Original Article

Rituximab, IVIg, and Tetracosactide (ACTH1–24)

Combination Immunotherapy (“RITE-CI”) for
Pediatric Opsoclonus-Myoclonus Syndrome:
Immunomarkers and Clinical Observations
Michael R. Pranzatelli1 Elizabeth D. Tate1 Michael Alber2 Maha Awadalla3 Lubov Blumkin4
Elena S. Lina5 Steffen Leiz6 Judit Móser7

1 National Pediatric Myoclonus Center and National Pediatric Address for correspondence Prof. Dr. Michael R. Pranzatelli, MD,
Neuroinflammation Organization, Inc., Orlando, Florida National Pediatric Neuroinflammation Organization, Inc., 12001
2 Department of Neuropaediatrics, Developmental Neurology, Research Parkway, Suite 236, Orlando, FL 32826, United States
Social Paediatrics, University Children’s Hospital Tübingen, (e-mail: [email protected]).
Tübingen, Germany
3 Pediatric Neurology Unit, Dr. Erfan and Bagedo General Hospital,
Jeddah, Kingdom of Saudi Arabia
4 Pediatric Neurology Unit, Wolfson Medical Center, Holon, Sackler
School of Medicine, Tel-Aviv University, Holon, Israel

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5 Department of Psychoneurology No. 2, Federal State Medical
Institution, Russian Children’s Clinical Hospital, Ministry of Health
Russian Federation, Moscow, Russia
6 Pediatric Neurology Unit, Department of Pediatrics and Adolescent
Medicine, Hospital Dritter Orden, Munich, Germany
7 Department of Neurology, Heim Pal Children’s Hospital,
Budapest, Hungary

Neuropediatrics

Abstract Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder with perva-

sive morbidity that warrants better treatments. Twelve children with moderate/severe
OMS (total score 23
6) who did not remit to multiple immunotherapies were
evaluated for neuroinflammation in a case–control study using cerebrospinal fluid
(CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by
enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immuno-
fixation with isoelectric focusing. Observations made on empirical treatment with
rituximab, IVIg, and tetracosactide combination immunotherapy (coined “RITE-CI”)
Keywords were analyzed. All of the patients tested for multiple inflammatory markers were
► cosyntropin positive; 75% had 3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell
► neuroimmunology expansion; and 50 to 100%, elevated concentrations of multiple chemokines and
► neuroblastoma neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped
► paraneoplastic significantly in the group (85%, p < 0.0001) from moderate to trace, and by 2 to 4
syndrome severity categories in each patient. The 24-week schedule was well tolerated and
► pediatric clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is
neuroinflammation feasible and effective as rescue therapy and presents an initial option for children with
► chronic-relapsing moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient
OMS severity, propensity for relapse, and other factors.

received © Georg Thieme Verlag KG DOI https://doi.org/

February 15, 2017 Stuttgart · New York 10.1055/s-0037-1609038.
accepted after revision ISSN 0174-304X.
October 30, 2017
RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

Introduction it for OMS, there has been little published experience for
this indication. Observations from this study on the use of
The threat of neuroinflammation, the instigator of a bur- ACTH(1–24), IVIg, and rituximab combination immunotherapy
geoning group of serious neuroinflammatory disorders, and (RITE-CI) for OMS in children living outside the U.S. may provide
neuroblastoma, the most common solid noncentral nervous a basis from which a treatment protocol or clinical trial could
system (CNS) tumor of childhood, meet dramatically in be derived.
pediatric-onset opsoclonus-myoclonus syndrome (OMS).1
Although neuroblastoma is not detected in all children
Materials and Methods
with OMS despite thorough radiological investigations, the
resulting neurological syndrome in either case includes Study Design
cardinal features of opsoclonus, myoclonus, and ataxia, as Neuroimmunologic and clinical/demographic data were col-
well as other acute associations (insomnia, irritability).2,3 lected as part of an institutional review board (IRB)-approved
OMS treatment failure carries the risk of permanent motor case–control study of immunological abnormalities in pedia-
and neuropsychiatric abnormalities, even cognitive impair- tric-onset OMS at the National Pediatric Myoclonus Center (SIU
ment.4 It comes in the form of failure to achieve and retain School of Medicine, Springfield, Illinois, United States). Parents
remission, relapses with anti-inflammatory drug tapering or signed written consent for enrollment of their child into the
intercurrent illness, and other less understood factors.5 study. Per protocol, extra CSF and serum for research studies
Better understanding of neuroinflammation in partial was taken at the time of the lumbar puncture, which was
responders or treatment failures, who are often in the performed for clinical diagnostic purposes, such as testing for
chronic phase of OMS, was one goal of this study. Although neuroinflammation and infection. In four mostly severe pa-

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a diagnostic autoantibody in OMS has not been found despite tients, a lumbar puncture was performed later out of clinical
its likelihood,6 the presence of intrathecal inflammatory concerns, management issues, partial response, or relapse after
mediators affecting lymphocyte trafficking in pediatric parents of those patients were reconsented for the protocol.
OMS is well documented. The finding of cerebrospinal fluid Also, Western IRB (Puyallup, Washington, United States) made
(CSF) B cell “expansion,” or overrepresentation of B cells an exemption determination for the retrospective analysis of
above the <1% normal threshold, as the first immunomarker demographic, clinical, and laboratory data in this study. The
of disease activity in OMS,7 lead to the introduction of the investigator’s published neuroimmunologic data on noninflam-
anti-CD20 monoclonal antibody rituximab for the disor- matory pediatric neurological disorders10–12,14–17 are referred
der.8,9 We have published previously on single CSF and blood to herein as “controls.”
immunomarkers in OMS,7,10–17 but we now look across Treatments were empiric and clinically based, not part of
various markers to appreciate the extent of neuroinflamma- a drug trial, and given by or in collaboration with treating
tion to better understand why prior treatments were un- physicians. Patients we would have treated with ACTH
successful. This translational research is part of a long-term (1–39), which was not available in their country, were
multiplex chemokine profiling project with the eventual treated instead with ACTH(1–24) as part of multimodal
therapeutic aim of targeted inhibition. immunotherapy. Those observations are presented as a case
A second study goal was to retrospectively analyze observa- series. The ACTH(1–24) schedules included in this report
tions made during empiric treatment of partial responders or were developed by the National Pediatric Myoclonus Center
treatment failures with a new multimodal immunotherapy based on its ACTH(1–39) protocols, characterized by a high
combination created by the substitution of adrenocorticotropic starting dose26 and a long course to meet the needs of
hormone (ACTH)(1–24) for ACTH(1–39) in a previously de- relapsing-remitting and relapsing-progressive OMS.5 The
scribed protocol comprising ACTH(1–39), intravenous immu- schedules began at 52 weeks but were progressively shor-
noglobulin (IVIg), and rituximab. Supporting evidence for the tened and modified, resulting in three different shorter
latter included a phase I, open-label, clinical trial of ACTH(1–39), schedules for ACTH(1–39)1 and for ACTH(1–24) (presented
IVIg, and rituximab (ClinicalTrials.gov NCT00244361),8,18 an here). In a few patients, oral dexamethasone was added pre-
observational study of ACTH(1–39)-based immunotherapies emptively near the end as a transition to further shorten
(not a clinical trial),19 and an observational/retrospective time on ACTH injections and reduce side effects.
study.4 The problem is that ACTH has been available as porcine The pharmacokinetics of the two products are very different,
ACTH(1–39) (H.P. Acthar Gel) in the United States,20,21 but not in so the dosing regimen developed for Acthar Gel could not be
Europe and most other countries during the time of this study. directly translated to Synacthen Depot. After 1 mg of Synacthen
The alternative preparation was synthetic ACTH(1–24), an Depot IM, cortisol peaks over 4 to 12 hours but does not return
analogue of natural ACTH22 that comprises the first 24 amino to basal levels for 36 to 48 hours, and plasma concentrations of
acids of the molecule, hence the term corticotropin tetracosa- cosyntropin zinc hydroxide range between 200 and 300 pg/mL
peptide (C136H210N40O31S), tetracosactide or tetracosactrin for 12 hours.23 Therefore, Synacthen Depot was given much less
(Synacthen), and cosyntropin (Cortrosyn). For prolonged depot frequently.23 From a pharmacodynamic perspective, the expec-
action, ACTH(1–24) was linked to a zinc complex (amorphous tation was that ACTH(1–24) and ACTH(1–39) would have
zinc hydroxide-phosphate precipitate).23 Although case reports similar, though nonidentical, properties.20,27 The active site of
on the use of ACTH(1–24) alone as Synacthen in OMS date back ACTH contains N-terminal ACTH(1–24), which is a steroido-
to 197524 and 198525 and some physicians abroad prescribe genic fragment, so both ACTH(1–24) and ACTH(1–39) wield

