Clinical Profile and Outcome of Children With Opsoclonus-Myoclonus Syndrome

Methods

The medical records of all children admitted in the pediatric neurology unit of the department of pediatrics, Post-Graduate Institute of Medical Education and Research with a diagnosis of opsoclonus-myoclonus from 2000 to 2012, were retrieved and reviewed. Details of clinical symptoms, severity, investigations, and treatment were recorded on a prestructured proforma. The diagnosis of opsoclonus-myoclonus was based on a constellation of any 3 of the 4 clinical features: opsoclonus, myoclonus, ataxia, and irritability/behavioral change. ³ Idiopathic opsoclonus-myoclonus was defined as a disorder with no obvious etiology despite detailed workup. Outcome was assessed on follow-up by direct assessment and by telephonic interview.

Data were analyzed using the SPSS version 18.0 software (SPSS, Chicago, Illinois). Frequencies and means were calculated by descriptive analysis.

Results

A total of 11 patients with a diagnosis of opsoclonus-myoclonus were admitted over the 12-year period (Table 1). The median age at clinical presentation was 1.5 years (range 1-13 years). The male-female ratio was 5:6.

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Table 1.

Clinical Profile at Presentation and Outcome in 11 Children With Opsoclonus-Myoclonus Syndrome

Serial no./sex	Age at onset (in mo)	Antecedent history	Behavioral symptoms	Etiology	Treatment	Relapses	Duration of symptoms (mo)	Outcome
1/F	13	Fever for 1 d	Irritability	Neuroblastoma left suprarenal	ACTH, surgery, cyclophosphamide	0	9	At 9 mo follow-up, mild motor and ocular abnormalities, sleep difficulty, frequent awakening during sleep
2/F	18	No	Irritability	Idiopathic	Intravenous methylprednisolone pulses followed by oral corticosteroids	1	10	At 16 mo follow-up, complete recovery, normal development
3/M	12	Diarrhea 10 d ago	Irritability, aggression	Neuroblastoma (paraaortic)	IVIG, surgery cyclophosphamide,	0	12	At 18 mo follow-up, delayed motor milestones, aggression, frequent awakening during sleep, age- appropriate language, and cognitive skills
4/F	24	Two d after varicella vaccine	Lethargy	Neuroblastoma (retroperitoneum)	ACTH failed, response with IVIG	1	24	At 18 mo follow-up, significant motor and cognitive impairment, delayed language, no ocular abnormality
5/M	18	Diarrhea 7 d ago	Irritability, aggression	Idiopathic	IVIG	0	12	At 3.5 y follow-up, complete motor and ocular recovery, learning difficulty
6/F	14	Prodromal fever	Irritability	Ganglioneuroblastoma (suprarenal)	IVIG, surgery cyclophosphamide,	1	24	At 5.5 y follow-up, speech stuttering, learning difficulty
7/F	15	No	Irritability	Idiopathic	Oral corticosteroids	0	1	At 21 mo follow-up, normal development
8/M	156	Antecedent fever of 2 d	Anger behavior	Idiopathic	Oral corticosteroids	0	6	At 2 y follow-up, mild slurring of speech and gait deficits
9/F	18	No	Irritability	Idiopathic	Oral corticosteroids	0	19	At 2 y follow-up, mild motor impairment and gaze abnormalities
10/M	12	Antecedent 2 d fever	Irritability	Idiopathic	ACTH	0	1	At 3 y follow-up, asymptomatic, normal development
11/M	18	No	Irritability	Idiopathic	Spontaneous recovery	0	4	At 3.5 y follow-up, asymptomatic, normal development

Abbreviations: ACTH, adrenocorticotrophic hormone; IVIG, intravenous immunoglobulin; M, male; F, female.

All children had normal development before the onset of symptoms. Opsoclonus, myoclonus, ataxia, and encephalopathy were present in all during the clinical course. Irritability, ataxia, and motor regression were the earliest features. Symptoms were moderate to severe in all. Sleep disturbance was present in all. The median duration of symptoms at the time of presentation was 2 months (range 2 days to 12 months). The reasons for the delay in diagnosis included delayed referral, and misdiagnoses by referring pediatricians (such as viral encephalitis, acute cerebellar ataxia, and Guillain-Barré syndrome).

Of the 11, 4 children had paraneoplastic opsoclonus (2 with retroperitoneal neuroblastoma, 1 with suprarenal ganglioneuroblastoma, and 1 with suprarenal neuroblastoma). Onset of neurologic symptoms preceded the diagnosis of tumor in all the 4 cases. The tumor was detected on contrast-enhanced computed tomogram (CT) of the abdomen in all the 4 cases. It was missed on ultrasound abdomen in 3 cases. Iodine-123 metaiodobenzylguanidine scintigraphy scan was performed in 3 cases and it detected tumor in 1 case. Tests for urinary excretion of homovanillic acid and vanillylmandelic acid were negative in all cases.

Three children had atypical presentations. One child (case 2) presented with acute onset ataxia and irritability but without opsoclonus. An initial diagnosis of acute cerebellar ataxia was made and she was treated with intravenous methylprednisolone pulses followed by oral corticosteroids. She had a good response and recovered completely by 4 weeks. However, soon after stopping of corticosteroids at 12 weeks, she had recurrence of symptoms this time with opsoclonus. A diagnosis of opsoclonus-myoclonus syndrome was made and she was treated again with methylprednisolone pulses followed by oral corticosteroids with which she recovered completely. A detailed evaluation for neuroblastoma was negative. One child (case 4) had onset of symptoms 2 days after varicella vaccine. She was later diagnosed with neuroblastoma. One child (case 8) had late symptom onset at 13 years, and recovered with oral steroids.

