Cancer Letters 228 (2005) 275–282

www.elsevier.com/locate/canlet

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
Katherine K. Matthaya, Franz Blaesb, Barbara Heroc, Dominique Plantazd,
Pedro De Alarcone, Wendy G. Mitchellf, Michael Pikeg, Vito Pistoiah,*
a
Department of Pediatrics, University of California, San Francisco, CA, USA
b
Department of Neurology, Justus-Liebig-University, Giessen, Germany
c
Children’s Hospital, University of Cologne, Köln, Germany
d
Department of Pediatrics, CHU Grenoble, Grenoble, France
e
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
f
Neurology Division, Children’s Hospital, Los Angeles, CA, USA
g
Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford, UK
h
Laboratory of Oncology, Giannina Gaslini Children’s Hospital, Largo Gerolamo Gaslini 5, 16148 Genova, Italy
Received 27 December 2004; accepted 20 January 2005

Abstract
Opsoclonus-myoclonus syndrome (OMS) is a rare neurologic syndrome that, in children, associates with neuroblastoma in
more than half of the cases. The etiology of this condition is thought to be immune mediated, but, though immunosuppressive
therapies may ameliorate the acute symptoms, no effective treatment to prevent the common neuropsychologic sequelae has
been established. This paper summarizes the results obtained at the 2004 Advances in Neuroblastoma Research meeting,
providing status of the art information on immune pathogenesis, clinical features, acute and chronic neurologic manifestations,
current and novel therapeutic approaches. It is emphasized that, due to the rarity of OMS in general and neuroblastoma-
associated OMS in particular, international collaborations are needed to better define the pathogenesis and therapy of this
disease, propose common evaluation criteria and identify new treatment modalities.
q 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Opsoclonus-myclonus syndrome; Neuroblastoma; Immunopathogenesis; Clinical features; Novel therapies

1. Definition

Opsoclonus-myoclonus syndrome (OMS) is a rare

paraneoplastic or possibly post-viral serious neuro-
* Corresponding author. Tel.: C39 010 56 36342; fax: C39 010 logic syndrome. In children, OMS is associated in
377 9820. more than half of cases with neuroblastoma [1,2].
E-mail address: vitopistoia@ospedale-gaslini.ge.it (V. Pistoia).

0304-3835/$ - see front matter q 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2005.01.051
276 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
Often called ‘dancing eye syndrome’, OMS is defined
by acute onset of rapid and chaotic eye movements,
myoclonic jerking of the limbs and trunk, ataxia, and
behavioral disturbance. While children with OMS and
neuroblastoma most often display favorable prognos-
tic tumor characteristics and a high survival rate [3],
the majority of children also experience develop-
mental delays and long-term nervous system dysfunc-
tion, which may be devastating [2,4–7].
The etiology of this condition is thought to be
immune mediated, but the exact pathogenesis has not
yet been elucidated. Furthermore, though immuno-
suppressive therapies may ameliorate the acute
symptoms, no effective treatment to prevent the
common neuropsychologic sequelae has been estab-
lished. The recent workshop at the 2004 Advances in
Neuroblastoma Research meeting was held to sum-
marize recent results and propose international
collaborations in order to better define the pathogen-
esis and therapy of this disease, and propose common
evaluation criteria to be used.
2. Immune pathogenesis of opsoclonus-myoclonus
syndrome
Since autoantibodies have been described in both
adult and pediatric OMS, an autoimmune hypothesis
of the syndrome is suspected. Rare pathological
examinations of pediatric OMS suggest cerebellar
pathology; therefore, most investigators have
searched for autoantibodies against cerebellar struc-
tures [8]. One cooperative study in the Children’s
Cancer Group (CCG) compared sera from 16 patients
with neuroblastoma-associated OMS to age and stage
matched control sera from 48 non-OMS patients with
neuroblastoma, and showed a significantly higher
proportion of children with anti-neuronal antibodies
in the OMS group (81 versus 25%, P!0.001) [9].
