Opsoklonus

276
Opsoclonus Myoclonus Ataxia Syndrome
Veysel GÖK, Hüseyin PER
Erciyes University, Faculty of Medicine, Division of Pediatric Hematology and Oncology, Department of
Pediatrics, Kayseri, Turkey
INTRODUCTION
Opsoclonus myoclonus ataxia syndrome (OMAS), also known as dancing eye syndrome,
is a rare neurological disorder, characterized by rapid, chaotic, and synchronous eye
movements (opsoclonus), spontaneous muscle jerking (myoclonus), ataxia, and irritability.1,2 Ganglioneuroma/blastoma or neuroblastoma is detected in almost half of pediatric
OMAS patients. Similarly, 1-2% of neuroblastomas are associated with OMAS. The other
half develops due to parainfectious and idiopathic causes.3,4 There is an autoinflammatory
process on the background of this disease. Although no single pathogenic autoantibody
has been identified in individuals with OMAS, increased B cell function and the presence
of oligoclonal bands in cerebrospinal fluid (CSF) support underlying autoimmunity and
the importance of B cells in the pathophysiology of OMAS.5,6 Therefore, the recovery of
neurological symptoms responds to immunotherapy. There are many treatment options
as immunotherapy, including corticosteroids, adrenocorticotrophic hormone (ACTH), intravenous immunoglobulin (IVIG), cyclophosphamide, plasmapheresis, rituximab, and
mycophenolate mofetil.7-9
EPIDEMIOLOGY
OMAS is a rare; autoimmune neurological disorder, mainly affects young children with
a mean age of 1.5 to 2 years. One prospective study in the United Kingdom estimated an
incidence of 0.18 cases per million per year.10 Some series have found a higher prevalence
in girls in some countries such as; 52% females in the UK,11 56% females in Japan,12 65%
females in France,13 62.5%, and 56% females in the US.14,15 A female predominance is
characteristic of most, but not all, autoimmune disorders. The reason for the higher prevalence in girls can be attributable to autoimmunity.
CLINICAL FEATURES
In 1963, opsoclonus myoclonus ataxia syndrome (dancing eye syndrome) was first described by Kinsbourne based on the observation of six children with the main symptoms
such as ataxia, myoclonus, and opsoclonus.16 In recent years, researchers have focused on
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neuropsychological disorders such as learning disability, language, and mental retardation
in OMAS children.17,18 Opsoclonus is a rapid, conjugate, multidirectional eye movement
which is usually intermittent and could continue during asleep at 6-15 Hz. While myoclonus is observed mainly in the form of irregular jerks in the body muscles, it makes children
extremely difficult to walk with ataxic movements in the body and limbs. Diagnosis can
be delayed weeks or months later, since all classical features may not be available initially.
Occult neuroblastoma may present with some but not all, of the symptoms. Thus, the diagnosis of OMAS may be difficult in some patients and should be considered even when
only some of the features are present. The criteria for the diagnosis were established after
a consensus meeting held a few years ago. Three of the following four diagnostic criteria
should be present to describe the typical syndrome: (1) opsoclonus, (2) myoclonus/ataxia,
(3) behavioral change, and/or sleep disturbance, and (4) Neuroblastoma.19 OMAS symptoms typically improve with immunosuppressive therapy, although the recurrent course is
common and long-term neuropsychological disorders persist in 80% of patients.3,4,15
PATHOGENESIS
The etiology of OMAS is still unknown; however, it is claimed an underlying autoimmune
mechanism. Considering the other family members of children who developed OMAS, it
was observed that they are prone to autoimmunity compared to the control group. Furthermore, correlation with human leukocyte antigen class II locus DR B1 01 shows a genetic
predisposition to autoimmunity in affected patients.20 Evidences show that the abnormal immune-mediated response targeting the central nervous system plays an important role in the
pathophysiology of OMAS, the cause of which is likely paraneoplastic or para-infectious.5
Neuronal autoantibodies (anti-Hu, antineuronal, anti-neurofilament) were detected in the
serum of adults and rarely pediatric patients. In childhood OMAS, anti-Hu antibodies have
been observed in neuroblastoma-associated OMAS in high-titers, whereas some patients
with neuroblastoma without OMAS can have low-titers. Common surface-binding autoantibodies against the cerebellar structure and neuroblastoma cells have been identified.21
One of them is the glutamate receptor δ2 (GluD2) autoantibody in the cerebellum.22 Several
inflammatory changes such as increased IgG, IgM, and/or oligoclonal band may occur in
the CSF of the patient with OMAS. Furthermore, the demonstration of B cell activation in
the cerebrospinal fluid supports the autoimmune mechanism. In childhood OMAS, especially B-cell activating factor (BAFF) increase is observed. The B-cell expansion correlates
with disease severity and with the response to treatment with rituximab. These levels may
decrease with immunotherapeutic treatment such as steroid and ACTH.5,6,23
OPSOCLONUS MYOCLONUS ATAXIA SYNDROME AND NEUROBLASTOMA
OMAS in children can be seen as a paraneoplastic syndrome and non-paraneoplastic
syndrome (idiopathic, para-infectious). These paraneoplastic and infectious associated
opsoclonus/OMAS (IAO) are the most common causes in children, although IAO is more
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278
dominant in adults. Neuroblastoma is seen as paraneoplastic in 50% of children, whereas
small cell lung cancer and breast cancer are most common in adults. OMAS is accompanied by 1-2% of children with neuroblastoma. It is most commonly seen in children under
3 years of age, the median age is 18 months.15 The neuroblastoma that occurs with OMAS
has an excellent oncologic outcome, is usually localized, very small, and differentiated.
