar Sharawat1, MD; Renu Suthar1, DM

1. Pediatric Neurology and Neurodevelopment Unit, Department of Pediatrics, Postgraduate

Institute of Medical Education and Research, Chandigarh, India-160012.

Corresponding Author:

Dr. Renu Suthar

DM (Pediatric Neurology), Assistant Professor, Pediatric Neurology and Neurodevelopment

Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research,

Chandigarh, India-160012.

Email:drrenusuthar@gmail.com, Telephone: +919855483969, Fax: +91-172-2744401

Funding sources: None

Conflict of interest: None

Word count: 496

References: 4

Keywords: Chemokines, Dexamethasone, Immunotherapy, Opsoclonus-Myoclonus Syndrome,

Neuroblastoma.

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We read the recent article by Pranzatelli MR et al with great interest.1 The authors studied the

effectiveness of multimodal disease modifying immunotherapy DEXIR-CI (DEXamethasone,

IVIg and Rituximab) in comparison with dexamethasone alone or with IVIg in children with

opsoclonus myoclonus ataxia syndrome (OMS) and reported 69% reduction in the total OMS

severity score with DEXIR-CI therapy. Post DEXIR-CI authors have reported 95% reduction in

cerebrospinal fluid (CSF) B cell counts and 75% reduction in peripheral B cell counts. In

addition, 87% patient’s CSF was negative for neuro-inflammatory biomarkers. The strength of

the study is that in this proof of concept study authors have demonstrated ongoing neuro-

inflammation in children with OMS by measuring CSF B cells and chemokines.

However; some limitations of this study should be recognized. Study duration for patient

recruitment and data collection should have been mentioned. Recruitment of study subjects over

prolonged period of time could be a potential source of bias; as the clinician’s attitude;

supportive services; and parent’s awareness about disease tend to evolve with time. In this cohort

of children with OMS, 66% children in the DEXIR-CI group had received some form of

immunotherapy either with ACTH, IVIg or cyclophosphamide in last 8 months. Prior treatment

might have reduced the severity of OMS in this group, supported by the fact that 67% were mild

OMS and group mean total severity score was 14±3 in DEXIR-CI group. Further immune-

suppression with DEXIR-CI therapy possibly resulted in the enhanced clinical results.

For primary outcome assessment authors have used 12 point OMS severity score for monitoring

the therapeutic response.2 This scale primarily focuses on motor symptoms and completely

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misses on sleep disturbance, irritability, hyperactivity, cognitive impairment and other behavioral

manifestations. Lack of inclusion of these features in the OMS severity assessment scale might

have led to false positive results.

The rational for choosing dexamathsone dosage in the current study is not very clear;

21mg/kg/day dexamethasone would be a supratherapeutic dose. In the methodology section it

remained unclear whether the DEXIR-CI group received multimodal therapy simultaneously or

sequentially. It will be important for the readers to know the dosage and schedule of both

DEXIR-CI and comparison group to understand the response rate and duration.

Another point would be that apart from measurement of chemokines CXCL10, CXCL 13 and

CCL22 in CSF, inclusion of chemokines CCR7, CXCR4 and CXCR5 specifically expressed on

the infiltrating lymphoid cells and neuroblastoma cells would have been useful.3 We have

observed that CXCL10 levels remained persistently elevated in the post DEXIR-CI group (pre

DEXIR-CI =157±52 and post 208±21). This highlights role of CCXL10 in maintain ongoing

neuro-inflammation in children with OMA syndrome. In murine neuroblastoma model, CXCL10

has been shown to be pivotal for generation of tumor-specific T-cells and tumor protective

immunity during interleukin-12 therapy.4

Finally, pediatric neurologists should carefully interpret these findings as this study shows

marginal benefits of DEXIR-CI therapy. Multimodal therapy may increase the cost of treatment

and may leads to treatment defaulters particularly in resource limited country.

Page 3 of 4
References:

1. Pranzatelli MR, Tate ED. Dexamethasone, Intravenous Immunoglobulin, and Rituximab

Combination Immunotherapy for Pediatric Opsoclonus-Myoclonus Syndrome. Pediatr

Neurol. 2017;73:48–56.

2. 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;19:770–7.

3. Raffaghello L, Conte M, De Grandis E, Pistoia V. Immunological mechanisms in

opsoclonus-myoclonus associated neuroblastoma. Eur J Paediatr Neurol. 2009;13:219–

23.

4. Vinet J, deJong EK, Boddeke HWG, et al. Expression of CXCL10 in cultured cortical

neurons. J Neurochem. 2010;112:703–14.

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