The first autoantibody described was anti-neurofi-
lament [10]. However, this antibody was not specifi-
cally associated with OMS and was observed even in
healthy controls [11]. In some children with para-
neoplastic OMS, anti-Hu antibodies could be detected
in the serum [9,12]. The anti-Hu autoantibody is
mainly associated with paraneoplastic encephalomye-
litis and small cell lung cancer in adults [13]. In some
adults with OMS and breast cancer, an autoantibody
called anti-Ri can be found in the serum of the patients
[14]. In contrast to adult OMS, the pediatric disease
has not been associated with anti-Ri antibodies. The
most frequently described autoimmune reactivities in
pediatric OMS are directed against Purkinje cell
cytoplasmic antigens [15]. Other authors failed to
detect a common autoantigen [9], and in our own
investigations a reactivity against a 55 kD protein was
the only common autoantibody in some OMS children
(Blaes et al., unpublished results).
The lack of a universal autoantibody in these
children led to the suspicion of a predominantly T-cell
driven autoimmune process in OMS. However, recent
work demonstrated marked B-cell activation in the
CSF of OMS children [16]. Additionally, OMS
children often show a favorable response to steroids
and intravenous immunoglobulin [17], which makes
an auto-antibody mediated disease more likely.
Recently, we detected IgG surface-binding and pro-
apoptotic effects of OMS-IgG to neuroblastoma cells
in vitro (Blaes et al., unpublished results), which also
supports the idea of an auto-antibody-mediated
disease. Taken together, there is evidence for a
cross-reactive autoimmunity between neuroblastoma
and nervous system tissue in OMS, and the identifi-
cation of the underlying auto-antigen is an important
goal for further research.
New clues to a better understanding of OMS
immunopathogenesis have come from the histological
and immunohistochemical investigation of neuroblas-
toma tumors affecting children with associated OMS.
These tumors are usually ganglioneuroblastomas with
interstitial or perivascular lymphoid infiltrates, that
often organize in aggregates closely resembling
secondary lymphoid follicles. Although these features
may be found also in ganglioneuroblastomas not
associated with OMS, lymphoid infiltrates are more
prominent in OMS-related tumors, and the number
and size of follicles is definitely higher in the latter
tumors [18,19]. Immunophenotyping of lymphoid
cells infiltrating OMS-associated ganglioneuroblasto-
mas showed that the follicles had typical germinal
centers containing a mesh of CD21C follicular
dendritic cells. CD20C B lymphocytes were the
major component of the GC and the follicular mantle,
where a minority of CD3C T cells were also detected.
The bulk of T lymphocytes localized around
the follicles and displayed mainly a CD8C
 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
immunophenotype, although also CD4C T cells were
observed. [18,19].
The germinal center reaction is a T cell-dependent
phenomenon initiated by an antigen-activated naïve B
cell that migrates to a lymphoid follicle where it gives
rise first to centroblasts and subsequently to centro-
cytes. Those centrocytes selected to survive differen-
tiate into memory B cells or plasma cells. Memory B
cells, in turn, can undergo multiple passages through
germinal centers to improve the affinity, and there-
fore, the quality, of antibody responses [20]. These
rules apply not only to secondary follicles in lymphoid
organs, but also to ectopic lymphoid follicles devel-
oping in inflamed tissues in the course of autoimmune
disorders. Thus, detection of huge lymphoid follicles
in OMS-associated ganglioneuroblastoma may
suggest the occurrence of T cell dependent responses
to tumor-associated antigens with subsequent B cell
activation and antibody production, a hypothesis
supported by the detection of plasma cells in the
interfollicular areas.
As discussed by Raffaghello and coworkers in this
supplement, one of the major mechanisms of immune
escape used by neuroblastoma cells is the down-
regulation of HLA class I molecules from the cell
surface, that prevents presentation of peptides from
processed tumor-associated antigens to specific
CD8C T cells. Nonetheless, since locally produced
interferon (IFN)-g might upregulate HLA class I
molecules on tumor cells, we investigated by
immunohistochemistry whether neuroblasts from
patients with ganglioneuroblastoma and OMS
expressed these molecules. The results of these
experiments demonstrated that malignant cells were
completely HLA class I negative, as opposed to
infiltrating lymphoid cells that displayed evident
staining [19]. Altogether, these results provide
compelling evidence, although do not prove, that
lymphoid infiltration is unrelated to an antigen
specific T cell response directed against neuroblasts.
