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Therapeutic results in three cases of ganglioneuroblastoma associated with opsoclonus myoclonus ataxia syndrome
Ivan A Shtarbanov, Ivan K Boronsuzov, Ivan R Chakarov, Dobrin N Konstantinov
Department of Oncology, Clinic of Pediatric Hematology and Oncology, University Hospital “Tsaritsa Yoanna – ISUL” – Sofia, Bulgaria
Ivan A Shtarbanov,
Department of Oncology, Clinic of Pediatric Hematology and Oncology, University Hospital “Tsaritsa Yoanna – ISUL” – Sofia
Source of Support: None, Conflict of Interest: None
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Shtarbanov IA, Boronsuzov IK, Chakarov IR, Konstantinov DN. Therapeutic results in three cases of ganglioneuroblastoma associated with opsoclonus myoclonus ataxia syndrome. Indian J Cancer [Epub ahead of print] [cited 2020 Jan 17]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=274084
Opsoclonus myoclonus ataxia syndrome (OMA) is a rare syndrome. During childhood, OMA is primarily a paraneoplastic syndrome associated with neuroblastoma, ganglioneuroblastoma or ganglioneuroma. The acute phase is characterized by chaotic eye movements, non-epileptic twitching of the limbs and unsteady gait. The chronic phase is characterized by cognitive disturbances and developmental delay, which are often persistent. Here, we report three cases of OMA associated with ganglioneuroblastoma.
| » Case 1|| |
A 21 month old girl presented with complaints that included tremors of left upper and lower limb initially associated with head trauma. After a CT scan, an organic cause for the symptoms was excluded. Subsequently, the tremor covered all four limbs, the gait became unstable. The child was hospitalized one month after the onset of symptoms and diagnosed with OMA. Homovanillic and vanilmandelic acid in urine showed values within reference range. A metaiodobenzylguanidine (MIBG) scintigraphy was performed, and did not detect pathologically increased radiopharmaceutical fixation. A paraspinal tumor entering the spinal canal at the T1-T3 level was detected following a whole body CT scan. The primary illness was successfully treated with partial excision of the tumor and eight chemotherapy courses for intermediate risk neuroblastoma. At present, after two years and nine months there is, no evidence of delay in the child's neuropsychological development.
| » Case 2|| |
A 21 month old girl presented with complaints that included increased irritability, crying, full body tremor accompanied by chaotic eye movements, for one month. Based on the clinical manifestation of an OMA, targeted studies for detection of neuroblastoma were conducted. Single photon emission computed tomography (SPECT) with MIBG analysis revealed a tumor in the left carotid space [Figure 1]. The primary illness was treated with partial excision, and eight chemotherapy courses for intermediate risk neuroblastoma. At present, after two years and ten months, the child is in complete remission and there is no evidence of delay in neuropsychological development.
|Figure 1: MIBG analysis revealing a tumor formation in the left carotid space. The arrow points to the tumor formation in the left carotid space|
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| » Case 3|| |
An 18 month old girl presented with complaints of delay in neuropsychological development and difficult gait for four months. Opsoclonus was noticed. SPECT with MIBG analysis revealed a metabolically active tumor formation of the size of 7 x 6 cm in the retroperitoneum. High levels of homovanillic and vanilmandelic acid in urine were also detected. There were four courses of chemotherapy for intermediate risk neuroblastoma, followed by partial excision of the tumor three more chemotherapy courses, a second non-radical operation, four courses of post-operative chemotherapy, primary tumor irradiation, and per-oral maintenance treatment with cis-retinoic acid. At present, after two years and eight months, the child is in complete remission from the primary disease [Figure 2]a and [Figure 2]b, with evidence for cognitive deficits with speech retardation, but in a significantly improved condition compared to the first hospitalization, where the patient was in a generalized hypotonia with inability to move and self-feed, and in a need for parenteral nutrition.
|Figure 2: Case 3. (a) CT scan at initiation of treatment - a retroperitoneal formation is established (arrow). (b) CT scan three months after the end of the treatment - a residual retroperitoneal formation (arrow) with a maximum size of 3.5 cm is established that does not change as compared to previous imaging and cannot be considered as activity of the underlying disease|
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The opsoclonus myoclonus ataxia syndrome is a rare but serious neurological disease with an annual incidence of 0.18/1,000,000. The etiology of the syndrome is explained as an autoimmune reaction resulting from an infection or a paraneoplastic process. The pathogenesis of the disease is attributed to disturbances in humoral immunity. Although there are no universally established serum autoantibodies for the diagnosis, B cell clonal expansion as well as an increased concentration of oligoclonal antibodies have been observed in OMA patients. Neuro-radiological analysis reveal morphological changes that correlate with the severity of the disease, such as reduction in gray matter volume in the cerebellum, especially in the vermis, as well as extra-cerebellar changes such as thinning of the motor and the visual cortex.
The main diagnostic criteria for OMA syndrome are:
- Opsoclonus-fast, involuntary, arrhythmic eye movements in multiple directions (vertical, horizontal, torsional)
- Presence of myoclonus or ataxia
- Behavioral changes (most often irritability) or sleep disturbances and
- Diagnosed neuroblastoma is detected in 50% of cases of OMA in childhood.
Three of the four criteria are needed to make the diagnosis.
Myoclonus manifestation ranges from mild tremor of the extremities, to severe motor disorders, obstructing purposeful fine movements. Ataxia can range from discreet gait violations to the inability to move requiring long-term assistance.
It manifests with ataxia, but also with possible changes in eye movements that are more identifiable as nystagmus rather than as an opsoclonus. The distinction between the two conditions is important because acute cerebellar ataxia is a benign, self-healing disease, whereas the diagnosis of OMA requires active treatment and implies investigation for neuroblastoma.
Neuroblastoma associated with OMA is characterized by its favorable biology, high incidence of localized disease and excellent prognosis for the oncological disease. Even in the case of localized disease, the clinical data on OMA are an independent favorable prognostic marker. In patients with OMA I, II, or III clinical stage neuroblastoma, the 3-year survival rate was 100% compared to 77% for the same group without OMA.
From a genetic perspective, neuroblastoma associated with OMA is characterized by low frequency of amplification of the MYCN gene, and in a significant percentage of cases, segmental chromosomal abnormalities, which also have an unfavorable prognostic value, are detected. Hiyama et al. described cases of neuroblastoma with OMA in which the disease presented in clinical stage IV with overexpression of the MYCN gene. Bobev et al. described two cases of neuroblastoma with OMA, in one of which neuroblastoma was in clinical stage IV and had an unfavorable course.
In a study of six cases of neuroblastoma with OMA, scintigraphy was positive in two cases, whereas levels of homovanillic and vanilmandelic acid in urine were normal in all six patients. In Case 1 described here, both scintigraphy and urinary catecholamine levels were negative.
Opsoclonus myoclonus ataxia syndrome is a serious neurological disease that in childhood necessitates a focused study of neuroblastoma. Despite the excellent prognosis regarding the oncological disease, more than two third of the patients with diagnosed opsoclonus myoclonus syndrome have a long-term lag in neuropsychological development. The timing of diagnosis and initiation of treatment is important in terms of the extent of neurological recovery.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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