Opsoclonus is a kind of ocular motility disorder characterized by spontaneous, multidirectional, arrhythmic conjugate saccades. Opsoclonus is frequently associated with limb and/or truncal jerking (myoclonus), marked gait ataxia along with behavioral changes [Video 1]. Opsoclonus myoclonus syndrome has variably been described as dancing eyes and dancing feet syndrome or Kinsbourne syndrome. The diagnosis of opsoclonus myoclonus is largely clinical and the condition is frequently mistaken for acute cerebellar ataxia.
In the pediatric age group, opsoclonus myoclonus syndrome has two predominant etiological factors: it may either be paraneoplastic or para-infectious (that is infective or post-infective). In both the conditions, the pathogenesis is considered to be immune mediated. Huddar and co-workers, in a case series, described their experience in treating 14 pediatric patients (aged 5 years or less) suffering from the opsoclonus myoclonus syndrome, encountered in the span of last 10 years. In 8 cases, the common referral diagnosis was acute cerebellar ataxia. In this retrospective review, 7 cases were either caused by infective/parainfective etiology. The remaining 7 patients had an underlying tumor and were considered paraneoplastic. An underlying neuroblastoma/paraganglioma was detected in the all the 7 patients with a paraneoplastic etiology. In majority of the patients, symptoms related with opsoclonus myoclonus syndrome responded to immunotherapy, but in a few of them, behavioral abnormalities persisted for a long duration. In the study by Huddar and co-workers, the mean duration of symptoms was approximately 4 months (range: 15 days to 16 months). It is difficult to comprehensively differentiate paraneoplastic opsoclonus myoclonus syndrome from that of para/post-infectious or idiopathic opsoclonus myoclonus syndrome. Pranzatelli and co-workers, in a large study (n = 356 patients), noted that patients with the paraneoplastic opsoclonus myoclonus syndrome had a higher incidence of tumor; resection scar; or, that they had a visible tumor or surgical complications following tumor resection, like the presence Horner's syndrome.
We also reviewed all published Indian cases that were available in the PubMed database (searched on 8 August, 2018). The clinical features, etiology, treatment and outcome of 37 reported cases is summarized in [Table 1]. The age of the patients ranged from 11 months to 60 years. The duration of illness ranged from a few days to 12 months. Opsoclonus-myoclonus along with ataxia and irritable behavior were the most common clinical features. The neuroimaging and cerebrospinal fluid examination were not contributory in almost all of the cases. The etiology was paraneoplastic in 13 (35.1%) cases, neuroblastoma being the most common tumor; a post-infectious etiology was seen in 5 cases; other etiologies were cerebral malaria, dengue, human immunodeficiency virus infection, scrub typhus and poisoning with the pesticide ‘chlorpyrifos'. The patients were most commonly treated with adrenocorticotropic hormone therapy, corticosteroids, and intravenous immunoglobulins. The outcome was generally good, with 36 out of 37 cases showing improvement. Our analysis revealed that an infectious or post-infectious etiology can be identified on the basis of a shorter duration of symptom onset (2-10 days),,,,,,,,,,,,,,,,,,,,[Table 1].
Table 1: Summary of all Indian cases published in PubMed on the opsoclonus-myoclonus syndrome
A number of viruses have been associated with opsoclonus-myoclonus syndrome, across the globe. These viruses include Chikungunya, Dengue, Japanese encephalitis, West-Nile Virus, Mumps, Human herpes virus-6, Influenza A, Varicella zoster, Coxsackie, Rotavirus and Epstein-Barr viruses.,,
Adult-onset opsoclonus-myoclonus syndrome is also either paraneoplastic or parainfectious. The most common primary malignant lesions associated with the adult-onset opsoclonus-myoclonus syndrome are carcinomas of the lung and breast. Paraneoplastic opsoclonus-myoclonus syndrome is seen in older adults and has a higher frequency of encephalopathy. In many cases, the opsoclonus-myoclonus syndrome was observed in human immunodeficiency virus infected patients, presumed to be of para-infectious nature. The most common antibody detected in adult patients with this syndrome are the antineuronal nuclear antibodies type 2. In adult patients, complete remission is achieved following administration of immunotherapy.