Neuropediatrics
 RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

potent steroidogenic properties.27 Also, as a melanocortin pep- Treatment

tide (β1–24-corticotrophin), ACTH(1–24) is a full agonist at all
melanocortin receptors (MCRs), and its binding properties RITE-CI
relative to ACTH(1–39) are equivalent.28 All patients received RITE-CI. ACTH(1–24) was administered as
tetracosactide (Synacthen Depot, Novartis AG), a repository
Patients injection, which is supplied as 1 mg/mL (1 mg ¼ 100 IU
Twelve patients from nine countries (four Russia, two Germany, ACTH).23 Before 2010, the 52-week schedule was used, but
one each for Chile, Hungary, Israel, Poland, Romania, and Syria) after that, the 16-, 24-, or 34-week schedules were applied
were evaluated by two pediatric OMS experts (M.R.P. and E.D.T) instead (►Table 1). Patient case numbers are identified in row
at the National Pediatric Myoclonus Center, the largest inter- 2 of the table. The 34- and 52-week dose schedules are
national center for pediatric-onset OMS, and the diagnosis of provided in (►Supplementary Material Table S1, online
OMS was made or confirmed clinically. The first visits to this only). The 16-week schedule was shorter and started at a
tertiary referral center were between 2006 and 2013. All lower dose. The 52-week schedule was longer and started at a
testing for neuroinflammation was performed at the National higher dose, and was based on a flat starting dose of 100 IU
Pediatric Myoclonus Center. Patients were treated by their local ACTH(1–24). Using a body surface area estimator retrospec-
physicians. tively based on pediatric age-norms, the ACTH(1–24) starting

Table 1 ACTH(1–24) dose schedules

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Weeks of ACTH
16 24 34 52
a
% reduction in wk 69 54 35 0
Patients 1, 2 3–7 8 9–12
Starting dose (IU/m2) 70 150 150 174b
Time on max dose (wk) 1 2 2 2
Weekdays at max M, W, F M, W, F M, W, F M, W, F
Weekdays on taper M, Th M, Th M, Th M, Th
2
Ending dose (IU/m ) 9 5 5 5
c
If DEX added, wk # n.d. 20 or 23 n.d. n.d.
Patients with DEX none 4–7 None None
16-wk schedule (lower dose) 24-wk schedule (higher dose)
2
Week/s Dose (IU/m ) Days Week/s Dose (IU/m2) Days
1 70 M, W, F 1 150 M, W, F
2 70 M, Th 2 80 M, W, F
3–4 61 M, Th 3–4 75 M, Th
5–6 53 M, Th 5–7 70 M, Th
7–8 44 M, Th 8–10 65 M, Th
9–10 35 M, Th 11–12 60 M, Th
11–12 26 M, Th 13–14 55 M, Th
13–14 18 M, Th 15–16 50 M, Th
15–16 9 M, Th 17–18 45 M, Th
19 40 M, Th
20 35 M, Th
21 30 M, Th
22 20 M, Th
23 10 M, Th
24 5 M, Th

Abbreviations: ACTH, adrenocorticotropic hormone; DEX, dexamethasone; n.d., not done in other schedules; SD, standard deviation.
a
Compared with 52-week schedule. The 34- and 52-week schedules are posted in ►Supplementary Materials.
b
Mean calculated retrospectively from pediatric body surface area estimator. SD ¼ 12.
c
Pulse DEX added in 3 patients on the 24-week schedule only.

Neuropediatrics
RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

doses may have been 156 IU/m2 for patient 10 and 182 IU/m2 taken promptly to the flow cytometry laboratory. CSF and
for patients 9 and 11. An exception was patient 12, who was sera were aliquoted and stored at 80°C in a biorepository
started at 150 IU for the first week (>200 IU/m2), then 100 IU until use. Routine blood screening also was done. Patients 5,
the second week, and tapered over 36 weeks. Patients also 7, and 9 were vitamin D deficient or insufficient, a risk noted
received 1,200 to 1,500 mg/m2 rituximab in four divided recently in OMS,5 and were placed on vitamin D replacement
weekly doses (Mabthera) and 1 to 2 g/kg IVIg (no single brand) therapy. Some of the patients had commercial paraneoplas-
for induction and maintenance per previous reports.8,19 Pa- tic autoantibody screening, which was negative.
tients were on tapering doses of IVIg for another 6 months after
completing ACTH(1–24) at the discretion of treating physi- Biomarker Quantification
cians and depending on OMS course. Four patients in the 24- Chemokines/cytokines B cell activation factor (BAFF), C-X-C
week schedule received pulse–dose dexamethasone (20 mg/ chemokine ligand 13 (CXCL13), C-X-C chemokine ligand 10
m2 in three divided doses/day  3 days) pre-emptively near (CXCL10), and C-X-C chemokine ligand 12 (CXCL12) were
the tail of the ACTH(1–24) tapering, which was also weaned. measured by enzyme-linked immunoadsorption assays
(ELISA) in the Pranzatelli Neuroimmunology Laboratory per
Prophylactic Measures the manufacturer’s instructions and our previous reports.11–13
Several standard prophylactic measures and safety monitoring Samples from some patients also were analyzed for C-C
for ACTH-treated patients in our practice had been recom- chemokine ligand 22 (CCL22), C-C chemokine ligand 21
mended.19 Salt intake is restricted to 1 to 2 g/day. Prophylactic (CCL21), neurofilament light chain (NFL), as described be-
treatments included ranitidine to prevent acid reflux/gastritis, fore.11–17 The selection of analytes as biomarkers was as
trimethoprim/sulfamethoxazole to prevent pneumocystis, and follows: BAFF and CXCL13 for B cells,11,12 CXCL10 for T helper