An alternative hypothesis to explain tumor infiltra-
tion by lymphoid cells is that malignant neuroblasts
produce chemokines capable of attracting lympho-
cytes within the tumor mass [21]. Key players in
lymphoid neogenesis are the chemokines CCL19,
CCL21, CXCL12 and CXCL13, that interact with
their cognate receptors, i.e. CCR7 (for CCL19 and
CCL21, CXCR4 (for CXCL12) and CXCR5
277
(for CXCL13) [22]. In preliminary experiments, we
have investigated expression of these receptors in
OMS-related tumors by immunohistochemistry.
CCR7, CXCR4 and CXCR5 were found to be
expressed on the majority of tumor cells, with higher
intensity on the more differentiated component.
CXCR5, but not CXCR4 or CCR7, was detected on
infiltrating lymphoid cells (Raffaghello et al., unpub-
lished results). Studies on expression of the ligands of
these receptors are in progress. These preliminary
results suggest that chemokine–chemokine receptor
interactions are indeed involved in lymphoid recruit-
ment into OMS-associated ganglioneuroblastomas.
3. Clinical features
OMS of childhood is diagnosed primarily between
age one and 3 years (median age 18–22 months), not
significantly different than neuroblastoma as a whole
[2,5,23]. However, unlike neuroblastoma in general, it
is very rare before age 1. It occurs in 2–3% of all
children diagnosed with neuroblastoma [1,2].
Although in most patients the syndrome itself leads
to the diagnosis of neuroblastoma, it may rarely occur
after tumor resection or at relapse [24–26]. Literature
review suggests that in at least half of the children
affected, OMS is associated with underlying occult or
clinically apparent neuroblastoma. In one author’s
personal experience [WG Mitchell] of 30 patients,
however, more than 80% of children with OMS who
underwent extensive evaluation including thin-cut
computerized tomography (CT), had neuroblastoma
that in some cases had escaped detection with the
usual diagnostic procedures. Given this observation, it
seems possible that a small undetectable neuroblastic
tumor or one that had already regressed completely
may have occurred in the patients with ‘idiopathic’
OMS. Although an advantage of tumor resection for
ultimate neurological outcome is not proven, it often
ameliorates the acute symptoms of OMS.
A thorough diagnostic evaluation for neuroblas-
toma at presentation is necessary in all patients with
OMS, after exclusion of central nervous system
pathology, with brain MRI and lumbar puncture.
This should include CT or magnetic resonance
imaging (MRI) with thin cuts through the adrenals if
278 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
appropriate, 123I-metaiodobenzylguanidine (MIBG)
scan [27,28], and urinary VMA, HVA, and dopamine.
The tumor is usually localized, very small and
differentiated (ganglioneuroblastoma). Recent
reported series show that 90% of patients were
without metastases at diagnosis, compared to 40–
50% in non-OMS patients. Tumor biology, including
MYCN copy number and Shimada histopathologic
classification are usually favorable in OMS patients,
which correlates with the excellent survival rate found
in patients with OMS and neuroblastoma, even when
survival analysis is stratified by age at diagnosis and
stage [2,3,5].
Although death from tumor progression is rare
in this condition, late neurological deficits are
frequent, seen in 70–80% of children affected
by OMS, long after the acute opsoclonus and
myoclonus have resolved. Several detailed studies
with follow-up times of 5–20 years have shown
persistent neurologic deficits in more than 70% of
patients in speech, coordination, and, occasionally,
eye movements. More than half the patients displayed
deficits on detailed testing in cognition, adaptive
behavior, and development, ranging from mild to
severe [2,4–7,23,29].
4. Acute neurologic findings of OMS
Children with OMS with or without neuroblastoma
present with an acute or sub-acute onset of ataxia,
losing the ability to walk and/ or sit over a period of
one to several days - occasionally weeks. The
movement disorder is accompanied by severe irrit-
ability and, at some point, by opsoclonus. The first
neurological diagnosis proposed for most children
who are ultimately found to have OMS is almost
invariably post-infectious acute cerebellar ataxia of
childhood. In fact, until opsoclonus appears, the
conditions are clinically similar, and acute cerebellar
ataxia of childhood is far more common. While
opsoclonus is occasionally seen in the first day or two
of OMS, it may appear as late as a few weeks after the
onset of motor symptoms.