The precise anatomic substrate that is affected in opsoclonus myoclonus syndrome is not known. A serial structural magnetic resonance imaging and fluorodeoxyglucose (FDG)-positron emission tomography (PET) evaluation in a patient revealed increased metabolism in structures around the deep cerebellar nuclei (particularly, the fastigial nucleus) and a relatively reduced metabolism in bilateral occipital lobes. These imaging changes normalized over 12 months. Functional connectivity increased initially between the oculomotor and visual systems, including the visual cortex, frontal eye fields, superior colliculus, and cerebellar oculomotor vermis, and then decreased in the chronic stage as the symptoms resolved. Another magnetic resonance imaging-based study noted a reduced connectivity between the cerebellum and motor cortex, but an increased connectivity with occipito-parietal regions.
An autoimmune pathophysiology is considered responsible for the presence of childhood paraneoplastic opsoclonus myoclonus syndrome. Autoantibodies to glutamate receptor δ2 (GluD2) are common in patients with childhood opsoclonus myoclonus syndrome. The glutamate receptor δ2 is a cerebellar-specific receptor and is responsible for synaptic organization in the cerebellum. In adult cases, neuropathologically, cerebellum was found to be affected. There was a diffuse loss of Purkinje cells and dentate neurons in the cerebellum.
The ideal treatment for opsoclonus myoclonus syndrome is largely unknown so far and is based on experiences gained with treating individual cases, as presented in various case reports. Corticosteroids and adrenocorticotropic hormone are the most frequently administered treatment options. Intravenous immunoglobulin or plasmapheresis are now being increasingly used. Lately, many cases have been treated with rituximab or low-dose cyclophosphamide. A combination immunotherapy is better in the management of this syndrome. A recent randomized trial compared the efficacy of prednisone and chemotherapy (cyclophosphamide) in children with a neuroblastoma associated opsoclonus myoclonus syndrome with addition of 12 cycles of intravenous immunoglobulin to the prednisone and cyclophosphamide regimen. Response was assessed periodically on an opsoclonus myoclonus ataxia syndrome severity scale, up to one year. A larger proportion of patients in the ‘intravenous immunoglobulin' group had resolution of the opsoclonus myoclonus syndrome symptoms than was observed in the ‘no intravenous immunoglobulin' group. The latest observations have noted that patients with an idiopathic opsoclonus myoclonus syndrome respond better to immunotherapy in comparison to those with a paraneoplastic opsoclonus myoclonus syndrome. For symptomatic treatment of myoclonus, clonazepam is the preferred drug.
In conclusion, both paraneoplastic and infective/post-infective opsoclonus myoclonus syndrome are equally encountered in the pediatric age group. A diagnostic work up must include imaging modalities to detect an underlying neuroblastoma/paraganglioma. A combination immunotherapy is often successful in alleviating the disabling symptoms of the syndrome.
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Meena JP, Seth R, Chakrabarty B, Gulati S, Agrawala S, Naranje P. Neuroblastoma presenting as opsoclonus-myoclonus: A series of six cases and review of literature. J Pediatr Neurosci 2016;11:373-7. [PUBMED] [Full text]
do Rosário MS, Giovanetti M, de Jesus PA, Farias DS, Faria NR, de Lima CP, et al. Opsoclonus-myoclonus-ataxia syndrome associated with chikungunya and dengue virus coinfection. Int J Infect Dis 2018. pii: S1201-9712(18)34480-1.
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de Alarcon PA, Matthay KK, London WB, Naranjo A, Tenney SC, Panzer JA, et al. Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): A randomised, open-label, phase 3 trial. Lancet Child Adolesc Health 2018;2:25-34.
Armangué T, Sabater L, Torres-Vega E, Martínez-Hernández E, Ariño H, Petit-Pedrol M, et al. Clinical and immunological features of opsoclonus-myoclonus syndrome in the era of neuronal cell surface antibodies. JAMA Neurol 2016;73:417-24.