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vitamin D and calcium to prevent osteopenia/osteoporosis. The cell type 1 (Th1) cells,14 CXCL12 for innate immune cells/
blood pressure recommendation is monitoring daily for the first vascular endothelial cells,12 NFL for neurons (neuronal/axo-
week, weekly for 4 weeks, then (in the absence of problems) nal),17 CCL22 for Th2 cells, and CCL21 for dendritic and
monthly for the duration. If hypertension occurs on the high- other cells.16 Assays were run in duplicate in batches. Human
dose end of the schedule, adding a diuretic or angiotensin- ELISA kits were purchased from R & D (Minneapolis, Minne-
converting enzyme (ACE) inhibitor is suggested. Laboratory sota, United States). CSF lymphocyte subsets, including
tests, such as complete blood count, basic metabolic panel, CD19þCD3- B cells, CD3þCD45þ T cells, CD3þCD4þ T cells,
and urinalysis, are suggested weekly for the first month, then CD3þCD8þ T cells, CD3þCD25þ T cells, and CD16/56þ natural
monthly. We recommended a baseline electrocardiography killer cells, were measured ex vivo by flow cytometry at the
(EKG), echocardiogram, and ophthalmological examination. clinical laboratory per our published protocol.7 The CD4/CD8
Ephedrine/pseudoephedrine are on the list of medications to T cell ratio was calculated as an index of T cell dysregulation
avoid to prevent hypertensive crisis. The use of ACTH(1–24) (indicated by a low ratio).7 Oligoclonal bands (OCBs) were
heeded the manufacturer’s cautions that it is not for neonates quantitated by isoelectric focusing with immunofixation at
(contains benzyl alcohol vehicle) or for intravenous (IV) use, and ARUP Laboratory (OCB profile #0080440).10 CSF leukocytes
it can cause a hypersensitivity reaction (not for asthmatics).23 were counted in the clinical laboratory. Immunophenotyping
data were complete in most patients. Not all patients were able
Clinical Evaluations to partake of the full biomarker battery because some of the
Patients were videotaped with written parental consent at the assays were developed only later or because there were fewer
initial evaluation before starting RITE-CI and at a later time. As sample aliquots or they had been consumed by other assays.
an objective test measure, videos were scored by an experi-
enced blinded observer using a validated 36-point, 12-item Statistical Analysis
severity scale, as detailed previously.19 The total score (TS) was Statistical analyses were calculated using the GraphPad Prism
used for severity classification into mild, moderate, or severe. software (La Jolla, California, United States). Because of the
The lower part of the mild category was considered trace. caveats associated with the statistical analysis of small data
Seven patients returned for rescoring; posttreatment videos sets, both parametric and nonparametric hypothesis tests
from the other five were scored from home video clips made were evaluated, but showed similar results. Independent
per our written instructions. groups were analyzed as means and standard deviation by
The mean interval between pre- and postassessments for two-tailed t-tests. Medians with first and third quartiles were
the 12 patients was 18
13 months (median, 10). For those computed for comparison, but were similar to means except
receiving RITE-CI schedules of 6 months in duration, it when the n value was very low, as noted in those instances. Pre-
was 12
10 months (median, 10). In the group on RITE-CI and posttreatment comparisons, including TS or cytokine
for >6 months, the mean reassessment interval was 26
14 concentrations, were made by paired t-tests and presented
months (median, 33). The longer interval in the latter group as means and standard error of the mean (SEM). The Wilcoxon
reflects the longer period of time the patients were treated and paired signed-rank test was used as an alternative to the paired
other factors. t-test. Frequencies of response by severity categories were
CSF and blood samples were obtained on the day follow- handled as descriptive statistics because chi-square is only
ing the clinic visit and handled as previously described.7,12 valid when all expected >1 (here there were zeros) and 20% of
Fresh CSF collected on ice and parallel blood samples were expected values at least are >5. Note that p-value of <0.05 was

Neuropediatrics
 RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

considered statistically significant. Data were first analyzed for the time. Despite that, six patients were severe and six were in
the 12 patients collectively. Secondary analysis was performed the moderately severe category. In the OMS duration categories,
on the shorter protocols (16 or 24 weeks, n ¼ 7) versus the three (25%) were subacute (<3-month duration) and nine (75%)
longer protocols (34 or 52 weeks, n ¼ 5), as a clinically relevant were chronic (>1-year duration). The average OMS duration was
comparison. Otherwise, only 24- and 52-week groups had the 1.5 years. Six of eight (75%) had relapsed previously. A para-
minimum sample size for direct comparison. neoplastic etiology was demonstrated in 10 patients. From the
data available in eight patients (1, 3, 6, 7, 8, 10–12), median time
to diagnosis was 0.5 months (interquartile range [IQR], 0.08, 3.3);
Results
mean, 1.9
3.1 (SD) months. The median time from OMS onset
Demographic and Disease Characteristics of the to treatment with the first agent was 0.87 months (0.25, 1.9), and
Patient Groups 2.5 months (0.69, 9.25) to the second agent; mean, 1.0
0.82
Demographic and clinical characteristics are shown in ►Table 2. months from onset until first agent. The time elapsed from
All of the patients had been treated previously with corticoster- starting the first treatment agent (corticosteroids) to the im-
oids, including prednisone, prednisolone, methylprednisolone, munodiagnostic lumbar puncture was 14 (3.5, 48) months;
or dexamethasone, or with IVIg, and five were on treatment at mean, 19
15 months. The second agent (IVIg) was added

Table 2 Demographic and clinical characteristics at initial evaluation (sorted by eventual RITE-CI schedule)

Casea Country Age (y) Sex Dur. (y) NBTb Prior Rxc Cur. Rxd Sev. TS Cat.e Prior Rel.f

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(16 wk)
1 Syria 3.9 F 1.3 Y S,I none þþþþ 28 ?
2 Romania 3.4 F 1.9 Y S,I,C none þþþ 16 Y
(24 wk)
3 Germany 1.6 M 0.48 Y S D þþþ 20 N
4 Russia 2.7 F 0.33 Y D none þþþþ 26 Y
5 Russia 7.5 M 1.6 N I/D none þþþ 14 Y
6 Germany 1.9 M 0.4 Y S D þþþ 16 N
7 Russia 5.0 M 4.2 Y S,I none þþþ 23 ?
(34 wk)
8 Hungary 4.2 F 1.8 Y S, I none þþþþ 26 Y
(52 wk)
9 Chile 2.2 F 1.4 Y S,I,C S,I þþþþ 26 Y
10 Russia 4.0 M 2.8 Y S,I S þþþ 13 Y
11 Poland 2.1 M 1.0 Y S,I I þþþþ 30 Y
12 Israel 3.0 M 1.3 N S,I none þþþþ 29 Y
Total: Mean 3.4 7M 1.5 10Y 10 S 3S 6 sev 22 8Y
(SD) (1.7) 5F (1) 2N 9I 2I 6 mod (6) 2N
2D 1D 2?
2C 7 none