Opsoclonus is a distinctive eye movement
rarely seen in other childhood conditions, and is
dissimilar to nystagmus, which is more often seen in
other acute cerebellar ataxias. Opsoclonus is
conjugate, non-phasic, fast, and multi-directional. It
tends to occur in bursts and, when mild, can some-
times be provoked by change in gaze fixation, usually
from far to near. If it is not prominent, identification of
the opsoclonus may require a period of close
observation with elicited changes in fixation [30–32].
The shaky movements of OMS are variable in
quality ranging from tremulous polymyoclonia to
coarse multi-focal jerks. They may involve all body
parts including extremities, trunk and face. Whilst they
may be persistent, they are more often exacerbated by
attempts at movement and by emotional distress.
Personality change and developmental regression
typically occur involving loss of speech and language
in addition to the obvious motor deficits. Severe
irritability and sleep disturbance occur in almost all
children and provide a useful distinguishing feature
from other acquired ataxias. The typical child with
OMS appears extremely uncomfortable, often pre-
senting in the office or hospital screaming incon-
solably and being passed back and forth between
distraught parents who find that they cannot put the
child down without exacerbating the distress. Vomit-
ing occurs in some children, often associated with
changes in position [6,33,34]. Children with OMS in
whom irritability is less prominent may present with
apathy, loss of social interaction and unwillingness to
engage in age-appropriate play.
Very occasionally occult neuroblastoma may
present with some, but not all, of the features
described [6,35]. Nor is every case of childhood
OMS paraneoplastic in origin. Given this element of
variability diagnostic criteria have been proposed—
the presence of at least 3 out of the following four
features: (1) opsoclonus, (2) myoclonus/ataxia,
(3) behavioral change and/or sleep disturbance,
(4) neuroblastoma.
5. Chronic neurological findings
With or without treatment, opsoclonus usually
resolves eventually. Residual opsoclonus may
reappear after apparent complete resolution with
reduction in medication dose, or with intercurrent
illnesses. Minimal opsoclonus may be elicited by
having the child repeatedly re-fixate from near to far, or
by having them partially squeeze the eye-lids shut, then
 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
allow them to be partly opened by the examiner. Even
with resolution of opsoclonus, abnormalities of smooth
pursuit eye movements and hypometric saccades are
commonly seen even years after treatment.
Motor deficits generally remain significant without
immunosuppressive treatment (and may be proble-
matic in spite of treatment). With treatment, children
with OMS usually walk independently, but even with
vigorous treatment they are usually not as coordinated
as their peers throughout childhood and adolescence.
Speech and language are also significantly affected
by this condition. Most children who have had OMS
continue to show expressive language and speech
deficits. Receptive language tends to be better than
expressive language. When all OMS symptoms are
controlled with immunosuppressive medication, some
children will experience catch-up in their speech and
language skills, but most will be left with residual
learning and language disabilities and will require
educational assistance and speech therapy well into their
elementary school years, often longer [2,4–7,29,36,37].
As patients with OMS reach their teen years,
cognitive deficits may become more evident with
increasingly difficult academic tasks. Adequate pre-
vocational planning and support is essential for
progression into successful and independent function-
ing in young adulthood. Behavior problems including
aggressive and impulsive behavior, mood disorders
and sleep disturbances may persist indefinitely, with
some OMS patients manifesting night terrors well past
the toddler years. Better overall control of OMS
symptoms with immunosuppressive medication
sometimes produces improvement in behavioral
symptoms as well as improving motor function.
However, psychotropic medications may be necessary
in selected children who have OMS sequelae with
severe behavioral or sleep disturbances. There is some
evidence that even very late treatment with corticos-
teroids, corticotropin or other immunosuppression,
years after onset, will improve motor function.
However, cognitive deficits, particularly when long-
standing, do not generally reverse.
6. Treatment approaches
So far, no prospective trial has been carried out to
address treatment and its correlation with long-term
279
outcome in patients with OMS. Published results are
sparse and report only on small patient numbers
ranging from 10 to 29 patients per series [2,4–7,23,29,
36]. Current evidence suggests that the disease is
mediated by an immune response directed against the
tumor and cross-reacting with central neuronal
tissues, particularly cerebellum. Therefore, treatment
of OMS has been with immunosuppressive therapy,
primarily with either long term corticosteroids or
ACTH. Although acute symptoms may be relieved by
steroid treatment, exacerbations often occur with
weaning of the drugs or intercurrent viral illness.