Such small tumors may escape ultrasound imaging but may need a more careful approach
using thin-cut imaging modalities. Therefore, it can be assumed that the actual percentage
of OMAS associated with neuroblastoma is much higher.23,24 The autoimmune process
in OMAS with neuroblastoma is usually triggered by infectious agents or tumor development. Neuroblastoma shows diffuse lymphocytic infiltration. In neuroblastoma with
OMAS, lymphocytic infiltration is observed more frequently than that without OMAS.
Neuroblastoma cells can also synthesize BAFF, which is the trigger of lymphocytic infiltration. Antineuronal antibodies were also found in control patients with neuroblastoma without opsoclonus myoclonus syndrome, although at a significantly lower rate.
Especially, anti-Hu antibodies have been observed in neuroblastoma-associated OMAS
in high-titers. Complete remission can be achieved only by surgery or sometimes with
surgery plus standard chemotherapy. Tumors in children with paraneoplastic OMAS appear to have a better prognosis than tumors in patients without paraneoplastic symptoms.
The association of high-risk neuroblastoma and OMAS is very rare.5,21
OPSOCLONUS MYOCLONUS ATAXIA SYNDROME WITH INFECTIOUS
Non-paraneoplastic OMAS in children is believed to have a parainfectious origin in some
cases. Viral infections are the main trigger of autoimmunity. Bacterial infections such
as Rickettsia, mycoplasma, salmonella, streptococcus, borreliosis, tuberculosis; Fungal
infections such as cryptococcosis and protozoal infections such as malaria were also reported to be the causes.25,26 Among viruses, human immunodeficiency virus, influenza,
mumps, herpes viruses, hepatitis C virus, arboviruses, and enteroviruses were identified.27,28
TREATMENT AND PROGNOSIS
Because of the claimed immune mechanism, immunomodulatory treatment, especially
corticosteroid, has been the cornerstone of OMAS therapy. In the last 30 years, treatment
regimens consisted of corticosteroids and ACTH. Many symptoms improved with this
treatment regimen, but OMAS in children tends to continue for a long time with recurrence and behavioral disorders. Therefore, steroid therapy should be continued for a long
time and may cause serious side effects. Different treatment protocols are tried to prevent
long-term use of steroids and to avoid side effects. In addition to this classical treatment,
intravenous immunoglobulin (IVIG), rituximab, therapeutic plasma exchange, chemotherapeutic drugs such as methotrexate and cyclophosphamide have been used.2,29 Furthermore, the purpose of OMAS treatment is not only to reduce neurological symptoms
but also to improve learning and behavioral skills. ACTH and steroids are effective in
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279
reducing neurological symptoms, whereas they are not sufficient in neuropsychological
recovery and preventing relapse. IVIG is good at reducing neurological symptoms with a
different mechanism of action, but it is insufficient in the improvement of neuropsychological symptoms. Therefore, recent studies suggest that aggressive multiple therapies
can improve outcomes in OMAS.30 In a study, the combination of pulse steroid, IVIG,
rituximab, and/or therapeutic plasma exchange has been shown to be effective in both
neurological and neuropsychological healing.29,31,32 In other studies, immunotherapy with
ACTH instead of steroids, combined with IVIG and rituximab has been found effective
in terms of benefits and no side effects.33,34 Furthermore, cyclophosphamide added treatments reduced B cell activity in CSF.35 Autologous stem cell transplantation (ASCT)
is increasingly used in the treatment of autoimmune diseases. Transplantation has been
reported in autoimmune diseases with neuroinflammatory factors such as chronic demyelinating polyneuropathy, multiple sclerosis, and myasthenia gravis. The aim of ASCT in
autoimmune diseases is removing pathogenic autoreactive cells and replace them with de
novo repertoire immune cells.36
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