Abbreviations: RITE-CI, rituximab, IVIg, and tetracosactide combination immunotherapy; SD, standard deviation.
a
Cases are listed from shorter to longer schedules, not in chronological order of study entry (the 52-week schedule came first).
b
NBT ¼ neuroblastic tumor: 4 neuroblastoma, 4 ganglioneuroblastoma, 1 ganglioneuroma, 1unspecified; locations: 5 adrenal, 2 thoracic,
1 abdominal paravertebral, 2 pelvic, 1 unspecified. Y ¼ yes; N ¼ no.
c
Prior Rx ¼ treatment prior to evaluation. Treatments: S ¼ corticosteroids; I ¼ intravenous immunoglobulin; D ¼ dexamethasone pulses;
C ¼ cyclophosphamide. Marked response to initial treatment in case 3 (D at 1.75 months after OMS onset), 6 (D at 1.25 months), 10 (prednisone at
0.25 months, I at 9 months.), and 11 (not to prednisone at 0.25 months, but to I at 9 months). No such response in cases 7 (prednisone at 2 months,
I at 10 months), 8 (prednisone at 0.5 months, I at 2 months), or 12 (prednisone at 2 months, I at 3 months). No initial response data in case 1
(prednisone at 2.5 months, I at 0.5 months), 4 (D p.o. pulse; I  4 months), 2, 3, 5, or 9 (D  delay 9 months).
d
Cur. Rx ¼ treatment at time of initial evaluation. Drugs and biologicals had been used at standard doses: oral steroids, 1–2 mg/kg tapering
schedule; IVIg, 1 g/kg/month; dexamethasone pulse dose, 20 mg/m2/day for three consecutive days/month. Other drug doses: Case 5 had received
I  8 out of 12 months; he vomited brief prednisone and D. Case 6 was on D  4 months. Case 10 was on I for 7 months, then stopped; prednisolone
until 1 week prior to visit.
e
Sev. Cat. ¼ severity category; TS ¼ total score; severity category: 0 ¼ none, þ ¼ trace (TS 1–6), þþ ¼ mild (TS 7–12), þþþ ¼ moderate
(TS 13–24), þþ þ þ ¼ severe (25–36).
f
Prior Rel. ¼ prior relapse before RITE therapy. ? ¼ unknown.

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RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

8 months (1.25, 8.75) later (n ¼ 6). Seven of the 12 patients (58%) between evaluations. In the three patients who were not relap-
were off therapy at initial evaluation for variable periods of time. sing at the time of reassessment (# 9, 10, 12), the CSF B cell
Three patients remained on one or more of their starting agents; frequency had dropped from 2.1
0.4 to 0.47
0.2%
two had been switched from prednisone to dexamethasone. (p ¼ 0.052/not significant [NS]). In contrast, the CSF CD4/CD8
T cell ratio was low at 2.0
0.4 pre- and remained low at
Neuroinflammation Testing 1.8
0.2 posttreatment (NS).
Despite prior immunotherapy, the patients displayed neuroim- In the relapsing patient (# 11), CSF OCB had changed from
munologic abnormalities reported previously in untreated negative to positive, CSF B cells rose to the brink of expansion
OMS (►Table 3). The data are presented both for individuals designation at 1.9% (versus 2%), and the CSF concentration of
—to allow comparison of clinical and immunological informa- CXCL13 became elevated. Though reduced from high pre-
tion, and to reveal similarities and differences in biomarker treatment concentrations, CSF CXCL10 remained elevated.
concentrations between patients—and also as summary data in There was some improvement in the CSF/serum BAFF ratio
the lower third of the table under “Totals.” Group means for (2.3 pre, 0.15 post) and the CSF/plasma CXCL12 ratio (245
markers known to be increased in untreated OMS (CSF OCB, B pre, 557 post).
cell %, CXCL10, CXCL13, NFL) exceeded the 75th IQR for controls.
Also, the group means for markers that are decreased in OMS Troubleshooting and Outcome
(CSF CD4/CD8 T cell ratio, CXCL12) were below the 25th IQR Outcome data are shown in ►Table 5. Patient 4 was retreated
of controls. Inflammatory marker testing had a higher yield 1 year later for mild residual OMS symptomatology seen off
(50–100%) in diagnosing neuroinflammation than did the CSF immunotherapy. The patient was put on a new 6-month
leukocyte count alone (18%) (►Fig. 1A). All of the patients had treatment plan, entailing ACTH(1–24), IVIg, and low-dose

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at least one biomarker abnormality, and some had several cyclophosphamide (850 mg  0.78 SA ¼ 625 mg). She had a
(►Fig. 1B). There were interindividual differences in number very good response, with no more myoclonus or tremors,
or types of positive markers. Elevated CSF B cell frequency was better mood and behavior, and more confident motor per-
associated with presence of at least one other positive marker, formance, and is now considered to be in remission.
but normal B cell frequency did not preclude presence of other Five patients relapsed (# 5, 6, 9, 11, 12); four had relapsed
positive markers. previously (# 5, 9, 11, 12). Two (# 9, 11) relapsed during
treatment; the others afterwards. Relapses varied in severity.
Clinical Response to RITE-CI For patient 9, the relapses involved opsoclonus and myoclo-
At the outset, the meanTS for the group was at the upmost end of nus, not ataxia, and were managed by ACTH dose escalation,
the moderate severity range (►Fig. 1C). TS dropped by 85% from then transition to dexamethasone and IVIg. Patient 11
22.2
1.8 to 3.2
0.8 (p < 0.0001). This 19-point delta was >1 relapsed on ACTH(1–24) dose tapering. Patient 5 relapsed
severity category (each category is 12 points) (►Fig. 1D). due to a febrile viral infection. Patient 6 also had a single
Meaningful clinical improvement in OMS occurred with relapse when febrile, and was temporarily put back on IVIg
each of the RITE combination therapy schedules, as evi- and dexamethasone with resolution of OMS signs.
denced by a reduction in TS in every patient. Statistically Long-term outcome information was available on 10
significant reduction characterized the response to RITE-CI patients. Nine were off immunotherapy; one, whose IVIg
protocols 6 months in duration, with a net decline in TS of dose interval was weaned to q 12 weeks, was to receive his
88% from 20.4
2.0 to 2.4
0.9 (p ¼ 0.0003), with lowered last IVIg dose. Seven had not relapsed, eight had no OMS
TS in individual patients (►Fig. 1E). TS reduction also accom- motor residual, and five had learning problems at school as
panied use of the longer RITE-CI protocols, with TS dropping reported by parents.
by 82% from 24.8
3.1 to 4.4
1.5 (p ¼ 0.0039) (►Fig. 1F).
Data were sufficient to separately analyze the 24-week
Discussion
(n ¼ 5) and 52-week schedule data (n ¼ 4). In the 24-week
group, TS decreased significantly from 91.8
2.2 to This small case series, in which ACTH (1–24) was combined
1.6
0.75 (92%) (p ¼ 0.0008). In the 52-week group, it with IVIg and rituximab treatment, makes several salient
declined from 24.5
3.9 to 5.5
1.3 (78%) (p ¼ 0.018). points. First, the majority of patients seeking treatment har-
There was also a frequency shift in severity category bored multiple markers of neuroinflammation despite corti-
(►Table 4) away from the more severe to the less severe costeroid or IVIg prior therapy, indicating that disease activity
end of the severity scale. In the pretreatment group of 12, 6 was inadequately controlled; they had not achieved freedom
patients were severe and 6 were moderate, with no mild, from disease activity. Second, the application of modern
trace, or zero scores. After RITE, none were severe or mod- multiplex immunomarker testing had a high diagnostic yield,
erate; three became mild, six trace, and three had a score of whereas routine CSF leukocyte counts alone had a compara-
zero. Similar patterns were observed in the 16-/24-week tively low diagnostic yield and were not predictive of the
schedules and the 34-/52-week schedules. extent and components of neuroinflammation. Third, RITE-CI
was associated with significant reduction in motor manifesta-
Immunological Response to RITE-CI tions of OMS, even in chronic cases who had responded
Very limited posttreatment data were available to show whether partially or not at all to prior treatment. Fourth, the multi-
RITE therapy corrected neuroimmunologic abnormalities modal/multimechanistic protocol allowed shortening of ACTH