Intravenous application of immunoglobulin has been
used in some children with success, either in
combination with steroids or alone [38–40]. Other
immunomodulating therapies, including cyclopho-
sphamide, azathioprine and plasmapheresis [41,42],
have been reported to occasionally be effective in the
treatment of acute symptoms of OMS. Resection
of the neuroblastoma often improves the acute
symptoms, but only rarely prevents neurologic
sequelae [4,6,36].
Despite immunosuppressive treatment for the
acute symptoms of OMS, many children have
significant neurological and developmental deficits
[2,4–7,23,29]. Therefore, retrospective analyses have
been performed to see if any particular therapy helped
to decrease the incidence of these devastating late
sequelae. Although in most patients, surgical resec-
tion was the only anti-tumor treatment necessary due
to the frequency of low stage tumors, some patients
received chemotherapy as part of their treatment.
Retrospective analysis of 29 patients with OMS in
Pediatric Oncology Group (POG) trials showed a
significant benefit for resolution of symptoms in
patients who where treated with chemotherapy [5]. On
the other hand, neither the Children’s Cancer Group
study of 19 evaluable patients nor a French study of
16 evaluable patients was able to show a significant
decrease in late neurologic problems for those
children treated with chemotherapy [2,23]. However,
the combination of the 64 patients from these
cooperative group series showed that only 12/25
patients (48%) treated with chemotherapy had
neurologic sequelae, compared to 32/39 (82%) who
did not receive chemotherapy [2,5,23]. It remains
unclear whether this benefit is due to a positive effect
of chemotherapy or due to less severe activation of
280 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
the immune system in patients with more advanced
stages of the tumor. Similarly, the role of intravenous
immunoglobulin in the treatment of OMS is not clear.
In the past immunoglobulin may have been used in
patients with severe symptoms or with problems when
weaning of steroids, thus impeding interpretation of
retrospective results.
7. Current approaches
The poor neurologic outcome despite steroid
treatment and the possible positive effect seen after
chemotherapeutic intervention led to the current
hypothesis that prompt and strong immunosuppres-
sion is necessary in the treatment of OMS. Because of
the rarity of the disease and the difficulties in
interpretation of retrospective analyses, prospective
cooperative trials have been initiated, with inter-
national collaboration.
The COG has opened a Phase III study for patients
with OMS and neuroblastoma. All patients will
receive prednisone and will be randomized to either
receive intravenous immunoglobulin or not. Patients
with low risk neuroblastoma who would otherwise not
receive chemotherapy will receive immunosuppres-
sion with cyclophosphamide, while patients with
intermediate or high-risk neuroblastoma will receive
chemotherapy according the appropriate trial. Stan-
dardized neurocognitive, developmental and beha-
vioral testing will be performed at specified intervals,
and further investigation of the pathogenesis of the
syndrome will be assessed with tumor and cerebrosp-
inal fluid biology studies, anti-neuronal antibodies
and blood lymphocyte studies, and serial brain MRI
scans to evaluate anatomic changes.
In the European countries a study is currently
planned for patients with OMS with or without the
diagnosis of neuroblastoma with stepwise intensifica-
tion of treatment, starting with dexamethasone pulse
therapy, adding first intravenous immunoglobulin and
second immunosuppression with cyclophosphamide
for patients with insufficient response. This study will
also incorporate similar biologic and neurocognitive
testing.
Both studies plan a systematic registration of
symptoms with a common, newly elaborated scoring
system for neurologic exam, opsoclonus, myoclonus,
behavior and cognition and the regular cognitive
assessment in the follow up of patients, so that the
comparison of the long-term results of both studies
will be feasible in the future.