Of the 7 cases with idiopathic opsoclonus-myoclonus patients, 3 were treated with oral corticosteroids, 1 with adrenocorticotrophic hormone, 1 with intravenous immunoglobulin, and 1 with methylprednisolone pulses followed by oral corticosteroids. One child had spontaneous improvement and complete recovery without specific immunomodulator therapy. Of the 4 cases with paraneoplastic opsoclonus-myoclonus syndrome; 3 were treated with tumor resection, chemotherapy, and intravenous immunoglobulin. In 1 child, adrenocorticotrophic hormone followed by intravenous immunoglobulin were given, but tumor resection and chemotherapy were deferred as parents were not willing for surgery.

Relapse of opsoclonus-myoclonus symptoms occurred in 3 cases. Two of them had paraneoplastic opsoclonus-myoclonus, and 1 had idiopathic. Five cases had complete recovery. All of them were idiopathic. All 4 cases with paraneoplastic etiology had mild to moderate sequelae. Of the 4 cases, 2 had sleep difficulty in form of frequent sleep disruptions; 1 had persistent aggressive behavior, 1 had significant cognitive and motor impairment, and 1 had learning difficulty.

Discussion

Our study represents the largest case series from India and has important observations. It illustrates the rarity of the syndrome in our population, similar to other studies. According to data from the United Kingdom, the estimated incidence of this syndrome was 0.18 new cases per million total populations per year. ¹ The prolonged duration of symptoms prior to referral and initial misdiagnoses highlights the fact that most pediatricians in our country are not aware of the syndrome. Pediatricians making the diagnosis of acute cerebellar ataxia in a toddler should be aware of possibility of opsoclonus-myoclonus syndrome. The existence of opsoclonus excludes the diagnosis of acute cerebellar ataxia. The presence of excessive irritability or sleep disturbances in coexistence of acute-onset ataxia, even in the absence of opsoclonus, should raise the suspicion of opsoclonus-myoclonus syndrome. Akin to previously published studies, we observed a similar median age at clinical presentation, no gender bias, common antecedent illness, acute/subacute onset of presentation, association of neuroblastoma, and response to immunomodulator therapy. ^{1 , 6} However, in contrast with the reported high sensitivity (up to 95%) of metaiodobenzylguanidine scintigraphy scan for detection of neuroblastoma, we found that its sensitivity for tumor detection was low as compared to an abdominal CT scan. We also observed poor sensitivity of urine catecholamines in our cases. Similarly, Brunklaus and colleagues ⁷ have reported poorer sensitivities for metaiodobenzylguanidine scintigraphy scan and urine catecholamines, reflecting the stage of maturation and predominant neurotransmitters of the cells comprising these tumors. ⁸

In our series, only 4 of 11 cases had paraneoplastic opsoclonus-myoclonus syndrome. Previously published studies have reported a paraneoplastic etiology in about 50% of children. ⁶ However, none of the investigative modalities has a 100% sensitivity to detect neuroblastoma; also, this tumor is known to have spontaneous regression. Therefore, a possibility of a very small tumor that escaped detection even after investigations and regressed spontaneously cannot be excluded. ⁹

We observed a good therapeutic response with immunomodulators, including adrenocorticotrophic hormone, intravenous immunoglobulin, and parenteral and oral corticosteroids. It is difficult to compare these therapies because of the small number of patients. One child with paraneoplastic opsoclonus-myoclonus failed to respond with adrenocorticotrophic hormone but had a significant response with intravenous immunoglobulin. In recent studies, rituximab, an anti-CD 20 monoclonal antibody, has been shown to be effective and safe for treatment of pediatric opsoclonus-myoclonus syndrome. ^{10 , 11} We were not able to use rituximab in our patients because of cost constraints. Recently, Tate and colleagues ¹² conducted the largest study on comparison of adrenocorticotrophic hormone-based immunotherapies for pediatric opsoclonus-myoclonus syndrome. They reported greater efficacy of adrenocorticotrophic hormone–based multimodal therapy compared with adrenocorticotrophic hormone alone and greater response to adrenocorticotrophic hormone than corticosteroid-based therapy. ¹² There are also anecdotal reports of benefit with topiramate, clonazepam, and oral high-dose dexamethasone pulses.^13–15

Neurologic relapses in our series were less than those reported by Tate and colleagues (up to 52 %). ⁶ This could perhaps be due to the small number of patients in our study. Also, in our series, the outcome was better in those with idiopathic opsoclonus-myoclonus syndrome whereas in the study by Tate and colleagues, the outcome was independent of etiology. Interestingly, Bataller and colleagues ¹⁶ have also observed better outcome of idiopathic opsoclonus-myoclonus syndrome in adult patients. Mitchell and colleagues ¹⁷ described development and neurologic sequelae in 17 children with opsoclonus-ataxia caused by neuroblastoma. They observed substantial developmental sequelae and increased deficits in older children. They postulated that this represents a progressive encephalopathy rather than a time-limited single insult. ¹⁷ We did not observe progressive developmental and behavioral syndrome in our patients, which could be due to small number of patients of paraneoplastic etiology, short-follow-up, and lack of objective psychometric testing. Brunklaus and colleagues ¹⁸ studied clinical predictors of long-term outcome and demonstrated that severe initial symptoms and very young age at disease onset are important risk factors of developing long-term sequelae.

To conclude, opsoclonus-myoclonus syndrome is a rare but one of the few immunomodulator-responsive pediatric neurologic disorders. Screening for an occult neuroblastoma is necessary in children with the syndrome. Paraneoplastic opsoclonus had a poor outcome in our experience.