Neuropediatrics
 Table 3 Initial neuroinflammation test results (cross-sectional)

CSFa Seruma # Pos. Markers/ Total (%)b

Clin. Laboratory Flow Laboratory Research Laboratory: Cytokines/chemokines
3
Case WBC/ mm OCB# %B CD4/8 ratio BAFF CXCL13 CXCL10 CXCL12 NFL CCL22 CCL21
1 2 4" 1.8 2.2  15 "    1695 "  3/5 (60)
2 2 3" 1.2 1.4 ↓  3.3 "   188 1624 "  4/6 (67)
3 1 0 5.7 " 1.4 ↓  8.4 "    959  2/5 (40)
4 3 5" 5.0 " 1.4 ↓        3/3 100
5 2 5" 2.4 " 1.2 ↓        3/3 100
6 0 1 4.8 "    98  359 "  _ 2/4 (50)
7   1.9 1.7 ↓        
8 4 6" 2.5 " 1.5 ↓ 114 22 "  22 ↓  1868 " 611 " 7/8 (88)
9 3 1 2.3 " 1.2 ↓ 20 0 91 125 ↓  456 163 3/9 (33)
10 3 0 1.3 2.3 139 3.4 " 247 " 236 ↓ 592 " 1456 " 528 5/10 50
11 7" 0 1.0 1.4 ↓ 213 " 0  245 ↓ 675 " 589 658 " 5/9 (56)
12 8"  2.6 " 2.6 186 " 15 " 1520 " 294 ↓ 170 1631 " 572 " 7/9 (78)
Total:
Mean 3.2 2.5 " 2.7 " 1.7 ↓ 134 8.4 " 489 " 184 ↓ 397 " 1285 386
(SD) (2.4) (2.4) (1.6) (0.5) (75) (8.1) (691) (110) (230) (541) (282)
Median 3.0 2.0 " 2.4 " 1.4 ↓ 139 5.9 " 173 236 ↓ 359 " 1,540 572 "
# pos. 2/11 5/10 7/12 8/11 2/5 6/8 2/4 5/5 3/5 5/8 3/5

Abbreviations: # pos., number of positive markers; # (Pos.), positive markers/total markers; % B, percentage of CSF B cells; % pos., percent of patients with positive markers; CD4/8 ratio, CD4/CD8 T cell ratio; Clin.
Laboratory, clinical laboratory; CSF, ;Flow Laboratory, flow cytometry laboratory; IQR, interquartile range; NFL, neurofilament light chain; OCB, oligoclonal band; OMS, opsoclonus-myoclonus syndrome; Research
Laboratory, neuroimmunology research laboratory; WBC, white blood cell.
Note: Up arrow indicates >75 percentile IQR of controls for markers known to be elevated in OMS: 2 for OCB, 2% for CSF B cells, 170 for BAFF, 2.5 for CXCL13, 200 for CXCL10, 300 for NFL, 1300 for CCL22, and 550
for CXCL21. Down arrow indicates <25th percentile IQR of controls for markers known to be decreased in OMS: <2 for CD4/CD8 ratio, <300 for CXCL12.
a
Concentrations are pg/mL for chemokines/cytokines and ng/mL for NFL. CSF leukocytes 0–4 considered normal.
b
Excludes CSF WBC.
RITE Therapy for Opsoclonus-Myoclonus Syndrome

Neuropediatrics
Pranzatelli et al.

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RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

A B
100
WBC

Percent of Patients
OCB
% B cells 80
CD4/CD8
BAFF 60
CXCL13
CXCL10 40
CXCL12
NFL 20
0 20 40 60 80 100
0
Percent of Patients
1+ <3 ≥3
Positive Negative
Number of Positive Markers/Patient
Positive Negative

C D
36 36 P < 0.0001
Severe
30 30

Total Score
Total Score

24 24

18 Moderate 18

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12 12 -85%
Mild
6 6
Trace
0 0
Pre- Post- Pre- Post-

E F
36 36
30 30
Total Score
Total Score

24 24
18 18
12 12
6 6
0 0
Pre- Post- Pre- Post-

Fig. 1 (A) Frequency analysis of patients positive or negative for a cerebrospinal fluid (CSF) immunobiomarker abnormality. (B) Comparative
frequency of patients based on number of positive biomarkers, ranging from at least 1 to 3 or more. N ¼ 11 (patient 7 excluded because only B
cell percentage was available). (C) Individual patient comparison of total score (TS) pre- and post-rituximab, IVIg, and tetracosactide
combination immunotherapy (RITE-CI). The clinical severity designations based on the severity scale are shown. (D) Box-and-whisker graph of
pre- versus post-RITE-CI. The mean is indicated as a plus sign; the median by the line through the box; the 25th/75th interquartile range at the
bottom and top of the box, respectively; and 5 to 95% confidence intervals as error bars. The treatment effect was statistically significant by the
paired test (shown) and also the Wilcoxon matched-pairs signed rank test (p ¼ 0.0005). (E) Individual responses to RITE-CI schedules 6 months
in duration. (F) Individual responses to RITE-CI schedules >6 months in duration.

maintenance therapy, just as protracting the length of steroid various diseases,31,32 hence the need for more than one bio-
use has been the rationale for steroid sparers. Fifth, having marker to be measured.32 CSF biomarkers are a reality in
performed well in chronic and higher-risk patients, RITE-CI contemporary neurology,33 and increasingly so in neuropedia-
provides a viable option for new-onset OMS. trics, where they have been used to explore neuroinflammation
What is the clinical relevance of CSF assessment of biomar- in demyelinating disorders, N-methyl-D-asparate receptor
kers? In the era of the “biomarker revolution,”29 biomarkers (NMDAR) encephalitis, neuropsychiatric systemic lupus erythe-
have become “the essence of the translational medicine strate- matosus, and other diseases.34 The importance of chemokines
gic focus on disease biomarkers, patient selection, and pharma- and other cytokines in neuroinflammation has been documen-
codynamic responses….”30 They are harnessed to improve the ted.35 It is now a matter of validating, utilizing, and incorporat-
predictability and success of treatment. Biomarkers are recog- ing these biomarkers into clinical drug studies.
nized as requisite for the attainment of “personalized medicine,” The biomarker abnormalities revealed a pattern. There were
which is the goal of modern medicine.29 Combinatorial panels increases in B cell/humoral markers (CXCL13, OCB), a Th1
are being developed to improve diagnostic and prediction for marker (CXCL10), and a marker of neuronal/axonal injury