8. New approaches
The current response to steroid therapy, immune
globulin therapy and chemotherapy as well as the
presence of anti neural tissue antibodies in patients
with neuroblastoma associated OMS strongly support
investigation of other immunosuppressive approaches
to therapy in patients who fail traditional therapy. A
single patient with this syndrome with severe ataxia
who had failed to respond to therapy with ACTH,
intravenous immune globulin and azathioprine,
underwent plasmapheresis in combination with ster-
oid and azathioprine [41]. Within 1 week of therapy
the subject had improved and 6 months later was able
to ambulate without support and attended school. In
the series of patients from the POG, two patients were
treated with azathioprine without full resolution of
their symptoms [5]. High dose steroids (30 mg/kg/day
or methylprednisolone for 10 days) have been used
successfully in a patient for whom therapy with
prednisone was ineffective [43]. Pranzatelli and co-
workers have documented the presence of activated T
and B lymphocytes in the cerebrospinal fluid of
subjects with OMS, in both idiopathic or neuroblas-
toma-associated cases [16]. Rituximab is a humanized
monoclonal antibody against CD20. It has been used
for therapy of autoimmune disorders as well as CD20
positive non-Hodgkin lymphoma [44,45]. Based on
the expansion of B cells reported in the CSF of some
children with OMS, rituximab is being tested in pilot
studies for children unresponsive to steroid therapy. It
is important that these alternative therapies be utilized
in a systematic and prospective study so that we can
evaluate their role and not be left with anecdotal
experience as it is now the case for much of the
therapy for OMS.
Acknowledgements
The idea of organizing a workshop devoted to the
Dancing Eye/Opsoclonus Myoclonus Syndrome in
 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
the frame of the 11th Conference ‘Advances in
Neuroblastoma Research’ (Genova, Italy, June 16–
19, 2004) came from the Second Workshop on
Dancing Eye Syndrome, Clinical and Basic Science,
held in Abingdon, UK (February 6th–8th, 2003) and
sponsored by The Dancing Eye Syndrome Support
Trust. The Authors are grateful to this charity that
undertook the brave effort of bringing together basic
and clinical scientists in the field and providing them
with an unique opportunity of informal and in depth
discussion.
References
[1] M.R. Pranzatelli, The neurobiology of the opsoclonus-
myoclonus syndrome, Clin. Neuropharmacol. 15 (1992)
186–228.
[2] E. Rudnick, Y. Khakoo, N.L. Antunes, R.C. Seeger,
G.M. Brodeur, H. Shimada, et al., Opsoclonus-myoclonus-
ataxia syndrome in neuroblastoma: clinical outcome and
antineuronal antibodies-a report from the Children’s Cancer
Group Study, Med. Pediatr. Oncol. 36 (2001) 612–622.
[3] A.J. Altman, R.L. Baehner, favorable prognosis for survival in
children with coincident opso-myoclonus and neuroblastoma,
Cancer 37 (1976) 846–852.
[4] P.S. Koh, J.G. Raffensperger, S. Berry, M.B. Larsen,
H.S. Johnstone, P. Chou, et al., Long-term outcome in
children with opsoclonus-myoclonus and ataxia and coinci-
dent neuroblastoma, J. Pediatr. 125 (1994) 712–716.
[5] C. Russo, S.L. Cohn, M.J. Petruzzi, P.A. de Alarcon, Long-
term neurologic outcome in children with opsoclonus-
myoclonus associated with neuroblastoma: a report from the
Pediatric Oncology Group, Med. Ped. Oncol. 28 (1997) 284–
288.
[6] W.G. Mitchell, Y. Davalos-Gonzalez, V.L. Brumm,
S.K. Aller, E. Burger, S.B. Turkel, et al., Opsoclonus-ataxia
caused by childhood neuroblastoma: developmental and
neurologic sequelae, Pediatrics 109 (2002) 86–98.
[7] K. Hayward, R.J. Jeremy, S. Jenkins, A.J. Barkovich,
S.H. Gultekin, J. Kramer, 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. 139 (2001) 552–559.
[8] F.A. Ziter, P.F. Bray, P.A. Cancilla, Neuropathologic findings
in a patient with neuroblastoma and myoclonic encephalo-
pathy, Arch. Neurol. 36 (1979) 51.
[9] N.L. Antunes, Y. Khakoo, K.K. Matthay, R.C. Seeger,
D.O. Stram, E. Gerstner, et al., Antineuronal antibodies in
patients with neuroblastoma and paraneoplastic opsoclonus-
myoclonus, J. Pediatr. Hematol. Oncol. 22 (2000) 315–320.
[10] M.J. Noetzel, L.P. Cawley, V.L. James, B.J. Minard,
H.C. Agrawal, Anti-neurofilament protein antibodies in
opsoclonus-myoclonus, J. Neuroimmunol. 15 (1987) 137–145.
281
[11] K. Stefansson, L.S. Marton, M.E. Dieperink, G.K. Molnar,
W.W. Schlaepfer, C.M. Helgason, Circulating autoantibodies
to the 200,000-dalton protein of neurofilaments in the serum of
healthy individuals, Science 228 (1985) 1117–1119.
[12] P.G. Fisher, D.S. Wechsler, H.S. Singer, Anti-Hu antibody in a
neuroblastoma-associated paraneoplastic syndrome, Pediatr.
Neurol. 10 (1994) 309–312.
[13] F. Blaes, Immunotherapeutic approaches to paraneoplastic
neurological disorders, Expert Opin. Biol. Ther. 2 (2002) 419–
430.
[14] N.E. Anderson, C. Budde-Steffen, M.K. Rosenblum, F. Graus,
D. Ford, B.J. Synek, J.B. Posner, Opsoclonus, myoclonus,
ataxia, and encephalopathy in adults with cancer: a distinct
paraneoplastic syndrome, Medicine (Baltimore) 67 (1988)
100–109.
[15] A.M. Connolly, A. Pestronk, S. Mehta, M.R. Pranzatelli III,
M.J. Noetzel, Serum autoantibodies in childhood opsoclonus-
myoclonus syndrome: an analysis of antigenic targets in neural
tissues, J. Pediatr. 130 (1997) 878–884.
[16] M.R. Pranzatelli III, A.L. Travelstead, E.D. Tate, T.J. Allison,
E.J. Moticka, D.N. Franz, et al., B- and T-cell markers in
opsoclonus-myoclonus syndrome: immunophenotyping of
CSF lymphocytes, Neurology 62 (2004) 1526–1532.
[17] M.R. Pranzatelli III, The immunopharmacology of the
opsoclonus-myoclonus syndrome, Clin. Neuropharmacol. 19
(1996) 1–47.
[18] R. Cooper, Y. Khakoo, K.K. Matthay, J.N. Lukens,
R.C. Seeger, D.O. Stram, et al., Opsoclonus-myoclonus-ataxia
syndrome in neuroblastoma: histopathologic features-a report
from the Children’s Cancer Group, Med. Pediatr. Oncol. 36
(2001) 623–629.
[19] C. Gambini, M. Conte, G. Bernini, P. Angelini, A. Pession,
P. Paolucci, et al., Neuroblastic tumors associated with
opsoclonus-myoclonus syndrome: histological, immunohisto-
chemical and molecular features of 15 Italian cases, Virchows
Arch. 442 (2003) 555–562.
[20] I.C. MacLennan, Germinal centers, Annu. Rev. Immunol. 12
(1994) 117–139.
[21] L.S. Metelitsa, H.W. Wu, H. Wang, Y. Yang, Z. Warsi,
S. Asgharzadeh, et al., Natural killer T cells infiltrate
neuroblastomas expressing the chemokine CCL2, J. Exp.
Med. 199 (2004) 1213–1221.
[22] P. Hjelmstrom, Lymphoid neogenesis: de novo formation of
lymphoid tissue in chronic inflammation through expression of
homing chemokines, J. Leukoc. Biol. 69 (2001) 331–339.
[23] D. Plantaz, J. Michon, D. Valteau-Couanet, C. Coze,
P. Chastagner, C. Bergeron, et al., Opsoclonus-myoclonus
syndrome associated with non-metastatic neuroblastoma.
Long-term survival. Study of the French Society of Pediatric
Oncologists, Arch. Pediatr. 7 (2000) 621–628.
[24] C. Delalieux, C. Ebinger, R. Maurus, H. Sliwowski, Letter:
myoclonic encephalopathy and neuroblastoma, N. Engl.
J. Med. 292 (1975) 46–47.
[25] L. Rupprecht, W. Mortier, Cerebellar motor disorder and
neuroblastoma, Monatsschr. Kinderheilkd. 123 (1975)
392–393.
282 K.K. Matthay et al. / Cancer Letters 228 (2005) 275–282
[26] W.T. Basco Jr., M. Abboud, K.R. Holden, Opsoclonus-
myoclonus and recurrent neuroblastoma, J. Pediatr. 126
(1995) 847–848.