Neuropediatrics
 RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

Table 4 Video-scored clinical effects of RITE-CI on OMS severity (total score) and severity category

6 mo RITE-CI schedules >6 mo RITE-CI schedules

Case Time TS Sev. Cat. Case Time TS Sev. Cat.
(16 wk) (34 wk)
1 Pre- 28 þþþþ 8 Pre- 26 þþþþ
Post- 2 þ Post- 0 0
2 Pre- 16 þþþ
Post- 2 þ (52 wk)
9 Pre- 26 þþþþ
(24 wk) Post- 7 þþ
3 Pre- 20 þþþ 10 Pre- 13 þþþ
Post- 0 0 Post- 5 þ
4 Pre- 26 þþþþ 11 Pre- 30 þþþþ
Post- 2 þ Post- 8 þþ
5 Pre- 14 þþþ 12 Pre- 29 þþþþ
Post- 2 þ Post- 2 þ

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6 Pre- 16 þþþ
Post- 0 0
7 Pre- 23 þþþ
Post- 4 þ
Freq. Sev. Cat. Severe Moderate Mild Trace None
6 mo RITE
Pre- 2 5 0 0 0
Post- 0 0 0 5 2
>6 mo RITE
Pre- 4 1 0 0 0
Post- 0 0 2 2 1
All patients
Pre- 6 6 0 0 0
Post- 0 0 3 6 3

Abbreviations: Freq. Sev. Cat. ¼ frequency of each severity category; OMS, opsoclonus-myoclonus syndrome; RITE-CI, rituximab, IVIg, and
tetracosactide combination immunotherapy; TS, total score.

(NFL); an index of T cell dysregulation (decreased CD4/CD8 T cell ports early treatment decisions, and can uncover incipient
ratio); and a decreased CNS vascular endothelial cell/innate treatment failure.36,37 No evidence of biological disease
immune cell marker. The immunologic significance of the in- activity (persistence of neuroinflammatory biological pro-
dividual markers has been discussed elsewhere,11,12,14–17 sum- cesses) in CSF is one criterion.38 Given the multiple in-
mating involvement of both the adaptive and innate immune flammatory components and the failure of commonly
systems in OMS, but the two clinical points should be noted accepted treatment modalities, the need in OMS is no
here. First, multiple components of neuroinflammation were less important. For instance, in the case of a child present-
revealed, two of which can be accessed by clinicians through the ing with symptomatic chronic OMS, are the symptoms
clinical and flow cytometry laboratories at their hospitals. indicative of ongoing neuroinflammation (treatable with
Second, the neuroinflammatory pattern is serious and should intensive immunotherapy) or resulting brain injury (not
alert treating physicians that the brain is indeed under attack. helped by further immunotherapy)? This study provides
The case for demonstrating “no evidence of disease exploratory immunobiomarkers that could be measured
activity” (NEDA)36 or “freedom from disease activity”37 and remeasured in OMS.
has been made in multiple sclerosis, but is being applied The clinical benefit of RITE-CI is not solely attributable to
in other neuroinflammatory disorders as well. It allows the ACTH(1–24). Abundant medical literature documents the fail-
capacity of disease-modifying agents to be verified, sup- ure of ACTH or corticosteroid therapy (with or without IVIg) to

Neuropediatrics
RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

Table 5 Long-term outcome after RITE-CI therapy

Case Cur. age (y) Off Rx Relapse Y/N Motor residual Learning problems Comments
(16 wk)
1 8.0 Y N N Y ADHD
2 7.8 Y N N N
(24 wk)
3 5.6 Y N

IQ 97, speech therapy
4 5.1 Y N N Y (mild)
5 10 Y Y (1) N Y (mild)
6 6.7 Y Y (1) N
Aggressive at home
(34 wk)
8 8.4 Y N N Y (mild) Started school 1 year late
(52 wk)
9 8.7 Y N
a Y
10 10 Y N N N Speech therapy
12 14 Y Y(2) Y Y (severe) Behavior, speech, cog.

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problems, spec. ed.
Total: Mean 8.4 9Y 3Y 1Y 6Y
(SD) (2.6) 1N 7N 7N 2N
2
2

Abbreviations:
, trace; ADHD, attention deficit hyperactivity disorder; cog. problems, cognitive problems; RITE-CI, rituximab, IVIg, and
tetracosactide combination immunotherapy; SD, standard deviation; spec. ed., special education schooling.
Note: No long-term outcome information available on patients 7 and 11. Relapse was defined as a discrete return or exacerbation of OMS motor signs
lasting 48–72 hours (ref. 5). Learning problems were per report by parents.
a
Transient mild imbalance when ill.

dependably protect against OMS relapse and poor neurological The use of multiple agents prevents attribution of specific
or cognitive outcome.3,5,39 The benefit of high-intensity multi- effects to any one agent, but our previous research provides
modal immunotherapy initiated at disease onset derives from some insights. In cross-sectional, case–control studies, chil-
rapid delivery of multimechanistic, disease-modifying agents dren treated with ACTH(1–39)-based immunotherapy had
applied for a sufficiently immunoprotective period to allow lower CSF B cell activating factor (BAFF),11 B cell attractant-1
eradication of neuroinflammation and reestablishment of (CXCL13),12 and OCBs.10 IVIg monotherapy did not signifi-
immune quiescence.5 These data, and data from first long- cantly alter concentrations of the chemokines/cytokines
acting injectable regimen (FLAIR) combination therapy,9 may measured here.11,12 Rituximab monotherapy resulted in a
encourage treating physicians to seriously consider deploying small transient decrease in serum CXCL13 and an increase in
upfront combination immunotherapies in the initial induction serum BAFF until B cell repletion occurred.13 These data
treatment of OMS. Alternative approaches also are being afford the opportunity for a unique comparison with ACTH
studied, such as escalating therapy (dexamethasone, cyclo- (1–24) in future studies, which might help elucidate phar-
phosphamide, rituximab) according to treatment response, as macodynamic properties of the two agents. However, IVIg
per a European OMS treatment protocol. The pros and cons of and rituximab also have a multitude of other immunological
grouped initial treatment versus stepwise-escalation drug effects outside the study parameters.40
strategies have been compared recently.1 Dosing of ACTH(1–24) based on body surface area improves
RITE-CI did best against the “criteria” neurological man- on the manufacturer’s age-based dosing and less specific
ifestations of OMS (opsoclonus, myoclonus, ataxia). In some recommendations (3–5 versus 5–12 years old).23 This should
of these mostly chronic, partial- or nonresponders, “non- help prevent over- or underdosing. Determining the optimal
criteria” neuropsychiatry and neurodevelopmental manifes- dosing of ACTH(1–24) will require further studies, as higher
tations of OMS persisted, appearing to have been set early, doses do not increase the pharmacodynamic effect but increase
prior to RITE-CI. Though motor signs usually remit with duration of action.23 The 16-week schedule, which was shorter
combination immunotherapy, chronic-relapsing patients and started at a lower dose, and the 24-week schedule (with or
can develop progressive OMS, especially when initial therapy without dexamethasone) performed well. We coin the term
is delayed or insufficient.5 The relapse rate in OMS is high,3,39 “RITED-CI” when pulse–dose dexamethasone is added toward
as seen in the relapse frequency at initial evaluation and the end of the ACTH taper to shorten time on ACTH(1–24). The
during RITE-CI treatment. 52-week schedule, which was longer and started at a higher