[27] J.F. Swart, J. de Kraker, N. van der Lely, Metaiodobenzyl-
guanidine total-body scintigraphy required for revealing
occult neuroblastoma in opsoclonus-myoclonus syndrome,
Eur. J. Pediatr. 161 (2002) 255–258.
[28] M.T. Parisi, R.S. Hattner, K.K. Matthay, B.O. Berg,
E.D. Sandler, Optimized diagnostic strategy for neuroblastoma
in opsoclonus-myoclonus, J. Nucl. Med. 34 (1993) 1922–1926.
[29] P.H. Papero, M.R. Pranzatelli, L.J. Margolis, E. Tate,
L.A. Wilson, P. Glass, Neurobehavioral and psychosocial
functioning of children with opsoclonus-myoclonus syn-
drome, Dev. Med. Child. Neurol. 37 (1995) 915–932.
[30] H.E. Brissaud, P. Beauvais, Opsoclonus and neuroblastoma,
N. Engl. J. Med. 280 (1969) 1242.
[31] E. Boltshauser, T. Deonna, H.R. Hirt, Myoclonic encephalo-
pathy of infants or ‘dancing eyes syndrome’. Report of 7 cases
with long-term follow-up and review of the literature (cases
with and without neuroblastoma), Helv. Paediatr. Acta 34
(1979) 119–133.
[32] J. Blake, C. Fitzpatrick, Eye signs in neuroblastoma, Trans.
Ophthalmol. Soc. UK 92 (1972) 825–833.
[33] P.G. Moe, G. Nellhaus, Infantile polymyoclonia-opsoclonus
syndrome and neural crest tumors, Neurology 20 (1970) 756–
764.
[34] W.G. Mitchell, S.R. Snodgrass, Opsoclonus-ataxia due to
childhood neural crest tumors: a chronic neurologic syndrome,
J. Child Neurol. 5 (1990) 153–158.
[35] K.B. Roberts, Cerebellar ataxia and ‘occult neuroblastoma’
without opsoclonus, Pediatrics 56 (1975) 464–465.
[36] M.S. Hammer, M.B. Larsen, C.V. Stack, Outcome of children
with opsoclonus-myoclonus regardless of etiology, Pediatr.
Neurol. 13 (1995) 21–24.
[37] K.R. Pohl, J. Pritchard, J. Wilson, Neurological sequelae of the
dancing eye syndrome, Eur. J. Pediatr. 155 (1996) 237–244.
[38] M.J. Petruzzi, P.A. de Alarcon, Neuroblastoma-associated
opsoclonus-myoclonus treated with intravenously adminis-
tered immune globulin G, J. Pediatr. 127 (1995) 328–329.
[39] C. Borgna-Pignatti, R. Balter, P. Marradi, V. Colamaria,
Treatment with intravenously administered immunoglobulins
of the neuroblastoma-associated opsoclonus-myoclonus,
J. Pediatr. 129 (1996) 179–180.
[40] E. Veneselli, M. Conte, R. Biancheri, A. Acquaviva, B. De
Bernardi, Effect of steroid and high-dose immunoglobulin
therapy on opsoclonus-myoclonus syndrome occurring in
neuroblastoma, Med. Pediatr. Oncol. 30 (1998) 15–17.
[41] V.W. Yiu, T. Kovithavongs, L.F. McGonigle, P. Ferreira,
Plasmapheresis as an effective treatment for opsoclonus-
myoclonus syndrome, Pediatr. Neurol. 24 (2001) 72–74.
[42] S.R. Sheela, P.J. Mani, Opsoclonus myoclonus syndrome:
response to plasmapheresis, Indian Pediatr. 41 (2004) 499–
502.
[43] W.L. Yeung, C.K. Li, E.A. Nelson, K.W. Chik, G.M. Joynt,
E. Yuen, C.K. Yeung, Unusual neurological presentation of
neuroblastoma, Hong Kong Med. J. 9 (2003) 142–144.
[44] B. Coiffier, New treatment strategies in lymphomas: aggres-
sive lymphomas, Ann. Hematol. 83 (Suppl. 1) (2004) S73–
S74.
[45] L. Virgolini, V. Marzocchi, Rituximab in autoimmune
diseases, Biomed. Pharmacother. 58 (2004) 299–309.