Neuropediatrics
 RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

dose, appeared to give rise to more Cushingoid side effects provides as a template for the design of a prospective clinical
without more benefit, making dose escalation in the manage- drug trial with biomarker metrics.
ment of relapse difficult. In our current practice, if a patient
with OMS has not remitted by 6 months of treatment on a high- Conflict of Interest
dose, triple-therapy protocol, we add another disease-modify- None.
ing immunotherapy agent, and do not to rely on ACTH dose
escalation or schedule prolongation.5 Funding
It is established that ACTH exerts powerful corticosteroid This research did not receive any specific grant from funding
effects through activation of steroid pathways. There has also agencies in the public, commercial, or not-for-profit sectors.
been interest in potential corticosteroid-independent melano-
cortin pathways to downregulate cytokine-producing immune Acknowledgments
cells.28,41 ACTH is a full agonist at all MCRs.28 Four of the five The authors thank all participating patients, families, refer-
subtypes of mammalian MCRs (MC1R, MC3R, MC4R, MC5R) are ring physicians, and translators, including Prof. Dr. Wolf-
expressed in the brain,42 but only MC4R is expressed in gang Müller-Felber, from Dr. von Hauner Children’s Hospital
astrocytes.43,44 MC3R and MC4R agonists exert anti-inflam- Linikum der Universität München Campus Innenstadt
matory effects.43 Increased anti-inflammatory and reduced (München, Germany), for translating the German reference.
pro-inflammatory cytokines by melanocortin peptides may Ronald McDonald Charities of Central Illinois (Springfield,
be mediated by MC3R.45 ACTH is the only known ligand for Illinois, United States) provided over-night stay for some of
MC2R, which is highly expressed in adrenal cortex.46 How the families, and Nathan R. McGee, B.S., performed the
these MCRs relate to clinical effects in OMS is unknown, chemokine/cytokine assays in Dr. Pranzatelli’s laboratory.

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because corticosteroids also exert significant effects on inflam- We also thank treating physician Juan A. Quintana, Jefe
matory mediators CXCL13 and BAFF in CSF and CCL21 and Unidad De Oncologia Pedia, Pediatria Oncologia, Clinic
CCL22 in serum.11,12,15,16 Davila, Santiago, Chile.
Strengths of this study were the clinical evaluation by two
OMS experts, combined clinical and multiple neuroimmu-
nologic markers of neuroinflammation, the standard use of
References
video-documentation and blinded scoring, the formal case–
1 Pranzatelli MR, Tate ED. Opsoclonus myoclonus syndrome. In:
control design for assessment of neuroinflammation, the use Swaiman, et al. eds. Swaiman’s Pediatric Neurology: Principles
of a single reference laboratory for neuroimmunologic data and Practice. 6th ed., Chapter 120. Oxford: Elsevier; 2017
avoiding variability between laboratories, and the novelty of 2 Kinsbourne M. Myoclonic encephalopathy of infants. J Neurol
the approach. The data presentation allows clinical, neu- Neurosurg Psychiatry 1962;25(03):271–276
3 Tate ED, Allison TJ, Pranzatelli MR, Verhulst SJ. Neuroepidemio-
roimmunologic, and outcome data to be tracked in individual
logic trends in 105 US cases of pediatric opsoclonus-myoclonus
patients, and provides summary data as well. syndrome. J Pediatr Oncol Nurs 2005;22(01):8–19
Limitations of the study included small sample size, the 4 Mitchell WG, Wooten AA, O’Neil SH, Rodriguez JG, Cruz RE,
observational/retrospective nature of the treatment (not a Wittern R. Effect of increased immunosuppression on develop-
clinical trial), paucity of posttreatment neuroimmunologic mental outcome of opsoclonus myoclonus syndrome (OMS).
data to establish NEDA, and follow-up data were not always J Child Neurol 2015;30(08):976–982
5 Pranzatelli MR, Tate ED. Trends and tenets in relapsing and
completely available. The children were previously treated,
progressive opsoclonus-myoclonus syndrome. Brain Dev 2016;
not immunotherapy naive. Neuropsychological assessment 38(05):439–448
was not performed, and hence cognitive outcome reporting 6 Fühlhuber V, Bick S, Tschernatsch M, et al. Autoantibody-
is extremely limited. Multimodal therapy for OMS is not mediated cytotoxicity in paediatric opsoclonus-myoclonus syn-
new, but this combination has not been evaluated drome is dependent on ERK-1/2 phophorylation. J Neuroimmunol
2015;289:182–186
previously.
7 Pranzatelli MR, Travelstead AL, Tate ED, et al. B- and T-cell markers
in opsoclonus-myoclonus syndrome: immunophenotyping of CSF
Conclusions lymphocytes. Neurology 2004;62(09):1526–1532
8 Pranzatelli MR, Tate ED, Verhulst SJ, et al. Pediatric dosing of
This study demonstrates that the basis of steroid- and IVIg- rituximab revisited: serum concentrations in opsoclonus-myoclo-
treatment failure or partial response was unrecognized multi- nus syndrome. J Pediatr Hematol Oncol 2010;32(05):e167–e172
9 Pranzatelli MR, Tate ED, Swan JA, et al. B cell depletion therapy for new-
component neuroinflammation, which was discovered by mod-
onset opsoclonus-myoclonus. Mov Disord 2010;25(02):238–242
ern, not routine, diagnostic approaches. RITE-CI was clinically 10 Pranzatelli MR, Slev PR, Tate ED, Travelstead AL, Colliver JA, Joseph
effective against the motor features of OMS despite disease SA. Cerebrospinal fluid oligoclonal bands in childhood opsoclo-
chronicity and prior lack of remission, and provides one more nus-myoclonus. Pediatr Neurol 2011;45(01):27–33
therapeutic option for children with OMS, a devastating dis- 11 Pranzatelli MR, Tate ED, Hoefgen E, Swan J, Colliver JA. Therapeutic
order, for which effective treatment options are limited. Taken down-regulation of central and peripheral B-cell activating factor
(BAFF) production in pediatric opsoclonus-myoclonus syndrome.
together, the data suggest that the standard of care of OMS
Cytokine 2008;44(01):26–32
should be not only rapid, durable, clinical improvement but 12 Pranzatelli MR, Tate ED, McGee NR, et al. Key role of CXCL13/
verification of immune quiescence (NEDA). The further utility of CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric
this report, even in a small patient sample, is the information it OMS. J Neuroimmunol 2012;243(1-2):81–88

Neuropediatrics
RITE Therapy for Opsoclonus-Myoclonus Syndrome Pranzatelli et al.

13 Pranzatelli MR, Tate ED, Travelstead AL, Verhulst SJ. Chemokine/ 30 Day M, Rutkowski JL, Feuerstein GZ. Translational medicine–a
cytokine profiling after rituximab: reciprocal expression of BCA- paradigm shift in modern drug discovery and development: the
1/CXCL13 and BAFF in childhood OMS. Cytokine 2011;53(03): role of biomarkers. Adv Exp Med Biol 2009;655:1–12
384–389 31 Edwards KR, Goyal J, Plavina T, et al. Feasibility of the use of
14 Pranzatelli MR, Tate ED, McGee NR, Travelstead AL, Verhulst SJ, combinatorial chemokine arrays to study blood and CSF in multi-
Ransohoff RM. Expression of CXCR3 and its ligands CXCL9, -10 ple sclerosis. PLoS One 2013;8(11):e81007
and -11 in paediatric opsoclonus-myoclonus syndrome. Clin Exp 32 Han S, Lin YC, Wu T, et al. Comprehensive immunophenotyping of
Immunol 2013;172(03):427–436 cerebrospinal fluid cells in patients with neuroimmunological
15 Pranzatelli MR, Tate ED, McGee NR, Ransohoff RM. CCR4 agonists diseases. J Immunol 2014;192(06):2551–2563
CCL22 and CCL17 are elevated in pediatric OMS sera: rapid and 33 Bielekova B. Perspective: who dares, wins. Nature 2016;540
selective down-regulation of CCL22 by ACTH or corticosteroids. (7631):S10
J Clin Immunol 2013;33(04):817–825 34 Kothur K, Wienholt L, Mohammad SS, et al. Utility of CSF cytokine/
16 Pranzatelli MR, Tate ED, McGee NR, Ransohoff RM. CCR7 signal- chemokines as markers of active intrathecal inflammation: com-
ing in pediatric opsoclonus-myoclonus: upregulated serum parison of demyelinating, anti-NMDAR and enteroviral encepha-
CCL21 expression is steroid-responsive. Cytokine 2013;64(01): litis. PLoS One 2016;11(08):e0161656. Doi: 10.1371/journal.
331–336 pone.0161656
17 Pranzatelli MR, Tate ED, McGee NR, Verhulst SJ. CSF neurofilament 35 Becher B, Spath S, Goverman J. Cytokine networks in neuroin-
light chain is elevated in OMS (decreasing with immunotherapy) flammation. Nat Rev Immunol 2017;17(01):49–59
and other pediatric neuroinflammatory disorders. J Neuroimmu- 36 Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G. No
nol 2014;266(1-2):75–81 evidence of disease activity: indirect comparisons of oral thera-
18 Pranzatelli MR, Tate ED, Travelstead AL, Colliver JA. Long-term pies for the treatment of relapsing-remitting multiple sclerosis.
cerebrospinal fluid and blood lymphocyte dynamics after ritux- Adv Ther 2014;31(11):1134–1154
imab for pediatric opsoclonus-myoclonus. J Clin Immunol 2010; 37 Havrdova E, Galetta S, Stefoski D, Comi G. Freedom from disease

Downloaded by: University of Utrecht. Copyrighted material.

30(01):106–113 activity in multiple sclerosis. Neurology 2010;74(Suppl 3):S3–S7
19 Tate ED, Pranzatelli MR, Verhulst SJ, et al. Active comparator- 38 Bonnan M, Marasescu R, Demasles S, Krim E, Barroso B. No
controlled, rater-blinded study of corticotropin-based immu- evidence of disease activity (NEDA) in MS should include CSF
notherapies for opsoclonus-myoclonus syndrome. J Child Neurol biology - towards a ‘Disease-Free Status Score’. Mult Scler Relat
2012;27(07):875–884 Disord 2017;11:51–55
20 Montero-Melendez T. ACTH: The forgotten therapy. Semin Im- 39 Tate ED, McGee NM, Pranzatelli MR. Clinical and demographic
munol 2015;27(03):216–226. Doi: 10.1016/j.smim.2015.02.003 features of 389 children with OMS: an international cohort.
21 Baker JR, Bennett HP, Hudson AM, McMartin C, Purdon GE. On the Proceedings of the 13th International Child Neurol Congress,
metabolism of two adrenocorticotrophin analogues. Clin Endo- Iguaza Falls, Brazil, May 4–9, 2014;FP79:27
crinol (Oxf) 1976;5(Suppl):61S–72S 40 Kaufman GN, Massoud AH, Dembele M, Yona M, Piccirillo CA,
22 Gettig J, Cummings JP, Matuszewski K. H.p. Acthar gel and Mazer BD. Induction of regulatory T cells by intravenous immu-
cosyntropin review: clinical and financial implications. P&T noglobulin: a bridge between adaptive and innate immunity.
2009;34(05):250–257 Front Immunol 2015;6:469. Doi: 10.3389/fimmu.2015.00469
23 Package Leaflet: Synacthen® Depot Ampules 1 mg/ml Tetraco- 41 Dores RM. Adrenocorticotropic hormone, melanocyte-stimulat-
sactide acetate ing hormone, and the melanocortin receptors: revisiting the work
24 Lipinski D, Kratzer W, Daum R. Die infantile myoklonische of Robert Schwyzer: a thirty-year retrospective. Ann N Y Acad Sci
enzephalopathie—ein paraneoplastiches Syndrom bei Neuroblas- 2009;1163:93–100
toma [Myoclonic encephalopathy of infants—a paraneoplastic 42 Muceniece R, Dambrova M. Melanocortins in brain inflammation:
syndrome in neuroblastoma]. Z Kinderchir 1975;16:11–117 the role of melanocortin receptor subtypes. Adv Exp Med Biol
25 Corrias A, Nurchi AM, Rossi G, Sorcinelli R, Pusceddu G, Corda R. 2010;681:61–70
Opsoclonic encephalopathy in childhood (Kinsbourne syndrome) 43 Caruso C, Carniglia L, Durand D, Scimonelli TN, Lasaga M. Astro-
[in Italian]. Pediatr Med Chir 1985;7(03):437–441 cytes: new targets of melanocortin 4 receptor actions. J Mol
26 Snead OC III. Treatment of infantile spasms. Pediatr Neurol 1990;6 Endocrinol 2013;51(02):R33–R50
(03):147–150 44 Kokubo M, Asai K, Yamamoto N, et al. ACTH(1-24) down-regulates
27 Pranzatelli MR. On the molecular mechanism of adrenocortico- expression of ciliary neurotrophic factor mRNA in cultured rat
trophic hormone in the CNS: neurotransmitters and receptors. astrocyte. Pediatr Res 2002;52(06):950–957
Exp Neurol 1994;125(01):142–161 45 Loram LC, Culp ME, Connolly-Strong EC, Sturgill-Koszycki S.
28 Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechan- Melanocortin peptides: potential targets in systemic lupus er-
isms of action of adrenocorticotropic hormone and other mela- ythematosus. Inflammation 2015;38(01):260–271. Doi: 10.1007/
nocortins relevant to the clinical management of patients with s10753-014-0029-5
multiple sclerosis. Mult Scler 2013;19(02):130–136 46 Dores RM, Londraville RL, Prokop J, Davis P, Dewey N, Lesinski N.
29 Bonnefoy J-Y. The biomarker revolution: a step toward persona- Molecular evolution of GPCRs: melanocortin/melanocortin re-
lized medicine. Per Med 2008;5(06):553–556 ceptors. J Mol Endocrinol 2014;52(03):T29–T42

Neuropediatrics